Clinical presentation of acute myeloid leukaemia - A decade-long institutional follow-up.

Science.gov (United States)

Kulsoom, Bibi; Shamsi, Tahir Sultan; Ahmed, Nikhat; Hasnain, Syed Nazrul

2017-12-01

To analyse a decade-long pattern of clinical presentation of acute myeloid leukaemia patients and compare it with contemporary data. The retrospective cohort study was conducted at the National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, and comprised of medical record of acute myeloid leukaemia patients from March 2006 to October 2016. Data noted age at presentation, gender, medical history, physical examination, blood and bone marrow investigations such as, haemoglobin levels, blood cell count myeloperoxidase activity, periodic acid-Schiff and reticulin staining as well as final diagnosis. Comparison, where possible, was done with contemporary literature. SPSS 19 was used for data analysis. Of the 626 subjects, 248(39.6%) were females and 378(60.4%) males. The overall mean age was 35.3±17.1 years. The most common age group was 15-40 years with 354(56.5%) patients. The most common subtype was acute myeloid leukaemia with maturation 183(33.6%). Myeloperoxidase activity was positive for the majority of the acute myeloid leukaemia patients. Periodic acid-Schiff test, done on only selected patients, was mostly negative. Reticulin staining was positive for 113(65.3%) patients. The most common presenting complaints were fever 266(71.9%) and weakness 168(45.4%). Mean haemoglobin and red blood cell count were 8.3 ± 2.4 g/dL and 2.9 ± 1.2 1012/L, respectively. Acute myeloid leukaemia was found to be a highly variable disease that presented with non-specific signs and symptoms.

Acute myeloid and chronic lymphoid leukaemias and exposure to low-level benzene among petroleum workers

Science.gov (United States)

Rushton, L; Schnatter, A R; Tang, G; Glass, D C

2014-01-01

Background: High benzene exposure causes acute myeloid leukaemia (AML). Three petroleum case–control studies identified 60 cases (241 matched controls) for AML and 80 cases (345 matched controls) for chronic lymphoid leukaemia (CLL). Methods: Cases were classified and scored regarding uncertainty by two haematologists using available diagnostic information. Blinded quantitative benzene exposure assessment used work histories and exposure measurements adjusted for era-specific circumstances. Statistical analyses included conditional logistic regression and penalised smoothing splines. Results: Benzene exposures were much lower than previous studies. Categorical analyses showed increased ORs for AML with several exposure metrics, although patterns were unclear; neither continuous exposure metrics nor spline analyses gave increased risks. ORs were highest in terminal workers, particularly for Tanker Drivers. No relationship was found between benzene exposure and risk of CLL, although the Australian study showed increased risks in refinery workers. Conclusion: Overall, this study does not persuasively demonstrate a risk between benzene and AML. A previously reported strong relationship between myelodysplastic syndrome (MDS) (potentially previously reported as AML) at our study's low benzene levels suggests that MDS may be the more relevant health risk for lower exposure. Higher CLL risks in refinery workers may be due to more diverse exposures than benzene alone. PMID:24357793

Splenic irradiation before bone marrow transplantation for chronic myeloid leukaemia

International Nuclear Information System (INIS)

Gratwohl, A.; Hermans, J.; Biezen, A.V.

1996-01-01

A total of 229 patients with chronic myeloid leukaemia (CML) in chronic phase were randomized between 1986 and 1990 to receive or not receive additional splenic irradiation as part of their conditioning prior to bone marrow transplantation (BMT). Both groups, 115 patients with and 114 patients without splenic irradiation, were very similar regarding distribution of age, sex, donor/recipient sex combination, conditioning, graft-versus-host disease (GvHD) prevention method and blood counts at diagnosis or prior to transplant. 135 patients (59%) are alive as of October 1995 with a minimum follow-up of 5 years. 52 patients have relapsed (23%), 26 patients in the irradiated, 26 patients in the non-irradiated group (n.s.) with a relapse incident at 6 years of 28%. The main risk factor for relapse was T-cell depletion as the method for GvHD prevention, and an elevated basophil count in the peripheral blood prior to transplant. Relapse incidence between patients with or without splenic irradiation was no different in patients at high risk for relapse, e.g. patients transplanted with T-cell-depleted marrows (P = n.s.) and in patients with low risk for relapse, e.g. patients transplanted with non-T-cell-depleted transplants and basophil counts 3% basophils in peripheral blood). In this patient group, relapse incidence was 11% at 6 years with splenic irradiation but 32% in the non-irradiated group (P = 0.05). Transplant-related mortality was similar whether patients received splenic irradiation or not. This study suggests an advantage in splenic irradiation prior to transplantation for CML in this subgroup of patients and illustrates the need for tailored therapy. (Author)

The molecular biology of radiation-induced carcinogenesis: thymic lymphoma, myeloid leukaemia and osteosarcoma

Energy Technology Data Exchange (ETDEWEB)

Janowski, M [Centre d' Etude de l' Energie Nucleaire, Mol (Belgium); Cox, R [Medical Research Council, Harwell (UK). Radiobiological Research Unit; Strauss, P G [GSF, Neuherberg (Germany, F.R.). Abt. fuer Molekulare Zellpathologie

1990-04-01

In mice, external X- or {gamma}-irradiation may induce thymic lymphomas or myeloid leukaemias, while bone-seeking {alpha}-emitters may induce osteosarcomas, and to a lesser extent acute myeloid leukaemia. The paper reviews briefly some experimental data in respect to molecular mechanisms underlying these radio-carcinogenic processes. Thymic lymphomagenesis proceeds by an indirect mechanism in which recombinant proviruses could be involved. Myeloid leukaemogenesis is characterized by a very early putative initiating event, consisting of non-random rearrangements and/or deletions of chromosome 2. Osteosarcomagenesis in mice is often associated with the expression of proviruses, and the tumors often contain somatically acquired proviruses. (UK).

Induction chemotherapy in acute myeloid leukaemia: origins and emerging directions.

Science.gov (United States)

Upadhyay, Vivek A; Fathi, Amir T

2018-03-01

This review summarizes the hallmark developments in induction chemotherapy for acute myeloid leukaemia and further describes future directions in its evolution. We describe the origin of induction chemotherapy. We also describe notable modifications and adjustments to 7+3 induction chemotherapy since its development. Finally, we describe new efforts to modify and add new agents to induction therapy, including '7+3 Plus' combinations. Induction chemotherapy remains the standard of care for the majority of patients with acute myeloid leukaemia. However, its success is limited in a subset of patients by toxicity, failure to achieve remission and potential for subsequent relapse. Novel agents such as mutant fms like tyrosine kinase 3 inhibitors, mutant isocitrate dehydrogenase inhibitors, CD33-antibody drug conjugates and liposomal formulations have demonstrated significant potential as modifications to traditional induction chemotherapy.

Therapy related Acute Myeloid Leukaemia 8 Years after Treatment ...

African Journals Online (AJOL)

Hodgkin's Disease (HD) is a curable malignancy even in Nigeria, our limitations in health care delivery notwithstanding. However, secondary malignancies especially Acute Myeloid Leukaemia (AML) may occur as late complications following alkylating cytotoxic drugs therapy, with or without radiotherapy. This is a case ...

Myeloid sarcoma in a child with acute myeloblastic leukaemia

International Nuclear Information System (INIS)

Ahmad, J.; Zafar, L.; Hussain, G.

2011-01-01

We report a rare occurrence of myeloid sarcoma in a 7 years old child with acute myeloblastic leukaemia (AML - FAB type M2). He presented with fever, generalized weakness, bilateral proptosis and left parotid swelling. CT scan revealed a mass in paranasal sinuses extending into brain and retro-orbital region. Diagnosis of AML M2 was made on bone marrow aspiration and special stains. Induction therapy for AML was given according to standard protocol. The extramedullary lesion as well as the acute leukaemia went into complete remission. (author)

Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

NARCIS (Netherlands)

J.E. Park (Julie E.); H.F. Yuen (Hiu Fung); J.B. Zhou (Jian Biao); A.Q.O. Al-aidaroos (Abdul Qader); K. Guo (Ke); P.J.M. Valk (Peter); S.D. Zhang (Shu Dong); W.J. Chng (Wee); C.W. Hong (Cheng William); K. Mills (Ken); Q. Zeng (Qi)

2013-01-01

textabstractFLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD

Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X-irradiation and glucocorticoids

Energy Technology Data Exchange (ETDEWEB)

Amos, T.A.S.; Lewis, J.L.; Grand, F.H.; Gooding, R.P.; Goldman, J.M.; Gordon, M.Y. [Royal Postgraduate Medical School, London (United Kingdom)

1995-10-01

Inhibition of apoptosis (genetically programmed active cell death) by p210 BCR-ABL expression is a mechanism that might contribute to clonal expansion in chronic myeloid leukaemia (CML). Since cell death following exposure to ionizing radiation and many chemotherapeutic agents can occur by the apoptotic pathway, inhibition of apoptosis would be expected to confer a relative resistance to these treatments. Similarly, cells deprived of growth factors in vitro die by apoptosis, and inhibition of apoptosis would therefore be expected to allow cells to survive better in growth factor-deprived conditions. We found that the survival of normal and CML myeloid progenitors was the same after in vitro incubation in deprived conditions and after treatment with X-irradiation or glucocorticoids. We also found that mature cells in colonies produced by CML progenitors (CFU-GM) did not survive better than those produced by normal progenitor cells. Flow cytometric analysis of propidium iodide-stained cells provided a direct indication that the degree of apoptosis may correspond to the degree of deprivation. These results suggest that inhibition of apoptosis may not be the primary mechanism whereby BCR-ABL influences the expansion of the malignant clone in CML. (Author).

Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X-irradiation and glucocorticoids

International Nuclear Information System (INIS)

Amos, T.A.S.; Lewis, J.L.; Grand, F.H.; Gooding, R.P.; Goldman, J.M.; Gordon, M.Y.

1995-01-01

Inhibition of apoptosis (genetically programmed active cell death) by p210 BCR-ABL expression is a mechanism that might contribute to clonal expansion in chronic myeloid leukaemia (CML). Since cell death following exposure to ionizing radiation and many chemotherapeutic agents can occur by the apoptotic pathway, inhibition of apoptosis would be expected to confer a relative resistance to these treatments. Similarly, cells deprived of growth factors in vitro die by apoptosis, and inhibition of apoptosis would therefore be expected to allow cells to survive better in growth factor-deprived conditions. We found that the survival of normal and CML myeloid progenitors was the same after in vitro incubation in deprived conditions and after treatment with X-irradiation or glucocorticoids. We also found that mature cells in colonies produced by CML progenitors (CFU-GM) did not survive better than those produced by normal progenitor cells. Flow cytometric analysis of propidium iodide-stained cells provided a direct indication that the degree of apoptosis may correspond to the degree of deprivation. These results suggest that inhibition of apoptosis may not be the primary mechanism whereby BCR-ABL influences the expansion of the malignant clone in CML. (Author)

CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients.

Science.gov (United States)

Barratt, Daniel T; Cox, Hannah K; Menelaou, Andrew; Yeung, David T; White, Deborah L; Hughes, Timothy P; Somogyi, Andrew A

2017-08-01

The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients. We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400-800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc). CYP2C8*3 (n = 34) and *4 (n = 15) carriers had significantly higher (P  50% higher for CYP2C8*1/*4 than for CYP2C8*1/*1 and CYP2C8*3 carriers (2.18 ± 0.66 vs. 1.45 ± 0.74 [P < 0.05] and 1.36 ± 0.98 μg/mL [P < 0.05], respectively). CYP2C8 genotype significantly alters imatinib metabolism in patients through gain- and loss-of-function mechanisms.

Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy

DEFF Research Database (Denmark)

Grövdal, Michael; Karimi, Mohsen; Khan, Rasheed

2010-01-01

This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction ......-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients....

Acute myeloid leukaemia presenting as bilateral proptosis in a young child

Directory of Open Access Journals (Sweden)

Charudutt Kalamkar

2016-06-01

Full Text Available Myeloid sarcoma is an extramedullary manifestation of acute myeloid leukaemia (AML. Aims We are reporting a paediatric case presenting with bilateral proptosis, which we were able to diagnose with peripheral blood smear (PBS examination. Methods Case Report Results This case highlights the utility of simple routinely available PBS test in diagnosing this rare disease. Conclusion Our case highlights the importance of haemogram and peripheral blood smear in the initial evaluation of proptosis. Correct diagnosis of this rare entity is vital especially in cases where (myeloid sarcoma MS is the presenting feature of AML.

Activity of Bruton's tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells.

Science.gov (United States)

Rushworth, Stuart A; Pillinger, Genevra; Abdul-Aziz, Amina; Piddock, Rachel; Shafat, Manar S; Murray, Megan Y; Zaitseva, Lyubov; Lawes, Matthew J; MacEwan, David J; Bowles, Kristian M

2015-05-01

Roughly 80% of patients with acute myeloid leukaemia have high activity of Bruton's tyrosine-kinase (BTK) in their blast cells compared with normal haemopoietic cells, rendering the cells sensitive to the oral BTK inhibitor ibrutinib in vitro. We aimed to develop the biological understanding of the BTK pathway in acute myeloid leukaemia to identify clinically relevant diagnostic information that might define a subset of patients that should respond to ibrutinib treatment. We obtained acute myeloid leukaemia blast cells from unselected patients attending our UK hospital between Feb 19, 2010, and Jan 20, 2014. We isolated primary acute myeloid leukaemia blast cells from heparinised blood and human peripheral blood mononuclear cells to establish the activity of BTK in response to CD117 activation. Furthermore, we investigated the effects of ibrutinib on CD117-induced BTK activation, downstream signalling, adhesion to primary bone-marrow mesenchymal stromal cells, and proliferation of primary acute myeloid leukaemia blast cells. We used the Mann-Whitney U test to compare results between groups. We obtained acute myeloid leukaemia blast cells from 29 patients. Ibrutinib significantly inhibited CD117-mediated proliferation of primary acute myeloid leukaemia blast cells (p=0·028). CD117 activation increased BTK activity by inducing phosphorylated BTK in patients with CD117-positive acute myeloid leukaemia. Furthermore, ibrutinib inhibited CD117-induced activity of BTK and downstream kinases at a concentration of 100 nM or more. CD117-mediated adhesion of CD117-expressing blast cells to bone-marrow stromal cells was significantly inhibited by Ibrutinib at 500 nM (p=0·028) INTERPRETATION: As first-in-man clinical trials of ibrutinib in patients with acute myeloid leukaemia commence, the data suggest not all patients will respond. Our findings show that BTK has specific pro-tumoural biological actions downstream of surface CD117 activation, which are inhibited by ibrutinib

Chronic myeloid leukaemia following radioiodine therapy for carcinoma thyroid

Energy Technology Data Exchange (ETDEWEB)

Bundi, R S; Scott, J S; Halnan, K E [Institute of Radiotherapeutics, Glasgow (UK)

1977-01-01

The majority of cases reported in the literature of leukemia following treatment of thyroid disease (thyrotoxicosis and carcinoma) are of acute variety. A description is given of the development of chronic myeloid leukemia in a case of carcinoma of the thyroid treated with radioiodine and megavoltage X-ray therapy. The case history contains details of radioiodine and X-ray doses administered over the years 1961 to 1972 to a male patient, on whom a right hemithyroidectomy was carried out in 1960. The results of blood counts are also recorded for the period up to 1973. The patient died, at 57, in 1974. A total of 860 mCi of /sup 131/I was administered and the first abnormal blood count was noted two months after the last therapeutic dose. Estimates have been made of blood and thyroid doses from /sup 131/I. There has been only one other report in the literature of the development of chronic myeloid leukemia following radioiodine therapy for carcinoma of the thyroid, and although the leukemogenic hazard of /sup 131/I cannot be ruled out for this patient, it is possible that the development of leukemia was coincidental rather than due to the radioiodine therapy.

Myeloid Sarcoma of the Uterine Cervix as Presentation of Acute Myeloid Leukaemia after Treatment with Low-Dose Radioiodine for Thyroid Cancer: A Case Report and Review of the Literature

Directory of Open Access Journals (Sweden)

Anne Sophie Weingertner

2009-01-01

Full Text Available The development of acute myeloid leukaemia after low-dose radioiodine therapy and its presentation as a myeloid sarcoma of the uterine cervix are both rare events. We report a case of acute myeloid leukaemia revealed by a myeloid sarcoma of the uterine cervix in a 48-year-old woman, 17 months after receiving a total dose of 100 mCi 131I for papillary thyroid cancer. A strict hematological follow-up of patients treated with any dose of 131I is recommended to accurately detect any hematological complications which might have been underestimated. Unusual presentations, such as chloroma of the uterine cervix, may reveal myeloid malignancy and should be kept in mind.

Case report: Concomitant Chronic Lymphocytic Leukaemia and Cytogenetically Normal de novo Acute Leukaemia in a Patient.

Science.gov (United States)

Kajtár, Béla; Rajnics, Péter; Egyed, Miklós; Alizadeh, Hussain

2015-01-01

The simultaneous occurrence of acute myeloid leukaemia with untreated chronic lymphocytic leukemia is extremely rare. We report a case of a 74-year-old man who was evaluated for macrocytic anaemia. Based on the morphology and immunophenotyping analysis of peripheral blood, a diagnosis of chronic lymphocytic leukemia was established. Subsequently, the bone marrow examination revealed the presence of two distinct, coexisting CLL and AML clones. Cytogenetic and molecular genetic analysis detected deletion 13q14.3 and unmutated immunoglobulin variable heavy-chain in the CLL clone, only. The AML and CLL clones did not share clonality, and the AML did not involve the peripheral blood. A diagnosis of cytogenetically normal de novo AML occurring concurrently with untreated CLL has not been reported previously in English literature. © 2015 by the Association of Clinical Scientists, Inc.

Morphology of leukaemias

Directory of Open Access Journals (Sweden)

W. Ladines-Castro

2016-04-01

Full Text Available Acute leukaemias are characterised by uncontrolled proliferation of immature blood cells with lymphoid or myeloid lineage. Morphological classification is based on the identification of the leukaemia cell line and its stage of differentiation. The first microscopic descriptions dating from the 1930s pointed to 2 different types of leukaemia cells: lymphoid and myeloid. In 1976, the consensus that led to the French-American-British (FAB classification was achieved. This includes criteria for identifying myeloid and lymphoid leukaemias, and gives a list of morphological subtypes, describing how these affect the patient's prognosis. Today, despite new classifications based on sophisticated studies, FAB classification is widely used by experts due to its technical simplicity, good diagnostic reliability and cost-effectiveness.

Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells.

Directory of Open Access Journals (Sweden)

Bernhard F Gibbs

Full Text Available Stem cell factor (SCF is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1 in hematopoietic cells--a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation--an important stage of the myeloid leukaemia cell life cycle.

Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats

DEFF Research Database (Denmark)

Mortensen, B T; Jensen, P O; Helledie, N

1998-01-01

The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats....

Dose-response for X-ray induction of myeloid leukaemia in male CBA/H mice

Energy Technology Data Exchange (ETDEWEB)

Mole, R H; Papworth, D G; Corp, M J [Medical Research Council, Harwell (UK). Radiobiological Research Unit

1983-02-01

The form of the dose-response for induction of malignant diseases in vivo by ionizing radiation is not yet established in spite of its scientific interest and its practical importance. Considerably extended observations have confirmed that the dose-response for acute myeloid leukaemia induced in male CBA/H mice by X-ray exposure is highly curvilinear. The dose-response was well fitted by the expression aD/sup 2/esup(-..gamma..D) (D = dose) in agreement with induction at the cellular level in proportion to D/sup 2/ over the whole dose range 0.25-6.0 Gy. The factor esup(-..gamma..D) accounts for the inescapable concomitant inactivating action of the inducing irradiation. The quantitative aspects of induction of myeloid leukaemia by ionizing radiation are unlike the induction of genetic mutation or cell inactivation and suggest that interaction of two adjoining cells is an essential element in radiation leukaemogenesis.

Bi-allelic silencing of the Fanconi anaemia gene FANCF in acute myeloid leukaemia.

NARCIS (Netherlands)

Tischkowitz, M; Ameziane, N.; Waisfisz, Q.; Winter, de J.P.; Harris, R; Taniguchi, T; Andrea, d' A; Hodgson, SV; Mathew, C.G.; Joenje, H.

2003-01-01

Fanconi anaemia (FA) is a chromosomal instability disorder associated with a high risk of acute myeloid leukaemia (AML). Previous work has shown that the AML cell line CHRF-288, derived from a sporadic AML-M7 patient, does not express FANCF protein and exhibits a cellular FA phenotype. We show that

Leukaemia at Queen Elizabeth Central Hospital in Blantyre, Malawi.

Science.gov (United States)

Mukiibi, J M; Nyirenda, C M; Adewuyi, J O; Mzula, E L; Magombo, E D; Mbvundula, E M

2001-07-01

To determine the patterns of leukaemias seen in Malawians at Queen Elizabeth Central Hospital (QECH) and to compare the findings with those from elsewhere. An overview of the problems encountered in the management of leukaemia in developing countries especially those in sub-Saharan Africa are highlighted. Retrospective descriptive analysis of consecutive leukaemia cases seen from January 1994 through December 1998. Of the 95 leukaemia patients diagnosed during the study period, childhood (0-15 years) leukaemia occurred in 27 (28.4%) patients while adulthood (above 15 years) leukaemia accounted for 68 (71.6%) patients. The main leukaemia types were: acute lymphoblastic leukaemia (ALL) 14 (14.7%), acute myeloblastic leukaemia (AML) 25 (26.3%), chronic myeloid (granulocytic) leukaemia (CML) 32 (33.7%), chronic lymphocytic (lymphatic) leukaemia (CLL) 22 (23.2%) and hairy cell leukaemia (HCL) two (2.1%) patients. Most of the acute leukaemia (AL) cases occurred in the six to 15 year age bracket with a male preponderance. In ALL, lymphadenopathy was the commonest presenting feature followed by pallor (92.9%) while in the AML group, pallor occurred in 80% of cases. Abdominal swelling (87.5%) due to splenomegaly (81.3%) were the main clinical features in the CML group whereas lymphadenopathy (63.6%) followed by splenomegaly (59.1%) were the dominant presenting features in CLL. Haematologically, although leucocytosis characterised both acute and chronic leukaemias, most cases of acute leukaemia presented with more severe anaemia (Hb charitable organisations.

Measuring the impact of a restrictive transfusion guideline in patients with acute myeloid leukaemia

DEFF Research Database (Denmark)

Hoeg, R T; Leinoe, E B; Andersen, P

2013-01-01

practice, but has not been used to evaluate behavioral interventions. We examined the effect of a Danish National Board of Health December 2007 transfusion guideline on the behavior of clinicians treating acute myeloid leukaemia (AML). We compared the effect of the guideline on pre-transfusion haemoglobin...

Rapid Evolution to Blast Crisis Associated with a Q252H ABL1 Kinase Domain Mutation in e19a2 BCR-ABL1 Chronic Myeloid Leukaemia

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Sarah L. McCarron

2013-01-01

Full Text Available A minority of chronic myeloid leukaemia (CML patients express variant transcripts of which the e19a2 BCR-ABL1 fusion is the most common. Instances of tyrosine kinase inhibitor (TKI resistance in e19a2 BCR-ABL1 CML patients have rarely been reported. A case of e19a2 BCR-ABL1 CML is described in whom imatinib resistance, associated with a Q252H ABL1 kinase domain mutation, became apparent soon after initiation of TKI therapy. The patient rapidly transformed to myeloid blast crisis (BC with considerable bone marrow fibrosis and no significant molecular response to a second generation TKI. The clinical course was complicated by comorbidities with the patient rapidly succumbing to advanced disease. This scenario of Q252H-associated TKI resistance with rapid BC transformation has not been previously documented in e19a2 BCR-ABL1 CML. This case highlights the considerable challenges remaining in the management of TKI-resistant BC CML, particularly in the elderly patient.

A novel inherited mutation of the transcription factor RUNX1 causes thrombocytopenia and may predispose to acute myeloid leukaemia.

Science.gov (United States)

Walker, Logan C; Stevens, Jane; Campbell, Hamish; Corbett, Rob; Spearing, Ruth; Heaton, David; Macdonald, Donald H; Morris, Christine M; Ganly, Peter

2002-06-01

The RUNX1 (AML1, CBFA2) gene is a member of the runt transcription factor family, responsible for DNA binding and heterodimerization of other non-DNA binding transcription factors. RUNX1 plays an important part in regulating haematopoiesis and it is frequently disrupted by illegitimate somatic recombination in both acute myeloid and lymphoblastic leukaemia. Germline mutations of RUNX1 have also recently been described and are dominantly associated with inherited leukaemic conditions. We have identified a unique point mutation of the RUNX1 gene (A107P) in members of a family with autosomal dominant inheritance of thrombocytopenia. One member has developed acute myeloid leukaemia (AML).

How Is Chronic Myeloid Leukemia Diagnosed?

Science.gov (United States)

... Myeloid Leukemia? More In Chronic Myeloid Leukemia About Chronic Myeloid Leukemia Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treatment After Treatment Back To Top Imagine a world ...

Summary curves for patients transplanted for chronic myeloid leukaemia salvaged by a donor lymphocyte infusion: the current leukaemia-free survival curve

DEFF Research Database (Denmark)

Klein, John P.; Keiding, Niels; Shu, Youyi

2000-01-01

CML, donor lymphocyte infusion, leukaemia-free survival, current leukaemia-free survival, statistical methods......CML, donor lymphocyte infusion, leukaemia-free survival, current leukaemia-free survival, statistical methods...

Environmental factors and leukaemia

Energy Technology Data Exchange (ETDEWEB)

Brandt, L

1985-01-01

Investigations on the association between environmental hazards and the development of various types of leukaemia are reviewed. Regarding acute non-lymphocytic leukaemia (ANLL) exposure to ionizing radiation is a well-documented risk factor. According to several recent studies exposure to strong electromagnetic fields may be suspected to be of etiologic importance for ANLL. There is evidence that occupational handling of benzene is a risk factor and other organic solvents may also be leukaemogenic. Occupational exposure to petrol products has been proposed to be a risk factor although the hazardous substances have not yet been defined. Results of cytogenetic studies in ANLL suggest that exposure to certain environmental agents may be associated with relatively specific clonal chromosome aberrations. Exposure in utero to ionizing radiation has been proposed to be a risk factor for acute lymphocytic leukaemia (ALL) in children. Unlike ANLL there seems at present to be little evidence that ALL is related to exposure to some chemicals. Chronic myeloid leukaemia (CML) may follow exposure to high doses of ionizing radiation whereas such exposure seems to be of insignificant importance for the development of chronic lymphocytic leukaemia (CLL). According to some studies an abnormally high incidence of CLL may be found among farmers in the USA. These results have not been confirmed in Scandinavian studies. There seems to be little evidence that CML or CLL are related to occupational handling of some chemicals. 35 references.

Low dose irradiation and risk of leukaemia: A case-control study

International Nuclear Information System (INIS)

Chobanova, N.; Bayrakova, A.

1997-01-01

The effect of low dose irradiation (medical X-ray diagnostic) on the developing of leukaemias in adults is investigated. The influence of non-radiation agents (occupational exposure to chemical carcinogens, past viral infections, family aggregations) to leukaemias are considered also. During this retrospective study 228 patients have been examined with the following diagnosis: acute myeloid leukaemia, chronic myelogenous leukaemias, myelodisplastic syndrome and non-Hodgkin lymphoma (diagnosed between 1991-1993). Each case has been matched with two controls. Statistically significant increase has been found in the risk of developing leukaemias after X-ray diagnostic irradiation (OR = 1.98, 95% CI = 1.14 ./. 3.46). Exposure to chemical agents is also associated with significant increase in the risk (OR = 1.98, 95% CI = 1.25 ./. 2.86). (author)

Omacetaxine Mepesuccinate for Chronic Myeloid Leukemia.

Science.gov (United States)

Rosshandler, Yasmin; Shen, Ann Q; Cortes, Jorge; Khoury, Hanna Jean

2016-05-01

Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.

Quantification of hydroxyurea in human plasma by HPLC-MS/MS and its application to pharmacokinetics in patients with chronic myeloid leukaemia.

Science.gov (United States)

Hai, Xin; Guo, Meihua; Gao, Chunlu; Zhou, Jin

2017-04-15

Hydroxyurea (HU) has been used in the treatment of chronic myeloid leukaemia (CML) and other myeloproliferative malignancies. Considering patient's wide variation in clinical response to HU, a new and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to monitor patients' compliance to treatment and investigate the pharmacokinetics of HU in patients with CML. Stable isotope labeled HU- 13 C 1 , 15 N 2 was used as internal standard. Plasma samples were treated with acetonitrile to precipitate protein. The supernatant was injected directly without derivatization and separated on a hydrophilic interaction liquid chromatography column. HU was quantitatively analyzed with a mobile phase of acetonitrile-1.5mM ammonium formate (90:10, V:V) within 3min. The proposed method provided a linearity range of 1-200μg/mL. The coefficients of variation for intra- and inter-day precision were less than 2.07% and 4.28%, respectively, while the accuracy (bias) was in the range of -3.77 to 2.96%. This method was satisfactorily applied to the determination of HU in two patients with CML. It is suitable for supporting pharmacokinetic studies and clinical therapeutic monitoring. Copyright © 2017 Elsevier B.V. All rights reserved.

Updated estimates of survival and cost effectiveness for imatinib versus interferon-alpha plus low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukaemia.

Science.gov (United States)

Reed, Shelby D; Anstrom, Kevin J; Li, Yanhong; Schulman, Kevin A

2008-01-01

For trials in which participants are followed beyond the main study period to assess long-term outcomes, economic evaluations conducted using short-term data should be systematically updated to reflect new information. We used 60-month survival data from the IRIS (International Randomized study of Interferon vs STI571) trial to update previously published cost-effectiveness estimates, based on 19 months of follow-up, of imatinib versus interferon (IFN)-alpha plus low-dose cytarabine in patients with chronic-phase chronic myeloid leukaemia. For patients treated with imatinib, we used the 60-month data to calibrate the survival curves generated from the original cost-effectiveness model. We used historical data to model survival for patients randomized to IFNalpha. We updated costs for medical resources using 2006 Medicare reimbursement rates and applied average wholesale prices (AWPs) and wholesale acquisition costs (WACs) to study medications. Five-year survival for patients randomized to imatinib was better than predicted in the original model (89.4% vs 83.2%). We estimated remaining life expectancy with first-line imatinib to be 19.1 life-years (3.8 life-years over the original model) and 15.2 QALYs (3.1 QALYs over the original estimate). Estimates for IFNalpha remained at 9.1 life-years and 6.3 QALYs. When we applied AWPs to study medications, incremental cost-effectiveness ratios (ICERs) were $US 51,800-57,500 per QALY. When we applied WACs, ICERs were $US 42,000-46,200 per QALY. Although the analysis revealed that the original survival estimates were conservative, the updated cost-effectiveness ratios were consistent with, or slightly higher than, the original estimates, depending on the method for assigning costs to study medications.

Genetics Home Reference: chronic myeloid leukemia

Science.gov (United States)

... Central Quintás-Cardama A, Cortes JE. Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc. 2006 Jul;81(7):973-88. Review. Citation on PubMed Skorski T. Genetic mechanisms of chronic myeloid leukemia blastic transformation. Curr Hematol Malig Rep. 2012 Jun; ...

Analysis of the Fanconi anaemia complementation group A gene in acute myeloid leukaemia.

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Condie, Alison; Powles, Raymond L; Hudson, Chantelle D; Shepherd, Valerie; Bevan, Stephen; Yuille, Martin R; Houlston, Richard S

2002-09-01

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. Around 10-15% of individuals with recessively inherited Fanconi anaemia (FA) develop AML. FA is one of a group of recessive syndromes characterized by excessive spontaneous chromosomal breakage in which heterozygote carriers appear to display an increased risk of cancer and there is some indirect evidence that FA carriers may also be at increased risk of AML. This suggests that FA genes may play a role in the development of AML in the wider context. To examine this proposition, further, we have screened samples from 79 AML patients for mutations in the major FA gene, FANCA. No truncating FANCA mutations were detected. One missense mutation previously designated as pathogenic and five novel missense mutations causing non-conservative amino acid substitutions were detected. The data suggests that while FANCA mutations are rare, FANCA mutations may contribute to the development of the disease in a subset of AML.

Chronic myeloid leukaemia in Spain: Its presentation characteristics have changed. Spanish section of the EUTOS population-based registry.

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Osorio, S; Casado, L F; Giraldo, P; Maestro, B; Andrade, M; Redondo, S; García-Gutiérrez, V; Ayala, R; Garcia, N; Steegmann, J L

2016-01-01

To provide more reliable data on the epidemiology of chronic myeloid leukaemia (CML) in Spain than are currently available. The EUTOS population-based project of European LeukemiaNet is a population registry of new CML cases in patients 18 years of age or older from 22 European areas. The Spanish section included the autonomous communities of Madrid, Castilla-La Mancha and Aragon, from 1-2-2010 to 31-12-2012. A total of 250 cases were recorded in 35 months. The overall incidence was 1.08 cases/10(5) inhabitants-year, with a predominance of men (58%) and clear differences among the communities. The incidence standardised by age was similar (overall, 1.04; men, 1.31; women, 0.81). The median age was 54 years. The incidence increased with age, reaching a peak at>65 years, although 31.7% of cases appeared between the ages of 20 and 44 years. Four percent of cases were diagnosed in advanced stages (2.4% in accelerated phase, 1.6% in blast crisis), 56% were asymptomatic, 38% had splenomegaly, and the Sokal score was high in 11% (lower than what was previously reflected in the literature). The current incidence of CML in Spain is higher than previously reported and similar to that of the European studies. Unlike the classical descriptions, CML presented mostly in asymptomatic form, with no splenomegaly, less leucocytosis and in stages with better prognosis. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

A Ten Year Descriptive Study of Adult Leukaemia at Al-Jomhori Teaching Hospital in Sana'a, Yemen

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Jameel Al-Ghazaly

2014-12-01

Full Text Available Background: There is scarcity of data of the epidemiology of leukaemia in Arab countries including Yemen. Understanding patterns of leukaemia underpins epidemiology and can provide insight into disease etiology. The aim of this research is to determine the epidemiologic pattern of adult leukaemia in Yemen. Methods: The research is a descriptive cross-sectional study. We analyzed the data of 702 adult patients with leukaemia, who were newly diagnosed over a ten-year period between October 1999 and October 2009 at the referral haematology centre in Sana’a at Al-Jomhori Teaching Hospital, according to type of leukaemia, age, sex, geographic distribution and time of diagnosis. Results: Acute Myeloid Leukaemia (AML was found to be the most common (45.1% followed by Chronic Myeloid Leukaemia (CML (26.5%, Acute Lymphoid Leukaemia (ALL (17.7% and Chronic Lymphoid Leukaemia (CLL (10.7%, respectively. There was an almost equal prevalence of AML and CML for males and females but males had significantly more cases of ALL and CLL (p =0.008. A significant variation in geographic pattern showed that the highest number of cases is seen the Central mountainous region and the least number of cases in the South-eastern region which is coastal and lowland (p<0.001. The seasonal variation showed that higher number of ALL cases was seen in the summer months (33% compared with other seasons (21% in the spring, 24.2% in autumn and 21.8% in winter. Conclusions: The pattern of adult leukaemia in Yemen is different from that seen in western countries which could be attributed to different environmental exposure. The geographic pattern indicates a possible role of certain environmental factors which warrant further investigations. The pattern of seasonal variation needs further studies for evaluating the seasonality.

Improved outcome after relapse in children with acute myeloid leukaemia

DEFF Research Database (Denmark)

Abrahamsson, Jonas; Clausen, Niels; Gustafsson, Göran

2007-01-01

investigated. The study included all 146 children in the Nordic countries diagnosed with AML between 1988 and 2003, who relapsed. Data on disease characteristics and relapse treatment were related to outcome. Sixty-six percentage achieved remission with survival after relapse (5 years) 34 +/- 4%. Of 122......In the Nordic Society for Paediatric Haematology and Oncology paediatric study acute myeloid leukaemia (AML) 93, event-free survival was 50% and overall survival was 66%, indicating that many patients were cured following relapse. Factors influencing outcome in children with relapsed AML were...... patients who received re-induction therapy, 77% entered remission with 40 +/- 5% survival. Remission rates were similar for different re-induction regimens but fludarabine, cytarabine, granulocyte colony-stimulating factor-based therapy had low treatment-related mortality. Prognostic factors for survival...

Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

Science.gov (United States)

Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

2012-01-01

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

Do We Know What Causes Chronic Myeloid Leukemia?

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... Be Prevented? More In Chronic Myeloid Leukemia About Chronic Myeloid Leukemia Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treatment After Treatment Back To Top Imagine a world ...

(/sup 3/H)ouabain binding to leukaemic cells and intralymphocytic sodium content in chronic lymphocytic leukaemia; no evidence for alterations of the Na/sup +//K/sup +/-pump

Energy Technology Data Exchange (ETDEWEB)

Berntorp, E; Berntorp, K

1987-01-01

The number of specific (/sup 3/H)ouabain binding sites and dissociation constants (K/sub d/) were determined by Scatchard analysis of values for leucocytes from patients with B-cell chronic lymphocytic leukaemia (CCL), chronic myeloid leukaemia (CML), acute blastic leukaemia (AL) and healthy subjects. CCL lymphocytes and normal B-cells bound significantly less (/sup 3/H)ouabain than did normal T-lymphocytes. CML granulocytes showed the same binding characteristics as normal granulocytes, while blast cells from AL patients bound significantly more (/sup 3/H)ouabain than did normal granulocytes or B-cells. The increased binding capacity in blast cells might, at least partly, reflect their larger cell size. A decrease in K/sub d/ values was only found in CLL lymphocytes, as compared with normal B-cells. Intralymphocytic sodium content in CLL lymphocytes was significantly increased, as sompared with that in T-cell-enriched normal lymphocytes. (/sup 3/H)ouabain binding did not show any relationship to different prognostic variables in CLL. The present data mainly argue against altered Na/sup +//K/sup +/-ATPase enzyme activity as an indicator of malignancy.

immunophenotyping of acute leukaemias by flow cytometry

African Journals Online (AJOL)

2009-12-01

Dec 1, 2009 ... acute leukaemias and selection of monoclonal antibodies. Data sources: The literature review ... step towards diagnosis of leukaemia. It should be ... antibodies, (B-cell, T-cell, myeloid, monocytic, plasma cells) which is based ...

Molecular response to imatinib & its correlation with mRNA expression levels of imatinib influx & efflux transporters in patients with chronic myeloid leukaemia in chronic phase

Directory of Open Access Journals (Sweden)

Hemant Malhotra

2015-01-01

Full Text Available Background & objectives: Imatinib is the standard first-line treatment for chronic myeloid leukaemia (CML patients. About 20 to 30 per cent patients develop resistance to imatinib and fail imatinib treatment. One of the mechanisms proposed is varying expression levels of the drug transporters. This study was aimed to determine the expression levels of imatinib transporter genes (OCT1, ABCB1, ABCG2 in CML patients and to correlate these levels with molecular response. Methods: Sixty three CML chronic phase patients who were on 400 mg/day imatinib for more than two years were considered for gene expression analysis study for OCT1, ABCB1 and ABCG2 genes. These were divided into responders and non-responders. The relative transcript expression levels of the three genes were compared between these two categories. The association between the expression values of these three genes was also determined. Results: No significant difference in the expression levels of OCT1, ABCB1 and ABCG2 was found between the two categories. The median transcript expression levels of OCT1, ABCB1 and ABCG2 genes in responders were 26.54, 10.78 and 0.64 versus 33.48, 7.09 and 0.53 in non-responders, respectively. A positive association was observed between the expression of the ABCB1 and ABCG2 transporter genes (r=0.407, P<0.05 while no association was observed between the expression of either of the ABC transporter genes with the OCT1 gene. Interpretation & conclusions: Our findings demonstrated that the mRNA expression levels of imatinib transporter genes were not correlated with molecular response in CML patients. Further studies need to be done on a large sample of CML patients to confirm these findings.

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.

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Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R; Herrmann, Harald; Sison, Edward A; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J; Johns, Christopher; Chicas, Agustin; Mulloy, James C; Kogan, Scott C; Brown, Patrick; Valent, Peter; Bradner, James E; Lowe, Scott W; Vakoc, Christopher R

2011-08-03

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial.

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Clark, Richard E; Polydoros, Fotios; Apperley, Jane F; Milojkovic, Dragana; Pocock, Christopher; Smith, Graeme; Byrne, Jenny L; de Lavallade, Hugues; O'Brien, Stephen G; Coffey, Tony; Foroni, Letizia; Copland, Mhairi

2017-07-01

Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4. We did this interim analysis of a non-randomised, phase 2 trial at 20 hospitals in the UK. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase who had received TKI for 3 years or more and were either in stable MR4 (BCR-ABL1:ABL1 ratio 0·1%) on two consecutive samples. The primary endpoint of this interim analysis was the proportion of patients who lost MMR on de-escalation and regained MMR on TKI resumption. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985. Between Dec 16, 2013 and April 10, 2015, we enrolled 174 patients into the MMR cohort (n=49) or the MR4 cohort (n=125). During the 12 months of half-dose therapy, 12 patients (7%) had molecular recurrence, all of whom regained MMR within 4 months of full-dose TKI resumption (median time to recovery 77 days). Recurrence was significantly lower in the MR4 cohort (three [2%; 90% CI 0·2-4·8] of 121 evaluable patients) than in the MMR cohort (nine [19%; 90% CI 9·5-28·0] of 48 evaluable patients; hazard ratio 0·12, 90% CI 0·04-0·37; p=0·0007), but was unrelated to previous TKI or TKI therapy duration. Adverse events (eg, lethargy, diarrhoea, rash, and nausea) improved during the first 3 months of de-escalation, though not thereafter. 16 serious adverse events were reported, including one fatality due to worsening pre-existing peripheral arterial occlusive disease in a patient who had received only imatinib. TKI de

HLA-DRB1*16-restricted recognition of myeloid cells, including CD34+ CML progenitor cells

NARCIS (Netherlands)

Ebeling, Saskia B.; Ivanov, Roman; Hol, Samantha; Aarts, Tineke I.; Hagenbeek, Anton; Verdonck, Leo F.; Petersen, Eefke J.

2003-01-01

The therapeutic effect of a human leucocyte antigen (HLA)-identical allogeneic stem cell transplantation (allo-SCT) for the treatment of haematological malignancies is mediated partly by the allogeneic T cells that are administered together with the stem cell graft. Chronic myeloid leukaemia (CML)

Alginate foam-based three-dimensional culture to investigate drug sensitivity in primary leukaemia cells.

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Karimpoor, Mahroo; Yebra-Fernandez, Eva; Parhizkar, Maryam; Orlu, Mine; Craig, Duncan; Khorashad, Jamshid S; Edirisinghe, Mohan

2018-04-01

The development of assays for evaluating the sensitivity of leukaemia cells to anti-cancer agents is becoming an important aspect of personalized medicine. Conventional cell cultures lack the three-dimensional (3D) structure of the bone marrow (BM), the extracellular matrix and stromal components which are crucial for the growth and survival of leukaemia stem cells. To accurately predict the sensitivity of the leukaemia cells in an in vitro assay a culturing system containing the essential components of BM is required. In this study, we developed a porous calcium alginate foam-based scaffold to be used for 3D culture. The new 3D culture was shown to be cell compatible as it supported the proliferation of both normal haematopoietic and leukaemia cells. Our cell differential assay for myeloid markers showed that the porous foam-based 3D culture enhanced myeloid differentiation in both leukaemia and normal haematopoietic cells compared to two-dimensional culture. The foam-based scaffold reduced the sensitivity of the leukaemia cells to the tested antileukaemia agents in K562 and HL60 leukaemia cell line model and also primary myeloid leukaemia cells. This observation supports the application of calcium alginate foams as scaffold components of the 3D cultures for investigation of sensitivity to antileukaemia agents in primary myeloid cells. © 2018 The Author(s).

Ponatinib for Treating Chronic Myeloid Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

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Pandor, Abdullah; Stevenson, Matt; Stevens, John; James, Marrissa Martyn-St; Hamilton, Jean; Byrne, Jenny; Rudin, Claudius; Rawdin, Andrew; Wong, Ruth

2018-02-26

As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures ponatinib (Inclusig ® ; Incyte Corporation) to submit evidence for the clinical and cost effectiveness for previously treated chronic myeloid leukaemia (CML) and Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). This paper focusses on the three phases of CML: the chronic phase (CP), the accelerated phase (AP) and the blast crisis phase (BP). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). This article presents the critical review of the company's submission by the ERG and the outcome of the NICE guidance. Clinical evidence for ponatinib was derived from a phase II, industry-sponsored, single-arm, open-label, multicentre, non-comparative study. Despite the limited evidence and potential for biases, this study demonstrated that ponatinib was likely to be an effective treatment (in terms of major cytogenetic response and major haematological response) with an acceptable safety profile for patients with CML. Given the absence of any head-to-head studies comparing ponatinib with other relevant comparators, the company undertook a matching-adjusted indirect comparison (MAIC) of ponatinib with bosutinib. The approach was only used for patients with CP-CML because comprehensive data were not available for the AP- or BP-CML groups to allow the matching technique to be used. Despite the uncertainty about the MAIC approach, ponatinib was considered likely to offer advantages over bosutinib in the third-line setting, particularly for complete cytogenetic response. The company developed two health economic models to assess the cost effectiveness of ponatinib for the treatment of patients in CP-CML or in advanced CML (AP- or BP-CML, which were modelled separately). The company did

European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia.

Science.gov (United States)

Steegmann, J L; Baccarani, M; Breccia, M; Casado, L F; García-Gutiérrez, V; Hochhaus, A; Kim, D-W; Kim, T D; Khoury, H J; Le Coutre, P; Mayer, J; Milojkovic, D; Porkka, K; Rea, D; Rosti, G; Saussele, S; Hehlmann, R; Clark, R E

2016-08-01

Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better

Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.

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Lucas, C M; Harris, R J; Holcroft, A K; Scott, L J; Carmell, N; McDonald, E; Polydoros, F; Clark, R E

2015-07-01

High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome.

Myeloid leukaemia frequency after protracted exposure to ionizing radiation: experimental confirmation of the flat dose-response found in ankylosing spondylitis after a single treatment course with x-rays

Energy Technology Data Exchange (ETDEWEB)

Mole, R H; Major, I R [Medical Research Council, Harwell (UK). Radiobiological Research Unit

1983-01-01

The dose-response for leukaemia induction by exposure to ionizing radiation protracted over several weeks was largely independent of dose not only in X-rayed patients with ankylosing spondylitis but also in experimentally ..gamma..-rayed CBA/H mice. In the experiment the induced leukaemia frequency of acute myeloid leukaemia was independent of a several thousand-fold variation in physical dose rate. Any difference in leukaemia induction between brief and protracted exposures must therefore depend on specifically biological consequences of protracted exposures. Experimental analysis is required to provide the guides for inference about risks of low level exposure from observations on relatively heavily irradiated populations.

CD33 monoclonal antibody conjugated Au cluster nano-bioprobe for targeted flow-cytometric detection of acute myeloid leukaemia

Science.gov (United States)

Retnakumari, Archana; Jayasimhan, Jasusri; Chandran, Parwathy; Menon, Deepthy; Nair, Shantikumar; Mony, Ullas; Koyakutty, Manzoor

2011-07-01

Protein stabilized gold nanoclusters (Au-NCs) are biocompatible, near-infrared (NIR) emitting nanosystems having a wide range of biomedical applications. Here, we report the development of a Au-NC based targeted fluorescent nano-bioprobe for the flow-cytometric detection of acute myeloid leukaemia (AML) cells. Au-NCs with ~ 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of ~ 0.8 nm were prepared by bovine serum albumin assisted reduction-cum-stabilization in aqueous phase. The protein protected clusters were conjugated with monoclonal antibody against CD33 myeloid antigen, which is overexpressed in ~ 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of ~ 12 nm retained bright fluorescence over an extended duration of ~ a year, as the albumin protein protects Au-NCs against degradation. Nanotoxicity studies revealed excellent biocompatibility of Au-NC conjugates, as they showed no adverse effect on the cell viability and inflammatory response. Target specificity of the conjugates for detecting CD33 expressing AML cells (KG1a) in flow cytometry showed specific staining of ~ 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of ~ 8.2% in human peripheral blood cells (PBMCs) which are CD33low. The confocal imaging also demonstrated the targeted uptake of CD33 conjugated Au-NCs by leukaemia cells, thus confirming the flow cytometry results. This study demonstrates that novel nano-bioprobes can be developed using protein protected fluorescent nanoclusters of Au for the molecular receptor targeted flow cytometry based detection and imaging of cancer cells.

CD33 monoclonal antibody conjugated Au cluster nano-bioprobe for targeted flow-cytometric detection of acute myeloid leukaemia

International Nuclear Information System (INIS)

Retnakumari, Archana; Jayasimhan, Jasusri; Chandran, Parwathy; Menon, Deepthy; Nair, Shantikumar; Mony, Ullas; Koyakutty, Manzoor

2011-01-01

Protein stabilized gold nanoclusters (Au-NCs) are biocompatible, near-infrared (NIR) emitting nanosystems having a wide range of biomedical applications. Here, we report the development of a Au-NC based targeted fluorescent nano-bioprobe for the flow-cytometric detection of acute myeloid leukaemia (AML) cells. Au-NCs with ∼ 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of ∼ 0.8 nm were prepared by bovine serum albumin assisted reduction-cum-stabilization in aqueous phase. The protein protected clusters were conjugated with monoclonal antibody against CD33 myeloid antigen, which is overexpressed in ∼ 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of ∼ 12 nm retained bright fluorescence over an extended duration of ∼ a year, as the albumin protein protects Au-NCs against degradation. Nanotoxicity studies revealed excellent biocompatibility of Au-NC conjugates, as they showed no adverse effect on the cell viability and inflammatory response. Target specificity of the conjugates for detecting CD33 expressing AML cells (KG1a) in flow cytometry showed specific staining of ∼ 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of ∼ 8.2% in human peripheral blood cells (PBMCs) which are CD33 low . The confocal imaging also demonstrated the targeted uptake of CD33 conjugated Au-NCs by leukaemia cells, thus confirming the flow cytometry results. This study demonstrates that novel nano-bioprobes can be developed using protein protected fluorescent nanoclusters of Au for the molecular receptor targeted flow cytometry based detection and imaging of cancer cells.

CD33 monoclonal antibody conjugated Au cluster nano-bioprobe for targeted flow-cytometric detection of acute myeloid leukaemia

Energy Technology Data Exchange (ETDEWEB)

Retnakumari, Archana; Jayasimhan, Jasusri; Chandran, Parwathy; Menon, Deepthy; Nair, Shantikumar; Mony, Ullas; Koyakutty, Manzoor, E-mail: manzoork@aims.amrita.edu, E-mail: ullasmony@aims.amrita.edu [Amrita Centre for Nanoscience and Molecular Medicine, Amrita Institute of Medical Science, Cochin 682 041 (India)

2011-07-15

Protein stabilized gold nanoclusters (Au-NCs) are biocompatible, near-infrared (NIR) emitting nanosystems having a wide range of biomedical applications. Here, we report the development of a Au-NC based targeted fluorescent nano-bioprobe for the flow-cytometric detection of acute myeloid leukaemia (AML) cells. Au-NCs with {approx} 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of {approx} 0.8 nm were prepared by bovine serum albumin assisted reduction-cum-stabilization in aqueous phase. The protein protected clusters were conjugated with monoclonal antibody against CD33 myeloid antigen, which is overexpressed in {approx} 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of {approx} 12 nm retained bright fluorescence over an extended duration of {approx} a year, as the albumin protein protects Au-NCs against degradation. Nanotoxicity studies revealed excellent biocompatibility of Au-NC conjugates, as they showed no adverse effect on the cell viability and inflammatory response. Target specificity of the conjugates for detecting CD33 expressing AML cells (KG1a) in flow cytometry showed specific staining of {approx} 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of {approx} 8.2% in human peripheral blood cells (PBMCs) which are CD33{sup low}. The confocal imaging also demonstrated the targeted uptake of CD33 conjugated Au-NCs by leukaemia cells, thus confirming the flow cytometry results. This study demonstrates that novel nano-bioprobes can be developed using protein protected fluorescent nanoclusters of Au for the molecular receptor targeted flow cytometry based detection and imaging of cancer cells.

Chronic myeloid leukemia: reminiscences and dreams

Science.gov (United States)

Mughal, Tariq I.; Radich, Jerald P.; Deininger, Michael W.; Apperley, Jane F.; Hughes, Timothy P.; Harrison, Christine J.; Gambacorti-Passerini, Carlo; Saglio, Giuseppe; Cortes, Jorge; Daley, George Q.

2016-01-01

With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. This work was also of major importance to support the idea that cytogenetic changes were drivers of leukemogenesis. John Goldman originally made seminal contributions to the use of autologous and allogeneic stem cell transplantation from the late 1970s onwards. Then, in collaboration with Brian Druker, he led efforts to develop ABL1 tyrosine kinase inhibitors for the treatment of patients with chronic myeloid leukemia in the late 1990s. He also led the global efforts to develop and harmonize methodology for molecular monitoring, and was an indefatigable organizer of international conferences. These conferences brought together clinicians and scientists, and accelerated the adoption of new therapies. The abundance of praise, tributes and testimonies expressed by many serve to illustrate the indelible impressions these two passionate and affable scholars made on so many people’s lives. This tribute provides an outline of the remarkable story of chronic myeloid leukemia, and in writing it, it is clear that the historical triumph of biomedical science over this leukemia cannot be considered without appreciating the work of both Janet Rowley and John Goldman. PMID:27132280

Pattern of Leukaemia Patients Admitted in Ayub Teaching Hospital Abbottabad

International Nuclear Information System (INIS)

Khan, T. M.

2016-01-01

Background: Any tissue of the body can give rise to cancer. However, those tissues which multiply rapidly are at high risk of developing cancer and haematopoietic system is one of them. Neoplasms of this system are known as leukaemia and lymphoma, according to the types of white cells involved.Study of cancer patterns in different societies, however can contribute a substantial knowledge about the aetiology of cancer. The present Study was designed and aimed to estimate the frequency of different types of leukaemia in patients admitted in Ayub Teaching hospital Abbottabad. Methods: Data from the patients admitted at oncology Department of Ayub Teaching Hospital Abbottabad from 2010 to 2015 was collected and analysed to calculate cumulative and year-wise frequency of leukaemia and its major types. Frequency distribution with reference to gender and age was also calculated. Results: In our analysis about 16 percent patients had acute myelocytic leukaemia and 32 percent patients had acute lymphocytic leukaemia; while chronic myeloid leukaemia outnumbered chronic lymphocytic leukaemia (11 percent and 3 percent); Hodgkin lymphoma was seen in 18 percent cases while Non Hodgkin lymphoma (NHL) was present in 20 percent cases. Out of the total, 150 cases (75 percent) belonged to mountainous areas of Hazara, i.e., 40 cases belonged to Kohistan, another 40 cases were residents of Battagram, 45 cases belonged to hilly areas of Mansehra and 25 cases to Kaghan valley, while only 50 (25 percent) cases were from the plain areas of Abbottabad and Haripur districts, i.e., 20 and 30 cases respectively. Conclusion: Leukaemia is more common in hilly areas of Hazara, since majority of the cases belonged to well-known mountainous regions of Kohistan, Battagram, Kaghan or Mansehra and only few cases belonged to the plain areas of Abbottabad and Haripur districts. (author)

Chronic lymphocytic leukaemia manifestating as exfoliative dermatitis

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Dhir R

1995-01-01

Full Text Available A 60-year-old patient reported with a history of redness and peeling of the skin, and sensations of chills and tightness of the skin of three months duration. Clinical examination revealed exfoliative dermatitis, generalised lymphadenopathy and hepatosplenomegely. A peripheral smear showed features of chronic lymphocytic leukaemia.

MPLW515L mutation in acute megakaryoblastic leukaemia.

Science.gov (United States)

Hussein, K; Bock, O; Theophile, K; Schulz-Bischof, K; Porwit, A; Schlue, J; Jonigk, D; Kreipe, H

2009-05-01

The thrombopoietin receptor gene (MPL) is expressed in megakaryocytes and exhibits the gain of function point mutation W515K/L in approximately 5% of patients with primary myelofibrosis/idiopathic myelofibrosis (PMF) representing one subtype of the chronic myeloproliferative disorders (myeloproliferative neoplasm). A series of primary and secondary acute myeloid leukaemias (AML) with megakaryoblastic phenotype and myelofibrosis unrelated to PMF (n=12) was analysed for the MPL(W515K/L) mutation by pyrosequencing. In three cases (25%), MPL(W515L) was found and in two of these a combination with trisomy 21 or the Philadelphia chromosome occurred. None of the secondary AML cases evolving from pre-existing PMF showed MPL(W515K/L) (n=4). We conclude that MPL(W515L) occurs in a considerable proportion of acute megakaryoblastic leukaemias with myelofibrosis unrelated to PMF.

A single nucleotide polymorphism in cBIM is associated with a slower achievement of major molecular response in chronic myeloid leukaemia treated with imatinib.

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Vanessa Augis

Full Text Available BIM is essential for the response to tyrosine-kinase inhibitors (TKI in chronic myeloid leukaemia (CML patients. Recently, a deletion polymorphism in intron 2 of the BIM gene was demonstrated to confer an intrinsic TKI resistance in Asian patients. The present study aimed at identifying mutations in the BIM sequence that could lead to imatinib resistance independently of BCR-ABL mutations.BIM coding sequence analysis was performed in 72 imatinib-treated CML patients from a French population of our centre and in 29 healthy controls (reference population as a case-control study. Real-time quantitative PCR (RT qPCR was performed to assess Bim expression in our reference population.No mutation with amino-acid change was found in the BIM coding sequence. However, we observed a silent single nucleotide polymorphism (SNP c465C>T (rs724710. A strong statistical link was found between the presence of the T allele and the high Sokal risk group (p = 0.0065. T allele frequency was higher in non responsive patients than in the reference population (p = 0.0049. Similarly, this T allele was associated with the mutation frequency on the tyrosine kinase domain of BCR-ABL (pT SNP of BIM could be useful for predicting the outcome of imatinib-treated CML patients.

Various distinctive cytogenetic abnormalities in patients with acute myeloid leukaemia aged 60 years and older express adverse prognostic value : results from a prospective clinical trial

NARCIS (Netherlands)

van der Holt, Bronno; Breems, Dimitri A.; Beverloo, H. Berna; van den Berg, Eva; Burnett, Alan K.; Sonneveld, Pieter; Lowenberg, Bob

Diagnostic cytogenetic abnormalities are considered important prognostic factors in patients with acute myeloid leukaemia (AML). However, the prognostic assessments have mainly been derived from patients with AML aged <60 years. Two recent studies of AML patients of 60 years and older proposed

Cost-effectiveness and quality-of-life assessment of GM-CSF as an adjunct to intensive remission induction chemotherapy in elderly patients with acute myeloid leukaemia

NARCIS (Netherlands)

Uyl-de Groot, CA; Lowenberg, B; Vellenga, E; Suciu, S; Willemze, R; Rutten, FFH

We conducted a prospective, randomized, multicentre clinical trial comparing the effects and costs of GM-CSF as an adjunct to intensive chemotherapy in elderly patients with acute myeloid leukaemia (AML). The patients were randomized to either daunomycin-cytosine arabinoside (control arm: rr = 161)

Intelligent Techniques Using Molecular Data Analysis in Leukaemia: An Opportunity for Personalized Medicine Support System.

Science.gov (United States)

Banjar, Haneen; Adelson, David; Brown, Fred; Chaudhri, Naeem

2017-01-01

The use of intelligent techniques in medicine has brought a ray of hope in terms of treating leukaemia patients. Personalized treatment uses patient's genetic profile to select a mode of treatment. This process makes use of molecular technology and machine learning, to determine the most suitable approach to treating a leukaemia patient. Until now, no reviews have been published from a computational perspective concerning the development of personalized medicine intelligent techniques for leukaemia patients using molecular data analysis. This review studies the published empirical research on personalized medicine in leukaemia and synthesizes findings across studies related to intelligence techniques in leukaemia, with specific attention to particular categories of these studies to help identify opportunities for further research into personalized medicine support systems in chronic myeloid leukaemia. A systematic search was carried out to identify studies using intelligence techniques in leukaemia and to categorize these studies based on leukaemia type and also the task, data source, and purpose of the studies. Most studies used molecular data analysis for personalized medicine, but future advancement for leukaemia patients requires molecular models that use advanced machine-learning methods to automate decision-making in treatment management to deliver supportive medical information to the patient in clinical practice.

The development of a three-dimensional scaffold for ex vivo biomimicry of human acute myeloid leukaemia.

Science.gov (United States)

Blanco, Teresa Mortera; Mantalaris, Athanasios; Bismarck, Alexander; Panoskaltsis, Nicki

2010-03-01

Acute myeloid leukaemia (AML) is a cancer of haematopoietic cells that develops in three-dimensional (3-D) bone marrow niches in vivo. The study of AML has been hampered by lack of appropriate ex vivo models that mimic this microenvironment. We hypothesised that fabrication and optimisation of suitable biomimetic scaffolds for culturing leukaemic cells ex vivo might facilitate the study of AML in its native 3-D niche. We evaluated the growth of three leukaemia subtype-specific cell lines, K-562, HL60 and Kasumi-6, on highly porous scaffolds fabricated from biodegradable and non-biodegradable polymeric materials, such as poly (L-lactic-co-glycolic acid) (PLGA), polyurethane (PU), poly (methyl-methacrylate), poly (D, L-lactade), poly (caprolactone), and polystyrene. Our results show that PLGA and PU supported the best seeding efficiency and leukaemic growth. Furthermore, the PLGA and PU scaffolds were coated with extracellular matrix (ECM) proteins, collagen type I (62.5 or 125 microg/ml) and fibronectin (25 or 50 microg/ml) to provide biorecognition signals. The 3 leukaemia subtype-specific lines grew best on PU scaffolds coated with 62.5 microg/ml collagen type I over 6 weeks in the absence of exogenous growth factors. In conclusion, PU-collagen scaffolds may provide a practical model to study the biology and treatment of primary AML in an ex vivo mimicry. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Observations on transition of polycythaemia vera into acute or chronic granulocytic leukaemia during treatment with radioactive phosphorus 32P

International Nuclear Information System (INIS)

Krasnik, W.

1975-01-01

In a group of 172 cases of polycythaemia vera treated with radioactive phosphorus 32 P acute granulocytic leukaemia developed in 3 cases and chronic granulocytic leukaemia in 6 cases. Development of acute granulocytic leukaemia during treatment with radioactive phosphorus for polycythaemia vera may be considered with some probability as a result of leukaemia-inducing action of ionizing radiation. Transition of polycythaemia vera into chronic granulocytic leukaemia seems to a natural outcome of this complex myeloproliferative syndrome in patients with survival prolonged by treatment with 32 P. (author)

Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype

Directory of Open Access Journals (Sweden)

Virijevic Marijana

2016-12-01

Full Text Available Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2 genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK. The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up.

Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia

DEFF Research Database (Denmark)

Saglio, Giuseppe; Kim, Dong-Wook; Issaragrisil, Surapol

2010-01-01

Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.......Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase....

Radiation-induced acute myeloid leukaemia in mice

Energy Technology Data Exchange (ETDEWEB)

Bouffler, S.D.; Silver, A.R.J.; Cox, R. [National Radiological Protection Board, Chilton (United Kingdom)

2000-07-01

Ample epidemiological studies of human populations implicate ionizing radiation as a carcinogen and these quantitative studies provide the foundation for the core estimates of radiation cancer risk. The majority of the epidemiological data originate from situations of radiation exposure at high dose and high dose rate. The relevance of risk estimates based on such exposures to the more commonly encountered low dose and dose rate situation has been questioned frequently. Thus, there is a need to investigate and quantitate low dose and dose rate effects. A number of approaches may be considered, for example, very large scale epidemiology, very large scale animal experimentation; however, both of these present problems of a practical and/or ethical nature. A further possible approach is that of mechanistic modelling. This requires a fairly detailed understanding of neoplastic disease and how it develops post-irradiation. Many factors and variables have to be taken into consideration in mechanistic modelling approaches. Testing of mechanistic modelling schemes is best carried out using animal model systems. Acute myeloid leukaemia (AML) is a radiogenic cancer of significance in man and several good mouse models of the disease are available. Here, recent studies conducted at NRPB with the aim of elucidating the post-irradiation development of AML will be discussed. In particular three areas critical for developing a sound mechanistic model will be covered, definition of the initiating event; study of disease progression, this addresses the question of the frequency of conversion of initiated cells into the neoplastic state and the influence of genetic background on leukaemogenesis. (author)

Induction of myeloid leukaemia by whole-body single exposure of CBA male mice to X-rays

Energy Technology Data Exchange (ETDEWEB)

Major, I R [Medical Research Council, Harwell (UK). Radiobiological Research Unit

1979-12-01

A curvilinear dose response of myeloid leukaemia induction in CBA male mouse was obtained after single whole-body X-irradiation at about 3 months of age. This strain has a very low spontaneous incidence of the disease and no cases were found in the unirradiated controls. The incidence was independent of dose rate over the range used (4.2-552 rad/min). Diagnosis required histopathological examination of various body tissues, the gross anatomical changes being easily confused with other haemopoietic disorders, but a few cases were recognized in life from blood samples. Curve-fitting to various models based on theories of radiocarcinogenic mechanism is described.

Clinical pathway for patients with Chronic Myeloid Leukaemia: The Euriclea Project.

Science.gov (United States)

Botti, Stefano; Gargiulo, Gianpaolo; Bombaci, Felice; Artioli, Giovanna; Cosentino, Chiara; Pignatelli, Adriana Concetta; Torino, Daniela; Lionetti, Maria Marcella; Samarani, Emanuela; Cappucciati, Lorella; Bordiga, Paola; Diodati, Antonella; Caffarri, Cristiana; Rosini, Irene; Pane, Fabrizio

2017-07-18

The use of Tirosine Kinase Ihnibitors (TKIs) for the treatment of Chronic Myeloid Leukemia (CML) has definitely represented a turning point in the treatment of the onco-hematological diseases. Over the years, the interest of physicians, nurses, patients and caregivers has increasingly focused on the aspects of the humanization of care, the management of side effects and on the full and constant therapeutic adherence. The aim of the project was to define patient-oriented care processes, based on a proactive approach that can fully respond to the new health needs of CML patients. A nursing expert Working Group (WG) was established. WG reviewed literature about CML patients assistance and then it was conducted a survey on organizational models for the treatment of CML patients, adopted by Italian haematologic and transplant centers.  Finally, the main issues regarding CML patients care were identified and discussed on a multiprofessional basis. Euriclea Project for care of CML patients with the description of a new and expanded nurse role was defined. The Nurse Case Manager or Nursing Clinical Experts were identified as key people for the management of the side effects of treatment, the promotion of the therapeutic adherence and the evaluation of efficacy and effectiveness of the process through the identification of specific indicators for structure, process and outcome. The focal areas of the care process were identified so as to define a different approach to the CML patient, through a holistic view of care and the multidisciplinary interventions.

Acute leukaemia: making sense of a complex blood cancer.

LENUS (Irish Health Repository)

Meenaghan, Teresa

2012-01-01

Acute leukaemia represents a diverse group of blood cancers that affect both children and adults. Treatment schedules for these haematology cancers are often prolonged, with many associated side effects and complications. Nurses caring for patients with acute leukaemia require an anticipatory approach, where care is aimed at minimizing the side effects of treatment and being constantly vigilant for any impending adverse effects. Moreover, patients require support for the psychosocial issues that can arise for patients during their illness. This article provides an overview of acute lymphoblastic leukaemia and acute myeloid leukaemia. Nursing considerations in the care of patients being treated for acute leukaemia are also explored.

The predictive value of early molecular response in chronic myeloid leukaemia patients treated with imatinib in a single real-world medical centre in a developing country.

Science.gov (United States)

Bee, Ping Chong; Sekaran, Veera; Ng, Richard Rui Jie; Kweh, Ting Yi; Gan, Gin Gin

2017-03-01

The prognosis of patients with chronic myeloid leukaemia (CML) has improved since the introduction of imatinib. However, patients who do not achieve complete cytogenetic response (CCyR) and major molecular response (MMR) have poorer prognosis. Recent clinical trials have demonstrated that early and deeper cytogenetic and molecular responses predict a better long-term outcome. This study aimed to analyse the relationship between early molecular response and clinical outcome in a real-life setting. This retrospective study included all patients with CML, in chronic or accelerated phase, who were treated with imatinib at University of Malaya Medical Centre, Malaysia. A total of 70 patients were analysed. The median follow-up duration was 74 months, and the cumulative percentages of patients with CCyR and MMR were 80.0% and 65.7%, respectively. Overall survival (OS) and event-free survival (EFS) at ten years were 94.3% and 92.9%, respectively. Patients who achieved CCyR and MMR had significantly better OS and EFS than those who did not. At six months, patients who had a BCR-ABL level ≤ 10% had significantly better OS and EFS than those who had a BCR-ABL level > 10%. The target milestone of CCyR at 12 months and MMR at 18 months showed no survival advantage in our patients. Our data showed that imatinib is still useful as first-line therapy. However, vigilant monitoring of patients who have a BCR-ABL level > 10% at six months of treatment should be implemented so that prompt action can be taken to provide the best outcome for these patients. Copyright: © Singapore Medical Association

The Danish National Chronic Myeloid Neoplasia Registry

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Bak M

2016-10-01

Full Text Available Marie Bak,1 Else Helene Ibfelt,2 Thomas Stauffer Larsen,3 Dorthe Rønnov-Jessen,4 Niels Pallisgaard,5 Ann Madelung,6 Lene Udby,1 Hans Carl Hasselbalch,1 Ole Weis Bjerrum,7 Christen Lykkegaard Andersen1,7 1Department of Hematology, Zealand University Hospital, University of Copenhagen, Roskilde, 2Research Centre for Prevention and Health, Rigshospitalet Glostrup, University of Copenhagen, Glostrup, 3Department of Hematology, Odense University Hospital, Odense, 4Department of Hematology, Vejle Hospital, Vejle, 5Department of Surgical Pathology, Zealand University Hospital, University of Copenhagen, Roskilde, 6Department of Surgical Pathology, Zealand University Hospital, University of Copenhagen, Næstved, 7Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Aim: The Danish National Chronic Myeloid Neoplasia Registry (DCMR is a population-based clinical quality database, introduced to evaluate diagnosis and treatment of patients with chronic myeloid malignancies. The aim is to monitor the clinical quality at the national, regional, and hospital departmental levels and serve as a platform for research. Study population: The DCMR has nationwide coverage and contains information on patients diagnosed at hematology departments from January 2010 onward, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, unclassifiable myeloproliferative neoplasms, chronic myelomonocytic leukemia, and chronic myeloid leukemia. Main variables: Data are collected using standardized registration forms (so far up to four forms per patient, which are consecutively filled out online at time of diagnosis, after 2-year and 5-year follow-ups, and at end of follow-up. The forms include variables that describe clinical/paraclinical assessments, treatment, disease progression, and survival – disease-specific variables – as well as variables that are identical for all chronic myeloid malignancies. Descriptive

Diagnostic radiography as a risk factor for chronic myeloid and monocytic leukaemia (CML)

International Nuclear Information System (INIS)

Preston-Martin, S.; Thomas, D.C.; Yu, M.C.; Henderson, B.E.

1989-01-01

The study included 136 Los Angeles County residents aged 20-69 with chronic myeloid and monocytic leukemia CML diagnosed from 1979 to 1985 (cases) and 136 neighbourhood controls. During 3-20 years before diagnosis more cases than controls had radiographic examinations of back, gastrointestinal (GI) tract and kidneys, and cases more often had GI and back radiography on multiple occasions (odds ratio (OR) for back X-rays on five or more occasions = 12.0; P < 0.01). Published estimates were used to assign a minimum dose to active bone marrow for various radiographic procedures. ORs were estimated for cumulative marrow doses for each of four time periods (3-5 years, 6-10 years, 11-20 years and 3-20 years before diagnosis). ORs for exposure to 0.99, 100-999, 1000-1999 and ≥ 2000 mrad in the 3-20 years before diagnosis were 1.0, 1.4, 1.6 and 2.4 (P for highest exposure category and P for trend both < 0.05). The association was strongest for 6-10 years before diagnosis, and effects of radiation exposure during this period remained significant after consideration of other risk factors in a logistic regression analysis. (author)

Non-invasive imaging of retinal blood flow in myeloproliferative neoplasms

DEFF Research Database (Denmark)

Willerslev, Anne; Hansen, Mathias M; Klefter, Oliver Niels

2017-01-01

PURPOSE: To study the circulation in the retinal vessels in patients with blood dyscrasia due to myeloproliferative neoplasms using non-invasive retinal imaging. METHODS: Prospective consecutive case series of seven treatment-naïve patients with chronic myeloid leukaemia (n = 2), polycythemia vera...... present at baseline in patients with chronic myeloid leukaemia and were replaced by normal patterns at follow-up. Retinopathy, in the form of cotton-wool spots and retinal haemorrhages, was found at presentation in the two patients with chronic myeloid leukaemia and in one patient with polycythemia vera...

Clofarabine in the treatment of poor risk acute myeloid leukaemia.

LENUS (Irish Health Repository)

Krawczyk, Janusz

2010-09-01

Clofarabine is a second generation nucleoside analogue. It inhibits DNA repair and activates the mitochondrial apoptotic pathway leading to cell death. In vitro clofarabine has demonstrated synergy with daunorubicin and Ara-C and in phase II clinical trials has shown promising activity in poor risk Acute myeloid leukaemia (AML) patients. In our institution over a 24 month period 22 AML patients (11 M, 11 F) with poor risk features, deemed unsuitable for standard therapy, were treated with clofarabine, alone (eight patients) or in combination (14 patients) for up to three cycles of treatment. The median age was 67.5 years (24-76) with 16 patients > 60 years. At the time of treatment 18 patients had active AML. Four patients intolerant of standard induction received clofarabine as consolidation. The overall response rate (ORR) for the 18 patients with active AML was 61%, nine patients (50%) achieving a complete response (CR). Induction and consolidation were well tolerated with no unexpected toxicities. Predictably, all patients developed grade 4 neutropenia but the median duration was only 20 days (17-120). Induction mortality was acceptable at 17%. In conclusion, clofarabine (alone or in combination) is active in poor risk AML with an acceptable safety profile and should be considered a potential option in poor risk AML patients.

Auricular Oedema and Dyshidrotic Eczema in a Patient with Acute Myeloid Leukaemia Treated with Cytarabine

Directory of Open Access Journals (Sweden)

K. Brandt

2010-10-01

Full Text Available Cytarabine is an effective drug in the treatment of haematological malignancies. The therapy is associated with various complications. Frequencies of dermatological side-effects range from 2–72% and occur most commonly after high-dose regimens. Although most cutaneous reactions are mild and resolve spontaneously within several days, they may result in an increased risk of infection and alterations in comfort. In some cases, severe life-threatening reactions have been reported. Here we describe the case of a patient with acute myeloid leukaemia, who developed severe exceptional skin toxicity in terms of auricular oedema and palmar dyshidrotic eczema after the application of low-dose cytarabine. Re-administration of the drug resulted in reduced skin toxicity during further cycles of chemotherapy. Negative epicutaneous patch-testing supported the existence of cytarabine-provoked toxicity.

Chronic lymphocytic leukaemia: An immunobiology approach

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Kostareli Efterpi

2008-01-01

Full Text Available B cell chronic lymphocytic leukaemia (CLL is the most common adult leukaemia that follows an extremely variable clinical course. Several important prognostic parameters defining pathogenic and clinical subgroups of CLL have been identified and validated recently. The biological significance of immunoglobulin (Ig heavy chain variable region gene (IgHV mutational status and associated ZAP-70 over-expression, CD38 and chromosomal aberrations have enabled to identify patients at high risk for early disease progression and inferior survival. Moreover, studies of the B cell antigen receptor (BCR structure and receptor signaling have been most helpful in revealing some new aspects of the biology of this disease. In particular, the analysis of IG genes has revealed that the expressed IgHV/IgKV/IgLV gene repertoires of CLL cells differ from those of normal B cells. A further unique feature of the CLL IG repertoire is the existence of subsets of cases with "stereotyped" BCRs. Accumulating molecular and phenotypic data support the notion that CLL development and evolution is not a simple scholastic event and strongly indicates a role for antigen in driving the cell of origin for at least some subsets of CLL cases.

Radioimmunotherapy for treatment of acute myeloid leukaemia and myelodysplastic syndrome. Conceptual chances

International Nuclear Information System (INIS)

Buchmann, I.; Helisch, A.; Bartenstein, P.; Meyer, R.G.; Herr, W.

2005-01-01

The prognosis of patients with acute myeloid leukaemia (AML) has improved considerably by introduction of aggressive consolidation chemotherapy and haematopoietic stem cell transplantation (SCT). Nevertheless, only 20-30% of patients with AML achieve long-term disease-free survival after SCT. The most common cause of treatment failure is relapse. Additionally, mortality rates are significantly increased by therapy-related causes such as toxicity of chemotherapy and complications of SCT. Including radioimmunotherapies in the treatment of AML and myelodyplastic syndrome (MDS) allows for the achievement of a pronounced antileukaemic effect for the reduction of relapse rates on the one hand. On the other hand, no increase of acute toxicity and later complications should be induced. These effects are important for the primary reduction of tumour cells as well as for the myelblative conditioning before SCT. This paper provides a systematic and critical review of the currently used radionuclides and immunoconjugates for the treatment of AML and MDS and summarizes the literature on primary tumour cell reductive radioimmunotherapies on the one hand and conditioning radioimmunotherapies before SCT on the other hand. (orig.)

Constitutional sequence variation in the Fanconi anaemia group C (FANCC) gene in childhood acute myeloid leukaemia.

Science.gov (United States)

Barber, Lisa M; McGrath, Helen E N; Meyer, Stefan; Will, Andrew M; Birch, Jillian M; Eden, Osborn B; Taylor, G Malcolm

2003-04-01

The extent to which genetic susceptibility contributes to the causation of childhood acute myeloid leukaemia (AML) is not known. The inherited bone marrow failure disorder Fanconi anaemia (FA) carries a substantially increased risk of AML, raising the possibility that constitutional variation in the FA (FANC) genes is involved in the aetiology of childhood AML. We have screened genomic DNA extracted from remission blood samples of 97 children with sporadic AML and 91 children with sporadic acute lymphoblastic leukaemia (ALL), together with 104 cord blood DNA samples from newborn children, for variations in the Fanconi anaemia group C (FANCC) gene. We found no evidence of known FANCC pathogenic mutations in children with AML, ALL or in the cord blood samples. However, we detected 12 different FANCC sequence variants, of which five were novel to this study. Among six FANCC variants leading to amino-acid substitutions, one (S26F) was present at a fourfold greater frequency in children with AML than in the cord blood samples (odds ratio: 4.09, P = 0.047; 95% confidence interval 1.08-15.54). Our results thus do not exclude the possibility that this polymorphic variant contributes to the risk of a small proportion of childhood AML.

Prevention of Resistance in Chronic Myeloid Leukemia: the role of combination therapy

NARCIS (Netherlands)

W. Deenik (Wendy)

2010-01-01

textabstractChronic myeloid leukemia (CML) is a rare disease with a worldwide incidence of approximately 1-2 cases per 100,000 individuals. Chronic myeloid leukemia occurs slightly more frequently in men than in women. The median age at diagnosis is approximately 60 years, and although the incidence

RJHS Vol 4(1).cdr

African Journals Online (AJOL)

ABEOLUGBENGAS

Chronic myeloid leukaemia presenting with priapism as the only symptom: A case report ... related penile erection was found to have chronic myeloid leukaemia (CML) following peripheral and bone marrow .... are trauma to the penis, leukemia, cancerous invasion of the ... Urological Association that systemic treatment of.

BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia.

Science.gov (United States)

Cuellar, Sandra; Vozniak, Michael; Rhodes, Jill; Forcello, Nicholas; Olszta, Daniel

2017-01-01

The management of chronic myeloid leukemia with BCR-ABL1 tyrosine kinase inhibitors has evolved chronic myeloid leukemia into a chronic, manageable disease. A patient-centered approach is important for the appropriate management of chronic myeloid leukemia and optimization of long-term treatment outcomes. The pharmacist plays a key role in treatment selection, monitoring drug-drug interactions, identification and management of adverse events, and educating patients on adherence. The combination of tyrosine kinase inhibitors with unique safety profiles and individual patients with unique medical histories can make managing treatment difficult. This review will provide up-to-date information regarding tyrosine kinase inhibitor-based treatment of patients with chronic myeloid leukemia. Management strategies for adverse events and considerations for drug-drug interactions will not only vary among patients but also across tyrosine kinase inhibitors. Drug-drug interactions can be mild to severe. In instances where co-administration of concomitant medications cannot be avoided, it is critical to understand how drug levels are impacted and how subsequent dose modifications ensure therapeutic drug levels are maintained. An important component of patient-centered management of chronic myeloid leukemia also includes educating patients on the significance of early and regular monitoring of therapeutic milestones, emphasizing the importance of adhering to treatment in achieving these targets, and appropriately modifying treatment if these clinical goals are not being met. Overall, staying apprised of current research, utilizing the close pharmacist-patient relationship, and having regular interactions with patients, will help achieve successful long-term treatment of chronic myeloid leukemia in the age of BCR-ABL1 tyrosine kinase inhibitors.

Molecular alterations in acute myeloid leukemia and their clinical and therapeutical implications.

Science.gov (United States)

Infante, María Stefania; Piris, Miguel Ángel; Hernández-Rivas, José Ángel

2018-06-09

Acute myeloid leukaemia is the most common form of acute leukaemia, and its incidence increases with age. The disease derives from a transformed multipotent malignant haematopoietic stem cell that acquires consequent genomic alterations. The identification of recurrent cytogenetic anomalies associated with different patterns of acute myeloid leukaemia clinical presentation has led to the incorporation of genetic markers in clinical decision-making. In addition, the observation that these anomalies may mark therapeutic responses and relapse and survival rates have been incorporated into the World Health Organisation's recent molecular classification and stratification and the European Leukaemia Net, with the aim of creating prognostic categories that help rationalise better diagnosis, prognosis, re-evaluation of the disease and the combination of therapeutic protocols in order to increase the survival rate of these patients. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

Effect of daily low dose gamma irradiation on growth and differentiation of human myeloid leukaemic bone marrow in diffusion chambers

Energy Technology Data Exchange (ETDEWEB)

Greenberger, J S [Joint Center for Radiation Therapy, Department of Radiation and Sidney Farber Cancer Institute; Chang, J M; King, V; Fulmer, S; Balzuno, S; Moloney, W C [Division of Hematology, Department of Medicine, Brigham and Women' s Hospital Harvard Medical School, Boston, USA

1981-01-01

Bone marrow from each of 8 untreated patients with myeloproliferative disorders was grown in diffusion chambers in 760 rad total body irradiated rats. Rats were exposed to 11.5, 57.5, or 108.5 rad daily for 14-21 and cell growth compared to that detected in unirradiated chambers. Cells from acute myelogenous leukaemia patients exposed to 11.5 rad per d grew for 11-21 d and there was no consistent stimulation of differentiation of immature granulocytic cells to mature granulocytes that was attributable to irradiation. Cells from a chronic myeloid leukaemia patient in chronic phase or blast crisis, and a polycythaemia vera patient with myeloid metaplasia showed signigicant morphologic differentiation from immature to mature granulocytes in control chambers with no additional effect of daily irradiation. Marrow specimens from 2 AML patients exposed to each of 3 daily dose fractions over 14 d revealed a dose-dependent decrease in immature granulocytes with no persistent increase in mature granulocytes. In both irradiated and control chambers, macrophages increased over 21 d. Thus, cells from patients with myeloprofilerative disorders may not necessarily differentiate to mature granulocytes following in vivo exposure to ionizing irradiation.

All trans retinoic acid abrogates spontaneous monocytic growth in juvenile chronic myelomonocytic leukaemia.

Science.gov (United States)

Cambier, N; Menot, M L; Schlageter, M H; Balitrand, N; Leblanc, T; Bordigoni, P; Rohrlich, P; Lamagnère, J P; Donadieu, J; Herbelin, C; Puissant, C; Gourand, F; Baruchel, A; Chomienne, C

2001-01-01

All trans retinoic acid, the active metabolite of vitamin A, exerts profound effects on cell differentiation. On normal myeloid progenitors, retinoids switch the differentiation program of granulo-macrophagic progenitors towards the granulocytic lineage and consequently reduce CFU-M colony formation. Bone marrow and peripheral blood mononuclear cells from children with Juvenile Chronic Myelomonocytic Leukaemia show typical spontaneous monocytic growth. We questioned whether in this disease, retinoids could switch myelomonocytic growth and inhibit the abnormal CFU-M colony proliferation. Ten JCML samples were studied in the presence of ATRA in methyl cellulose colony assay, before (CFU-C) or after (pre-CFU) liquid suspension culture. In vitro characteristics of JCML such as spontaneous monocytic growth in the absence of growth factor was noted in all patients. In the presence of leucocyte-conditioned medium, nine samples showed only CFU-M growth and one sample CFU-GM growth. Incubation with ATRA inhibited CFU-M colony formation in nine cases. Enhancement of granulocytic differentiation (CFU-G) was noted in nine cases. ATRA also inhibited CD34+ JCML monocytic growth and GM-CSF hypersensitivity. These data suggest that, in JCML progenitors, retinoid pathways are functional and inhibition of immature monocytic progenitors cells may be achieved with retinoids, without impeding granulocytic cell growth.

Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

Science.gov (United States)

Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah

2016-07-01

Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. © 2016 John Wiley & Sons A/S.

Firstline treatment for chronic phase chronic myeloid leukemia patients should be based on a holistic approach.

Science.gov (United States)

Breccia, Massimo; Alimena, Giuliana

2015-02-01

New selective and more potent drugs for the cure of chronic phase chronic myeloid leukemia patients are now available: physicians in some countries must decide the best option, selecting one of the drugs available. What the main prognostic factors are in order to make this selection remains a matter of discussion. Introducing a 'holistic approach' for the first time in chronic myeloid leukemia, as practiced in other diseases, and looking at the patient in a complete picture, considering several variables, such as comorbidities, age, concomitant drugs, lifestyle and patient expectations, may be of help to understand, patient by patient, the best therapeutic strategy.

Haemostatic function and biomarkers of endothelial damage before and after platelet transfusion in patients with acute myeloid leukaemia

DEFF Research Database (Denmark)

Larsen, A M; Leinøe, E B; Johansson, P I

2015-01-01

and after platelet transfusion in patients with acute myeloid leukaemia. MATERIALS AND METHODS: Blood was sampled before, 1 and 24 h after platelet transfusion. Primary and secondary haemostasis was evaluated by whole blood aggregometry (Multiplate) and thromboelastography (TEG). Endothelial biomarkers (s......OBJECTIVES: The beneficial effect of platelet transfusion on haemostasis is well established, but there is emerging evidence that platelet transfusion induces an inflammatory response in vascular endothelial cells. BACKGROUND: We investigated haemostatic function and endothelial biomarkers before......ICAM-1, syndecan-1, sThrombomodulin, sVE-Cadherin) and platelet activation biomarkers (sCD40L, TGF-beta) were investigated along with haematology/biochemistry analyses. RESULTS: Twenty-two patients were included. Despite continued low platelet counts, platelet transfusion normalised the median values...

Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia

DEFF Research Database (Denmark)

Karlsson, Lene; Forestier, Erik; Hasle, Henrik

2017-01-01

Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children...... relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS5y ) was 39 ± 4% for the whole group and 43 ± 4......, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 ± 5%. Four of 19 children (21%) survived without...

Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival.

Science.gov (United States)

January

2016-04-01

codynamic interactions are also likely in view of its adverse effect profile. There is no consensus on the treatment of patients with refractory or relapsed mantle cell lymphoma, or for patients with relapsed or possibly refractory chronic lymphocytic leukaemia. Ibrutinib inhibits an enzyme involved in regulating B lymphocyte activity. It has been authorised in the European Union for these conditions. Clinical evaluation of ibrutinib in mantle cell lymphoma is based on a single non-comparative trial in 111 patients, in which the median overall survival time was 22.5 months. Clinical evaluation of ibrutinib in chronic lymphocytic leukaemia is based on two randomised trials. One unblinded trial compared ibrutinib versus ofatumumab and involved 391 patients, most of whom were sufficiently fit to receive anticancer combination therapy. Ibrutinib was more effective than ofatumumab, but the choice of this comparator might not have been appropriate for most of the patients who received it. The other double-blind, placebo-controlled trial involved 578 patients with relapsed or refractory chronic lymphocytic leukaemia. Ibrutinib was added to the bendamustine + rituximab combination. No significant difference in mortality was observed between the two groups. The main adverse effects of ibrutinib were: gastrointestinal disorders such as diarrhoea; life-threatening infections and bleeding disorders; and cardiac disorders, including atrial fibrillation. Ibrutinib carries a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely in view of its adverse effect profile.

Luteoloside Inhibits Proliferation of Human Chronic Myeloid ...

African Journals Online (AJOL)

Purpose: To investigate the effects of luteoloside on the proliferation of human chronic myeloid leukemia K562 cells and whether luteoloside induces cell cycle arrest and apoptosis in K562 cells. Methods: Luteoloside's cytotoxicity was assessed using a cell counting kit. Cell cycle distribution was analysed by flow cytometry ...

DNA apoptosis and stability in B-cell chronic lymphoid leukaemia: implication of the DNA double-strand breaks repair system by non homologous recombination

International Nuclear Information System (INIS)

Deriano, L.

2005-01-01

After an introduction presenting the diagnosis and treatment of chronic lymphoid leukaemia, its molecular and genetic characteristics, and its cellular origin and clonal evolution, this research thesis describes the apoptosis (definition and characteristics, cancer and chemotherapy, apoptotic ways induced by gamma irradiation), the genotoxic stresses, the different repair mechanisms for different damages, and the DNA repair processes. It reports how human chronic lymphocytic leukaemia B cells can escape DNA damage-induced apoptosis through the non-homologous end-joining DNA repair pathway, and presents non-homologous end-joining DNA repair as a potent mutagenic process in human chronic lymphocytic leukaemia B cells

Peripheral retinal nonperfusion associated with chronic myeloid leukemia.

NARCIS (Netherlands)

Nobacht, S.; Vandoninck, K.F.; Deutman, A.F.; Klevering, B.J.

2003-01-01

PURPOSE: To report a case of peripheral retinal nonperfusion and chronic myeloid leukemia in a 23-year-old woman. DESIGN: Observational case report. METHODS: A complete ophthalmic and systemic evaluation was performed. RESULTS: Ophthalmic examination revealed peripheral retinal nonperfusion with

[Prostatic localization revealing an acute myeloid leukemia. Apropos of a case].

Science.gov (United States)

Smaoui, S; Lecomte, M J; Peraldi, R; Pernin, F

1998-09-01

The authors report an original case of acute myeloid leukaemia (AML) presenting in the form of acute urinary retention, confirmed by prostatic biopsy, with complete absence of any non-urological clinical features. Prostatic sites of leukaemia are frequent and classically reported, but often occur during the course of known leukaemia, and are rarely symptomatic, justifying biopsies in the presence of any prostatic symptoms. Immunolabelling represents the key to the diagnosis in the presence of undifferentiated cells demonstrated on prostatic biopsies. The outcome was fatal in this case, despite early chemotherapy. The clinical features, clinical course and therapeutic aspects of prostatic leukaemia are discussed.

Environmental radon and cancer risk

Energy Technology Data Exchange (ETDEWEB)

Haque, A K.M.M.; Kirk, A E [South Bank Polytechnic, London (United Kingdom)

1992-01-01

Data collected from the office of Population Censuses and Surveys (OPCS) statistics and those published by the Leukaemia Research Fund (LRF) have been analysed with a view to examining whether radon is a possible causative agent in the induction of leukaemias. Radon concentration values have been taken from a NRPB survey. Positive correlation has been observed between radon concentration and incidence of acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL) and chronic lymphoid leukaemia (CLL). Employing the method of BEIR IV, the lifetime probability of leukaemia incidence, R[sub o], of a non-exposed person (zero radon concentration) has been calculated for AML, CML, ALL and CLL, which agree well with those values obtained from extrapolation of linear graphs of leukaemia deaths versus radon concentration. (author).

SL-401 and SL-501, Targeted Therapeutics Directed at the Interleukin-3 Receptor, Inhibit the Growth of Leukaemic Cells and Stem Cells in Advanced Phase Chronic Myeloid Leukaemia

Science.gov (United States)

Frolova, Olga; Benito, Juliana; Brooks, Chris; Wang, Rui-Yu; Korchin, Borys; Rowinsky, Eric K.; Cortes, Jorge; Kantarjian, Hagop; Andreeff, Michael; Frankel, Arthur E.; Konopleva, Marina

2014-01-01

SUMMARY While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34+/CD38− BCR-ABL1+ CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388-IL3) and SL-501 (DT388-IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34+/CD38−/CD123+ CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk. PMID:24942980

Bone marrow transplantation for patients with chronic myeloid leukemia

International Nuclear Information System (INIS)

Goldman, J.M.; Apperley, J.F.; Jones, L.

1986-01-01

Between February 1981 and December 1984 we treated 52 patients with chronic myeloid leukemia in the chronic phase and 18 patients with more advanced disease by high-dose chemoradiotherapy followed by allogeneic bone marrow transplantation using marrow cells from HLA-identical sibling donors. In addition, the 40 patients who had not previously undergone splenectomy received radiotherapy to the spleen. To prevent graft versus host disease, cyclosporine was given either alone or in conjunction with donor marrow depleted of T cells. Of the 52 patients treated in the chronic phase, 38 are alive after a median follow-up of 25 months (range, 7 to 50); the actuarial survival at two years was 72%, and the actuarial risk of relapse was 7%. Of the 18 patients with more advanced disease, 4 have survived; the actuarial two-year survival was 18%, and the actuarial risk of relapse was 42%. We conclude that the probability of cure is highest if transplantation is performed while the patient remains in the chronic phase of chronic myeloid leukemia. T-cell depletion may have reduced the incidence and severity of graft versus host disease. The value of irradiation to the spleen before transplantation has not been established

Interferon alpha for treatment of chronic myeloid leukemia

DEFF Research Database (Denmark)

Simonsson, Bengt; Hjorth-Hansen, Henrik; Bjerrum, Ole Weis

2011-01-01

Treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-a) was introduced in the early 1980s. Several clinical trials showed a survival advantage for patients treated with IFN-a compared to conventional chemotherapy. Some patients achieved longstanding complete cytogenetic remissions...

The effect of total body irradiation dose and chronic graft-versus-host disease on leukaemic relapse after allogeneic bone marrow transplantation

Energy Technology Data Exchange (ETDEWEB)

Frassoni, F; Bacigalupo, A [Ospedale San Martino (Italy). Centro Trapianti Midollo Osseo; Scarpati, D [Univ. di Genova (Italy). Ist. di Radiologia; and others

1989-10-01

One-hundred and five patients undergoing allo-geneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) (n=61) and chronic myeloid leukaemia (n=44) were analysed for risk factors associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 330 cGy on each of the three days prior to transplantation. A multivariate Cox analysis indicated that a lower TBI dose (less than 990 cGy) was the most significant factor associated with relapse and the second most important factor associated with recurrence of leukaemia was the absence of chronic graft-versus-host-disease (cGvHD). Actuarial relapse incidence was 62%, 28% and 18% for patients with no, limited or extensive chronic GvHD respectively. However, chronic GvHD had no significant impact on survival. Combined stratification for TBI dose and cGvHD showed that the dose effect of TBI on relapse was evident both in patients with and without cGvHD. Chronic GvHD influenced the risk of relapse only in patients receiving less than 990 cGy. These results suggest that a higher dose of TBI, within this schedule, produced long-term disease-free survival in the majority of AMLs and CMLs. Minor radiobiological side effects were experienced, but a small reduction of the dose may significantly increase the risk of relapse. (author).

The effect of total body irradiation dose and chronic graft-versus-host disease on leukaemic relapse after allogeneic bone marrow transplantation

International Nuclear Information System (INIS)

Frassoni, F.; Bacigalupo, A.; Scarpati, D.

1989-01-01

One-hundred and five patients undergoing allo-geneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) (n=61) and chronic myeloid leukaemia (n=44) were analysed for risk factors associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 330 cGy on each of the three days prior to transplantation. A multivariate Cox analysis indicated that a lower TBI dose (less than 990 cGy) was the most significant factor associated with relapse and the second most important factor associated with recurrence of leukaemia was the absence of chronic graft-versus-host-disease (cGvHD). Actuarial relapse incidence was 62%, 28% and 18% for patients with no, limited or extensive chronic GvHD respectively. However, chronic GvHD had no significant impact on survival. Combined stratification for TBI dose and cGvHD showed that the dose effect of TBI on relapse was evident both in patients with and without cGvHD. Chronic GvHD influenced the risk of relapse only in patients receiving less than 990 cGy. These results suggest that a higher dose of TBI, within this schedule, produced long-term disease-free survival in the majority of AMLs and CMLs. Minor radiobiological side effects were experienced, but a small reduction of the dose may significantly increase the risk of relapse. (author)

Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia

International Nuclear Information System (INIS)

Cowan-Jacob, Sandra W.; Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W.

2006-01-01

A case study showing how the determination of multiple cocrystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery, resulting in a compound effective in the treatment of chronic myelogenous leukaemia. Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery

Chemotherapy in a transplantable myeloid leukaemia in brown Norway rats : studies on BNML as a model for human acute myeloid leukaemia

NARCIS (Netherlands)

L.P. Colly

1980-01-01

textabstractLeukaemia accounts for less than 5% of the total number of malignant diseases in the USA {McCredie et al., 1976),· while about 9% of all neeplasros in the Netherlands originate in the lymphatic and blood forming organs. Because of the relatively easy accessibility of the turnoor cells in

Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice.

Science.gov (United States)

McCullough, Rebecca L; McMullen, Megan R; Das, Dola; Roychowdhury, Sanjoy; Strainic, Michael G; Medof, M Edward; Nagy, Laura E

2016-07-01

Complement is implicated in the development of alcoholic liver disease. C3 and C5 contribute to ethanol-induced liver injury; however, the role of C5a receptor (C5aR) on myeloid and non-myeloid cells to progression of injury is not known. C57BL/6 (WT), global C5aR-/-, myeloid-specific C5aR-/-, and non-myeloid-specific C5aR-/- mice were fed a Lieber-DeCarli diet (32%kcal EtOH) for 25 days. Cultured hepatocytes were challenged with ethanol, TNFα, and C5a. Chronic ethanol feeding increased expression of pro-inflammatory mediators in livers of WT mice; this response was completely blunted in C5aR-/- mice. However, C5aR-/- mice were not protected from other measures of hepatocellular damage, including ethanol-induced increases in hepatic triglycerides, plasma alanine aminotransferase and hepatocyte apoptosis. CYP2E1 and 4-hydroxynonenal protein adducts were induced in WT and C5aR-/- mice. Myeloid-specific C5aR-/- mice were protected from ethanol-induced increases in hepatic TNFα, whereas non-myeloid-specific C5aR-/- displayed increased hepatocyte apoptosis and inflammation after chronic ethanol feeding. In cultured hepatocytes, cytotoxicity induced by challenge with ethanol and TNFα was completely eliminated by treatment with C5a in cells from WT, but not C5aR-/- mice. Further, treatment with C5a enhanced activation of pro-survival signal AKT in hepatocytes challenged with ethanol and TNFα. Taken together, these data reveal a differential role for C5aR during ethanol-induced liver inflammation and injury, with C5aR on myeloid cells contributing to ethanol-induced inflammatory cytokine expression, while non-myeloid C5aR protects hepatocytes from death after chronic ethanol feeding. Copyright © 2016 Elsevier Ltd. All rights reserved.

Characterization of miRNomes in Acute and Chronic Myeloid

Directory of Open Access Journals (Sweden)

Qian Xiong

2014-04-01

Full Text Available Myeloid leukemias are highly diverse diseases and have been shown to be associated with microRNA (miRNA expression aberrations. The present study involved an in-depth miRNome analysis of two human acute myeloid leukemia (AML cell lines, HL-60 and THP-1, and one human chronic myeloid leukemia (CML cell line, K562, via massively parallel signature sequencing. mRNA expression profiles of these cell lines that were established previously in our lab facilitated an integrative analysis of miRNA and mRNA expression patterns. miRNA expression profiling followed by differential expression analysis and target prediction suggested numerous miRNA signatures in AML and CML cell lines. Some miRNAs may act as either tumor suppressors or oncomiRs in AML and CML by targeting key genes in AML and CML pathways. Expression patterns of cell type-specific miRNAs could partially reflect the characteristics of K562, HL-60 and THP-1 cell lines, such as actin filament-based processes, responsiveness to stimulus and phagocytic activity. miRNAs may also regulate myeloid differentiation, since they usually suppress differentiation regulators. Our study provides a resource to further investigate the employment of miRNAs in human leukemia subtyping, leukemogenesis and myeloid development. In addition, the distinctive miRNA signatures may be potential candidates for the clinical diagnosis, prognosis and treatment of myeloid leukemias.

Dasatinib for the treatment of chronic myeloid leukemia: patient selection and special considerations.

Science.gov (United States)

Keskin, Dilek; Sadri, Sevil; Eskazan, Ahmet Emre

2016-01-01

Dasatinib is one of the second-generation tyrosine kinase inhibitors used in imatinib resistance and/or intolerance, as well as in the frontline setting in patients with chronic myeloid leukemia-chronic phase, and also in patients with advanced disease. It is also utilized in Philadelphia chromosome-positive acute lymphocytic leukemia. While choosing the appropriate tyrosine kinase inhibitor (ie, dasatinib) for each individual patient, comorbidities and BCR-ABL1 kinase domain mutations should always be taken into consideration, among other things. This review mainly focuses on patient selection prior to dasatinib administration in the treatment of chronic myeloid leukemia.

Radiation-associated chronic myelogenous leukaemia in younger people

International Nuclear Information System (INIS)

Shimaoka, K.; Sokal, J.E.

1978-01-01

Chronic myelogenous leukaemia (CML) is known to be induced by exposure to ionizing radiation, as is acute leukaemia. However, CML has been recorded only rarely as a complication of radiation exposure early in life. During the period from 1973 to 1976, 75 patients with CML were admitted to Roswell Park Memorial Institute (RPMI). In addition, 64 patients admitted to RPMI previously were also available for study in 1973. Among 79 patients who were born after 1925, information regarding radiation exposure was obtained in 89%; 49 were interviewed and 21 responded to a mailed questionnaire. Consultation with parents was achieved in 52 of the 70 responding cases (74%). Replies were obtained from 15 of the 18 patients below the age of 25, and were confirmed by parents or siblings in all instances. Replies to the mailed questionnaire were obtained from 45 age- and sex-matched controls. In addition to two patients already known to have radiation exposure for treatment of malignant neoplasms, these inquiries yielded a total of nine patients with histories of radiation exposure for benign conditions. Three had therapeutic irradiation, two for thymic enlargement and one for eczema. Three had exposure in utero by pelvimetry. Two had diagnostic exposure during the perinatal period and one had occupational exposure as a nurse. Four of these patients were below the age of 25. All nine patients had the Ph' chromosome. The course of CML in these patients was not different from that of other patients with Ph' chromosome-positive CML without a history of radiation exposure. A history of radiation exposure was elicited in one-fourth of the younger patients (<25) in this study, compared with one of 45 age- and sex-matched controls without leukaemia (p<0.02)

Splenic Trapping of Heat-Treated Erythrocytes in Leukaemia and Allied Conditions

Energy Technology Data Exchange (ETDEWEB)

Badrawi, H. S.; Razzak, M. A.; Guirgis, B. [Department of Medicine and Division of Nuclear Medicine, Faculty of Medicine, Cairo University, Cairo, United Arab Republic (Egypt)

1971-02-15

In a trial to find whether or not the enlarged spleen plays a role in the production of the form of anaemia commonly encountered in leukaemias and allied conditions, 44 patients suffering from these disease states were studied using {sup 51}Cr-labelled erythrocytes heated at 50 Degree-Sign C for 60 min. Cells altered in this manner have been shown by various workers to be selectively sequestered by the spleen. As a control, the test was performed on 24 normal subjects. In these normals, the disappearance half-time of radioactivity from the circulation (T{sub Vulgar-Fraction-One-Half} amounted to 172 {+-} 69 min (mean {+-} 1 S.D.), the lowest limit being 74 min. Accordingly, patients with less than 74 min were considered to have an abnormally rapid disappearance of heat-treated erythrocytes from the circulation and consequently exaggerated splenic sequestration of these altered cells. Splenic trapping of heat-treated erythrocytes was most marked in acute leukaemia (four out of six patients). However, three had associated normoblastic hypoplasia of the sternal marrow. Corticosteroids induced a remission with reversion of both processes responsible for the anaemia in two out of the four patients. In chronic myeloid leukaemia, exaggerated splenic sequestration of altered cells was seen in four of the 15 cases examined. This condition was of extra-erythrocytic origin, since repetition of the test using normal donor heat-treated erythrocytes did not significantly alter the disappearance half-time. However, there was no correlation between the size of the spleen and its avidity for trapping the altered cells. Follow-up studies showed that therapy caused prolongation of the half-time of heat-treated erythrocytes, the effect being more apparent after corticosteroids than with X-rays or Endoxan, In Hodgkin's disease, increased red cell trapping was observed in two out of the seven patients studied. In contrast, five cases of chronic lymphatic leukaemia, six lymphosarcoma and

Myeloid sarcoma developing in pre-existing pyoderma gangrenosum

DEFF Research Database (Denmark)

Kristensen, Ida Bruun; Møller, Hanne; Kjaerskov, Mette Wanscher

2009-01-01

We report here a case of pyoderma gangrenosum in a patient with myelodysplastic syndrome developing into myeloid sarcoma as a sign of transformation to acute leukaemia. The patient was treated successfully with intensive chemotherapy and achieved complete remission, and her otherwise expanding...

Splenic irradiation in chronic myeloid leukemia

Energy Technology Data Exchange (ETDEWEB)

Hukku, S.; Baboo, H.A.; Venkataratnam, S.; Vidyasagar, M.S.; Patel, N.L. (Department of Radiation Therapy, Gujarat Cancer Research Institute, Ahmedabad, India)

1983-01-01

Results of splenic irradiation as the initial and only method of treatment are reported in 25 patients with chronic myeloid leukemia. Peripheral remission was induced in all the patients. Induction was achieved after a short period of 11 to 30 days in the majority of the patients, the longest period being 40 days. Several patients were in remission 9 months after treatment. The results are compared with those obtained by chemotherapy. Some advantages of splenic irradiation over chemotherapy are emphasized.

Induction-related cost of patients with acute myeloid leukaemia in France.

Science.gov (United States)

Nerich, Virginie; Lioure, Bruno; Rave, Maryline; Recher, Christian; Pigneux, Arnaud; Witz, Brigitte; Escoffre-Barbe, Martine; Moles, Marie-Pierre; Jourdan, Eric; Cahn, Jean Yves; Woronoff-Lemsi, Marie-Christine

2011-04-01

The economic profile of acute myeloid leukaemia (AML) is badly known. The few studies published on this disease are now relatively old and include small numbers of patients. The purpose of this retrospective study was to evaluate the induction-related cost of 500 patients included in the AML 2001 trial, and to determine the explanatory factors of cost. "Induction" patient's hospital stay from admission for "induction" to discharge after induction. The study was performed from the French Public Health insurance perspective, restrictive to hospital institution costs. The average management of a hospital stay for "induction" was evaluated according to the analytical accounting of Besançon University Teaching Hospital and the French public Diagnosis-Related Group database. Multiple linear regression was used to search for explanatory factors. Only direct medical costs were included: treatment and hospitalisation. Mean induction-related direct medical cost was estimated at €41,852 ± 6,037, with a mean length of hospital stay estimated at 36.2 ± 10.7 days. After adjustment for age, sex and performance status, only two explanatory factors were found: an additional induction course and salvage course increased induction-related cost by 38% (± 4) and 15% (± 1) respectively, in comparison to one induction. These explanatory factors were associated with a significant increase in the mean length of hospital stay: 45.8 ± 11.6 days for 2 inductions and 38.5 ± 15.5 if the patient had a salvage course, in comparison to 32.9 ± 7.7 for one induction (P cost for patients with AML.

Secondary Leukemia in a non-Hodgkin's Lymphoma Patient Presenting as Myeloid Sarcoma of the Breast

Directory of Open Access Journals (Sweden)

Vincenzo Pitini

2011-01-01

Full Text Available As defined by the World Health Organization classification of tumors of hematopoietic and lymphoid tissue, myeloid sarcoma (MS is a tumor mass of myeloblasts or immature myeloid cells that can arise before, concurrent with, or following acute myeloid leukaemia. We describe a case of secondary leukemia presenting itself as MS of the breast in a patient previously treated for a non-Hodgkin's Lymphoma.

Incidence and significance of FLT3-ITD and NPM1 mutations in patients with normal karyotype acute myeloid leukaemia.

LENUS (Irish Health Repository)

Haslam, K

2012-02-01

BACKGROUND: Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells. Approximately half of all adult AML patients have a normal karyotype (NK-AML) and an intermediate risk prognosis. AIMS: To determine the incidence and prognostic significance of NPM1 and FLT3-ITD mutations in a population of patients with NK-AML. METHODS: FLT3-ITD and NPM1 mutation status was retrospectively sought in presentation samples from 44 NK-AML patients. RESULTS: FLT3-ITD and NPM1 mutations were detected in 45.5 and 54.5% of patients, respectively, allowing stratification according to genotype. CONCLUSIONS: FLT3-ITD and NPM1 mutation status can be defined in NK-AML. Prospective screening for these mutations is advocated in all NK-AML patients, as the genotype is of clinical importance when considering treatment options including stem cell transplantation.

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: Recommendations for clinical practice from the French Chronic Myeloid Leukemia Study Group.

Science.gov (United States)

Rea, Delphine; Ame, Shanti; Berger, Marc; Cayuela, Jean-Michel; Charbonnier, Aude; Coiteux, Valérie; Cony-Makhoul, Pascale; Dubruille, Viviane; Dulucq, Stéphanie; Etienne, Gabriel; Legros, Laurence; Nicolini, Franck; Roche-Lestienne, Catherine; Escoffre-Barbe, Martine; Gardembas, Martine; Guerci-Bresler, Agnès; Johnson-Ansah, Hyacinthe; Rigal-Huguet, Françoise; Rousselot, Philippe; Mahon, François-Xavier

2018-05-03

The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice. Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucémies Myéloïdes Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice. Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction. This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

Chronic myeloid leukemia in a child with IgA nephropathy.

Science.gov (United States)

Udani, Amish; Vijayakumar, Mahalingam; Prahlad, Nageswaran; Ekambaram, Sudha

2012-08-01

We report an 11 year old boy with IgA nephropathy developing chronic myeloid leukemia on follow-up. This association suggests that a B cell defect might be involved in the pathogenesis of these two conditions.

Imaging findings of upper abdominal involvement by acute megakaryoblastic leukaemia

Energy Technology Data Exchange (ETDEWEB)

Amemiya, Shiori; Akahane, Masaaki; Ohtomo, Kuni [University of Tokyo, Department of Radiology, Graduate School of Medicine, Tokyo (Japan); Takita, Junko; Igarashi, Takashi [University of Tokyo, Department of Paediatrics, Graduate School of Medicine, Tokyo (Japan)

2008-04-15

Acute megakaryoblastic leukaemia (AMKL), a relatively rare type of acute myeloid leukaemia, is characterized by frequent involvement of the liver, spleen and lymph nodes in addition to myelofibrosis in children. Diagnosis is difficult both clinically and pathologically, and the hepatic or lymph node involvement is not uncommonly misinterpreted as solid tumour. We report the imaging findings of upper abdominal involvement by AMKL in an infant. The hepatic lesion, initially suspected to be hepatoblastoma, showed a distinctive appearance on MRI suggesting its infiltrative nature. With the association of splenic lesion and lymphadenopathy, the imaging findings were considered indicative of a haematological disorder. (orig.)

The impact of additional cytogenetic abnormalities at diagnosis and during therapy with tyrosine kinase inhibitors in Chronic Myeloid Leukaemia.

Science.gov (United States)

Crisan, A M; Coriu, D; Arion, C; Colita, A; Jardan, C

2015-01-01

Chronic Myeloid Leukemia's (CML) treatment was optimized since the development of tyrosine kinase inhibitors (TKI) and an increased overall survival during TKI was noticed. During the TKI era, protocols for assessing response and resistance to treatment were developed. Additional chromosomal abnormalities (ACAs) are strongly associated with disease progression but their prognostic impact and influence on treatment response are yet to be defined. The aim of this study was to analyze the impact of ACAs on time to achieve complete cytogenetic response (CCyR), treatment and overall survival. Since 2005 until 2013, the data from the Hematology and Bone Marrow Transplantation Department of Fundeni Clinical Institute was collected. In this observational retrospective single centre study, 28 CML patients with ACAs at diagnosis and during TKI treatment were included. From ACAs at diagnosis group, the most frequent major route ACAs were trisomy 8, trisomy 19 and second Philadelphia (Ph) chromosome and the most frequent minor route ACAs were monosomies and structural abnormalities (inversions and translocations). From the ACAs during the TKI group, the most frequent major route cytogenetic abnormalities in Ph positive and negative cells were trisomy 8, trisomy 19 and second Ph chromosome and the most frequent minor route cytogenetic abnormalities in Ph positive and negative cells were marker chromosomes and structural abnormalities (inversions, translocations and dicentric chromosomes). In both groups, the time to CCyR was longer and long-term results were inferior in comparison with standard patients but the differences were not significant and in accordance to published data. The 12 months follow-up after the study's end showed that 26 patients were alive and in long-term CCyR and 2 deaths were reported. CML = Chronic Myeloid Leukemia, BCR-ABL1 = Break Cluster Region - Abelson gene, TKI = tyrosine kinase inhibitor treatment, ACAs = additional cytogenetic abnormalities, CCy

Coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma with antecedent chronic lymphocytic leukemia: a case report and review of the literature.

Science.gov (United States)

Abuelgasim, Khadega A; Rehan, Hinna; Alsubaie, Maha; Al Atwi, Nasser; Al Balwi, Mohammed; Alshieban, Saeed; Almughairi, Areej

2018-03-11

Chronic lymphocytic leukemia and chronic myeloid leukemia are the most common types of adult leukemia. However, it is rare for the same patient to suffer from both. Richter's transformation to diffuse large B-cell lymphoma is frequently observed in chronic lymphocytic leukemia. Purine analog therapy and the presence of trisomy 12, and CCND1 gene rearrangement have been linked to increased risk of Richter's transformation. The coexistence of chronic myeloid leukemia and diffuse large B-cell lymphoma in the same patient is extremely rare, with only nine reported cases. Here, we describe the first reported case of concurrent chronic myeloid leukemia and diffuse large B-cell lymphoma in a background of chronic lymphocytic leukemia. A 60-year-old Saudi man known to have diabetes, hypertension, and chronic active hepatitis B was diagnosed as having Rai stage II chronic lymphocytic leukemia, with trisomy 12 and rearrangement of the CCND1 gene in December 2012. He required no therapy until January 2016 when he developed significant anemia, thrombocytopenia, and constitutional symptoms. He received six cycles of fludarabine, cyclophosphamide, and rituximab, after which he achieved complete remission. One month later, he presented with progressive leukocytosis (mostly neutrophilia) and splenomegaly. Fluorescence in situ hybridization from bone marrow aspirate was positive for translocation (9;22) and reverse transcription polymerase chain reaction detected BCR-ABL fusion gene consistent with chronic myeloid leukemia. He had no morphologic or immunophenotypic evidence of chronic lymphocytic leukemia at the time. Imatinib, a first-line tyrosine kinase inhibitor, was started. Eight months later, a screening imaging revealed new liver lesions, which were confirmed to be diffuse large B-cell lymphoma. In chronic lymphocytic leukemia, progressive leukocytosis and splenomegaly caused by emerging chronic myeloid leukemia can be easily overlooked. It is unlikely that chronic myeloid

Phenotypical difference in deamination of cytarabine is not evident in induction therapy for acute myeloid leukemia

DEFF Research Database (Denmark)

Krogh-Madsen, Mikkel; Hansen, Steen Honore'; Jensen, Morten Krogh

2013-01-01

Objective To investigate the uracil arabinoside/cytarabine (Ara-U/Ara-C) ratios with the lower dose in adult acute myeloid leukaemia (AML) induction therapy (100 mg/m2 Ara-C) where no enzyme saturation is expected. Methods A precise and robust high-performance liquid chromatography (HPLC) method...... for simultaneous determination of Ara-C and its main inactive metabolite Ara-U in human plasma was developed and validated. Nineteen patients with acute myeloid leukaemia were treated with Ara-C in a dose of 100 mg/m2 together with daunorubicin and etoposide. Plasma concentrations were used to construct...

Clinical features in accelerated phase of chronic myeloid leukemia

International Nuclear Information System (INIS)

Naqi, N.; Ayub, M.

2001-01-01

Objective: To identify the clinical indicators of accelerated phase in chronic myeloid leukemia (CML) diagnosed on hematological findings. Design: An observational and prospective study. Place and Duration of Study: The study was conducted at Oncology department of Combined Military Hospital, Rawalpindi and Armed Forces Institute of Pathology from April 1998 to April 1999. Subjects and Methods: The study on 51 patients of Philadelphia positive CML in chronic phase and on hydroxyurea therapy were carried out. Clinical features and hematological parameters in the peripheral blood examination were recorded and statistical analysis carried out to document reliable clinically indicators of accelerated phase of CML in reference to those reported in the literature. Results: Clinical, presence of unexplained fever, re-enlargement of spleen after successful regression with hydroxyurea therapy, and bleeding diathesis were found to be statistically significant pointers of progression into accelerated phase of CML. In the hematological features, with the exception of peripheral basophilia, the findings in the peripheral blood were consistent with those reported in the literature. Conclusion: It is concluded that the occurrences of the clinical features in the follow-up of chronic myeloid leukemia patients herald the accelerated phase of the disease. (author)

Hypercalcaemia associated with chronic lymphocytic leukaemia in a Giant Schnauzer.

Science.gov (United States)

Kleiter, M; Hirt, R; Kirtz, G; Day, M J

2001-05-01

A 7-year-old male Giant Schnauzer was referred with a history of severe vomiting, lethargy, weight loss, polydipsia and polyuria. Detailed investigations revealed leucocytosis with a marked lymphocytosis, mild non-regenerative anaemia, thrombocytopenia, hypercalcaemia and azotaemia. Circulating lymphocytes were small and well-differentiated, and the same lymphoid population was present in bone marrow. Chronic lymphocyctic leukaemia with associated paraneoplastic hypercalcaemia was diagnosed. Immunohistochemical staining of a bone marrow biopsy revealed a neoplastic B-cell line expressing CD79. The dog responded to therapy with prednisolone and chlorambucil for a period of 8 months.

Ibrutinib: A Review in Chronic Lymphocytic Leukaemia.

Science.gov (United States)

Deeks, Emma D

2017-02-01

Ibrutinib (Imbruvica ® ) is an oral irreversible inhibitor of Bruton's tyrosine kinase, a B-cell receptor (BCR) signalling kinase expressed by various haematopoietic cells, B-cell lymphomas and leukaemias. The drug is indicated for the treatment of certain haematological malignancies, including chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL), which are the focus of this review. In phase III CLL/SLL trials, ibrutinib monotherapy was more effective than chlorambucil in the first-line treatment of elderly patients (RESONATE-2) and more effective than ofatumumab in previously-treated adults (RESONATE). Likewise, a combination of ibrutinib, bendamustine and rituximab was more effective in previously-treated adults than bendamustine plus rituximab in a phase III placebo-controlled study (HELIOS). These ibrutinib regimens were associated with significantly better progression-free survival, overall response rates, and overall survival than the comparators (in protocol-specified or planned analyses), with ibrutinib therapy providing benefit regardless of adverse prognostic factors, such as del(17p)/TP53 mutation and del(11q). Ibrutinib has an acceptable tolerability profile, although certain adverse events (e.g. bleeding and atrial fibrillation) require consideration. Redistribution lymphocytosis can occur, but is not indicative of disease progression. Although longer-term data would be beneficial, ibrutinib is a welcome treatment option for patients with CLL, including those who have higher-risk disease or are less physically fit. Indeed, current EU and US guidelines recommend/prefer the drug for the first- and/or subsequent-line treatment of certain patients, including those with del(17p)/TP53 mutation.

Targeted resequencing for analysis of clonal composition of recurrent gene mutations in chronic lymphocytic leukaemia

NARCIS (Netherlands)

Jethwa, Alexander; Hüllein, Jennifer; Stolz, Tatjana; Blume, Carolin; Sellner, Leopold; Jauch, Anna; Sill, Martin; Kater, Arnon P.; te Raa, G. Doreen; Geisler, Christian; van Oers, Marinus; Dietrich, Sascha; Dreger, Peter; Ho, Anthony D.; Paruzynski, Anna; Schmidt, Manfred; von Kalle, Christof; Glimm, Hanno; Zenz, Thorsten

2013-01-01

Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were

Targeted resequencing for analysis of clonal composition of recurrent gene mutations in chronic lymphocytic leukaemia

DEFF Research Database (Denmark)

Jethwa, Alexander; Hüllein, Jennifer; Stolz, Tatjana

2013-01-01

Recurrent gene mutations contribute to the pathogenesis of chronic lymphocytic leukaemia (CLL). We developed a next-generation sequencing (NGS) platform to determine the genetic profile, intratumoural heterogeneity, and clonal structure of two independent CLL cohorts. TP53, SF3B1, and NOTCH1 were...

Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia.

Science.gov (United States)

Shiba, Norio; Yoshida, Kenichi; Shiraishi, Yuichi; Okuno, Yusuke; Yamato, Genki; Hara, Yusuke; Nagata, Yasunobu; Chiba, Kenichi; Tanaka, Hiroko; Terui, Kiminori; Kato, Motohiro; Park, Myoung-Ja; Ohki, Kentaro; Shimada, Akira; Takita, Junko; Tomizawa, Daisuke; Kudo, Kazuko; Arakawa, Hirokazu; Adachi, Souichi; Taga, Takashi; Tawa, Akio; Ito, Etsuro; Horibe, Keizo; Sanada, Masashi; Miyano, Satoru; Ogawa, Seishi; Hayashi, Yasuhide

2016-11-01

Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (8·3%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (8·3%), BCOR/BCORL1 in 7 patients (3·4%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence. © 2016 John Wiley & Sons Ltd.

Chronic Myeloid Leukemia with Variant Chromosomal Translocations: Results of Treatment with Imatinib Mesylate

Directory of Open Access Journals (Sweden)

Rohan Bhise

2013-01-01

Full Text Available Objective: To evaluate the efficacy of imatinib in chronic myeloid leukemia patients with variant translocations. Methods: Forty eight chronic myeloid leukemia patients carrying variant translocations and treated with imatinib at our institute were considered for the study. Survival and response rates were evaluated. Results: The median follow up was 48 months(m. Forty three (89.58% patients achieved complete hematologic response. Thirty one (64.58% patients achieved complete cytogenetic response and 19(39.58% achieved major molecular response anytime during their follow up period. Only 18.75% of the patients achieved complete cytogenetic response and major molecular response within the stipulated time frames.The estimated overall survival at 48 m median follow up was 81.2%.The progression free survival was also 81.2% and the event free survival was 79.1%.There was no significant survival difference between low vs intermediate and high risk sokal group. Conclusion: We report suboptimal responses to imatinib in chronic myeloid leukemia with variant translocations. Further studies with imatinib and the newer more active drugs dasatinib and nilotinib are justified.

Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study.

Science.gov (United States)

Ravandi, Farhad; Ritchie, Ellen K; Sayar, Hamid; Lancet, Jeffrey E; Craig, Michael D; Vey, Norbert; Strickland, Stephen A; Schiller, Gary J; Jabbour, Elias; Erba, Harry P; Pigneux, Arnaud; Horst, Heinz-August; Recher, Christian; Klimek, Virginia M; Cortes, Jorge; Roboz, Gail J; Odenike, Olatoyosi; Thomas, Xavier; Havelange, Violaine; Maertens, Johan; Derigs, Hans-Günter; Heuser, Michael; Damon, Lloyd; Powell, Bayard L; Gaidano, Gianluca; Carella, Angelo-Michele; Wei, Andrew; Hogge, Donna; Craig, Adam R; Fox, Judith A; Ward, Renee; Smith, Jennifer A; Acton, Gary; Mehta, Cyrus; Stuart, Robert K; Kantarjian, Hagop M

2015-09-01

Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355

Large granular lymphocytic leukaemia pathogenesis and management.

Science.gov (United States)

Dearden, Claire

2011-02-01

The WHO classification recognises three distinct disorders of large granular lymphocytes: T-cell large granular lymphocytic leukaemia (T-LGL), chronic lymphoproliferative disorders of NK-cells (CLPD-NK) and agressive NK-cell leukaemia. Despite the different cell of origin, there is considerable overlap between T-LGL and CLPD-NK in terms of clinical presentation and therapy. Many patients are asymptomatic and do not require treatment. Therapy, with immunosuppressant agents such as low dose methotrexate or ciclosporin, is usually indicated to correct cytopenias. In contrast, aggressive NK-cell leukaemia and the rare CD56(+) aggressive T-LGL leukaemia follow a fulminant clinical course, affect younger individuals and require more intensive combination chemotherapy followed by allogeneic stem cell transplant in eligible patients. The relative rarity of these disorders means that there have been few clinical trials to inform management. However, there is now considerable interest in the pathogenesis of the chronic LGL leukaemias and this has stimulated early trials to evaluate novel agents which target the dysregulated apoptotic pathways characteristic of this disease. © 2010 Blackwell Publishing Ltd.

Dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia: a systematic review and economic evaluation.

Science.gov (United States)

Loveman, E; Cooper, K; Bryant, J; Colquitt, J L; Frampton, G K; Clegg, A

2012-01-01

The present report was commissioned as a supplement to an existing technology assessment report produced by the Peninsula Technology Assessment Group (PenTAG), which evaluated the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in patients who are either resistant or intolerant to standard-dose imatinib. This report evaluates the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and high-dose imatinib within their licensed indications for the treatment of people with chronic myeloid leukaemia (CML) who are resistant to standard-dose imatinib. Bibliographic databases were searched from inception to January 2011, including The Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid), and MEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were screened, key conferences were searched, and experts were contacted to identify additional published and unpublished references. This report includes systematic reviews of clinical effectiveness and cost-effectiveness studies, an independent appraisal of information submitted by drug manufacturers to the National Institute for Health and Clinical Excellence (NICE), an independent appraisal of the PenTAG economic evaluation, and new economic analyses adapting the PenTAG economic model. Standard systematic procedures involving two reviewers to maintain impartiality and transparency, and to minimise bias, were conducted. Eleven studies met the inclusion criteria. Four of these studies included new data published since the PenTAG report; all of these were in chronic-phase CML. No relevant studies on the clinical effectiveness of nilotinib were found. The clinical effectiveness studies on dasatinib [one arm of a randomised controlled trial (RCT)] and high-dose imatinib (one arm of a RCT and three single-arm cohort studies) had major methodological limitations. These limitations precluded a comparison of the different arms within the RCT. Data from the studies are

PBSCT is associated with poorer survival and increased chronic GvHD than BMT in Japanese paediatric patients with acute leukaemia and an HLA-matched sibling donor.

Science.gov (United States)

Shinzato, Aki; Tabuchi, Ken; Atsuta, Yoshiko; Inoue, Masami; Inagaki, Jiro; Yabe, Hiromasa; Koh, Katsuyoshi; Kato, Koji; Ohta, Hideaki; Kigasawa, Hisato; Kitoh, Toshiyuki; Ogawa, Atsushi; Takahashi, Yoshiyuki; Sasahara, Yoji; Kato, Shun-Ichi; Adachi, Souichi

2013-09-01

Peripheral blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Since peripheral blood stem cell bank from unrelated volunteer donor has been started in Japan, use of PBSC allografts may be increased. Therefore we surveyed the outcomes of Japanese leukemia children after PBSC and BM transplantation. This retrospective study compared the outcomes of 661 children (0-18 years) with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) who received their first allogeneic peripheral blood stem cell transplantation (PBSCT; n = 90) or bone marrow transplantation (BMT; n = 571) from HLA-matched siblings between January 1996 and December 2007. Neutrophil recovery was faster after PBSCT than after BMT (ALL: P vs. 9.9%, P = 0.0066; AML: 41.6% vs. 11.1%, P vs. 57.1%, P = 0.0257). The 5-year overall survival (OS) was lower after PBSCT than after BMT for ALL (42.4% vs. 63.7%, P = 0.0032) and AML (49.8% vs. 71.8%, P = 0.0163). Multivariate analysis revealed the use of PBSC was a significant risk factor for DFS and OS. PBSCT and BMT did not differ in relapse rate, acute GvHD for ALL and AML, or in DFS for AML. PBSC allografts in Japanese children engraft faster but are associated with poorer survival and increased chronic GvHD. Copyright © 2013 Wiley Periodicals, Inc.

A review of therapy-related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) in Irish patients: a single centre experience.

Science.gov (United States)

Maung, Su W; Burke, Cathie; Hayde, Jennifer; Walshe, Janice; McDermott, Ray; Desmond, Ronan; McHugh, Johnny; Enright, Helen

2017-07-01

To demonstrate the incidence, characteristics, treatment and outcomes of patients with therapy-related myelodysplastic syndromes and therapy-related acute myeloid leukaemia (t-MDS/AML) in a tertiary referral centre. Patients meeting the diagnostic criteria for t-MDS/AML from 2003 to 2014 were reviewed to analyse their diagnostic features, details of antecedent disorder and treatment, approach to management and survival. 39 patients who developed t-MDS/AML were identified with incidence of 8.7%. Median age and gender distribution were similar to de novo MDS but t-MDS/AML patients had greater degree of cytopenia and adverse karyotypes. Time to development of t-MDS/AML was shortest for patients with antecedent haematological malignancy compared to solid tumours and autoimmune disorders (46, 85 and 109 months). Patients with prior acute leukaemia had the shortest latency and poor overall survival. Treatment options included best supportive care (56%), Azacitidine (31%) or intensive chemotherapy/allogeneic transplant (13%). Median OS of all patients was 14 months. Survival declined markedly after two years and 5-year OS was 13.8%. Longer survival was associated with blast count MDS/AML patients showed unique characteristics which influenced their treatment and outcomes. IPSS-R may be useful in risk-adapted treatment approaches and can predict outcomes. Survival remains poor but improved outcomes were seen with allogeneic transplantation. Azacitidine may be effective in patients unfit for intensive therapies.

Severe depression following á-interferon usage in a patient with ...

African Journals Online (AJOL)

... following á-interferon usage in a patient with chronic myeloid leukemia. ... Chronic myeloid leukaemia (CML), with a median age of 40 years, is one of the ... as a side effect of á-IFN in the treatment of CML Method: Clinical and laboratory ...

[Molecular characterization of atypical chronic myeloid leukemia and chronic neutrophilic leukemia].

Science.gov (United States)

Senín, Alicia; Arenillas, Leonor; Martínez-Avilés, Luz; Fernández-Rodríguez, Concepción; Bellosillo, Beatriz; Florensa, Lourdes; Besses, Carles; Álvarez-Larrán, Alberto

2015-06-08

Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) display similar clinical and hematological characteristics. The objective of the present study was to determine the mutational status of SETBP1 and CSF3R in these diseases. The mutational status of SETBP1 and CSF3R was studied in 7 patients with aCML (n = 3), CNL (n = 1) and unclassifiable myeloproliferative neoplasms (MPN-u) (n = 3). Additionally, mutations in ASXL1, SRSF2, IDH1/2, DNMT3A, and RUNX1 were also analyzed. SETBP1 mutations (G870S and G872R) were detected in 2 patients with MPN-u, and one of them also presented mutations in SRSF2 (P95H) and ASXL1 (E635fs). The CNL case showed mutations in CSFR3 (T618I), SETBP1 (G870S) and SRSF2 (P95H). No patient classified as aCML had mutations in SETBP1 or CSF3R. One of the patients with mutations evolved to acute myeloid leukemia, while the other 2 had disease progression without transformation to overt leukemia. The knowledge of the molecular alterations involved in these rare diseases is useful in the diagnosis and may have an impact on both prognosis and therapy. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

A novel RT-qPCR assay for quantification of the MLL-MLLT3 fusion transcript in acute myeloid leukaemia

DEFF Research Database (Denmark)

Abildgaard, Lotte; Ommen, Hans Beier; Lausen, Birgitte Frederiksen

2013-01-01

OBJECTIVES: Patients with acute myeloid leukaemia (AML) of the monocytic lineage often lack molecular markers for minimal residual disease (MRD) monitoring. The MLL-MLLT3 fusion transcript found in patients with AML harbouring t(9;11) is amenable to RT-qPCR quantification but because...... of the heterogeneity of translocation break points, the MLL-MLLT3 fusion gene is a challenging target. We hypothesised that MRD monitoring using MLL-MLLT3 as a RT-qPCR marker is feasible in the majority of patients with t(9;11)-positive AML. METHODS: Using a locked nucleic acid probe, we developed a sensitive RT......-qPCR assay for quantification of the most common break point region of the MLL-MLLT3 fusion gene. Five paediatric patients with t(9;11)-positive AML were monitored using the MLL-MLLT3 assay. RESULTS: A total of 43 bone marrow (BM) and 52 Peripheral blood (PB) samples were collected from diagnosis until...

Exploring the acute myeloid leukaemias

Directory of Open Access Journals (Sweden)

TB Thapa

2013-10-01

Full Text Available The acute myeloid leukemias are genetically a diverse group of neoplasm with varied clinical behavior and response to treatment. Advances in immunophenotyping, cytogenetics and molecular genetics have resulted in better understanding of their genesis. Risk stratification of different variants is now emerging. Therapy strategies are now increasingly being developed considering the inherent biological behavior of the different subtypes. It is anticipated that in the future, deeper secrets of these once fatal diseases will be unraveled by advances in newer genomic techniques. It is hoped that future use of gene specific tailored therapy and strategies will result in longer survival in cases showing poorer prognosis at present. DOI: http://dx.doi.org/10.3126/jpn.v3i6.9001 Journal of Pathology of Nepal (2013 Vol. 3, 497-501

Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

Science.gov (United States)

2017-03-27

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

Minimal residual disease in chronic lymphocytic leukaemia.

Science.gov (United States)

García Vela, José Antonio; García Marco, José Antonio

2018-02-23

Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis

International Nuclear Information System (INIS)

Darby, S.C.; Doll, R.; Gill, S.K.; Smith, P.G.

1987-01-01

Mortality to 1 January 1983 was studied in 14,106 ankylosing spondylitis patients after a single course of X-rays (1935-1954). For neoplasms other than leukaemia or colon cancer, mortality was 28% greater than the general population of England and Wales, proportional increase reaching a maximum 71% between 10.0 and 12.4 years post-irradiation. There was 7% mortality increase more than 25.0 years post-irradiation and only for oesophageal cancer was the relative risk significantly raised. Neither the relative risk, nor its post-irradiation temporal pattern, were greatly influenced by the patient's age. There was a threefold increase in leukaemia mortality, the relative risk highest between 2.5 and 4.9 years post-treatment, but not disappearing being nearly twice that of the general population more than 25 years post-treatment. There was evidence that acute myeloid, acute lymphatic and chronic myeloid leukaemia risks were increased, but no evidence of increase in chronic lymphatic leukaemia. The relative risk appeared greatest for acute myeloid leukaemia. Colon cancer mortality increased by 30%. Non-neoplastic conditions showed a 51% mortality increase, likely to be associated with the disease itself, and not confined to diseases associated with spondylitis. (UK)

Appearance and Disappearance of Chronic Myeloid Leukemia (CML) in Patient with Chronic Lymphocytic Leukemia (CLL)

OpenAIRE

Payandeh, Mehrdad; Sadeghi, Edris; Khodarahmi, Reza; Sadeghi, Masoud

2014-01-01

Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common leukemias of the elderly (>43 year). However, the sequential occurrence of CML followed by CLL in the same patient is extremely rare. In our report, a 52-year-old female was diagnosed with CLL (type of bone marrow (BM) infiltration was nodular and interstitial) and was treated with chlorambucil. 64 months after the diagnosis of CLL, she developed CML. She was treated with imatinib (400mg/day). After a fe...

Hypermethylation of the FANCC and FANCL Promoter Regions in Sporadic Acute Leukaemia

Directory of Open Access Journals (Sweden)

C. J. Hess

2008-01-01

Full Text Available Objective: Inactivation of the FA-BRCA pathway results in chromosomal instability. Fanconi anaemia (FA patients have an inherited defect in this pathway and are strongly predisposed to the development of acute myeloid leukaemia (AML. Studies in sporadic cancers have shown promoter methylation of the FANCF gene in a significant proportion of various solid tumours. However, only a single leukaemic case with methylation of one of the FA-BRCA genes has been described to date, i.e. methylation of FANCF in cell line CHRF-288. We investigated the presence of aberrant methylation in 11 FA-BRCA genes in sporadic cases of leukaemia.

Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents

DEFF Research Database (Denmark)

Millot, Frédéric; Guilhot, Joëlle; Suttorp, Meinolf

2017-01-01

The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression ...

Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents

NARCIS (Netherlands)

Millot, Frederic; Guilhot, Joelle; Suttorp, Meinolf; Gunes, Adalet Meral; Sedlacek, Petr; De Bont, Eveline; Li, Chi Kong; Kalwak, Krzysztof; Lausen, Birgitte; Culic, Srdjana; Dworzak, Michael; Kaiserova, Emilia; De Moerloose, Barbara; Roula, Farah; Biondi, Andrea; Baruchel, Andre

2017-01-01

The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression

ATM facilitates mouse gammaherpesvirus reactivation from myeloid cells during chronic infection.

Science.gov (United States)

Kulinski, Joseph M; Darrah, Eric J; Broniowska, Katarzyna A; Mboko, Wadzanai P; Mounce, Bryan C; Malherbe, Laurent P; Corbett, John A; Gauld, Stephen B; Tarakanova, Vera L

2015-09-01

Gammaherpesviruses are cancer-associated pathogens that establish life-long infection in most adults. Insufficiency of Ataxia-Telangiectasia mutated (ATM) kinase leads to a poor control of chronic gammaherpesvirus infection via an unknown mechanism that likely involves a suboptimal antiviral response. In contrast to the phenotype in the intact host, ATM facilitates gammaherpesvirus reactivation and replication in vitro. We hypothesized that ATM mediates both pro- and antiviral activities to regulate chronic gammaherpesvirus infection in an immunocompetent host. To test the proposed proviral activity of ATM in vivo, we generated mice with ATM deficiency limited to myeloid cells. Myeloid-specific ATM deficiency attenuated gammaherpesvirus infection during the establishment of viral latency. The results of our study uncover a proviral role of ATM in the context of gammaherpesvirus infection in vivo and support a model where ATM combines pro- and antiviral functions to facilitate both gammaherpesvirus-specific T cell immune response and viral reactivation in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.

Immunohistochemical loss of 5-hydroxymethylcytosine expression in acute myeloid leukaemia: relationship to somatic gene mutations affecting epigenetic pathways.

Science.gov (United States)

Magotra, Minoti; Sakhdari, Ali; Lee, Paul J; Tomaszewicz, Keith; Dresser, Karen; Hutchinson, Lloyd M; Woda, Bruce A; Chen, Benjamin J

2016-12-01

Genes affecting epigenetic pathways are frequently mutated in myeloid malignancies, including acute myeloid leukaemia (AML). The genes encoding TET2, IDH1 and IDH2 are among the most commonly mutated genes, and cause defective conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC), impairing demethylation of DNA, and presumably serving as driver mutations in leukaemogenesis. The aim of this study was to correlate 5hmC immunohistochemical loss with the mutation status of genes involved in epigenetic pathways in AML. Immunohistochemical staining with an anti-5hmC antibody was performed on 41 decalcified, formalin-fixed paraffin-embedded (FFPE) bone marrow biopsies from patients with AML. Archived DNA was subjected to next-generation sequencing for analysis of a panel of genes, including TET2, IDH1, IDH2, WT1 and DNMT3A. TET2, IDH1, IDH2, WT1 and DNMT3A mutations were found in 46% (19/41) of the cases. Ten of 15 cases (67%) with TET2, IDH1, IDH2 or WT1 mutations showed deficient 5hmC staining, whereas nine of 26 cases (35%) without a mutation in these genes showed loss of 5hmC. It is of note that all four cases with TET2 mutations showed deficient 5hmC staining. Overall, somatic mutations in TET2, IDH1, IDH2, WT1 and DNMT3A were common in our cohort of AML cases. Immunohistochemical staining for 5hmC was lost in the majority of cases harbouring mutations in these genes, reflecting the proposed relationship between dysfunctional epigenetic pathways and leukaemogenesis. © 2016 John Wiley & Sons Ltd.

Acute leukaemoid reaction following cardiac surgery

Directory of Open Access Journals (Sweden)

Webb Stephen T

2007-01-01

Full Text Available Abstract Chronic myelomonocytic leukaemia is an atypical myeloproliferative disorder with a natural history of progression to acute myeloid leukaemia, a complex and poorly understood response by the bone marrow to stress. Cardiac surgery activates many inflammatory cascades and may precipitate a systemic inflammatory response syndrome. We present a case of undiagnosed chronic myelomonocytic leukaemia who developed rapidly fatal multi-organ dysfunction following cardiac surgery due to an acute leukaemoid reaction.

Experiment designed to measure the RBE of tritium for the induction of myeloid leukaemia in animals

Energy Technology Data Exchange (ETDEWEB)

Johnson, J R; Myers, D K; Gragtmans, N J

1986-01-01

The range in RBE vales measured for tritium can be attributed to differences in the biological endpoints measured, the reference radiation to which the effects of tritium were compared, and the tritium dosimetry of the particular study. Since the principal risk of low-level irradiation is the induction of cancers, it would be desirable to utilise this endpoint in tritium RBE experiments if these experiments are to be used to evaluate the quality factor for tritium. Furthermore, it would be desirable to use 200 k Vp X rays as the reference radiation since this radiation was suggested by ICRP as the standard reference to be used in the calculation of dose equivalents. Acute myeloid leukaemia is one of the earliest recognised examples of radiogenic cancer in humans and this endpoint has also been the subject of animal studies. A brief review is given of these animal studies to see if this endpoint is suitable for an experiment to measure the tritium RBE relative to 200 k Vp X rays. It was concluded that the male CBA/H mouse would be a suitable species and an experiment involving 5000 animals in four to five year study would be required to provide a useful estimate of the RBE for tritium.

Management of chronic myeloid leukemia in blast crisis.

Science.gov (United States)

Saußele, S; Silver, Richard T

2015-04-01

Due to the high efficacy of BCR-ABL tyrosine kinase inhibition (TKI) in chronic phase (CP) chronic myeloid leukemia (CML), the frequency of blast crisis (BC) is greatly reduced compared to the pre-TKI era. However, TKI treatment of BC has only marginally improved the number of favorable responses, including remissions, which for the most part have only been transitory. Occasionally, they provide a therapeutic window to perform an allogeneic stem cell transplantation (allo-SCT). The challenge remains to improve management of BC with the limited options available. We review and summarize articles pertaining to the treatment of BC CML published after 2002. Additionally, we will discuss whether there is a need for a new definition of BC and/or treatment failure.

Transgenerational induction of leukaemia following parental irradiation. Genomic instability and the bystander in vivo

Energy Technology Data Exchange (ETDEWEB)

Lord, B.I. [Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester (United Kingdom)

2003-07-01

Internal radiation from small amounts of bone-incorporated plutonium-239 has been shown to result in long-term perturbation to haemopoiesis - in particular to the pluripotent bone marrow stem and progenitor cells - in mice. Associated with these changes is a small but finite induction of myeloid leukaemia. Preliminary experiments showed some instabilities in haemopoiesis following preconception, paternal irradiation (PPI) with {sup 239}Pu and these studies were extended to consider whether similar sensitivity to leukaemia induction might also arise in these offspring. Male mice were injected with 0, 128 or 256 Bq/g bodyweight with plutonium-239 citrate, 12 weeks before mating with normal untreated females. Bone marrow assays were conducted on their male offspring at 6-18 weeks after birth. Female offspring were injected with 50 mg/kg methyl nitrosourea (MNU), or irradiated with 3.3 Gy {gamma}-rays, at 10 weeks of age and observed continuously for onset of dysfunction when they were immediately sacrificed. In a parallel study set up by Stones and Humphreys (personal communication) incorporating significant numbers of offspring from PPI only, no case of leukaemia was observed. However, in this study, offspring of fathers treated with {sup 239}Pu showed significantly greater sensitivity than normal mice to treatment with known inducers of lympho-myeloid leukaemia such as MNU (or irradiation). Although a somewhat greater frequency of chromosomal abnormalities was seen in bone marrow of PPI offspring, the estimated mutation rates were insufficient to account for the degree of leukaemia induction and suggested an indirect mechanism. Detailed study of the bone marrow in individual offspring showed subtle changes in their stem cell content and in their haemopoietic inductive microenvironment, a component seen to be damaged also in the earlier radiation studies. It will be argued that low-dose radiation is rarely a direct cause of leukaemia (in mice). Rather that damage

Early mortality and complications in hospitalized adult Californians with acute myeloid leukaemia.

Science.gov (United States)

Ho, Gwendolyn; Jonas, Brian A; Li, Qian; Brunson, Ann; Wun, Ted; Keegan, Theresa H M

2017-06-01

Few studies have evaluated the impact of complications, sociodemographic and clinical factors on early mortality (death ≤60 days from diagnosis) in acute myeloid leukaemia (AML) patients. Using data from the California Cancer Registry linked to hospital discharge records from 1999 to 2012, we identified patients aged ≥15 years with AML who received inpatient treatment (N = 6359). Multivariate logistic regression analyses were used to assess the association of complications with early mortality, adjusting for sociodemographic factors, comorbidities and hospital type. Early mortality decreased over time (25·3%, 1999-2000; 16·8%, 2011-2012) across all age groups, but was higher in older patients (6·9%, 15-39, 11·4%, 40-54, 18·6% 55-65, and 35·8%, >65 years). Major bleeding [Odds ratio (OR) 1·5, 95% confidence interval (CI) 1·3-1·9], liver failure (OR 1·9, 95% CI 1·1-3·1), renal failure (OR 2·4, 95% CI 2·0-2·9), respiratory failure (OR 7·6, 95% CI 6·2-9·3) and cardiac arrest (OR 15·8, 95% CI 8·7-28·6) were associated with early mortality. Higher early mortality was also associated with single marital status, low neighbourhood socioeconomic status, lack of health insurance and comorbidities. Treatment at National Cancer Institute-designated cancer centres was associated with lower early mortality (OR 0·5, 95% CI 0·4-0·6). In conclusion, organ dysfunction, hospital type and sociodemographic factors impact early mortality. Further studies should investigate how differences in healthcare delivery affect early mortality. © 2017 John Wiley & Sons Ltd.

Radiation-induced acute myeloid leukemia in the mouse: experimental observations in vivo with implications for hypotheses about the basis of carcinogenesis

Energy Technology Data Exchange (ETDEWEB)

Mole, R H

1986-01-01

Acute myeloid leukaemia induction by X- and ..gamma..-rays in 4 mouse strains follows the same dose-response aD/sup 2/esup(-lambdaD). The (dose)/sup 2/ interaction disappears within 3 days. AML appears earlier when syngeneic marrow cells are injected 3 days after irradiation, minimum latent period and final frequency remaining unchanged. Dose-responses for brief and protracted exposures are quite different for non-myeloid 'leukemia'. The results seem incompatible with a common model for initiation of both leukaemia categories and with orthodox concepts that initiation is a stable state and must be followed by multiple events over a period of time before cells express fully malignant behaviour.

Radiation-induced acute myeloid leukemia in the mouse: experimental observations in vivo with implications for hypotheses about the basis of carcinogenesis

International Nuclear Information System (INIS)

Mole, R.H.

1986-01-01

Acute myeloid leukaemia induction by X- and γ-rays in 4 mouse strains follows the same dose-response aD 2 esup(-lambdaD). The (dose) 2 interaction disappears within 3 days. AML appears earlier when syngeneic marrow cells are injected 3 days after irradiation, minimum latent period and final frequency remaining unchanged. Dose-responses for brief and protracted exposures are quite different for non-myeloid 'leukemia'. The results seem incompatible with a common model for initiation of both leukaemia categories and with orthodox concepts that initiation is a stable state and must be followed by multiple events over a period of time before cells express fully malignant behaviour. (author)

Leukaemia risks and exposure to ionizing radiations. ASN seminar, Tuesday, June 9, 2015, report

International Nuclear Information System (INIS)

Niel, Jean-Christophe; Samain, Jean-Paul; Colonna, Marc; Maynadie, Marc; Richardson, David; Bey, Pierre; Leuraud, Klervi; Laurier, Dominique; Hemon, Denis; Spycher, Ben; Kosti, Ourania; Bouville, Andre; Grosche, Bernd; Ziegelberger, Gunde; Kesminiene, Ausrele; Clavel, Jacqueline; Smeesters, Patrick; Murith, Christophe

2015-08-01

This seminar aims at proposing a review of present knowledge on leukaemia risks for children and adults associated with ionizing radiations, and at sharing knowledge between experts. After an introduction which outlined the interest of the ASN in research issues, and the importance awarded by the ASN to the variety of points of view, a first session addressed leukaemia and exposures to ionizing radiations. The contributions addressed some general aspects (an overview of leukaemia in France, the different types of adult and child leukaemia), leukaemia and acute exposures to ionizing radiations (ionizing radiation and leukaemia among Japanese bomb survivors, risks of leukaemia after radiotherapy), leukaemia and chronic exposures to ionizing radiations (assessment of epidemiological studies for adult chronic exposures). The second session addressed childhood leukaemia and ionizing radiations. The contributions of this second session more particularly addressed the following topics: childhood leukaemia and natural radioactivity (French studies, synthesis of international studies and a new Swiss study), childhood leukaemia and proximity of nuclear base installations (assessment of national and international studies, analysis of cancer risks in populations near nuclear facilities in the US, calculation of dose at the medulla as example of dosimetry of ionizing radiations and leukaemia, conclusions of the 2012 MELODI workshop), childhood leukaemia and scanner (recent results and perspectives), childhood leukaemia and other risk factors (etiology of childhood leukaemia - presentation of French studies initiated by the INSERM, and presentation of studies initiated by BfS)

Nilotinib induced avascular necrosis of femoral head in an adult chronic myeloid leukemia patient.

Science.gov (United States)

Thekkudan, Shinto Francis; Nityanand, Soniya

2018-06-01

We report a rare case of avascular necrosis of femoral head (AVNFH) in an adult chronic myeloid leukemia - chronic phase (CML-CP) patient during due course of therapy with second line Tyrosine Kinase Inhibitor (TKI), Nilotinib. A high index of clinical suspicion should be kept in any symptomatic CML patient on TKI's.

Additional cytogenetic abnormalities and variant t(9;22) at the diagnosis of childhood chronic myeloid leukemia : The experience of the International Registry for Chronic Myeloid Leukemia in Children and Adolescents

NARCIS (Netherlands)

Millot, Frederic; Dupraz, Christelle; Guilhot, Joelle; Suttorp, Meinolf; Brizard, Francoise; Leblanc, Thierry; Gunes, Adalet Meral; Sedlacek, Petr; De Bont, Evelyne; Li, Chi Kong; Kalwak, Krzysztof; Lausen, Birgitte; Culic, Srdjana; Dworzak, Michael; Kaiserova, Emilia; De Moerloose, Barbara; Roula, Farah; Biondi, Andrea; Baruchel, Andre; Guilhot, Francois

2017-01-01

BACKGROUND: In the adult population with newly diagnosed chronic myeloid leukemia (CML), variant translocations are usually not considered to be impairing the prognosis, whereas some additional cytogenetic abnormalities (ACAs) are associated with a negative impact on survival. Because of the rarity

Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study.

Science.gov (United States)

O'Brien, Susan; Jones, Jeffrey A; Coutre, Steven E; Mato, Anthony R; Hillmen, Peter; Tam, Constantine; Österborg, Anders; Siddiqi, Tanya; Thirman, Michael J; Furman, Richard R; Ilhan, Osman; Keating, Michael J; Call, Timothy G; Brown, Jennifer R; Stevens-Brogan, Michelle; Li, Yunfeng; Clow, Fong; James, Danelle F; Chu, Alvina D; Hallek, Michael; Stilgenbauer, Stephan

2016-10-01

The TP53 gene, encoding tumour suppressor protein p53, is located on the short arm of chromosome 17 (17p). Patients with 17p deletion (del17p) chronic lymphocytic leukaemia have poor responses and survival after chemoimmunotherapy. We assessed the activity and safety of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, in relapsed or refractory patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma. We did a multicentre, international, open-label, single-arm study at 40 sites in the USA, Canada, Europe, Australia, and New Zealand. Patients (age ≥18 years) with previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was overall response in the all-treated population per International Workshop on Chronic Lymphocytic Leukaemia 2008 response criteria modified for treatment-related lymphocytosis. Preplanned exploratory analyses were progression-free survival, overall survival, sustained haematological improvement, and immunological improvement. Patient enrolment is complete, but follow-up is ongoing. Treatment discontinuation owing to adverse events, unacceptable toxicity, or death were collected as a single combined category. This study is registered with ClinicalTrials.gov, number NCT01744691. Between Jan 29, 2013, and June 19, 2013, 145 patients were enrolled. The all-treated population consisted of 144 patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma who received at least one dose of study drug, with a median age of 64 years (IQR 57-72) and a median of two previous treatments (IQR 1-3). At the prespecified primary analysis after a median follow-up of 11·5 months (IQR 11·1-13·8), 92 (64%, 95% CI 56-71) of 144 patients had an overall response according to independent review committee assessment; 119 patients (83%, 95% CI 76-88) had an overall

Radotinib and its clinical potential in chronic-phase chronic myeloid leukemia patients: an update.

Science.gov (United States)

Eskazan, Ahmet Emre; Keskin, Dilek

2017-09-01

Although imatinib has dramatically improved major outcomes in patients with chronic myeloid leukemia (CML), there are newer tyrosine kinase inhibitors (TKIs) approved worldwide for the treatment of resistant cases, and two second-generation TKIs (dasatinib, nilotinib) are approved in some nations for treating patients in the upfront setting. Radotinib (IY5511HCL, Supect® ) is a novel and selective second-generation BCR-ABL1 TKI, which is currently approved in Korea for the treatment of patients with CML both in the upfront and salvage settings. This review mainly focuses on the clinical potential of radotinib in patients with CML in chronic phase in terms of efficacy and safety.

[Platelet function in acute myeloid leukemia. II. Aggregation of isolated platelets].

Science.gov (United States)

Zawilska, K; Komarnicki, M; Mańka, B

1978-01-01

In 22 patients with acute myeloid leukaemia (17 cases of myeloblastic leukaemia, 4 cases of myelomonocytic leukaemia and 1 case of undifferentiated-cell leukaemia) platelets were isolated from the plasma by the method of Nicholls and Hampton as modified by Levy-Toledano by centrifugation in albumin gradient. The aim of platelet isolation was their "concentration" in cases of thrombocytopenia to values making possible aggregation tests, and platelet separation from the influence of plasma factors. Then aggregation of isolated platelets caused by ADP was studied. In 16 out of 22 patients a fall of aggregation was observed, with the mean values of aggregation rate and intensity were significantly lower. Parallelly done determinations of aggregating activity released from the platelets by thrombin showed lower values as compared with platelets from healthy subjects. In might be thought, in this connection, that the demonstrated reduction of isolated platelets is associated with a diminution of the nucleotide pool or disturbances of the platelet release reaction. The disturbances of the platelet release reaction. The disturbances of aggregation of isolated platelets and reduction of the aggregating activity were most pronounced in acute myelomonocytic leukaemia.

Ward Round - Recurrent anemia and infection in an HIV-positive ...

African Journals Online (AJOL)

Treatment and progress. The patient was ... due to sepsis itself, nutritional deficiencies, drugs, chronic infections such ... treatment of sepsis and other identifiable conditions before seeking more ... leukaemia as an acute lymphoid or myeloid leukaemia cannot .... and outcome of AIDS-related Burkitt's lymphoma or leukemia.

BCR-ABL1- positive chronic myeloid leukemia with erythrocytosis presenting as polycythemia vera: a case report.

Science.gov (United States)

Cornea, Mihaela I Precup; Levrat, Emmanuel; Pugin, Paul; Betticher, Daniel C

2015-04-08

The World Health Organization classification of chronic myeloproliferative disease encompasses eight entities of bone marrow neoplasms, among them Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1-positive chronic myeloid leukemia and polycythemia vera. Polycythemia vera requires, in the majority of cases (95%), the negativity of Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 rearrangement and the presence of the Janus kinase 2 mutation. We report a case of erythrocytosis as the primary manifestation of a chronic myeloid leukemia, with the presence of the Philadelphia chromosome and the Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion gene, and in the absence of any Janus kinase 2 mutation. A 68-year-old Caucasian woman, with a history of cigarette consumption and obstructive sleep apnoea syndrome (undergoing continuous positive airway pressure treatment) had presented to our institution with fatigue and a hemoglobin level of 18.6g/L, with slight leukocytosis at 16G/L, and no other anomalies on her complete blood cell count. Examination of her arterial blood gases found only a slight hypoxemia; erythropoietin and ferritin levels were very low and could not explain a secondary erythrocytosis. Further analyses revealed the absence of any Janus kinase 2 mutation, thus excluding polycythemia vera. Taken together with a high vitamin B12 level, we conducted a Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 gene analysis and bone marrow cytogenetic analysis, both of which returned positive, leading to the diagnosis of chronic myeloid leukemia. To date, this case is the first description of a Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1-positive chronic myeloid leukemia, presenting with erythrocytosis as the initial manifestation, and mimicking a Janus kinase 2 V617F-negative polycythemia vera. Her impressive response to imatinib

Incidence of second primary malignancies and related mortality in patients with imatinib-treated chronic myeloid leukemia.

Science.gov (United States)

Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Albano, Francesco; Iurlo, Alessandra; Intermesoli, Tamara; Abruzzese, Elisabetta; Levato, Luciano; D'Adda, Mariella; Pregno, Patrizia; Cavazzini, Francesco; Stagno, Fabio; Martino, Bruno; La Barba, Gaetano; Sorà, Federica; Tiribelli, Mario; Bigazzi, Catia; Binotto, Gianni; Bonifacio, Massimiliano; Caracciolo, Clementina; Soverini, Simona; Foà, Robin; Cavo, Michele; Martinelli, Giovanni; Pane, Fabrizio; Saglio, Giuseppe; Baccarani, Michele; Rosti, Gianantonio

2017-09-01

The majority of patients with chronic myeloid leukemia are successfully managed with life-long treatment with tyrosine kinase inhibitors. In patients in chronic phase, other malignancies are among the most common causes of death, raising concerns on the relationship between these deaths and the off-target effects of tyrosine kinase inhibitors. We analyzed the incidence of second primary malignancies, and related mortality, in 514 chronic myeloid leukemia patients enrolled in clinical trials in which imatinib was given as first-line treatment. We then compared the observed incidence and mortality with those expected in the age- and sex-matched Italian general population, calculating standardized incidence and standardized mortality ratios. After a median follow-up of 74 months, 5.8% patients developed second primary malignancies. The median time from chronic myeloid leukemia to diagnosis of the second primary malignancies was 34 months. We did not find a higher incidence of second primary malignancies compared to that in the age- and sex-matched Italian general population, with standardized incidence ratios of 1.06 (95% CI: 0.57-1.54) and 1.61 (95% CI: 0.92-2.31) in males and females, respectively. Overall, 3.1% patients died of second primary malignancies. The death rate in patients with second primary malignancies was 53% (median overall survival: 18 months). Among females, the observed cancer-related mortality was superior to that expected in the age- and sex-matched Italian population, with a standardized mortality ratio of 2.41 (95% CI: 1.26 - 3.56). In conclusion, our analysis of patients with imatinib-treated chronic myeloid leukemia did not reveal a higher incidence of second primary malignancies; however, the outcome of second primary malignancies in such patients was worse than expected. Clinicaltrials.gov: NCT00514488, NCT00510926. Copyright© 2017 Ferrata Storti Foundation.

Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia : 2-year follow-up from a randomized phase 3 trial (DASISION)

NARCIS (Netherlands)

Kantarjian, Hagop M.; Shah, Neil P.; Cortes, Jorge E.; Baccarani, Michele; Agarwal, Mohan B.; Soledad Undurraga, Maria; Wang, Jianxiang; Kassack Ipina, Juan Julio; Kim, Dong-Wook; Ogura, Michinori; Pavlovsky, Carolina; Junghanss, Christian; Milone, Jorge H.; Nicolini, Franck E.; Robak, Tadeusz; Van Droogenbroeck, Jan; Vellenga, Edo; Bradley-Garelik, M. Brigid; Zhu, Chao; Hochhaus, Andreas

2012-01-01

Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n =

Appearance and Disappearance of Chronic Myeloid Leukemia (CML) in Patient with Chronic Lymphocytic Leukemia (CLL).

Science.gov (United States)

Payandeh, Mehrdad; Sadeghi, Edris; Khodarahmi, Reza; Sadeghi, Masoud

2014-10-01

Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common leukemias of the elderly (>43 year). However, the sequential occurrence of CML followed by CLL in the same patient is extremely rare. In our report, a 52-year-old female was diagnosed with CLL (type of bone marrow (BM) infiltration was nodular and interstitial) and was treated with chlorambucil. 64 months after the diagnosis of CLL, she developed CML. She was treated with imatinib (400mg/day). After a few months, signs of CML were disappeared and CLL became dominant. This is first reported case.

MRI of perineural extramedullary granulocytic sarcoma

Energy Technology Data Exchange (ETDEWEB)

Graham, A. [Rehabilitation Medicine, Hunters Moor Neurological Rehabilitation Centre, Newcastle-Upon-Tyne (United Kingdom); Hodgson, T. [Neuroradiology Dept., Royal Hallamshire Hospital, Sheffield (United Kingdom); Jacubowski, J. [Neurosurgical Dept., Royal Hallamshire Hospital, Sheffield (United Kingdom); Norfolk, D. [Haematology Department, Leeds General Infirmary, Leeds LS1 3EX (United Kingdom); Smith, C. [Pathology Dept., Royal Hallamshire Hospital, Sheffield (United Kingdom)

2001-06-01

Granulocytic sarcoma is an extramedullary solid tumour consisting of myelogenous leukaemic blast cells, usually seen in acute myeloid leukaemia and less commonly in patients with chronic myeloid leukaemia or myeloproliferative disorders. Blast cells have a predilection for periosteal and perineural regions and rarely precede evidence of systemic disease. We present two patients, aleukaemic on peripheral blood counts, both at presentation and during subsequent treatment. We present the MRI features of this rare but important condition. (orig.)

Total body irradiation and marrow transplantation for acute leukaemia. The Royal Marsden Hospital experience

Energy Technology Data Exchange (ETDEWEB)

Barrett, A; Barrett, A J; Powles, R L [Institute of Cancer Research, Sutton (UK). Surrey Branch; Royal Marsden Hospital, London (UK))

1979-06-01

The experience with total body irradiation at the Royal Marsden Hospital is described for an elective program of transplantation in patients with acute myeloid leukaemia (AML) in first remission. Dose rate appears to be a critical factor in the reduction of radiation-associated damage and careful monitoring of the actual dose distribution and dose received is mandatory.

PDGFRα promoter polymorphisms and expression patterns influence risk of development of imatinib-induced thrombocytopenia in chronic myeloid leukemia: A study from India.

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Guru, Sameer Ahmad; Mir, Rashid; Bhat, Musadiq; Najar, Imtiyaz; Zuberi, Mariyam; Sumi, Mamta; Masroor, Mirza; Gupta, Naresh; Saxena, Alpana

2017-10-01

Platelet-derived growth factor receptor has been implicated in many malignant and non-malignant diseases. Platelet-derived growth factor receptor-α is a tyrosine kinase and a side target for imatinib, a revolutionary drug for the treatment of chronic myeloid leukemia that has dramatically improved the survival of chronic myeloid leukemia patients. Given the importance of platelet-derived growth factor receptor in platelet development and its inhibition by imatinib, it was intriguing to analyze the role of platelet-derived growth factor receptor-α in relation to imatinib treatment in the development of imatinib-induced thrombocytopenia in chronic myeloid leukemia patients. We hypothesized that two known functional polymorphisms, +68GA insertion/deletion and -909C/A, in the promoter region of the platelet-derived growth factor receptor-α gene may affect the susceptibility of chronic myeloid leukemia patients receiving imatinib treatment to the development of thrombocytopenia. A case-control study was conducted among a cohort of chronic myeloid leukemia patients admitted to the Lok Nayak Hospital, New Delhi, India. A set of 100 patients of chronic myeloid leukemia in chronic phase and 100 age- and sex-matched healthy controls were studied. After initiation of imatinib treatment, the hematological response of chronic myeloid leukemia patients was monitored regularly for 2 years, in which the development of thrombocytopenia was the primary end point. Platelet-derived growth factor receptor-α promoter polymorphisms +68GA ins/del and -909C/A were studied by allele-specific polymerase chain reaction. Platelet-derived growth factor receptor-α messenger RNA expression was evaluated by quantitative real-time polymerase chain reaction. The messenger RNA expression results were expressed as 2 -Δct ± standard deviation. The distribution of +68GA ins/del promoter polymorphism genotypes differed significantly between the thrombocytopenic and non-thrombocytopenic chronic

Serum concentrations of nitrite and malondialdehyde as markers of oxidative stress in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

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Maria Juracy Petrola

2012-01-01

Full Text Available BACKGROUND: Chronic myeloid leukemia is a neoplasm characterized by clonal expansion of hematopoietic progenitor cells resulting from the (9:22(q34,11 translocation. The tyrosine kinase abl fusion protein,the initial leukemogenic event in chronic myeloid leukemia, is constitutively activated thus inducing the production of reactive oxygen species. Of particular relevance is the fact that an increase in reactive oxygen species can facilitate genomic instability and may contribute to disease progression. OBJETIVE: To evaluate oxidative stress by determining the levels of malondialdehyde and nitrite in chronic myeloid leukemia patients under treatment with 1st and 2nd generation tyrosine kinase inhibitors monitored at a referral hospital in Fortaleza, Ceará. METHODS: A cross-sectional study was performed of 64 male and female adults. Patients were stratified according to treatment. The levels of malondialdehyde and nitrite were determined by spectrophotometry. Statistical differences between groups were observed using the Student t-test and Fisher's exact test. The results are expressed as mean ± standard error of mean. The significance level was set for a p-value < 0.05 in all analyses. RESULTS: The results show significantly higher mean concentrations of nitrite and malondialdehyde in chronic myeloid leukemia patients using second-generation tyrosine kinase inhibitors compared to patients on imatinib. Conclusion: It follows that chronic myeloid leukemia patients present higher oxidative activity and that the increases in oxidative damage markers can indicate resistance to 1st generation tyrosine kinase inhibitors.

Tyrosine Kinase Inhibitor Treatment for Newly Diagnosed Chronic Myeloid Leukemia.

Science.gov (United States)

Radich, Jerald P; Mauro, Michael J

2017-08-01

Chronic myeloid leukemia (CML) is a myeloproliferative disorder that accounts for approximately 10% of new cases of leukemia. The introduction of tyrosine kinase inhibitors has led to a reduction in mortalities. Thus, the estimated prevalence of CML is increasing. The National Comprehensive Cancer Network and the European Leukemia Net guidelines incorporate frequent molecular monitoring of the fusion BCR-ABL transcript to ensure that patients reach and keep treatment milestones. Most patients with CML are diagnosed in the chronic phase, and approximately 10% to 30% of these patients will at some time in their course meet definition criteria of resistance to imatinib. Copyright © 2017 Elsevier Inc. All rights reserved.

Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies.

Science.gov (United States)

Teh, Benjamin W; Tam, Constantine S; Handunnetti, Sasanka; Worth, Leon J; Slavin, Monica A

2018-04-23

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia with infections a leading cause of morbidity and mortality. Recently there has been a paradigm shift from the use of chemo-immunotherapies to agents targeting specific B-lymphocyte pathways. These agents include ibrutinib, idelalisib and venetoclax. In this review, the risks and timing of infections associated with these agents are described, taking into account disease and treatment status. Treatment with ibrutinib as monotherapy or in combination with chemo-immunotherapies is not associated with additional risk for infection. In contrast, the use of idelalisib is associated with a 2-fold risk for severe infection and opportunistic infections. Venetoclax does not appear to be associated with additional infection risk. The evolving spectrum of pathogens responsible infections in CLL patients, especially those with relapsed and refractory disease are described, and prevention strategies (prophylaxis, monitoring and vaccination) are proposed. Copyright © 2018 Elsevier Ltd. All rights reserved.

Tyrosine kinase inhibition: A therapeutic target for the management of chronic-phase chronic myeloid leukemia

Science.gov (United States)

Jabbour, Elias J; Cortes, Jorge E; Kantarjian, Hagop M

2014-01-01

Chronic myeloid leukemia (CML) is a hematologic neoplasm with a progressive, ultimately terminal, disease course. In most cases, CML arises owing to the aberrant formation of a chimeric gene for a constitutively active tyrosine kinase. Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target transforming the prognosis of patients with CML. New tyrosine kinase inhibitors (TKIs) continue to improve the management of CML, offering alternative options for those resistant to or intolerant of standard TKIs. Here we review the pathobiology of CML and explore emerging strategies to optimize the management of chronic-phase CML, particularly first-line treatment. PMID:24236822

Case of CML lymphoid blast crisis presenting as bilateral breast masses.

Science.gov (United States)

Hossain, Aneesha; Gupta, Kanika; Mener, Andrew; Tabbara, Imad

2016-08-10

A woman aged 42 years with a 1-month history of rapidly expanding bilateral breast masses presented with severe leucocytosis, anaemia, blurry vision, headaches and shortness of breath. Evaluation revealed chronic myeloid leukaemia in lymphoid blast crisis with extramedullary leukaemia involving her breasts. 2016 BMJ Publishing Group Ltd.

Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia

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Philipp Koehler

2012-01-01

Full Text Available B-cell chronic lymphocytic leukaemia (B-CLL remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19+ leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19+ B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells.

Dasatinib in the treatment of imatinib refractory chronic myeloid leukemia

Directory of Open Access Journals (Sweden)

Radhakrishnan Ramchandren

2009-05-01

Full Text Available Radhakrishnan Ramchandren, Charles A SchifferDivision of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USAAbstract: The development of imatinib for the treatment of chronic myeloid leukemia (CML has proven to be an example of medical success in the era of targeted therapy. However, imatinib resistance or intolerance occurs in a substantial number of patients. Additionally, patients who have progressed beyond the chronic phase of CML do relatively poorly with imatinib therapy. Mechanisms of imatinib resistance include BCR-ABL point mutations resulting in decreased imatinib binding, as well as mutation-independent causes of resistance such as SRC family kinase dysregulation, BCR-ABL gene amplification, drug influx/efflux mechanisms and other poorly understood processes. The options for therapy in these patients include stem cell transplantation, imatinib dose escalation as well as the use of second-generation tyrosine kinase inhibitors. Dasatinib is a second-generation multi-kinase inhibitor with several theoretical and mechanistic advantages over imatinib. Moreover, several studies have evaluated dasatinib in patients who have progressed on imatinib therapy with encouraging results. Other novel agents such as mTOR inhibitors, bosutinib and INNO 406 have also shown promise in this setting. Although treatment options have increased, the choice of second-line therapy in patients with CML is influenced by concerns surrounding the duration of response as well as toxicity. Consequently, there is no agreed upon optimal second-line agent. This paper reviews the current data and attempts to address these issues. Keywords: chronic myeloid leukemia (CML, dasatinib, imatinib, resistance (imatinib resistance, nilotinib, tyrosine kinase inhibitor

Chronic myeloid leukemia and interferon-alpha : a study of complete cytogenetic responders

NARCIS (Netherlands)

Bonifazi, F; de Vivo, A; Rosti, G; Guilhot, F; Guilhot, J; Trabacchi, E; Hehlmann, R; Hochhaus, A; Shepherd, PCA; Steegmann, JL; Kluin-Nelemans, HC; Thaler, J; Simonsson, B; Louwagie, A; Reiffers, J; Mahon, FX; Montefusco, E; Alimena, G; Hasford, J; Richards, S; Saglio, G; Testoni, N; Martinelli, G; Tura, S; Baccarani, M

2001-01-01

Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CIVIL) with interferon-alpha (IFN-alpha), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the

Additional cytogenetic abnormalities and variant t(9;22) at the diagnosis of childhood chronic myeloid leukemia

DEFF Research Database (Denmark)

Millot, Frédéric; Dupraz, Christelle; Guilhot, Joelle

2017-01-01

for Chronic Myeloid Leukemia in Children and Adolescents. RESULTS: Overall, 19 children (6.3%) presented with additional cytogenetic findings at diagnosis: 5 children (1.7%) had a variant t(9;22) translocation, 13 children (4.3%) had ACAs, and 1 had both. At 3 years, for children with a classic translocation......BACKGROUND: In the adult population with newly diagnosed chronic myeloid leukemia (CML), variant translocations are usually not considered to be impairing the prognosis, whereas some additional cytogenetic abnormalities (ACAs) are associated with a negative impact on survival. Because of the rarity...... of CML in the pediatric population, such abnormalities have not been investigated in a large group of children with CML. METHODS: The prognostic relevance of variant t(9;22) and ACAs at diagnosis was assessed in 301 children with CML in the chronic phase who were enrolled in the International Registry...

Single nucleotide polymorphism in IL1B is associated with infection risk in paediatric acute myeloid leukaemia.

Science.gov (United States)

Sung, L; Dix, D; Cellot, S; Gillmeister, B; Ethier, M C; Roslin, N M; Johnston, D L; Feusner, J; Mitchell, D; Lewis, V; Aplenc, R; Yanofsky, R; Portwine, C; Price, V; Zelcer, S; Silva, M; Bowes, L; Michon, B; Stobart, K; Traubici, J; Allen, U; Beyene, J; den Hollander, N; Paterson, A D

2016-06-01

We evaluated single nucleotide polymorphisms (SNPs) associated with infection risk in children with newly diagnosed acute myeloid leukaemia (AML). We conducted a multicentre, prospective cohort study that included children aged ≤18 years with de novo AML. DNA was isolated from blood lymphocytes or buccal swabs, and candidate gene SNP analysis was conducted. Primary outcome was the occurrence of microbiologically documented sterile site infection during chemotherapy. Secondary outcomes were Gram-positive and -negative infections, viridans group streptococcal infection and proven/probable invasive fungal infection. Interpretation was guided by consistency in risk alleles and microbiologic agent with previous literature. Over the study period 254 children and adolescents with AML were enrolled. Overall, 190 (74.8%) had at least one sterile site microbiologically documented infection. Among the 172 with inferred European ancestry and DNA available, nine significant associations were observed; two were consistent with previous literature. Allele A at IL1B (rs16944) was associated with decreased microbiologically documented infection, and allele G at IL10 (rs1800896) was associated with increased risk of Gram-positive infection. We identified SNPs associated with infection risk in paediatric AML. Genotype may provide insight into mechanisms of infection risk that could be used for supportive-care novel treatments. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

'Real-life' study of imatinib therapy in chronic phase-chronic myeloid leukemia: A novel retrospective observational longitudinal analysis.

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Merante, Serena; Ferretti, Virginia; Elena, Chiara; Calvello, Celeste; Rocca, Barbara; Zappatore, Rita; Cavigliano, Paola; Orlandi, Ester

2017-01-01

Imatinib is a cornerstone of treatment of chronic myeloid leukemia. It remains unclear whether transient treatment discontinuation or dose changes affect outcome and this approach has not yet been approved for use outside clinical trials. We conducted a retrospective single-institution observational study to evaluate factors affecting response in 'real-life' clinical practice in 138 chronic myeloid leukemia patients in chronic phase treated with imatinib. We used a novel longitudinal data analytical model, with a generalized estimating equation model, to study BCR-ABL variation according to continuous standard dose, change in dose or discontinuation; BCR-ABL transcript levels were recorded. Treatment history was subdivided into time periods for which treatment was given at constant dosage (total 483 time periods). Molecular and cytogenetic complete response was observed after 154 (32%) and 358 (74%) time periods, respectively. After adjusting for length of time period, no association between dose and cytogenetic complete response rate was observed. There was a significantly lower molecular complete response rate after time periods at a high imatinib dosage. This statistical approach can identify individual patient variation in longitudinal data collected over time and suggests that changes in dose or discontinuation of therapy could be considered in patients with appropriate biological characteristics.

Imatinib-induced fulminant liver failure in chronic myeloid leukemia: role of liver transplant and second-generation tyrosine kinase inhibitors: a case report.

Science.gov (United States)

Nacif, Lucas Souto; Waisberg, Daniel R; Pinheiro, Rafael Soares; Lima, Fabiana Roberto; Rocha-Santos, Vinicius; Andraus, Wellington; D'Albuquerque, Luiz Carneiro

2018-03-10

There is a worldwide problem of acute liver failure and mortality associated with remaining on the waiting for a liver transplant. In this study, we highlight results published in recent years by leading transplant centers in evaluating imatinib-induced acute liver failure in chronic myeloid leukemia and follow-up in liver transplantation. A 36-year-old brown-skinned woman (mixed Brazilian race) diagnosed 1 year earlier with chronic myeloid leukemia was started after delivery of a baby and continued for 6 months with imatinib mesylate (selective inhibitor of Bcr-Abl tyrosine kinase), which induced liver failure. We conducted a literature review using the PubMed database for articles published through September 2017, and we demonstrate a role of liver transplant in this situation for imatinib-induced liver failure. We report previously published results and a successful liver transplant after acute liver failure due to imatinib-induced in chronic myeloid leukemia treatment. We report a case of a successful liver transplant after acute liver failure resulting from imatinib-induced chronic myeloid leukemia treatment. The literature reveals the importance of prompt acute liver failure diagnosis and treatment with liver transplant in selected cases.

Diagnosis of chronic myeloid leukemia

International Nuclear Information System (INIS)

Demitrovicova, L.; Mikuskova, E.; Copakova, L.; Leitnerova, M.

2012-01-01

Chronic myeloid leukemia (CML) was the first cancer associated with the specific chromosomal aberration. Philadelphia chromosome due to translocation (9, 22) is present in 95% cases, fusion gene BCR/ABL is present in 100% cases at the time of diagnosis. Disease has its own characteristics detectable by physical examination, by the examination of blood count and differential and by cytomorhologic examination of bone marrow, however the diagnosis of CML is determined by cytogenetics and molecular genetics. If the diagnosis of Ph+ BCR/ABL positive CML is confirmed, the disease is treated by tyrosine kinase inhibitors (TKI). TKI don´t affect formation of leukemic gene BCR/ABL, but they can stop the action of this gene. The target therapy of tyrosine kinase inhibitors markedly improved the survival of patients with CML by inhibition the proliferation of leukemic clone on the clinically safety level of minimal disease, although probably this treatment cannot cure the CML. Cytogenetics and molecular genetics are very important at the monitoring of residual disease with sensitivity 10"-"6. (author)

Quercus Suber L. Cork Extracts Induce Apoptosis in Human Myeloid Leukaemia HL-60 Cells.

Science.gov (United States)

Bejarano, Ignacio; Godoy-Cancho, Belén; Franco, Lourdes; Martínez-Cañas, Manuel A; Tormo, María A

2015-08-01

Quercus suber L. cork contains a diversity of phenolic compounds, mostly low molecular weight phenols. A rising number of reports support with convergent findings that polyphenols evoke pro-apoptotic events in cancerous cells. However, the literature related to the anti-cancer bioactivity of Q. suber L. cork extractives (QSE) is still limited. Herein, we aim to describe the antitumor potential displayed by cork extractives obtained by different extraction methods in the human promyelocytic leukaemia cells. In order to quantify the effects of QSE on cancer cells viability, phosphatidylserine exposure, caspase-3 activity, mitochondrial membrane potential and cell cycle were evaluated. The results indicated that the QSE present a time-dependent and dose-dependent cytotoxicity in the human promyelocytic leukaemia cells. Such a noxious effect leads these leukaemia cells to their death through apoptotic processes by altering the mitochondrial outer membrane potential, activating caspase-3 and externalizing phosphatidylserine. However, cells cycle progression was not affected by the treatments. This study contributes to open a new way to use this natural resource by exploiting its anti-cancer properties. Moreover, it opens new possibilities of application of cork by-products, being more efficient in the sector of cork-based agriculture. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

The relation of illness perceptions to stress, depression, and fatigue in patients with chronic lymphocytic leukaemia.

Science.gov (United States)

Westbrook, Travis D; Maddocks, Kami; Andersen, Barbara L

2016-07-01

Chronic lymphocytic leukaemia (CLL) is the most prevalent adult leukaemia and is incurable. The course and treatment of CLL is unique and characterised by repeated cycles of treatment, stable disease and relapse. Utilising a Self-Regulatory Model framework, we examined the relationship between patients' illness perceptions and cancer-specific stress, depressive symptoms and fatigue. Our aim was to test illness perceptions as predictors of these outcomes when variance due to disease and treatment variables was controlled. Data were collected on 147 patients with relapsed/refractory CLL as they entered a phase II clinical trial of an investigational medication at a university affiliated, National Cancer Institute designated comprehensive cancer center. Cancer-specific stress, depressive symptoms and fatigue interference. . Hierarchical multiple regression was used. Consequences and emotional representation were related to all outcomes (ps stress (p fatigue interference (p stress, depressive symptoms and fatigue interference in relapsed/refractory CLL. Interventions targeted at restructuring maladaptive illness perceptions may have clinical benefit in this population.

Conditional survival in patients with chronic myeloid leukemia in chronic phase in the era of tyrosine kinase inhibitors.

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Sasaki, Koji; Kantarjian, Hagop M; Jain, Preetesh; Jabbour, Elias J; Ravandi, Farhad; Konopleva, Marina; Borthakur, Gautam; Takahashi, Koichi; Pemmaraju, Naveen; Daver, Naval; Pierce, Sherry A; O'Brien, Susan M; Cortes, Jorge E

2016-01-15

Tyrosine kinase inhibitors (TKIs) significantly improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). Conditional probability provides survival information in patients who have already survived for a specific period of time after treatment. Cumulative response and survival data from 6 consecutive frontline TKI clinical trials were analyzed. Conditional probability was calculated for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS) according to depth of response within 1 year of the initiation of TKIs, including complete cytogenetic response, major molecular response, and molecular response with a 4-log or 4.5-log reduction. A total of 483 patients with a median follow-up of 99.4 months from the initiation of treatment with TKIs were analyzed. Conditional probabilities of FFS, TFS, EFS, and OS for 1 additional year for patients alive after 12 months of therapy ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively. Conditional FFS for 1 additional year did not improve with a deeper response each year. Conditional probabilities of TFS, EFS, and OS for 1 additional year were maintained at >95% during the period. In the era of TKIs, patients with chronic myeloid leukemia in chronic phase who survived for a certain number of years maintained excellent clinical outcomes in each age group. Cancer 2016;122:238-248. © 2015 American Cancer Society. © 2015 American Cancer Society.

Disease burden of chronic lymphocytic leukaemia within the European Union.

Science.gov (United States)

Watson, Louise; Wyld, Peter; Catovsky, Daniel

2008-10-01

Whilst Chronic lymphocytic leukaemia (CLL) is considered a rare disease, to our knowledge, the current prevalence of CLL within the European Union (EU) member states is not published. Understanding the number of individuals with CLL is vital to assess disease burden within the wider population. Using 2002 data from the International Agency for Research on Cancer, we estimated the number of individuals with CLL (ICD-10 C91.1) from those reported for all leukaemias (C91-95) and extrapolated the figures by the population increase within the EU between 2002 and 2006, the last year with fully updated community population estimates. One- and 5-yr partial prevalence estimates are reported (i.e. the number of individuals still living 1-5 yr post-diagnosis). We then applied proportional estimates from the literature to assess those requiring immediate treatment, those under observation and their likely progression rates. We found that within the 27 EU states plus Iceland, Norway and Lichtenstein, 1- and 5-yr CLL partial prevalence estimates totalled approximately 13,952 and 46,633 individuals respectively in 2006. By applying Binet staging to the 1-yr estimate, 40% of patients will be stage B/C and require immediate treatment. Thus, 5581 individuals may be treated within the first year of diagnosis. Of the 60% (8371) under observation, by 5 yr up to 33% (2763) may have more advanced disease with increased risk of mortality. Whilst CLL is a rare disease, the number of individuals burdened by the disease within the EU is considerable and thousands of patients require treatment and physician care, which has cost implications for member states.

Current trends in molecular diagnostics of chronic myeloid leukemia.

Science.gov (United States)

Vinhas, Raquel; Cordeiro, Milton; Pedrosa, Pedro; Fernandes, Alexandra R; Baptista, Pedro V

2017-08-01

Nearly 1.5 million people worldwide suffer from chronic myeloid leukemia (CML), characterized by the genetic translocation t(9;22)(q34;q11.2), involving the fusion of the Abelson oncogene (ABL1) with the breakpoint cluster region (BCR) gene. Early onset diagnosis coupled to current therapeutics allow for a treatment success rate of 90, which has focused research on the development of novel diagnostics approaches. In this review, we present a critical perspective on current strategies for CML diagnostics, comparing to gold standard methodologies and with an eye on the future trends on nanotheranostics.

Platelet Dysfunction in Patients with Chronic Myeloid Leukemia: Does Imatinib Mesylate Improve It?

Directory of Open Access Journals (Sweden)

Olga Meltem Akay

2016-05-01

Full Text Available Objective: The aim of this study was to investigate the effects of imatinib mesylate on platelet aggregation and adenosine triphosphate (ATP release in chronic myeloid leukemia patients. Materials and Methods: Platelet aggregation and ATP release induced by 5.0 mM adenosine diphosphate, 0.5 mM arachidonic acid, 1.0 mg/ mL ristocetin, and 2 µg/mL collagen were studied by whole blood platelet lumi-aggregometer in 20 newly diagnosed chronic myeloid leukemia patients before and after imatinib mesylate treatment. Results: At the time of diagnosis, 17/20 patients had abnormal platelet aggregation results; 8 (40% had hypoactivity, 6 (30% had hyperactivity, and 3 (15% had mixed hypo- and hyperactivity. Repeat platelet aggregation studies were performed after a mean of 19 months (min: 5 months-max: 35 months in all patients who received imatinib mesylate during this period. After therapy, 18/20 (90% patients had abnormal laboratory results; 12 (60% had hypoactive platelets, 4 (20% had mixed hypo- and hyperactive platelets, and 2 (10% had hyperactive platelets. Three of the 8 patients with initial hypoactivity remained hypoactive, while 2 developed a mixed picture, 2 became hyperactive, and 1 normalized. Of the 6 patients with initial hyperactivity, 4 became hypoactive and 2 developed a mixed pattern. All of the 3 patients with initial hypo- and hyperactivity became hypoactive. Finally, 2 of the 3 patients with initial normal platelets became hypoactive while 1 remained normal. There was a significant decrease in ristocetin-induced platelet aggregation after therapy (p0.05. Conclusion: These findings indicate that a significant proportion of chronic myeloid leukemia patients have different patterns of platelet function abnormalities and imatinib mesylate has no effect on these abnormalities, with a significant impairment in ristocetin-induced platelet aggregation.

Thiotepa-based versus total body irradiation-based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission: a retrospective analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

Science.gov (United States)

Eder, Sandra; Labopin, Myriam; Arcese, William; Or, Reuven; Majolino, Ignazio; Bacigalupo, Andrea; de Rosa, Gennaro; Volin, Liisa; Beelen, Dietrich; Veelken, Hendrik; Schaap, Nicolaas P M; Kuball, Jurgen; Cornelissen, Jan; Nagler, Arnon; Mohty, Mohamad

2016-01-01

Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long-established ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a thiotepa-based (n = 121) or a cyclophosphamide/total body irradiation-based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after thiotepa-containing regimen versus 35% after TBI (P = 0.06). The 2-yr cumulative incidence of chronic graft-versus-host disease was 40.5% for thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia-free and overall survival at 2 yrs were not significantly different between the thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Treatments for chronic myeloid leukemia: a qualitative systematic review

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Ferdin

2012-08-01

Full Text Available Roxanne Ferdinand,1 Stephen A Mitchell,2 Sarah Batson,2 Indra Tumur11Pfizer, Tadworth, UK; 2Abacus International, Bicester, UKBackground: Chronic myeloid leukemia (CML is a myeloproliferative disorder of blood stem cells. The tyrosine kinase inhibitor (TKI imatinib was the first targeted therapy licensed for patients with chronic-phase CML, and its introduction was associated with substantial improvements in response and survival compared with previous therapies. Clinical trial data are now available for the second-generation TKIs (nilotinib, dasatinib, and bosutinib in the first-, second-, and third-line settings. A qualitative systematic review was conducted to qualitatively compare the clinical effectiveness, safety, and effect on quality of life of TKIs for the management of chronic-, accelerated-, or blast-phase CML patients.Methods: Included studies were identified through a search of electronic databases in September 2011, relevant conference proceedings and the grey literature.Results: In the first-line setting, the long-term efficacy (up to 8 years of imatinib has been confirmed in a single randomized controlled trial (International Randomized Study of Interferon [IRIS]. All second-generation TKIs reported lower rates of transformation, and comparable or superior complete cytogenetic response (CCyR, major molecular response (MMR, and complete molecular response rates compared with imatinib by 2-year follow-up. Each of the second-generation TKIs was associated with a distinct adverse-event profile. Bosutinib was the only second-generation TKI to report quality-of-life data (no significant difference compared with imatinib treatment. Data in the second- and third-line setting confirmed the efficacy of the second-generation TKIs in either imatinib-resistant or -intolerant patients, as measured by CCyR and MMR rates.Conclusion: Data from first-line randomized controlled trials reporting up to 2-year follow-up indicate superior response

Deep molecular responses for treatment-free remission in chronic myeloid leukemia.

Science.gov (United States)

Dulucq, Stéphanie; Mahon, Francois-Xavier

2016-09-01

Several clinical trials have demonstrated that some patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieve sustained deep molecular responses on tyrosine kinase inhibitor (TKI) therapy can safely suspend therapy and attempt treatment-free remission (TFR). Many TFR studies to date have enrolled imatinib-treated patients; however, the feasibility of TFR following nilotinib or dasatinib has also been demonstrated. In this review, we discuss available data from TFR trials and what these data reveal about the molecular biology of TFR. With an increasing number of ongoing TFR clinical trials, TFR may become an achievable goal for patients with CML-CP. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

LONG-TERM RESULTS OF TARGET THERAPY WITH FIRST AND * SECOND-LINE TYROSINE KINASE INHIBITORS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA

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L. L. Vysotskaya

2015-01-01

Full Text Available Aim: To assess long-term efficacy of firstand second-line tyrosine kinase inhibitors in non-selected patients with chronic myeloid leukemia in a real-life clinical setting.Materials and methods: The assessment is based on long-term results of a prospective single center comparative clinical trial that was based on non-selected groups of 116 patients with various stages of chronic myeloid leukemia being treated with a first generation tyrosine kinase inhibitor imatinib, and of 44 patients being treated with a second generation tyrosine kinase inhibitor nilotinib. We analyzed all-cause mortality, progression-free survival from April 2005 to April 2013, with a median of the follow-up of 128 months.Results: In 116 patients with chronic myeloid leukemia treated with imatinib, the Kaplan-Meier survival estimate was 120 months. In 44 patients at an early chronic phase, 5-year overall survival and progression-free survival was 93.2% and 8-year overall and progression-free survival was 79.5%. In 44 patients at a late chronic stage, 5-year overall and progression-free survival was 95.5%, 8-year overall and progression-free survival, 72.7%. In 28 patients at acceleration phase, 5-years overall survival was 78.6% and 8-year overall survival, 46%. Median of overall survival in patients treated with nilotinib was not reached. During 78.6 months of combination treatment with cytotoxic agents, tyrosine kinase inhibitors of the first (imatinib and second line (nilotinib, overall survival was 100%.Conclusion: In clinical practice, inclusion of patients with chronic myeloid leukemia and imatinib resistance (disease relapse or imatinib intolerance into the treatment program with frontline therapy with general cytotoxic agents and thereafter with firstand second-line tyrosine kinase inhibitors significantly improves overall survival.

Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia?

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Avital F. Barak

2011-12-01

Full Text Available The outcome and quality of life of chronic myeloid leukemia (CML patients has remarkably changed with the treatment of tyrosine kinase inhibitors (TKIs. Currently, hematopoietic stem cell transplantation (HSCT is considered mainly as a third line salvage therapy in cases of TKIs resistance or intolerance. Here we describe a patient with chronic phase CML who developed both resistance and late occurrence of s severe thrombocytopenia on first and second generation TKIs and eventually underwent HSCT. Although the mechanism of the myelosuppression is not fully understood, we showed for the first time the development of dose dependent platelet antibodies in the presence of TKIs, suggesting the possibility of TKIs induced thrombocytopenia. Our case emphasizes that late development of severe myelosuppression during imatinib treatment is probably an important indication for consideration of early HSCT.

Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

NARCIS (Netherlands)

Deenik, Wendy; Janssen, Jeroen J. W. M.; van der Holt, Bronno; Verhoef, Gregor E. G.; Smit, Willem M.; Kersten, Marie José; Daenen, Simon M. G. J.; Verdonck, Leo F.; Ferrant, Augustin; Schattenberg, Anton V. M. B.; Sonneveld, Pieter; van Marwijk Kooy, Marinus; Wittebol, Shulamit; Willemze, Roelof; Wijermans, Pierre W.; Beverloo, H. Berna; Löwenberg, Bob; Valk, Peter J. M.; Ossenkoppele, Gert J.; Cornelissen, Jan J.

2010-01-01

In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Having reported feasibility previously, we hereby

Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

NARCIS (Netherlands)

Deenik, W.; Janssen, J.J.W.M.; van der Holt, B.; Verhoef, G.E.G.; Smit, W.M.; Kersten, M.J.; Daenen, S.M.G.J.; Verdouck, L.F.; Ferrant, A.; Schattenberg, A.V.M.B.; Sonneveld, P.; Kooy, M.V.M.; Wittebol, S.; Willemze, R.; Wijermans, P.W.; Beverloo, H.B.; Lowenberg, B.; Valk, P.J.M.; Ossenkoppele, G.J.; Cornelissen, J.J.

2010-01-01

Background In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Design and Methods Having reported

Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

NARCIS (Netherlands)

Deenik, Wendy; Janssen, Jeroen J. W. M.; van der Holt, Bronno; Verhoef, Gregor E. G.; Smit, Willem M.; Kersten, Marie Jose; Daenen, Simon M. G. J.; Verdouck, Leo F.; Ferrant, Augustin; Schattenberg, Anton V. M. B.; Sonneveld, Pieter; Kooy, Marinus van Marwijk; Wittebol, Shulamit; Willemze, Roelof; Wijermans, Pierre W.; Beverloo, H. Berna; Lowenberg, Bob; Valk, Peter J. M.; Ossenkoppele, Gert J.; Cornelissen, Jan J.

Background In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Design and Methods Having reported

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Cytoreductive agents, which were hitherto the mainstay of treatment, neither induce cytogenetic nor haematologic remission. Alpha- interferon ... Key words : Chronic myeloid leukaemia, interferon-á, depression .... with very young children.

Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance : Minimum 24-month follow-up

NARCIS (Netherlands)

Gambacorti-Passerini, Carlo; Brümmendorf, Tim H; Kim, Dong-Wook; Turkina, Anna G; Masszi, Tamas; Assouline, Sarit; Durrant, Simon; Kantarjian, Hagop M; Khoury, H Jean; Zaritskey, Andrey; Shen, Zhi-Xiang; Jin, Jie; Vellenga, Edo; Pasquini, Ricardo; Mathews, Vikram; Cervantes, Francisco; Besson, Nadine; Turnbull, Kathleen; Leip, Eric; Kelly, Virginia; Cortes, Jorge E

Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib

Antibody responses to vaccination and immune function in patients with haematological malignancies - studies in patients with chronic lymphocytic leukaemia autologous stem cell recipients

NARCIS (Netherlands)

Velden, A.M.T. van der

2007-01-01

This thesis concerns the antibody responses to vaccination and immune function of patients with several forms of haematological diseases. Antibody responses in patients with chronic lymphocytic leukaemia (CLL) and in autologous stem cell transplant recipients were studied. In the autologous stem

Dendritic cells in chronic myelomonocytic leukaemia.

Science.gov (United States)

Vuckovic, S; Fearnley, D B; Gunningham, S; Spearing, R L; Patton, W N; Hart, D N

1999-06-01

Blood dendritic cells (DC) differentiate in vitro via two separate pathways: either directly from blood DC precursors (DCp) or from CD14+ monocytes. In chronic myelomonocytic leukaemia (CMML) abnormal bone marrow precursors contribute to blood monocyte development but DC development has not been studied previously. Monocytes comprised 60% of blood MNC in 15 CMML patients studied, compared with 20% in 16 age-matched controls. The increase in blood monocytes was accompanied by a reciprocal decrease in mean blood DC percentage (from 0.42% of MNC in normal individuals to 0.16% of MNC in CMML patients). Absolute blood DC numbers showed a minimal (non-significant) reduction from 9.8 x 10(6)/l in normal individuals to 7.5 x 10(6)/l in CMML patients. The CD14(low) WCD16+ monocyte subpopulation was not found in CMML patients. After culture in GM-CSF/IL-4, CMML CD14+ monocytes acquired the phenotype of immature monocyte derived DC (Mo-DC) with similar yields to normal blood Mo-DC generation. Addition of TNF-alpha or LPS induced both normal and CMML Mo-DC to express prominent dendritic processes, the CMRF44+ and CD83+ antigens and high levels of HLA-DR, CD80 and CD86. Treatment either with TNF-alpha or LPS increased the allostimulatory activity of normal Mo-DC, but had little effect on the allostimulatory activity of CMML Mo-DC, perhaps reflecting the underlying neoplastic changes in monocyte precursors. We conclude that the blood DC numbers are relatively unaffected in CMML, suggesting discrete regulation of monocyte and DC production.

P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients

International Nuclear Information System (INIS)

Tang, Ruoping; Legrand, Ollivier; Marie, Jean-Pierre; Cohen, Simy; Perrot, Jean-Yves; Faussat, Anne-Marie; Zuany-Amorim, Claudia; Marjanovic, Zora; Morjani, Hamid; Fava, Fanny; Corre, Elise

2009-01-01

AVE9633 is a new immunoconjugate comprising a humanized monoclonal antibody, anti-CD33 antigen, linked through a disulfide bond to the maytansine derivative DM4, a cytotoxic agent and potent tubulin inhibitor. It is undergoing a phase I clinical trial. Chemoresistance to anti-mitotic agents has been shown to be related, in part, to overexpression of ABC proteins. The aim of the present study was to investigate the potential roles of P-gp, MRP1 and BCRP in cytotoxicity in AVE9633-induced acute myeloid leukaemia (AML). This study used AML cell lines expressing different levels of P-gp, MRP1 or BCRP proteins and twenty-five samples from AML patients. Expression and functionality of the transporter protein were analyzed by flow cytometry. The cytotoxicity of the drug was evaluated by MTT and apoptosis assays. P-gp activity, but not MRP1 and BCRP, attenuated AVE9633 and DM4 cytotoxicity in myeloid cell lines. Zosuquidar, a potent specific P-gp inhibitor, restored the sensitivity of cells expressing P-gp to both AVE9633 and DM4. However, the data from AML patients show that 10/25 samples of AML cells (40%) were resistant to AVE9633 or DM4 (IC 50 > 500 nM), and this was not related to P-gp activity (p-Value: 0.7). Zosuquidar also failed to re-establish drug sensitivity. Furthermore, this resistance was not correlated with CD33 expression (p-Value: 0.6) in those cells. P-gp activity is not a crucial mechanism of chemoresistance to AVE9633. For patients whose resistance to conventional anthracycline AML regimens is related to ABC protein expression, a combination with AVE9633 could be beneficial. Other mechanisms such as microtubule alteration could play an important role in chemoresistance to AVE9633

The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era

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Ilana Zalcberg Renault

2011-12-01

Full Text Available Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging.

The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era

Science.gov (United States)

Renault, Ilana Zalcberg; Scholl, Vanesa; Hassan, Rocio; Capelleti, Paola; de Lima, Marcos; Cortes, Jorge

2011-01-01

Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging. PMID:23049363

The risk of chronic myeloid leukemia: Can the dose-response curve be U-shaped?

Czech Academy of Sciences Publication Activity Database

Radivoyevitch, T.; Kozubek, Stanislav; Sachs, R. K.

2002-01-01

Roč. 157, č. 1 (2002), s. 106-109 ISSN 0033-7587 R&D Projects: GA ČR GA202/01/0197; GA ČR GA301/01/0186; GA AV ČR IBS5004010 Keywords : radiation risk * chronic myeloid leukemia * chromosome translocation Subject RIV: BO - Biophysics Impact factor: 2.768, year: 2002

Hematologic and Immunologic care to children from areas affected by the Chernobyl accident

International Nuclear Information System (INIS)

Svarch, E.

1993-01-01

Since march 1992, 280 patients, most of them from Ukraine (248), but also from Russia (22), Byelorussian (9), and Moldavia (1) have been attended by the staff of the Paediatric Service at our Institute. The most frequent pathologies were the leukemias (116 cases) and among them, the acute lymphoid leukaemia (103), acute myeloid leukaemia (6), and chronic myeloid leukaemia (7). Six patients had medular aplasia, 16 patients suffered from idiopathic thrombocytopenia purpura, and 3 other patients had hemophilia A. The rest of the patients suffered from other either haematological or immunological disorders. Current protocols and therapeutic standards were applied to these children, and the results obtained in our Institute were similar to those described in Cuban as well as in foreign patients

Therapy for chronic myeloid leukemia: Past, present and future

International Nuclear Information System (INIS)

Tothova, E.

2012-01-01

Although chronic myeloid leukemia (CML) was probably first described in the early nineteenth century, there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 1960. Subsequent important landmarks were the recognition that the Ph chromosome results from a t(9;22) translocation and subsequently of BCR-ABL fusion gene. Between 1980 and 2000, allo grafting, despite the risks of morbidity and mortality, was the recommended initial treatment for younger patients with HLA-matched donors. Therapy has now been „revolutionized“ by the introduction on imatinib mesylate (IM), the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998. This paper will attempt to define approaches to management of the newly diagnosed patient with CML in chronic phase that are favored in 2012, but it is most probable these recommendations will need to be updated as further experience in gained with the use of TKI. (author)

Diagnosis of chronic myeloid and acute lymphocytic leukemias by detection of leukemia-specific mRNA sequences amplified in vitro

International Nuclear Information System (INIS)

Kawasaki, E.S.; Clark, S.S.; Coyne, M.Y.; Smith, S.D.; Champlin, R.; Witte, O.N.; McCormick, F.P.

1988-01-01

The Philadelphia chromosome is present in more than 95% of chronic myeloid leukemia patients and 13% of acute lymphocytic leukemia patients. The Philadelphia translocation, t(9;22), fuses the BCR and ABL genes resulting in the expression of leukemia-specific, chimeric BCR-ABL messenger RNAs. To facilitate diagnosis of these leukemias, the authors have developed a method of amplifying and detecting only the unique mRNA sequences, using an extension of the polymerase chain reaction technique. Diagnosis of chronic myeloid and acute lymphocytic leukemias by this procedure is rapid, much more sensitive than existing protocols, and independent of the presence or absence of an identifiable Philadelphia chromosome

Low expression of miR-196b enhances the expression of BCR-ABL1 and HOXA9 oncogenes in chronic myeloid leukemogenesis.

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Yue Liu

Full Text Available MicroRNAs (miRNAs can function as tumor suppressors or oncogene promoters during tumor development. In this study, low levels of expression of miR-196b were detected in patients with chronic myeloid leukemia. Bisulfite genomic sequencing PCR and methylation-specific PCR were used to examine the methylation status of the CpG islands in the miR-196b promoter in K562 cells, patients with leukemia and healthy individuals. The CpG islands showed more methylation in patients with chronic myeloid leukemia compared with healthy individuals (P<0.05, which indicated that low expression of miR-196b may be associated with an increase in the methylation of CpG islands. The dual-luciferase reporter assay system demonstrated that BCR-ABL1 and HOXA9 are the target genes of miR-196b, which was consistent with predictions from bioinformatics software analyses. Further examination of cell function indicated that miR-196b acts to reduce BCR-ABL1 and HOXA9 protein levels, decrease cell proliferation rate and retard the cell cycle. A low level of expression of miR-196b can cause up-regulation of BCR-ABL1 and HOXA9 expression, which leads to the development of chronic myeloid leukemia. MiR-196b may represent an effective target for chronic myeloid leukemia therapy.

Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes.

Science.gov (United States)

Stagno, Fabio; Stella, Stefania; Spitaleri, Antonio; Pennisi, Maria Stella; Di Raimondo, Francesco; Vigneri, Paolo

2016-01-01

The tyrosine kinase inhibitor Imatinib Mesylate has dramatically improved the clinical outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease, generating unprecedented rates of complete hematologic and cytogenetic responses and sustained reductions in BCR-ABL transcripts. Here, we present an overview on the efficacy and safety of Imatinib and describe the most important clinical studies employing this drug for the frontline treatment of chronic phase CML. We also discuss recent reports describing the long-term outcome of patients receiving Imatinib for their disease. The imminent availability of generic forms of Imatinib coupled with the approval of expensive second-generation tyrosine kinase inhibitors underlines an unmet need for early molecular parameters that may distinguish CML patients likely to benefit from the drug from those that should receive alternative forms of treatment.

Modeling of Chronic Myeloid Leukemia : An Overview of In Vivo Murine and Human Xenograft Models

NARCIS (Netherlands)

Sontakke, Pallavi; Jaques, Jenny; Vellenga, Edo; Schuringa, Jan Jacob

2016-01-01

Over the past years, a wide variety of in vivo mouse models have been generated in order to unravel the molecular pathology of Chronic Myeloid Leukemia (CML) and to develop and improve therapeutic approaches. These models range from (conditional) transgenic models, knock-in models, and murine bone

Potential mechanisms of disease progression and management of advanced-phase chronic myeloid leukemia

Science.gov (United States)

Jabbour, Elias J.; Hughes, Timothy P.; Cortés, Jorge E.; Kantarjian, Hagop M.; Hochhaus, Andreas

2014-01-01

Despite vast improvements in treatment of Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated phase or blast crisis, remain notoriously difficult to treat. Treatments that are highly effective against CML-CP produce disappointing results against advanced disease. Therefore, a primary goal of therapy should be to maintain patients in CP for as long as possible, by (1) striving for deep, early molecular response to treatment; (2) using tyrosine kinase inhibitors that lower risk of disease progression; and (3) more closely observing patients who demonstrate cytogenetic risk factors at diagnosis or during treatment. PMID:24050507

Leukaemia incidence among workers in the shoe and boot manufacturing industry: a case-control study

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Forand Steven P

2004-08-01

Full Text Available Abstract Background Previous reports have indicated an excess of leukaemia in Broome County, New York, particularly in the Town of Union. Surveillance of cancer incidence data indicates that a large proportion of these cases occurred among males ages 65 and older. Shoe and boot manufacturing has been the largest single industry in this area throughout much of the past century. Occupational studies from Europe suggest a link between leukaemia and employment in the shoe and boot manufacturing industry. However, researchers have not found a positive association between leukaemia and employment in the shoe industry among workers in the United States. Methods A matched case-control study was conducted to investigate the association between leukaemia incidence among males 65 and older and employment in the shoe and boot manufacturing industry. Thirty-six cases of leukaemia occurring between 1981–1990; among males age 65 and older; residing in the town of Union met the study case criteria. Death certificates were obtained for each of the cases. These were matched to death certificates of 144 controls on date of death and date of birth +/- 1 year. Death certificates were then examined to determine the employer and occupation of each study subject. Conditional logistic regression was used to determine the risk of leukaemia among those working in the industry. Results The risk of both leukaemia (OR = 1.47; 95% CI 0.70, 3.09 and acute myeloid leukaemia (OR = 1.19; 95% CI 0.33, 4.28 were elevated among those employed in the shoe and boot manufacturing industry, however neither was statistically significant. Conclusion The results, though suggestive of an association between leukaemia and employment in the shoe and boot manufacturing industry, were not statistically conclusive due mainly to limited study power. Several additional limitations may also have prevented the observance of more conclusive findings. Better exposure assessment, information on

Ovarian granulocytic sarcoma: a case report and magnetic resonance imaging findings

International Nuclear Information System (INIS)

Pereira, Licia Pacheco; Monte, Hipolito

2008-01-01

Granulocytic sarcoma (chloroma) is a tumor consisting of myeloid precursors in an extramedullary site. It is complication of both acute and chronic myelogenous leukemias. Although the lesion can occur at any site, ovarian involvement is rare. We report a case of ovary tumor associated with acute myeloid leukaemia and its imaging appearance on magnetic resonance. (author)

Ovarian granulocytic sarcoma: a case report and magnetic resonance imaging findings; Sarcoma granulocitico no ovario: relato de caso e achados na ressonancia magnetica

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Pereira, Licia Pacheco [Hospital Geral de Fortaleza (HGF), CE (Brazil). Servico de Diagnostico por Imagem], e-mail: licia_p@hotmail.com; Silveira, Claudio Regis Sampaio [Hospital Geral de Fortaleza (HGF), CE (Brazil). Servico de Radiologia; Costa, Fabricio da Silva [Universidade Estadual do Ceara (UECE), CE (Brazil); Monte, Hipolito [Hospital Monte Klinikum, Fortaleza, CE (Brazil)

2008-12-15

Granulocytic sarcoma (chloroma) is a tumor consisting of myeloid precursors in an extramedullary site. It is complication of both acute and chronic myelogenous leukemias. Although the lesion can occur at any site, ovarian involvement is rare. We report a case of ovary tumor associated with acute myeloid leukaemia and its imaging appearance on magnetic resonance. (author)

RhoA: A therapeutic target for chronic myeloid leukemia

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Molli Poonam R

2012-03-01

Full Text Available Abstract Background Chronic Myeloid Leukemia (CML is a malignant pluripotent stem cells disorder of myeloid cells. In CML patients, polymorphonuclear leukocytes (PMNL the terminally differentiated cells of myeloid series exhibit defects in several actin dependent functions such as adhesion, motility, chemotaxis, agglutination, phagocytosis and microbicidal activities. A definite and global abnormality was observed in stimulation of actin polymerization in CML PMNL. Signalling molecules ras and rhoGTPases regulate spatial and temporal polymerization of actin and thus, a broad range of physiological processes. Therefore, status of these GTPases as well as actin was studied in resting and fMLP stimulated normal and CML PMNL. Methods To study expression of GTPases and actin, Western blotting and flow cytometry analysis were done, while spatial expression and colocalization of these proteins were studied by using laser confocal microscopy. To study effect of inhibitors on cell proliferation CCK-8 assay was done. Significance of differences in expression of proteins within the samples and between normal and CML was tested by using Wilcoxon signed rank test and Mann-Whitney test, respectively. Bivariate and partial correlation analyses were done to study relationship between all the parameters. Results In CML PMNL, actin expression and its architecture were altered and stimulation of actin polymerization was absent. Differences were also observed in expression, organization or stimulation of all the three GTPases in normal and CML PMNL. In normal PMNL, ras was the critical GTPase regulating expression of rhoGTPases and actin and actin polymerization. But in CML PMNL, rhoA took a central place. In accordance with these, treatment with rho/ROCK pathway inhibitors resulted in specific growth inhibition of CML cell lines. Conclusions RhoA has emerged as the key molecule responsible for functional defects in CML PMNL and therefore can be used as a

Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.

Science.gov (United States)

O'Brien, Susan; Furman, Richard R; Coutre, Steven E; Sharman, Jeff P; Burger, Jan A; Blum, Kristie A; Grant, Barbara; Richards, Donald A; Coleman, Morton; Wierda, William G; Jones, Jeffrey A; Zhao, Weiqiang; Heerema, Nyla A; Johnson, Amy J; Izumi, Raquel; Hamdy, Ahmed; Chang, Betty Y; Graef, Thorsten; Clow, Fong; Buggy, Joseph J; James, Danelle F; Byrd, John C

2014-01-01

Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65-84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1-2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one

Recruitment of childhood leukaemia patients to clinical trials in Great Britain during 1980-2007: variation by birth weight, congenital malformation, socioeconomic status and ethnicity.

Science.gov (United States)

Shah, Anjali; Diggens, Nicole; Stiller, Charles; Richards, Sue; Stevens, Michael C G; Murphy, Michael F G

2014-05-01

To assess recruitment of children to national clinical trials for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in Great Britain during 1980-2007 and describe variation by some factors that might influence trial entry. Records of leukaemia patients aged 0-14 years at diagnosis were identified in the National Registry of Childhood Tumours and linked to birth registrations, Children's Cancer and Leukaemia Group records, Hospital Episode Statistics and Medical Research Council clinical trial registers. Trial entry rates were compared between categories of birth weight, congenital malformation, socioeconomic status and ethnicity. 9147 ALL and 1466 AML patients were eligible for national clinical trials during 1980-2007. Overall recruitment rates were 81% and 60% respectively. For ALL, rates varied significantly with congenital malformation (Down syndrome 61%, other malformations 80%, none 82%; p4000 g 67%; p=0.001) and congenital malformation (Down syndrome 28%, other malformations 56%, none 63%; pcongenital malformations.

miRNA analysis in B-cell chronic lymphocytic leukaemia : proliferation centres characterized by low miR-150 and high BIC/milk-155 expression

NARCIS (Netherlands)

Wang, M.; Tan, L. P.; Dijkstra, M. K.; van Lom, K.; Robertus, J-L; Harms, G.; Blokzijl, T.; Kooistra, K.; van t'Veer, M. B.; Rosati, S.; Visser, L.; Jongen-Lavrencic, M.; Kluin, P. M.; van den Berg, Anke

Several miRNAs have been reported to be associated with immunoglobulin heavy chain (IgH) mutation and ZAP-70 expression status in blood samples of B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma (B-CLL/SLL). In the bone marrow and lymphoid tissues, proliferation centres (PCs)

Mesenchymal Stem Cells (MSC Regulate Activation of Granulocyte-Like Myeloid Derived Suppressor Cells (G-MDSC in Chronic Myeloid Leukemia Patients.

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Cesarina Giallongo

Full Text Available It is well known that mesenchymal stem cells (MSC have a role in promotion of tumor growth, survival and drug-resistance in chronic myeloid leukemia (CML. Recent reports indicated that a subpopulation of myeloid cells, defined as granulocyte-like myeloid-derived suppressor cells (G-MDSC is increased in these patients. So far, the role of MSC in MDSC expansion and activation into the BM microenvironment remains unexplored. To address this question, here we use a specific experimental model in vitro, co-culturing MSC with peripheral blood mononucleated cells (PBMC from normal individuals, in order to generate MSC-educated G-MDSC. Although MSC of healthy donors (HD and CML patients were able to generate the same amount of MDSC, only CML-MSC-educated G-MDSC exhibited suppressive ability on autologous T lymphocytes. In addition, compared with HD-MSC, CML-MSC over-expressed some immunomodulatory factors including TGFβ, IL6 and IL10, that could be involved in MDSC activation. CML-MSC-educated G-MDSC expressed higher levels of ARG1, TNFα, IL1β, COX2 and IL6 than G-MDSC isolated from co-culture with HD-MSC. Our data provide evidence that CML-MSC may play a critical role in tumor microenvironment by orchestrating G-MDSC activation and regulating T lymphocytes-mediated leukemia surveillance, thus contributing to CML immune escape.

Mesenchymal Stem Cells (MSC) Regulate Activation of Granulocyte-Like Myeloid Derived Suppressor Cells (G-MDSC) in Chronic Myeloid Leukemia Patients.

Science.gov (United States)

Giallongo, Cesarina; Romano, Alessandra; Parrinello, Nunziatina Laura; La Cava, Piera; Brundo, Maria Violetta; Bramanti, Vincenzo; Stagno, Fabio; Vigneri, Paolo; Chiarenza, Annalisa; Palumbo, Giuseppe Alberto; Tibullo, Daniele; Di Raimondo, Francesco

2016-01-01

It is well known that mesenchymal stem cells (MSC) have a role in promotion of tumor growth, survival and drug-resistance in chronic myeloid leukemia (CML). Recent reports indicated that a subpopulation of myeloid cells, defined as granulocyte-like myeloid-derived suppressor cells (G-MDSC) is increased in these patients. So far, the role of MSC in MDSC expansion and activation into the BM microenvironment remains unexplored. To address this question, here we use a specific experimental model in vitro, co-culturing MSC with peripheral blood mononucleated cells (PBMC) from normal individuals, in order to generate MSC-educated G-MDSC. Although MSC of healthy donors (HD) and CML patients were able to generate the same amount of MDSC, only CML-MSC-educated G-MDSC exhibited suppressive ability on autologous T lymphocytes. In addition, compared with HD-MSC, CML-MSC over-expressed some immunomodulatory factors including TGFβ, IL6 and IL10, that could be involved in MDSC activation. CML-MSC-educated G-MDSC expressed higher levels of ARG1, TNFα, IL1β, COX2 and IL6 than G-MDSC isolated from co-culture with HD-MSC. Our data provide evidence that CML-MSC may play a critical role in tumor microenvironment by orchestrating G-MDSC activation and regulating T lymphocytes-mediated leukemia surveillance, thus contributing to CML immune escape.

Additional chromosome abnormalities in chronic myeloid leukemia

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Hui-Hua Hsiao

2011-02-01

Full Text Available The Philadelphia (Ph chromosome and/or Breakpoint cluster region-Abelson leukemia virus oncogene transcript are unique markers for chronic myeloid leukemia (CML. However, CML demonstrates heterogeneous presentations and outcomes. We analyzed the cytogenetic and molecular results of CML patients to evaluate their correlation with clinical presentations and outcome. A total of 84 newly diagnosed CML patients were enrolled in the study. Patients were treated according to disease status. Bone marrow samples were obtained to perform cytogenetic and molecular studies. Clinical presentations, treatment courses, and survival were reviewed retrospectively. Among 84 patients, 72 had chronic phase and 12 had accelerated phase CML. Cytogenetic study showed 69 (82.1% with the classic Ph chromosome, 6 (7.2% with a variant Ph chromosome, and 9 (10.7% with additional chromosome abnormalities. Fifty-four (64.3% cases harbored b3a2 transcripts, 29 (34.5% had b2a2 transcript, and 1 had e19a2 transcript. There was no difference in clinical presentations between different cytogenetic and molecular groups; however, additional chromosome abnormalities were significantly associated with the accelerated phase. Imatinib therapy was an effective treatment, as measured by cytogenetic response, when administered as first- and second-line therapy in chronic phase patients. Survival analysis showed that old age, additional chromosome abnormalities, high Sokal score, and no cytogenetic response in second-line therapy had a significant poor impact (p<0.05. In conclusion, we presented the cytogenetic and molecular pattern of CML patients and demonstrated that the additional chromosome abnormality was associated with poor outcome.

Statistical Analysis of Competing Risks: Overall Survival in a Group of Chronic Myeloid Leukemia Patients

Czech Academy of Sciences Publication Activity Database

Fürstová, Jana; Valenta, Zdeněk

2011-01-01

Roč. 7, č. 1 (2011), s. 2-10 ISSN 1801-5603 Institutional research plan: CEZ:AV0Z10300504 Keywords : competing risks * chronic myeloid leukemia (CML) * overall survival * cause-specific hazard * cumulative incidence function Subject RIV: IN - Informatics, Computer Science http://www.ejbi.eu/images/2011-1/Furstova_en.pdf

Acute myeloid leukaemia: expression of MYC protein and its association with cytogenetic risk profile and overall survival.

Science.gov (United States)

Mughal, Muhammad Kashif; Akhter, Ariz; Street, Lesley; Pournazari, Payam; Shabani-Rad, Meer-Taher; Mansoor, Adnan

2017-09-01

Acute myeloid leukaemia (AML) is a clinically aggressive disease with marked genetic heterogeneity. Cytogenetic abnormalities provide the basis for risk stratification into clinically favourable, intermediate, and unfavourable groups. There are additional genetic mutations, which further influence the prognosis of patients with AML. Most of these result in molecular aberrations whose downstream target is MYC. It is therefore logical to study the relationship between MYC protein expression and cytogenetic risk groups. We studied MYC expression by immunohistochemistry in a large cohort (n = 199) of AML patients and correlated these results with cytogenetic risk profile and overall survival (OS). We illustrated differential expression of MYC protein across various cytogenetic risk groups (p = 0.03). Highest expression of MYC was noted in AML patients with favourable cytogenetic risk group. In univariate analysis, MYC expression showed significant negative influence of OS in favourable and intermediate cytogenetic risk group (p = 0.001). Interestingly, MYC expression had a protective effect in the unfavourable cytogenetic risk group. In multivariate analysis, while age and cytogenetic risk group were significant factors influencing survival, MYC expression by immunohistochemistry methods also showed some marginal impact (p = 0.069). In conclusion, we have identified differential expression of MYC protein in relation to cytogenetic risk groups in AML patients and documented its possible impact on OS in favourable and intermediate cytogenetic risk groups. These preliminary observations mandate additional studies to further investigate the routine clinical use of MYC protein expression in AML risk stratification. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Myeloid malignancies in the real-world: Occurrence, progression and survival in the UK's population-based Haematological Malignancy Research Network 2004-15.

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Roman, Eve; Smith, Alex; Appleton, Simon; Crouch, Simon; Kelly, Richard; Kinsey, Sally; Cargo, Catherine; Patmore, Russell

2016-06-01

Population-based information on cancer incidence, prevalence and outcome are required to inform clinical practice and research; but contemporary data are lacking for many myeloid malignancy subtypes. Set within a socio-demographically representative UK population of ∼4 million, myeloid malignancy data (N=5231 diagnoses) are from an established patient cohort. Information on incidence, survival (relative & overall), transformation/progression, and prevalence is presented for >20 subtypes. The median diagnostic age was 72.4years (InterQuartile Range 61.6-80.2), but there was considerable subtype heterogeneity, particularly among the acute myeloid leukaemias (AML) where medians ranged from 20.3 (IQR 13.9-43.8) for AML 11q23 through to 73.7 (IQR 57.3-79.1) for AML with no recurrent genetic changes. Five-year Relative Survival (RS) estimates varied hugely; from 85% for indolent/treatable conditions like chronic myeloid leukaemia (89.8%, 95% CI 84.0-93.6). With a couple of notable exceptions, males experienced higher rates and worse survival than females: the age-standardized incidence rates of several conditions was 2-4 higher in males than females, and the 5-year RS for all subtypes combined was 48.8% (95% CI 46.5-51.2) and 60.4% (95% CI 57.7-62.9) for males and females respectively. During follow-up (potential minimum 2 years and maximum 11years) myelodysplastic syndrome (MDS) progression to AML ranged from 25% for refractory anaemia with excess blasts through to 5% for refractory anaemia with ring sideroblasts: the median interval between MDS and AML diagnosis was 9.0 months (IQR 4.8-17.4months). The marked incidence and outcome variations seen by subtype, sex and age, confirm the requirement for "real-world" longitudinal data to inform aetiological hypotheses, healthcare planning, and future monitoring of therapeutic change. Several challenges for routine cancer registration were identified, including the need to link more effectively to diagnostic and clinical

Dasatinib-Induced Rhabdomyolysis in a 33-Year-Old Patient with Chronic Myeloid Leukemia

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Andrew Stevenson Joel Chandranesan

2018-01-01

Full Text Available Rhabdomyolysis is a life-threatening syndrome due to breakdown of the skeletal muscle. It can be caused by massive trauma and crush injuries or occur as a side effect of medications. Here, we describe a case of a 33-year-old male with human immunodeficiency virus (HIV and newly diagnosed chronic myeloid leukemia (CML with severe life-threatening rhabdomyolysis due to a rare offending agent.

Recombinant EphB4-HSA Fusion Protein and Azacitidine or Decitabine for Relapsed or Refractory Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia Patients Previously Treated With a Hypomethylating Agent

Science.gov (United States)

2017-08-18

Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes; Recurrent Adult Acute Myeloid Leukemia

Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Science.gov (United States)

Poiré, Xavier; Labopin, Myriam; Maertens, Johan; Yakoub-Agha, Ibrahim; Blaise, Didier; Ifrah, Norbert; Socié, Gérard; Gedde-Dhal, Tobias; Schaap, Nicolaas; Cornelissen, Jan J; Vigouroux, Stéphane; Sanz, Jaime; Michaux, Lucienne; Esteve, Jordi; Mohty, Mohamad; Nagler, Arnon

2017-01-18

Acute myeloid leukaemia (AML) with 17p abnormalities (abn(17p)) carries a very poor prognosis due to high refractoriness to conventional chemotherapy, and allogeneic stem cell transplantation (allo-SCT) appears as the only potential curative option. To address outcomes after allo-SCT in patients with abn(17p), we retrospectively analysed de novo or secondary AML undergoing SCT between 2000 and 2013 from the EBMT registry. One hundred thirty-nine patients with confirmed abn(17p) have been selected. At the time of transplant, one hundred twenty-five were in first remission (CR1). Median age was 54 years old. Abn(17p) was associated with a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosomy 7 (-7) in 39% and both -5/5q and -7 in 27%. Seventy-three patients (59%) had a reduced-intensity conditioning regimen. The 2-year overall survival (OS) and leukaemia-free survival (LFS) were 28 and 24%, respectively. The 2-year non-relapse mortality (NRM) was 15%, and 2-year relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%. In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor types did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients' age. In contrast to the dismal prognosis reported for AML patients harbouring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides responses in about 25% of those patients transplanted in CR1.

A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome.

Science.gov (United States)

Kirschbaum, Mark; Gojo, Ivana; Goldberg, Stuart L; Bredeson, Christopher; Kujawski, Lisa A; Yang, Allen; Marks, Peter; Frankel, Paul; Sun, Xing; Tosolini, Alessandra; Eid, Joseph E; Lubiniecki, Gregory M; Issa, Jean-Pierre

2014-10-01

Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) may respond to treatment with epigenetic-modifying agents. Histone deacetylase inhibitors may synergize with hypomethylating agents. This phase 1 dose-escalation study was designed to determine the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of vorinostat plus decitabine in patients with relapsed/refractory AML, newly-diagnosed AML, or intermediate- to high-grade MDS. Thirty-four patients received concurrent therapy with decitabine plus vorinostat and 37 received sequential therapy with decitabine followed by vorinostat. Twenty-nine patients had relapsed/refractory AML, 31 had untreated AML and 11 had MDS. The target maximum administered dose (MAD) of decitabine 20 mg/m(2) daily for 5 d plus vorinostat 400 mg/d for 14 d was achieved for concurrent and sequential schedules, with one dose-limiting toxicity (Grade 3 QTc prolongation) reported in the sequential arm. Common toxicities were haematological and gastrointestinal. Responses were observed more frequently at the MAD on the concurrent schedule compared with the sequential schedule in untreated AML (46% vs. 14%), relapsed/refractory AML (15% vs. 0%) and MDS (60% vs. 0%). Decitabine plus vorinostat given concurrently or sequentially appears to be safe and well-tolerated. Concurrent therapy shows promising clinical activity in AML or MDS, warranting further investigation. © 2014 John Wiley & Sons Ltd.

Chronic Myeloid Leukemia In a Pregnant Woman: A Case Report

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Aytekin Tokmak

2015-12-01

Full Text Available Chronic myeloid leukemia (CML is a rare disease in pregnancy. Our aim is to present a 37 weeks of pregnant woman with chronic myelogenous leukemia. A 27 Years in multigravi (gravida 5, parity: 4, at 37 weeks gestation was admitted with the diagnosis of painful pregnancy and CML. Physical examination findings were normal, complete blood count and peripheral blood smear results were consistent with CML. The patient was diagnosed CML in the 30th week of pregnancy and were treated with hydroxyurea and interferon. Treatment depends on the mother and the fetus did not develop any side effects. Our patient with CML is interesting due to lack of perinatal effects and take the diagnosis at an early age. CML diagnosed during pregnancy requires a multidisciplinary approach and hydroxyurea and interferon treatment on the mother and fetus are at low risk of inducing adverse effects. [Cukurova Med J 2015; 40(4.000: 811-813

Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells

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Ahmad Hamad

2013-01-01

Full Text Available Chronic myeloid leukemia (CML is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML that have the potential to target CML stem cells and potentially provide cure for CML.

Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity

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Abooali, Maryam; Yasinska, Inna M.; Casely-Hayford, Maxwell A.; Berger, Steffen M.; Fasler-Kan, Elizaveta; Sumbayev, Vadim V.

2015-01-01

Correction of human myeloid cell function is crucial for the prevention of inflammatory and allergic reactions as well as leukaemia progression. Caffeine, a naturally occurring food component, is known to display anti-inflammatory effects which have previously been ascribed largely to its inhibitory actions on phosphodiesterase. However, more recent studies suggest an additional role in affecting the activity of the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways, although detailed molecular events underlying its mode of action have not been elucidated. Here, we report the cellular uptake of caffeine, without metabolisation, by healthy and malignant hematopoietic myeloid cells including monocytes, basophils and primary acute myeloid leukaemia mononuclear blasts. Unmodified caffeine downregulated mTOR signalling, which affected glycolysis and the release of pro-inflammatory/pro-angiogenic cytokines as well as other inflammatory mediators. In monocytes, the effects of caffeine were potentiated by its ability to inhibit xanthine oxidase, an enzyme which plays a central role in human purine catabolism by generating uric acid. In basophils, caffeine also increased intracellular cyclic adenosine monophosphate (cAMP) levels which further enhanced its inhibitory action on mTOR. These results demonstrate an important mode of pharmacological action of caffeine with potentially wide-ranging therapeutic impact for treating non-infectious disorders of the human immune system, where it could be applied directly to inflammatory cells. PMID:26384306

Availability of and access to orphan drugs: an international comparison of pharmaceutical treatments for pulmonary arterial hypertension, Fabry disease, hereditary angioedema and chronic myeloid leukaemia.

Science.gov (United States)

Blankart, Carl Rudolf; Stargardt, Tom; Schreyögg, Jonas

2011-01-01

Market authorization does not guarantee patient access to any given drug. This is particularly true for costly orphan drugs because access depends primarily on co-payments, reimbursement policies and prices. The objective of this article is to identify differences in the availability of orphan drugs and in patient access to them in 11 pharmaceutical markets: Australia, Canada, England, France, Germany, Hungary, the Netherlands, Poland, Slovakia, Switzerland and the US. Four rare diseases were selected for analysis: pulmonary arterial hypertension (PAH), Fabry disease (FD), hereditary angioedema (HAE) and chronic myeloid leukaemia (CML). Indicators for availability were defined as (i) the indications for which orphan drugs had been authorized in the treatment of these diseases; (ii) the application date; and (iii) the date upon which these drugs received market authorization in each country. Indicators of patient access were defined as (i) the outcomes of technology appraisals; (ii) the extent of coverage provided by healthcare payers; and (iii) the price of the drugs in each country. For PAH we analysed bosentan, iloprost, sildenafil, treprostinil (intravenous and inhaled) as well as sitaxentan and ambrisentan; for FD we analysed agalsidase alfa and agalsidase beta; for HAE we analysed icatibant, ecallantide and two complement C1s inhibitors; for CML we analysed imatinib, dasatinib and nilotinib. Most drugs included in this study had received market authorization in all countries, but the range of indications for which they had been authorized differed by country. The broadest range of indications was found in Australia, and the largest variations in indications were found for PAH drugs. Authorization process speed (the time between application and market authorization) was fastest in the US, with an average of 362 days, followed by the EU (394 days). The highest prices for the included drugs were found in Germany and the US, and the lowest in Canada, Australia and

Stringent or nonstringent complete remission and prognosis in acute myeloid leukemia

DEFF Research Database (Denmark)

Øvlisen, Andreas K; Oest, Anders; Bendtsen, Mette D

2018-01-01

Stringent complete remission (sCR) of acute myeloid leukemia is defined as normal hematopoiesis after therapy. Less sCR, including non-sCR, was introduced as insufficient blood platelet, neutrophil, or erythrocyte recovery. These latter characteristics were defined retrospectively as postremission...... transfusion dependency and were suggested to be of prognostic value. In the present report, we evaluated the prognostic impact of achieving sCR and non-sCR in the Danish National Acute Leukaemia Registry, including 769 patients registered with classical CR (ie,

High-flow priapism in acute lymphatic leukaemia

Energy Technology Data Exchange (ETDEWEB)

Mentzel, Hans-Joachim; Vogt, Susanna; Kaiser, Werner A. [Institute of Diagnostic and Interventional Radiology, Department of Pediatric Radiology, Friedrich-Schiller-Universitaet Jena, Bachstrasse 18, 07740, Jena (Germany); Kentouche, Karim; Doerfel, Claus; Zintl, Felix [Department of Paediatrics, University of Jena (Germany)

2004-07-01

Priapism is defined as prolonged and persistent erection of the penis without sexual stimulation. It is associated with excessive hyperleukocytosis (e.g. in acute or chronic leukaemia); however, this complication is rarely seen in the pediatric population. We report a 12-year-old boy suffering from acute leukaemia presenting with, at first intermittent, but increasingly persistent erection. Doppler US revealed signs of high-flow priapism. MRI excluded intrapelvic tumour masses, and three-dimensional contrast-enhanced MR angiography could not demonstrate an arteriovenous fistula or thrombosis. Cavernosal blood-gas measurement was in agreement with high-flow priapism. On the basis of the imaging findings, invasive therapeutic management was avoided in our patient with a successful outcome. (orig.)

High-flow priapism in acute lymphatic leukaemia

International Nuclear Information System (INIS)

Mentzel, Hans-Joachim; Vogt, Susanna; Kaiser, Werner A.; Kentouche, Karim; Doerfel, Claus; Zintl, Felix

2004-01-01

Priapism is defined as prolonged and persistent erection of the penis without sexual stimulation. It is associated with excessive hyperleukocytosis (e.g. in acute or chronic leukaemia); however, this complication is rarely seen in the pediatric population. We report a 12-year-old boy suffering from acute leukaemia presenting with, at first intermittent, but increasingly persistent erection. Doppler US revealed signs of high-flow priapism. MRI excluded intrapelvic tumour masses, and three-dimensional contrast-enhanced MR angiography could not demonstrate an arteriovenous fistula or thrombosis. Cavernosal blood-gas measurement was in agreement with high-flow priapism. On the basis of the imaging findings, invasive therapeutic management was avoided in our patient with a successful outcome. (orig.)

The Hepatocyte Growth Factor (HGF/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

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Marjorie Boissinot

2014-08-01

Full Text Available Met is the receptor of hepatocyte growth factor (HGF, a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML, and myeloproliferative neoplasms (MPNs. The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs.

The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

Energy Technology Data Exchange (ETDEWEB)

Boissinot, Marjorie [Translational Neuro-Oncology Group, Leeds Institute of Cancer and Pathology, University of Leeds, Level 5 Wellcome Trust Brenner Building, St James’s Hospital, Leeds LS9 7TF (United Kingdom); Vilaine, Mathias [Institute of Research on Cancer and Aging (IRCAN), CNRS-Inserm-UNS UMR 7284, U 1081, Centre A. Lacassagne, 33 Avenue Valombrose, Nice 06189 (France); Hermouet, Sylvie, E-mail: sylvie.hermouet@univ-nantes.fr [Centre Hospitalier Universitaire (CHU), Place Alexis Ricordeau, Nantes 44093 (France); Inserm UMR892, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Recherche en Santé, Université de Nantes, 8 quai Moncousu, Nantes cedex 44007 (France)

2014-08-12

Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs)

JAK2V617F mutation in chronic myeloid leukemia predicts early disease progression

International Nuclear Information System (INIS)

Pahore, Z.A.A.; Shamsi, T.S.; Taj, M.; Farzana, T.; Ansari, S.H.; Nadeem, M.; Ahmad, M.; Naz, A.

2011-01-01

Objective: To determine the association of JAK2V617F mutation along with BCR-ABL translocation or Philadelphia chromosome in chronic myeloid leukemia with early disease progression to advanced stages (accelerated phase or blast crisis) and poor outcome. Study Design: Case series. Place and Duration of Study: National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, from February 2008 to August 2009. Methodology: All the newly diagnosed cases of BCR-ABL or Philadelphia positive CML were tested for JAK2V617F mutation by Nested PCR. Demographic data, spleen size, hemoglobin levels, white blood cell and platelet counts were recorded. Independent sample t-test was used for age, haemoglobin level and spleen size. Fisher's exact test was applied to compare disease progression in JAK2V617F mutation positive and negative cases. Results: Out of 45 newly diagnosed cases of CML, 40 were in chronic phase, 01 in accelerated phase and 04 in blast crisis. JAK2V617F mutation was detected in 12 (26.7%) patients; 09 (22.5%) in chronic phase, none in accelerated phase and 03 (75%) in blast crisis. During a mean follow-up of 8 months, 03 patients in chronic phase transformed in blast crisis and 02 into accelerated phase. Overall 08 out of 11 (73%) JAK2V617F positive patients either had advanced disease or showed disease progression. Only 2 of 20 (10%) available patients, negative for the mutation, showed disease progression by transforming into blast crisis (p < 0.001). No statistically significant difference was seen in the age, spleen size, haemoglobin levels, white blood cells and platelets counts in JAK2V617F positive patients. Conclusion: JAK2V617F mutation was detected in 26.7% cases of chronic myeloid leukemia. A significant proportion of them showed early disease progression. (author)

Smoking and subsequent risk of acute myeloid leukaemia: A pooled analysis of 9 cohort studies in Japan.

Science.gov (United States)

Ugai, Tomotaka; Matsuo, Keitaro; Oze, Isao; Ito, Hidemi; Wakai, Kenji; Wada, Keiko; Nagata, Chisato; Nakayama, Tomio; Liu, Rong; Kitamura, Yuri; Tamakoshi, Akiko; Tsuji, Ichiro; Sugawara, Yumi; Sawada, Norie; Sadakane, Atsuko; Tanaka, Keitaro; Mizoue, Tetsuya; Inoue, Manami; Tsugane, Shoichiro; Shimazu, Taichi

2018-02-01

Smoking has been identified as a significant risk factor for acute myeloid leukaemia (AML). However, epidemiological evidence for the effect of smoking on the risk of AML among Asians is scarce. Here, we investigated the impact of smoking habits on the risk of AML by conducting a pooled analysis of 9 population-based prospective cohort studies in Japan. We analysed original data on smoking habits at baseline from 9 cohort studies. Hazard ratios (HRs) in the individual studies were calculated using a Cox proportional hazard model adjusted for potential confounders and combined using a random-effects model. During 4 808 175 person-years of follow-up for a total of 344 676 participants (165 567 men and 179 109 women), 245 AML cases (139 men and 106 women) were identified. For both sexes combined, current smokers had a marginally significant increased risk of AML compared to never smokers (HR = 1.44, 95% confidence interval [CI], 0.97-2.14). Ever smokers with more than 30 pack-years had a statistically significant increased risk of AML compared to never smokers among both sexes combined (HR = 1.66, 95% CI, 1.06-2.63). By sex, this significant association was observed only among men, with an HR of 1.69 (95% CI, 1.00-2.87) for ever smokers with more than 30 pack-years relative to never smokers. In conclusion, this study confirmed that cigarette smoking increases the risk of AML in Japanese. This study provides important evidence that smoking increases the risk of AML among Asians, which has already been shown in Western populations. Copyright © 2017 John Wiley & Sons, Ltd.

Profile of bosutinib and its clinical potential in the treatment of chronic myeloid leukemia

Directory of Open Access Journals (Sweden)

Keller-von Amsberg G

2013-03-01

Full Text Available Gunhild Keller-von Amsberg,1 Steffen Koschmieder21Department of Hematology and Oncology, University Cancer Center Hamburg, University Hospital Hamburg Eppendorf, 2Department of Medicine (Hematology, Oncology, and Stem Cell Transplantation, University Medical Center of Aachen and RWTH Aachen University, Aachen, GermanyAbstract: Bosutinib (SKI-606 is an orally available, once-daily, dual Src and Abl kinase inhibitor with promising clinical potential in first-, second-, and third-line treatment of chronic myeloid leukemia (CML. Bosutinib effectively inhibits wild-type BCR-ABL and most imatinib-resistant BCR-ABL mutations except for V299L and T315I. Low hematologic toxicity is a remarkable characteristic of this novel second-generation tyrosine kinase inhibitor, and this has been ascribed to its minimal activity against the platelet-derived growth factor receptor and KIT. Low-grade, typically self-limiting diarrhea, which usually appears within the first few weeks after treatment initiation, represents the predominant toxicity of bosutinib. Other treatment-associated adverse events are mostly mild to moderate. Bosutinib has been approved by the US Food and Drug Administration for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive CML in adult patients with resistance or intolerance to prior therapy. This review summarizes the main properties of bosutinib and the currently available data on its clinical potential in the treatment of CML.Keywords: bosutinib, chronic myeloid leukemia, BCR-ABL, Src/Abl kinase inhibitor, point mutation, imatinib resistance

Successful treatment with chemotherapy and subsequent allogeneic bone marrow transplantation for myeloid blastic crisis of chronic myelogenous leukemia following advanced Hodgkin's disease

NARCIS (Netherlands)

Punt, C. J.; Rozenberg-Arska, M.; Verdonck, L. F.

1987-01-01

A 33-year-old man was treated with intensive chemotherapy for myeloid blastic crisis of chronic myelogenous leukemia (CML), which developed after radiotherapy and chemotherapy for Hodgkin's disease. After achieving a second chronic phase, he underwent allogeneic bone marrow transplantation (BMT).

Myeloid malignancies: mutations, models and management

International Nuclear Information System (INIS)

Murati, Anne; Brecqueville, Mandy; Devillier, Raynier; Mozziconacci, Marie-Joelle; Gelsi-Boyer, Véronique; Birnbaum, Daniel

2012-01-01

Myeloid malignant diseases comprise chronic (including myelodysplastic syndromes, myeloproliferative neoplasms and chronic myelomonocytic leukemia) and acute (acute myeloid leukemia) stages. They are clonal diseases arising in hematopoietic stem or progenitor cells. Mutations responsible for these diseases occur in several genes whose encoded proteins belong principally to five classes: signaling pathways proteins (e.g. CBL, FLT3, JAK2, RAS), transcription factors (e.g. CEBPA, ETV6, RUNX1), epigenetic regulators (e.g. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), tumor suppressors (e.g. TP53), and components of the spliceosome (e.g. SF3B1, SRSF2). Large-scale sequencing efforts will soon lead to the establishment of a comprehensive repertoire of these mutations, allowing for a better definition and classification of myeloid malignancies, the identification of new prognostic markers and therapeutic targets, and the development of novel therapies. Given the importance of epigenetic deregulation in myeloid diseases, the use of drugs targeting epigenetic regulators appears as a most promising therapeutic approach

Autologous Stem Cell Transplantation in Patients with Acute Myeloid Leukemia: a Single-Centre Experience

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Kakucs Enikő

2013-04-01

Full Text Available Introduction: Autologous haemopoietic stem cell transplantation (SCT is an important treatment modality for patients with acute myeloid leukemia with low and intermediate risk disease. It has served advantages over allogenic transplantation, because it does not need a matched donor, there is no graft versus host disease, there are less complications and a faster immune reconstitution than in the allo-setting. The disadvantage is the lack of the graft versus leukaemia effect.

Case report: hydroquinone and/or glutaraldehyde induced acute myeloid leukaemia?

Directory of Open Access Journals (Sweden)

Alexopoulos Evangelos C

2006-07-01

Full Text Available Abstract Background Exposures to high doses of irradiation, to chemotherapy, benzene, petroleum products, paints, embalming fluids, ethylene oxide, herbicides, pesticides, and smoking have been associated with an increased risk of acute myelogenous leukemia (AML. Although there in no epidemiological evidence of relation between X-ray developer, fixer and replenisher liquids and AML, these included glutaraldehyde which has weakly associated with lymphocytic leukemia in rats and hydroquinone has been increasingly implicated in producing leukemia, causing DNA and chromosomal damage, inhibits topo-isomerase II, alter hematopoiesis and inhibit apoptosis of neoplastic cells. Case presentation Two white females (A and B hired in 1985 as medical radiation technologists in a primary care center, in Greece. In July 2001, woman A, 38-years-old, was diagnosed as having acute monocytic leukaemia (FAB M5. The patient did not respond to therapy and died threeweeks later. In August 2001, woman B, 35-year-old, was diagnosed with acute promyelocytic leukaemia (FAB M3. Since discharge, she is in continuous complete remission. Both women were non smokers without any medical history. Shortly after these incidents official inspectors and experts inspected workplace, examined equipment, archives of repairs, notes, interviewed and monitored employees. They concluded that shielding was inadequate for balcony's door but personal monitoring did not show any exceeding of TLV of 20 mSv yearly and cytogenetics analysis did not reveal findings considered to be characteristics of ionizing exposure. Equipment for developing photos had a long list of repairs, mainly leakages of liquids and increases of temperature. On several occasions the floor has been flooded especially during 1987–1993 and 1997–2001. Inspection confirmed a complete lack of ventilation and many spoiled medical x-ray films. Employees reported that an "osmic" level was continuously evident and frequently

Childhood Acute Myeloid Leukemia Treatment (PDQ®)—Health Professional Version

Science.gov (United States)

Acute myeloid leukemia (AML), juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML) account for about 20% of childhood myeloid leukemias. Other myeloid malignancies include transient abnormal myelopoiesis and myelodysplastic syndrome. Get detailed information about the classification, clinical presentation, diagnostic and molecular evaluation, prognosis, and treatment of newly diagnosed and recurrent disease in this summary for clinicians.

Characterisation and Clinical Significance of FLT3-ITD and non-ITD in Acute Myeloid Leukaemia Patients in Kelantan, Northeast Peninsular Malaysia.

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Yunus, Noraini Mat; Johan, Muhammad Farid; Ali Nagi Al-Jamal, Hamid; Husin, Azlan; Hussein, Abdul Rahim; Hassan, Rosline

2015-01-01

Mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor gene may promote proliferation via activation of multiple signaling pathways. FLT3-internal tandem duplication (FLT3-ITD) is the most common gene alteration found in patients diagnosed with acute myeloid leukaemia (AML) and has been associated with poor prognosis. We performed mutational analysis of exons 14-15 and 20 of the FLT3 gene in 54 AML patients using PCR-CSGE (conformational sensitive gel electrophoresis) followed by sequencing analysis to characterise FLT3 mutations in adult patients diagnosed with AML at Hospital USM, Kelantan, Northeast Peninsular Malaysia. FLT3 exon 14-15 mutations were identified in 7 of 54 patients (13%) whereas no mutation was found in FLT3 exon 20. Six ITDs and one non-ITD mutation were found in exon 14 of the juxtamembrane (JM) domain of FLT3. FLT3-ITD mutations were associated with a significantly higher blast percentage (p-value=0.008) and white blood cell count (p-value=0.023) but there was no significant difference in median overall survival time for FLT3-ITD+/FLT3-ITD- within 2 years (p-value=0.374). The incidence of FLT3-ITD in AML patients in this particular region of Malaysia is low compared to the Western world and has a significant association with WBC and blast percentage.

Circulating endothelial cells are increased in chronic myeloid leukemia blast crisis

Directory of Open Access Journals (Sweden)

C.R.T. Godoy

2015-06-01

Full Text Available We measured circulating endothelial precursor cells (EPCs, activated circulating endothelial cells (aCECs, and mature circulating endothelial cells (mCECs using four-color multiparametric flow cytometry in the peripheral blood of 84 chronic myeloid leukemia (CML patients and 65 healthy controls; and vascular endothelial growth factor (VEGF by quantitative real-time PCR in 50 CML patients and 32 healthy controls. Because of an increase in mCECs, the median percentage of CECs in CML blast crisis (0.0146% was significantly higher than in healthy subjects (0.0059%, P0.05. In addition, VEGF gene expression was significantly higher in all phases of CML: 0.245 in blast crisis, 0.320 in the active phase, and 0.330 in chronic phase patients than it was in healthy subjects (0.145. In conclusion, CML in blast crisis had increased levels of CECs and VEGF gene expression, which may serve as markers of disease progression and may become targets for the management of CML.

Anticancer activity of Pupalia lappacea on chronic myeloid leukemia K562 cells.

Science.gov (United States)

Ravi, Alvala; Alvala, Mallika; Sama, Venkatesh; Kalle, Arunasree M; Irlapati, Vamshi K; Reddy, B Madhava

2012-12-05

Cancer is one of the most prominent human diseases which has enthused scientific and commercial interest in the discovery of newer anticancer agents from natural sources. Here we demonstrated the anticancer activity of ethanolic extract of aerial parts of Pupalia lappacea (L) Juss (Amaranthaceae) (EAPL) on Chronic Myeloid Leukemia K562 cells. Antiproliferative activity of EAPL was determined by MTT assay using carvacrol as a positive control. Induction of apoptosis was studied by annexin V, mitochondrial membrane potential, caspase activation and cell cycle analysis using flow cytometer and modulation in protein levels of p53, PCNA, Bax and Bcl2 ratio, cytochrome c and cleavage of PARP were studied by Western blot analysis. The standardization of the extract was performed through reverse phase-HPLC using Rutin as biomarker. The results showed dose dependent decrease in growth of K562 cells with an IC50 of 40 ± 0.01 μg/ml by EAPL. Induction of apoptosis by EAPL was dose dependent with the activation of p53, inhibition of PCNA, decrease in Bcl2/Bax ratio, decrease in the mitochondrial membrane potential resulting in release of cytochrome c, activation of multicaspase and cleavage of PARP. Further HPLC standardization of EAPL showed presence 0.024% of Rutin. Present study significantly demonstrates anticancer activity of EAPL on Chronic Myeloid Leukemia (K562) cells which can lead to potential therapeutic agent in treating cancer. Rutin, a known anti cancer compound is being reported and quantified for the first time from EAPL.

Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

DEFF Research Database (Denmark)

Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

2011-01-01

Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remissio...

Pharmacokinetics and pharmacokinetic/pharmacodynamic associations of ofatumumab, a human monoclonal CD20 antibody, in patients with relapsed or refractory chronic lymphocytic leukaemia: a phase 1-2 study

DEFF Research Database (Denmark)

Coiffier, Bertrand; Losic, Nedjad; Rønn, Birgitte Biilmann

2010-01-01

The purpose of this phase 1-2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumu...

Tumour genesis syndrome: severe hypophosphatemia and hypokalemia may be ominous presenting findings in childhood acute myeloid leukaemia.

Science.gov (United States)

Chan, Winnie Ky; Chang, Kai On; Lau, Wing Hung

2017-08-01

We report a 16-year-old girl who was diagnosed with acute leukaemia and a marked leucocytosis >200 × 10 9 /L. She presented with marked hypophosphatemia, hypokalemia, acute renal failure and acute respiratory failure. These electrolytes disturbances may indicate rapid tumour genesis. These ominous findings required urgent treatment to halt the crises of rapid leukemic cell proliferation. Mark hypophosphatemia and hypokalemia may be presenting electrolyte abnormalities in a patient with acute leukaemia, and these may be indicators of aggressive tumour genesis. What is known: • Mild electrolyte disturbances are common in oncology patients • Tumour lysis syndrome is well recognized by paediatriaticians What is new: • Life-threatening hypophosphatemia is an uncommon presentation • These electrolytes disorders may indicate an aggressive tumour genesis process even at presentation and require urgent treatment.

Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia

DEFF Research Database (Denmark)

Cross, N. C. P.; White, H. E.; Colomer, D.

2015-01-01

Treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors has advanced to a stage where many patients achieve very low or undetectable levels of disease. Remarkably, some of these patients remain in sustained remission when treatment is withdrawn, suggesting that they may be at ...... of sensitivity. Here we present detailed laboratory recommendations, developed as part of the European Treatment and Outcome Study for CML (EUTOS), to enable testing laboratories to score MR in a reproducible manner for CML patients expressing the most common BCR-ABL1 variants....

Myeloid derived suppressor cells (MDSCs are increased and exert immunosuppressive activity together with polymorphonuclear leukocytes (PMNs in chronic myeloid leukemia patients.

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Cesarina Giallongo

Full Text Available Tumor immune tolerance can derive from the recruitment of suppressor cell population, including myeloid derived suppressor cells (MDSCs, able to inhibit T cells activity. We identified a significantly expanded MDSCs population in chronic myeloid leukemia (CML patients at diagnosis that decreased to normal levels after imatinib therapy. In addition, expression of arginase 1 (Arg1 that depletes microenvironment of arginine, an essential aminoacid for T cell function, resulted in an increase in patients at diagnosis. Purified CML CD11b+CD33+CD14-HLADR- cells markedly suppressed normal donor T cell proliferation in vitro. Comparing CML Gr-MDSCs to autologous polymorphonuclear leukocytes (PMNs we observed a higher Arg1 expression and activity in PMNs, together with an inhibitory effect on T cells in vitro. Our data indicate that CML cells create an immuno-tolerant environment associated to MDSCs expansion with immunosuppressive capacity mediated by Arg1. In addition, we demonstrated for the first time also an immunosuppressive activity of CML PMNs, suggesting a strong potential immune escape mechanism created by CML cells, which control the anti-tumor reactive T cells. MDSCs should be monitored in imatinib discontinuation trials to understand their importance in relapsing patients.

Behandling af akut myeloid leukæmi uden transfusion af blodprodukter hos et medlem af Jehovas Vidner

DEFF Research Database (Denmark)

Larsen, Christian; Jensen, Morten Krogh

2011-01-01

We present a case in which a young woman was diagnosed with acute myeloid leukaemia, FAB-classification type M2. As a member of Jehovah's Witnesses she refused to accept any treatment involving blood transfusions. A modified induction and consolidation chemotherapy regimen was applied, tailored...... to reduce prolonged myelosuppression. Despite severe anaemia, she survived to achieve complete remission. She is currently under treatment-free observation after two courses of consolidation treatment....

Minimal restsygdom ved maligne blodsygdomme II. Translation og terapeutiske konsekvenser

DEFF Research Database (Denmark)

Hokland, Peter; Ommen, Hans Beier; Nyvold, Charlotte Guldborg

2009-01-01

in following patients with chronic myeloid leukaemia treated with the tyrosine kinase inhibitor imatinib. Moreover, the methodology is being integrated in an increasing number of clinical trials, where it is expected to result in more rational and individualized clinical decision-making. A special point...

Oncogenic Kinase Bcr-Abl and Its Resistance to Pharmacological Inhibitors

Czech Academy of Sciences Publication Activity Database

Kryštof, Vladimír

2008-01-01

Roč. 102, č. 9 (2008), s. 795-800 E-ISSN 1213-7103 Institutional research plan: CEZ:AV0Z50380511 Keywords : imatinib * inhibitor * chronic myeloid leukaemia * kinase * cancer Subject RIV: CE - Biochemistry www.chemicke-listy.cz/docs/full/2008_09_795-800.pdf

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

Home; Journals; Journal of Genetics; Volume 96; Issue 4. Association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic myeloid leukaemia patients. SITI MAZIRAS MAKHTAR AZLAN HUSIN ABDUL AZIZ BABA RAVINDRAN ANKATHIL.

Accelerated phase chronic myeloid leukemia: evaluation of clinical criteria as predictors of survival, major cytogenetic response and progression to blast phase

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Vanessa Fiorini Furtado

2015-10-01

Full Text Available BACKGROUND: Published criteria defining the accelerated phase in chronic myeloid leukemia are heterogeneous and little is known about predictors of poor outcome.METHODS: This is a retrospective study of 139 subjects in the accelerated phase of chronic myeloid leukemia treated with imatinib at a single center in Brazil. The objective was to identify risk factors for survival, major cytogenetic response and progression to blast phase in this population. The factors analyzed were: blasts 10-29%, basophils ≥ 20%, platelets > 1 × 106/µL or 1 × 105/µL in the peripheral blood, as well as clonal evolution, splenomegaly, hemoglobin 12 months (p-value = 0.030.CONCLUSION: These data indicate that patients with the above risk factors have a worse prognosis. This information can guide the therapy to be used.

Chronic myeloid leukemia: an overview of the determinants of effectiveness and therapeutic response in the first decade of treatment with imatinib mesylate in a Brazilian hospital

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Danielle Maria Camelo Cid

2013-01-01

Full Text Available Background: In the last decade, there has been a revolution in chronic myeloid leukemia treatment with the introduction of tyrosine kinase inhibitors with imatinib mesylate becoming the frontline therapy. Objective: To evaluate the therapeutic efficacy of imatinib mesylate in treating chronic myeloid leukemia patients and to identify factors related to therapeutic efficacy. Methods: This retrospective study was based on information obtained from patients'records in the Hematology Service of Hospital Universitário Walter Cantídio of the Universidade Federal do Ceará (HUWC / UFC. All patients diagnosed with chronic myeloid leukemia that took imatinib mesylate for a minimum of 12 months in the period from January 2001 to January 2011 were included. From a population of 160 patients, 100 were eligible for analysis. Results: The study population consisted of 100 patients who were mostly male (51% with ages rangingbetween 21 and 40 years (42%, from the countryside (59%, in the chronic phase (95%, with high-riskprognostic factors (40%; the prognosis of high risk was not associated with complete hematologic responseor complete cytogenetic response, but correlated to complete molecular response or major molecularresponse. Reticulin condensation was associated with complete hematologic response and completecytogenetic response. It was found that 53% of patients had greater than 90% adherence to treatment. Thehigh adherence was correlated to attaining complete cytogenetic response in less than 12 months. Moreover,20% of patients had good response. Conclusion: Significant changes are indispensable in the monitoring of patients with chronic myeloid leukemia. Thus, the multidisciplinary team is important as it provides access to the full treatment and not just to medications.

Randomized study on hydroxyurea alone versus hydroxyurea combined with low-dose interferon-alpha 2b for chronic myeloid leukemia

NARCIS (Netherlands)

Kluin-Nelemans, JC; Delannoy, A; Louwagie, A; Le Cessie, S; Hermans, J; van der Burgh, JF; Hagemeijer, AM; Van den Berghe, H

1998-01-01

Interferon-alpha (IFN-alpha) is considered the standard therapy for chronic myeloid leukemia (CML) patients not suitable for allogeneic stem cell transplantation. From 1987 through 1992, 195 patients in the Benelux with recent untreated CML were randomized between low-dose IFN-alpha 2b (3 MIU, 5

Nuclear power and leukaemia

International Nuclear Information System (INIS)

Grimston, M.

1991-03-01

This booklet describes the nature of leukaemia, disease incidence in the UK and the possible causes. Epidemiological studies observing rates of leukaemia near nuclear power stations in the UK and other parts of the world are discussed. Possible causes of leukaemia excesses near nuclear establishments include radioactive discharges into the environment, paternal radiation exposure and viral causes. (UK)

Combined Population Dynamics and Entropy Modelling Supports Patient Stratification in Chronic Myeloid Leukemia

Science.gov (United States)

Brehme, Marc; Koschmieder, Steffen; Montazeri, Maryam; Copland, Mhairi; Oehler, Vivian G.; Radich, Jerald P.; Brümmendorf, Tim H.; Schuppert, Andreas

2016-04-01

Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer progression, biomarker identification and the design of individualized therapies. Using chronic myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patient-derived gene expression entropy separated established CML progression stages and uncovered additional heterogeneity within disease stages. Importantly, our patient data informed model enables quantitative approximation of individual patients’ disease history within chronic phase (CP) and significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized and genome-informed disease progression risk assessment that is independent and complementary to conventional measures of CML disease burden and prognosis.

Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells

International Nuclear Information System (INIS)

Askmyr, M; Ågerstam, H; Lilljebjörn, H; Hansen, N; Karlsson, C; Palffy, S von; Landberg, N; Högberg, C; Lassen, C; Rissler, M; Richter, J; Ehinger, M; Järås, M; Fioretos, T

2014-01-01

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34 + cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML

Rationale and motivating factors for treatment-free remission in chronic myeloid leukemia.

Science.gov (United States)

Caldemeyer, Lauren; Akard, Luke P

2016-12-01

With BCR-ABL1 tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, many patients with chronic myeloid leukemia in chronic phase (CML-CP) can expect to live near-normal life spans. Current treatment recommendations of the National Comprehensive Cancer Network and the European LeukemiaNet state that patients with CML-CP should remain on TKI therapy indefinitely. However, there is increasing evidence from clinical trials that some patients with sustained deep molecular responses may be able to achieve treatment-free remission (TFR), whereby they can suspend TKI therapy without losing previously achieved responses. With many patients achieving deep molecular responses to TKI therapy, there is growing interest in whether such patients can achieve TFR. In addition, adverse events (AEs) with long-term TKI therapy, including both the potential for later-emerging AEs and chronic, low-grade AEs, represent a major motivator for oncologists and their patients to investigate the feasibility of TFR. In this review, we provide an overview of data from TFR clinical trials, discuss the importance of achieving a deep molecular response to TKI treatment, and consider potential reasons for investigating TFR following TKI therapy.

Omitting cytogenetic assessment from routine treatment response monitoring in chronic myeloid leukemia is safe.

Science.gov (United States)

Geelen, Inge G P; Thielen, Noortje; Janssen, Jeroen J W M; Hoogendoorn, Mels; Roosma, Tanja J A; Valk, Peter J M; Visser, Otto; Cornelissen, Jan J; Westerweel, Peter E

2018-04-01

The monitoring of response in chronic myeloid leukemia (CML) is of great importance to identify patients failing their treatment in order to adjust TKI choice and thereby prevent progression to advanced stage disease. Cytogenetic monitoring has a lower sensitivity, is expensive, and requires invasive bone marrow sampling. Nevertheless, chronic myeloid leukemia guidelines continue to recommend performing routine cytogenetic response assessments, even when adequate molecular diagnostics are available. In a population-based registry of newly diagnosed CML patients in the Netherlands, all simultaneous cytogenetic and molecular assessments performed at 3, 6, and 12 months were identified and response of these matched assessments was classified according to European Leukemia Net (ELN) recommendations. The impact of discrepant cytogenetic and molecular response classifications and course of patients with additional chromosomal abnormalities were evaluated. The overall agreement of 200 matched assessments was 78%. In case of discordant responses, response at 24 months was consistently better predicted by the molecular outcome. Cytogenetic response assessments provided relevant additional clinical information only in some cases of molecular "warning." The development of additional cytogenetic abnormalities was always accompanied with molecular failure. We conclude that it is safe to omit routine cytogenetics for response assessment during treatment and to only use molecular monitoring, in order to prevent ambiguous classifications, reduce costs, and reduce the need for invasive bone marrow sampling. Cytogenetic re-assessment should still be performed when molecular response is suboptimal. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Targeted Therapies in Hematology and Their Impact on Patient Care: Chronic and Acute Myeloid Leukemia

Science.gov (United States)

Cortes, Elias Jabbour Jorge; Ravandi, Farhad; O’Brien, Susan; Kantarjian, Hagop

2014-01-01

Advances in the genetic and molecular characterizations of leukemias have enhanced our capabilities to develop targeted therapies. The most dramatic examples of targeted therapy in cancer to date are the use of targeted BCR-ABL protein tyrosine kinase inhibitors (TKI) which has revolutionized the treatment of chronic myeloid leukemia (CML). Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target, transforming the prognosis of patients with CML. In contrast, acute myeloid leukemia (AML) is an extremely heterogeneous disease with outcomes that vary widely according to subtype of the disease. Targeted therapy with monoclonal antibodies and small molecule kinase inhibitors are promising strategies to help improve the cure rates in AML. In this review, we will highlight the results of recent clinical trials in which outcomes of CML and AML have been influenced significantly. Also, novel approaches to sequencing and combining available therapies will be covered. PMID:24246694

Occurrence of chronic lymphocytic leukemia in patients with chronic myelogenous leukemia

Directory of Open Access Journals (Sweden)

Pritish K Bhattacharyya

2013-01-01

Full Text Available Chronic lymphocytic leukemia (CLL is the most common leukemia of adults in the western world and constitutes about 33% of all leukemia′s. The incidence of CLL increases with age and are more common in older population. Chronic myeloid leukemia (CML on the contrary occurs in both young adults and elderly and is a chronic myeloproliferative disease that originates from abnormal pluripotent stem cells and results in involvement of multiple hematopoietic lineages, but predominantly myeloid and less commonly lymphoid. Association between CLL and myeloid malignancies (CML, acute myeloid leukemia and MDS, myelodysplastic syndrome is rare. In literature documenting CLL and CML in same patients, occur either simultaneously or CML is preceded by CLL.

Optimized Treatment Schedules for Chronic Myeloid Leukemia.

Directory of Open Access Journals (Sweden)

Qie He

2016-10-01

Full Text Available Over the past decade, several targeted therapies (e.g. imatinib, dasatinib, nilotinib have been developed to treat Chronic Myeloid Leukemia (CML. Despite an initial response to therapy, drug resistance remains a problem for some CML patients. Recent studies have shown that resistance mutations that preexist treatment can be detected in a substantial number of patients, and that this may be associated with eventual treatment failure. One proposed method to extend treatment efficacy is to use a combination of multiple targeted therapies. However, the design of such combination therapies (timing, sequence, etc. remains an open challenge. In this work we mathematically model the dynamics of CML response to combination therapy and analyze the impact of combination treatment schedules on treatment efficacy in patients with preexisting resistance. We then propose an optimization problem to find the best schedule of multiple therapies based on the evolution of CML according to our ordinary differential equation model. This resulting optimization problem is nontrivial due to the presence of ordinary different equation constraints and integer variables. Our model also incorporates drug toxicity constraints by tracking the dynamics of patient neutrophil counts in response to therapy. We determine optimal combination strategies that maximize time until treatment failure on hypothetical patients, using parameters estimated from clinical data in the literature.

Mixed phenotype (T/B/myeloid) extramedullary blast crisis as an initial presentation of chronic myelogenous leukemia.

Science.gov (United States)

Qing, Xin; Qing, Annie; Ji, Ping; French, Samuel W; Mason, Holli

2018-04-01

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by the Philadelphia (Ph) chromosome generated by the reciprocal translocation t(9,22)(q34;q11). The natural progression of the disease follows a biphasic or triphasic course. Most cases of CML are diagnosed in the chronic phase. Extramedullary blast crisis rarely occurs during the course of CML, and is extremely rare as the initial presentation of CML. Here, we report the case of a 32-year-old female with enlarged neck lymph nodes and fatigue. She was diagnosed with B-lymphoblastic leukemia/lymphoma with possible mixed phenotype (B/myeloid) by right neck lymph node biopsy at an outside hospital. However, review of her peripheral blood smear and her bone marrow aspirate and biopsy showed features consistent with CML, which was confirmed by PCR and karyotyping. An ultrasound-guided right cervical lymph node core biopsy showed a diffuse infiltrate of blasts, near totally replacing the normal lymph node tissue, admixed with some hematopoietic cells including megakaryocytes, erythroid precursors and maturing myeloid cells. By flow cytometry and immunohistochemistry, the blasts expressed CD2, cytoplasmic CD3, CD5, CD7, CD56, TdT, CD10 (weak, subset), CD19 (subset), CD79a, PAX-5 (subset), CD34, CD38, CD117 (subset), HLA-DR (subset), CD11b, CD13 (subset), CD33 (subset), and weak cytoplasmic myeloperoxidase, without co-expression of surface CD3, CD4, CD8, CD20, CD22, CD14, CD15, CD16 and CD64, consistent with blasts with mixed phenotype (T/B/myeloid). A diagnosis of extramedullary blast crisis of CML was made. Chromosomal analysis performed on the lymph node biopsy tissue revealed multiple numerical and structural abnormalities including the Ph chromosome (46-49,XX,add(1)(p34),add(3)(p25),add(5)(q13),-6,t(9;22)(q34;q11.2),+10,-15,add(17)(p11.2),+19, +der(22)t(9;22),+mar[cp8]). After completion of one cycle of combined chemotherapy plus dasatinib treatment, she was transferred to City of Hope

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10)

DEFF Research Database (Denmark)

Eichhorst, Barbara; Fink, Anna-Maria; Bahlo, Jasmin

2016-01-01

BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less....... The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522. FINDINGS: 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included...

Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations

DEFF Research Database (Denmark)

Farooqui, Mohammed Z H; Valdez, Janet; Martyr, Sabrina

2015-01-01

BACKGROUND: Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy, resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53...... aberrations. METHODS: In this investigator-initiated, single-arm phase 2 study, we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until...... in one (2%) patient. INTERPRETATION: The activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings. FUNDING: Intramural...

Nilotinib-Induced Acute Pancreatitis in a Patient with Chronic Myeloid Leukemia

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Vihang Patel

2017-05-01

Full Text Available Nilotinib, a second-generation tyrosine kinase inhibitor, is used for treatment of chronic myeloid leukemia (CML; it has been widely used especially for imatinib-resistant CML. Despite being a novel drug in this therapeutic class, it has the potential to be harmful. We present the case of an elderly woman who developed life-threatening acute pancreatitis as an adverse event after having started the drug. There is only one reported case in the literature of nilotinib-induced acute pancreatitis. The purpose of this case report is to educate physicians who prescribe this medication to be aware of potential life-threatening adverse events. As more and more therapies are available, physicians should be aware of potential effects of cancer treatment that could be life-threatening to patients.

p53 Gene (NY-CO-13 Levels in Patients with Chronic Myeloid Leukemia: The Role of Imatinib and Nilotinib

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Hayder M. Al-kuraishy

2018-01-01

Full Text Available The p53 gene is also known as tumor suppressor p53. The main functions of the p53 gene are an anticancer effect and cellular genomic stability via various pathways including activation of DNA repair, induction of apoptosis, and arresting of cell growth at the G1/S phase. Normally, the p53 gene is inactivated by mouse double minute 2 proteins (mdm2, but it is activated in chronic myeloid leukemia (CML. Tyrosine kinase inhibitors are effective chemotherapeutic agents in the management of CML. The purpose of the present study was to evaluate the differential effect of imatinib and nilotinib on p53 gene serum levels in patients with CML. A total number of 60 patients with chronic myeloid leukemia with ages ranging from 47 to 59 years were recruited from the Iraqi Hematology Center. They started with tyrosine kinase inhibitors as first-line chemotherapy. They were divided into two groups—Group A, 29 patients treated with imatinib and Group B, 31 patients treated with nilotinib—and compared with 28 healthy subjects for evaluation p53 serum levels regarding the selective effect of either imatinib or nilotinib. There were significantly (p < 0.01 high p53 gene serum levels in patients with CML (2.135 ± 1.44 ng/mL compared to the control (0.142 ± 0.11 ng/mL. Patients with CML that were treated with either imatinib or nilotinib showed insignificant differences in most of the hematological profile (p > 0.05 whereas, p53 serum levels were high (3.22 ± 1.99 ng/mL in nilotinib-treated patients and relatively low (1.18 ± 0.19 ng/mL in imatinib-treated patients (p = 0.0001. Conclusions: Nilotinib is more effective than imatinib in raising p53 serum levels in patients with chronic myeloid leukemia.

Cumulative clinical experience from a decade of use: imatinib as first-line treatment of chronic myeloid leukemia

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Baran Y

2012-11-01

Full Text Available Yusuf Baran,1 Guray Saydam21Department of Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey; 2Department of Hematology, School of Medicine, Ege University, Izmir, TurkeyAbstract: Chronic myeloid leukemia (CML is a malignant disease that originates in the bone marrow and is designated by the presence of the Philadelphia (Ph+ chromosome, a translocation between chromosomes 9 and 22. Targeted therapy against CML commenced with the development of small-molecule tyrosine kinase inhibitors (TKIs exerting their effect against the oncogenic breakpoint cluster region (BCR-ABL fusion protein. Imatinib emerged as the first successful example of a TKI used for the treatment of chronic-phase CML patients and resulted in significant improvements in response rate and overall survival compared with previous treatments. However, a significant portion of patients failed to respond to the therapy and developed resistance against imatinib. Second-generation TKIs nilotinib and dasatinib were to have higher efficiency in clinical trials in imatinib- resistant or intolerant CML patients compared with imatinib. Identification of novel strategies such as dose escalation, drug combination therapy, and use of novel BCR-ABL inhibitors may eventually overcome resistance against BCR-ABL TKIs. This article reviews the history of CML, including the treatment strategies used prediscovery of TKIs and the preclinical and clinical data obtained after the use of imatinib, and the second-generation TKIs developed for the treatment of CML.Keywords: drug resistance, tyrosine kinase inhibitors, chronic myeloid leukemia, imatinib, BCR/ABL

Treating the chronic-phase chronic myeloid leukemia patient: which TKI, when to switch and when to stop?

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Patel, Ami B; Wilds, Brandon W; Deininger, Michael W

2017-07-01

With the discovery of imatinib mesylate nearly 20 years ago, tyrosine kinase inhibitors (TKIs) were found to be effective in chronic myeloid leukemia (CML). TKI therapy has since revolutionized the treatment of CML and has served as a paradigm of success for targeted drug therapy in cancer. Several new TKIs for CML have been approved over the last two decades that exhibit improved potency over imatinib and have different off-target profiles, providing options for individualized therapy selection. Areas covered: Current management of chronic phase CML, including guidance on the sequential use of imatinib and newer-generation TKIs and evolving treatment strategies such as TKI discontinuation. Relevant literature was identified by searching biomedical databases (i.e. PubMed) for primary research material. Expert commentary: Although survival outcomes have drastically improved for CML patients, treatment for CML has grown more complex with the introduction of next-generation TKIs and the advent of treatment-free remissions (TFR). Goals of therapy have shifted accordingly, with increased focus on improving quality of life, managing patient expectations and optimizing patient adherence.

Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital

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Samuel Roosevelt Campos dos Reis

2013-06-01

Full Text Available Objetive: The aim of this study was to identify the reasons for failure in adherence to imatinib mesylate treatment in chronic myeloid leukemia. Methods: A retrospective review was performed of 100 non-electronic records of patients with Ph+ chronic myeloid leukemia treated with imatinib mesylate. The study period was from January 2001 to January2011. Data were analyzed by Chi-Square and Correspondence analysis using the Statistical Analysis System software package. Results: At the beginning of treatment 41% of patients were in advanced stages of the disease. The unavailability of the drug (44.8% and myelotoxicity (25.7% were the most frequent reasons for interruption. The adherence rate was 95% induced complete cytogenetic response, major cytogenetic response and major molecular response. Conclusion: The population of this study obtained lower-than-expected therapeutic responses compared to other studies.

Impaired low-density lipoprotein receptor activity in chronic B-lymphocytic leukaemia cells

Energy Technology Data Exchange (ETDEWEB)

Juliusson, G.; Vitols, S.

1988-01-01

Cellular degradation of /sup 125/I-labelled low-density lipoprotein (LDL) was analysed in freshly isolated blood mononuclear cells from 26 patients with chronic B-lymphocytic leukaemia (CLL) and 8 healthy subjects, and in cells following 1,2 and 3 d of culture in medium containing 10% human lipoprotein-deficient serum (LPDS). Fresh CLL cells had lower LDL degradation rates than mononuclear cells from healthy subjects (p < 0.01). The LDL degradation rates increased during culture (p < 0.001), but to a lesser degree in CLL cells than in normal blood mononuclear cells (p < 0.001). The cellular degradation rate of /sup 125/I-LDL was markedly inhibited by an excess of unlabelled LDL, indicating that most of the /sup 125/I-LDL that was degraded had been internalized following binding to the LPDS-induced LDL degradation of CLL cells and the thymidine uptake in CLL cell cultures with (r = 0.70, p < 0.001) and without (r = 0.59, p < 0.01) the B cell mitogen, Epstein-Barr virus. The results indicate that LDL receptors might be involved in the regulation of CLL cell proliferation.

The role of peptide and DNA vaccines in myeloid leukemia immunotherapy

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Lin Chen

2013-02-01

Full Text Available Abstract While chemotherapy and targeted therapy are successful in inducing the remission of myeloid leukemia as acute myeloid leukemia (AML and chronic myeloid leukemia (CML, the disease remains largely incurable. This observation is likely due to the drug resistance of leukemic cells, which are responsible for disease relapse. Myeloid leukemia vaccines may most likely be beneficial for eradicating minimal residual disease after treatment with chemotherapy or targeted therapy. Several targeted immunotherapies using leukemia vaccines have been heavily investigated in clinical and preclinical trials. This review will focus on peptides and DNA vaccines in the context of myeloid leukemias, and optimal strategies for enhancing the efficacy of vaccines based on myeloid leukemia immunization are also summarized.

Age of onset and type of leukaemia

International Nuclear Information System (INIS)

Butturini, Anna; Gale, R.P.

1989-01-01

The factors that influence leukaemia type are complex and differ for various leukaemogenic agents. Some leukaemogens increase the age-related risk of specific leukaemia, whereas other induce several or a single leukaemia type without age correlation. In most situations, age has no influence on leukaemia type. Consequently, other factors may explain the pronounced age-related differences seen for ''spontaneously'' occurring leukaemias in human beings. (author)

[Clinical and biological prognostic factors in relapsed acute myeloid leukemia patients].

Science.gov (United States)

Yébenes-Ramírez, Manuel; Serrano, Josefina; Martínez-Losada, Carmen; Sánchez-García, Joaquín

2016-09-02

Acute myeloid leukemia (AML) is the most frequent type of acute leukemia in adults. Despite recent advances in the characterization of pathogenesis of AML, the cure rates are under 40%, being leukemia relapse the most common cause of treatment failure. Leukaemia relapse occurs due to clonal evolution or clonal escape. In this study, we aimed to analyze the clinical and biological factors influencing outcomes in patients with AML relapse. We included a total of 75 AML patients who experienced leukaemia relapse after achieving complete remission. We performed complete immunophenotyping and conventional karyotyping in bone marrow aspirates obtained at diagnosis and at leukemia relapse. Overall survival (OS) of the series was 3.7%±2.3, leukaemia progression being the most common cause of death. Patients relapsing before 12 months and those with adverse cytogenetic-molecular risk had statistically significant worse outcomes. A percentage of 52.5 of patients showed phenotypic changes and 50% cytogenetic changes at relapse. We did not find significant clinical factors predicting clonal evolution. The presence of clonal evolution at relapse did not have a significant impact on outcome. Patients with relapsed AML have a dismal prognosis, especially those with early relapse and adverse cytogenetic-molecular risk. Clonal evolution with phenotypic and cytogenetic changes occurred in half of the patients without predictive clinical factors or impact on outcome. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Environmental exposure to ionizing radiation and childhood leukaemia incidence

International Nuclear Information System (INIS)

Evrard, Anne-Sophie

2006-01-01

This thesis aimed at providing an epidemiological approach of the hypothesis of the existence of an association between environmental exposure to ionizing radiation and childhood leukaemia incidence. From 1990 to 2001, 5,330 cases of acute leukaemia were registered by the French National Registry of Childhood Leukemia and Lymphoma in children under 15 years of age and living in mainland France at the time of diagnosis. Indoor radon concentration was estimated using 13,240 measurements carried out by the Institute for Radiation Protection and Nuclear Safety (IRSN), and covering the whole country. Exposure to terrestrial gamma radiation was based on continuous measurements, using thermoluminescent dosimeters, at about 1,000 sites covering the whole of France, in order to monitor the level of environmental radioactivity in France. Analyses were conducted using Poisson regressions, including ecological co-variates, at the level of the 'Departments' (95 administrative geographical units in France). A significant positive ecological association between indoor radon concentration and the incidence of acute myeloid leukaemia was evidenced (SIR=1.19 per 100 Bq/m 3 - 95% confidence interval=[1.03-1.38]) and remained significant in multivariate regression analyses including exposure to terrestrial gamma radiation and/or some ecological co-variates. Conversely, there was no evidence of an ecological association between exposure to terrestrial gamma radiation and childhood leukaemia incidence. The epidemiological studies of the incidence of childhood leukaemia around nuclear sites analyzed incidence with respect to the distance from the plants, without considering any information on the levels or geographic distribution of the radiation dose due to discharges from the plants. The present study investigated for the first time the incidence of childhood leukaemia around French nuclear installations using a geographic zoning based on estimated doses due to gaseous

Age of onset and type of leukaemia

Energy Technology Data Exchange (ETDEWEB)

Butturini, Anna (Parma Univ. (Italy)); Gale, R.P. (California Univ., Los Angeles, CA (USA). Dept. of Medicine)

1989-09-30

The factors that influence leukaemia type are complex and differ for various leukaemogenic agents. Some leukaemogens increase the age-related risk of specific leukaemia, whereas other induce several or a single leukaemia type without age correlation. In most situations, age has no influence on leukaemia type. Consequently, other factors may explain the pronounced age-related differences seen for ''spontaneously'' occurring leukaemias in human beings. (author).

Self-Esteem and Academic Difficulties in Preadolescents and Adolescents Healed from Paediatric Leukaemia.

Science.gov (United States)

Tremolada, Marta; Taverna, Livia; Bonichini, Sabrina; Basso, Giuseppe; Pillon, Marta

2017-05-24

Adolescents with cancer may demonstrate problems in their self-esteem and schooling. This study aims to screen the preadolescents and adolescents more at risk in their self-esteem perception and schooling difficulties post-five years from the end of therapy. Twenty-five paediatric ex-patients healed from leukaemia were recruited at the Haematology-Oncologic Clinic (University of Padua). The mean age of the children was 13.64 years (Standard Deviation (SD)) = 3.08, range = 10-19 years), most were treated for acute lymphoblastic leukaemia (ALL) (84%) and relatively equally distributed by gender. They filled in the Multidimensional Self-Esteem Test, while parents completed a questionnaire on their child's schooling. Global self-esteem was mostly below the 50 percentile (58.5%), especially regarding interpersonal relationships (75%). An independent sample t -test showed significant mean differences on the emotionality scale ( t = 2.23; degree of freedom (df) = 24; p = 0.03) and in the bodily experience scale ( t = 3.02; df = 24; p = 0.006) with survivors of Acute Myeloid Leukaemia (AML) having lower scores. An Analysis of Variance (ANOVA ) showed significant mean differences in the bodily experience scale ( F = 12.31; df = 2, p = 0.0001) depending on the survivors' assigned risk band. The parent reports showed that 43.5% of children had difficulties at school. Childhood AML survivors with a high-risk treatment were more at risk in their self-esteem perceptions. Preventive interventions focusing on self-esteem and scholastic wellbeing are suggested in order to help their return to their normal schedules.

Leukaemia near british nuclear installations

International Nuclear Information System (INIS)

Hubert, D.

1991-01-01

An excess of childhood leukaemia has been seen near some British nuclear installations, especially near the Sellafield reprocessing plant. The same result was found in a more general study including a large number of nuclear sites. Similar studies made in USA, Canada and France have been negative. Moreover, epidemiological studies made in England have discovered other childhood leukaemia clusters in areas far from nuclear facilities, and especially near potential sites of nuclear installations. Several explanations are suggested but no definite conclusion is yet possible. Doses from radioactive releases seem to be too low to account for the additional deaths from leukaemia by environmental contamination. A virus activation, which might be associated with population influx into rural isolated areas, has been considered. The hypothesis of genetic mutation induced by ionising radiation in the fathers of children with leukaemia has been made because a higher risk of leukaemia was observed for children of fathers employed at Sellafield. No firm conclusion is possible considering the small number of observed cases and the lack of excess leukaemias in the offspring of Hiroshima and Nagasaki survivors. The possibility of internal contamination, chemicals or even radon is discussed as other causes. Studies in progress might allow to find an answer to the problem of leukaemia in the vicinity of British nuclear installations [fr

The concept of treatment-free remission in chronic myeloid leukemia

Science.gov (United States)

Saußele, S; Richter, J; Hochhaus, A; Mahon, F-X

2016-01-01

The advent of tyrosine kinase inhibitors (TKI) into the management of patients with chronic myeloid leukemia (CML) has profoundly improved prognosis. Survival of responders is approaching that of the general population but lifelong treatment is still recommended. In several trials, TKI treatment has been stopped successfully in approximately half of the patients with deep molecular response. This has prompted the development of a new concept in the evaluation of CML patients known as ‘treatment-free remission'. The future in CML treatment will be to define criteria for the safe and most promising discontinuation of TKI on one hand, and, on the other, to increase the number of patients available for such an attempt. Until safe criteria have been defined, discontinuation of therapy is still experimental and should be restricted to clinical trials or registries. This review will provide an overview of current knowledge as well as an outlook on future challenges. PMID:27133824

High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia.

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Pasquet, Marlène; Bellanné-Chantelot, Christine; Tavitian, Suzanne; Prade, Naïs; Beaupain, Blandine; Larochelle, Olivier; Petit, Arnaud; Rohrlich, Pierre; Ferrand, Christophe; Van Den Neste, Eric; Poirel, Hélène A; Lamy, Thierry; Ouachée-Chardin, Marie; Mansat-De Mas, Véronique; Corre, Jill; Récher, Christian; Plat, Geneviève; Bachelerie, Françoise; Donadieu, Jean; Delabesse, Eric

2013-01-31

Congenital neutropenia is a group of genetic disorders that involve chronic neutropenia and susceptibility to infections. These neutropenias may be isolated or associated with immunologic defects or extra-hematopoietic manifestations. Complications may occur as infectious diseases, but also less frequently as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Recently, the transcription factor GATA2 has been identified as a new predisposing gene for familial AML/MDS. In the present study, we describe the initial identification by exome sequencing of a GATA2 R396Q mutation in a family with a history of chronic mild neutropenia evolving to AML and/or MDS. The subsequent analysis of the French Severe Chronic Neutropenia Registry allowed the identification of 6 additional pedigrees and 10 patients with 6 different and not previously reportedGATA2 mutations (R204X, E224X, R330X, A372T, M388V, and a complete deletion of the GATA2 locus). The frequent evolution to MDS and AML in these patients reveals the importance of screening GATA2 in chronic neutropenia associated with monocytopenia because of the frequent hematopoietic transformation, variable clinical expression at onset, and the need for aggressive therapy in patients with poor clinical outcome. Mutations of key transcription factor in myeloid malignancies.

Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

Science.gov (United States)

Swords, Ronan T; Erba, Harry P; DeAngelo, Daniel J; Bixby, Dale L; Altman, Jessica K; Maris, Michael; Hua, Zhaowei; Blakemore, Stephen J; Faessel, Hélène; Sedarati, Farhad; Dezube, Bruce J; Giles, Francis J; Medeiros, Bruno C

2015-05-01

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed. © 2015 John Wiley & Sons Ltd.

Lymphocytosis after treatment with dasatinib in chronic myeloid leukemia: Effects on response and toxicity.

Science.gov (United States)

Schiffer, Charles A; Cortes, Jorge E; Hochhaus, Andreas; Saglio, Giuseppe; le Coutre, Philipp; Porkka, Kimmo; Mustjoki, Satu; Mohamed, Hesham; Shah, Neil P

2016-05-01

The proliferation of clonal cytotoxic T-cells or natural killer cells has been observed after dasatinib treatment in small studies of patients with chronic myeloid leukemia (CML). The incidence of lymphocytosis and its association with response, survival, and side effects were assessed in patients from 3 large clinical trials. Overall, 1402 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP), CML-CP refractory/intolerant to imatinib, or with CML in accelerated or myeloid-blast phase were analyzed. Lymphocytosis developed in 32% to 35% of patients and persisted for >12 months. This was not observed in the patients who received treatment with imatinib. Dasatinib-treated patients in all stages of CML who developed lymphocytosis were more likely to achieve a complete cytogenetic response, and patients who had CML-CP with lymphocytosis were more likely to achieve major and deep molecular responses. Progression-free and overall survival rates were significantly longer in patients with CML-CP who were refractory to or intolerant of imatinib and had lymphocytosis. Pleural effusions developed more commonly in patients with lymphocytosis. Overall, lymphocytosis occurred and persisted in many dasatinib-treated patients in all phases of CML. Its presence was associated with higher response rates, significantly longer response durations, and increased overall survival, suggesting an immunomodulatory effect. Prospective studies are warranted to characterize the functional activity of these cells and to assess whether an immunologic effect against CML is detectable. Cancer 2016;122:1398-1407. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Drawing the line with leukaemia

International Nuclear Information System (INIS)

Taylor, D.; Wilkie, D.

1988-01-01

The cluster of cases of childhood leukaemia near nuclear installations in the United Kingdom are considered. The paper examines whether these clusters have occurred by chance, or are an artefact of the statistical methodology, or the result of variability in the reporting of these leukaemias, or the result of some local agent, such as radiation. Statistical methodology including tests of significance involve choices available to researchers when boundaries of the test cells are selected. Choice of the wrong boundaries can lead to misleading results, such as in the town of Lydney, Gloucestershire where an apparent cluster of leukaemias was reported in 1987. The quality of data is also a problem, and there is evidence that some registration of childhood leukaemia is 'missed'. The authors conclude that it is easy to manipulate data and produce scare stories, and research workers on clusters of leukaemia near nuclear installations must be vigilant about the methods they employ. (U.K.)

Chronic myeloid leukemia may be associated with several bcr-abl transcripts including the acute lymphoid leukemia-type 7 kb transcript

NARCIS (Netherlands)

Selleri, L.; von Lindern, M.; Hermans, A.; Meijer, D.; Torelli, G.; Grosveld, G.

1990-01-01

In the majority of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) patients, the c-abl gene is fused to the bcr gene, resulting in the transcription of an 8.5 kb chimeric bcr-abl mRNA, which is translated into a p210bcr-abl fusion protein. In about 50% of the Ph-positive acute lymphoid

SAMJ

African Journals Online (AJOL)

phoma,12 the Philadelphia chromosome in chronic myeloid leukaemia") ... Target DNA. Primer. I. Since it was first described,I.2 the polymerase chain reaction (PCR) has had an enormous impact on the field of molecular biology. It is rapidly bec9m- ... the enzymatic production of new DNA strands comple- mentary £0 both ...

[Cardiovascular management of patients with chronic myeloid leukemia from a multidisciplinary perspective, and proposing action protocol by consensus meeting].

Science.gov (United States)

García-Gutiérrez, Valentín; Jiménez-Velasco, Antonio; Gómez-Casares, M Teresa; Sánchez-Guijo, Fermín; López-Sendón, Jose Luis; Steegmann Olmedillas, Juan Luis

2016-06-17

The second generation tyrosine kinase inhibitors (TKI, dasatinib and nilotinib) used in chronic myeloid leukemia (CML) treatment have shown a benefit compared to imatinib in responses achieved and disease progression. However, both have been related to some cardiovascular toxicity, being more frequent in patients with cardiovascular risk factors (CVRFs). Nowadays, due to the lack of recommendations for CML patients, CVRF management is carried out heterogeneously. The aim of this work is to develop recommendations on the prevention and monitoring of cardiovascular events (CVD) in patients with CML treated with TKIs. Experts from the Spanish Group of Chronic Myeloid Leukemia together with experts in cardiovascular risk have elaborated, after a consensus meeting, recommendations for the prevention and follow-up of CVE in patients with CML treated with TKI. Recommendations regarding the necessary information to be collected on clinical history, treatment decisions, as well as treatment and monitoring of CVRFs are shown in this document. TKI treatment requires comprehensive patient management from a multidisciplinary approach, in which both the prevention and management of CVRFs are essential. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Outcome of children with acute myeloid leukaemia (AML) experiencing primary induction failure in the AIEOP AML 2002/01 clinical trial.

Science.gov (United States)

Quarello, Paola; Fagioli, Franca; Basso, Giuseppe; Putti, Maria C; Berger, Massimo; Luciani, Matteo; Rizzari, Carmelo; Menna, Giuseppe; Masetti, Riccardo; Locatelli, Franco

2015-11-01

Paediatric patients with acute myeloid leukaemia (AML) who fail induction due to primary resistance to chemotherapy account for a significant proportion of cases and have a particularly dismal prognosis. We report the clinical and biological data, and final outcome of 48 paediatric patients with primary-resistant AML enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 clinical trial. These patients had a significantly higher white blood cell count at diagnosis compared to other AML patients. Cytogenetic and molecular features did not differ between patients with primary induction failure and patients allocated to the high-risk group. For the whole patient population, the probability of overall survival, event-free survival (EFS) and disease-free survival (DFS) was 21·8% ± 6·2, 20·4% ± 5·9, and 49·5% ± 11·3, respectively. Twenty-eight (58%) patients received haematopoietic stem cell transplantation (HSCT); 3 were autologous and 25 were allogeneic. Patients who underwent HSCT had improved EFS (31·2% vs. 5%, P < 0·0001). Only one of the 20 patients who did not receive HSCT is alive and disease free. The 19 patients in complete remission at time of HSCT showed significantly better DFS than the 9 with active disease (46% vs. 0%, P = 0·02). This study represents one of the largest series with long-term follow up of paediatric AML patients with primary refractory disease. Children who underwent transplantation had an encouraging long-term outcome. Disease recurrence remains the major cause of treatment failure; a better understanding of the disease biology is desirable to develop more effective treatment strategies. © 2015 John Wiley & Sons Ltd.

Variants forms of Philadelphia translocation in two patients with chronic myeloid leukemia

International Nuclear Information System (INIS)

Valent, A.; Zamecnikova, A.; Krizan, P.; Karlic, H.; Nowotny, H.

1996-01-01

During a 4-year period (December 1990-December 1994), among other diagnoses hundred cases of chronic myeloid leukemia (CML) were analyzed in our departments. We focused our attention on two cases with a variant form of Philadelphia translocation. Cytogenetic and molecular genetic studies were performed to resolve the status of BCR and ABL in the bone marrow or peripheral blood cells of the two CML patients with complex translocations involving chromosomes, 3, 9, 22 and 9, 12, 22 respectively. In the first case the presence of Ph chromosome was detected cytogenetically, BCR-ABL translocation was detected by Southern hybridization. In the second phase, only the PCR method showed BCR-ABL rearrangement. The second case, with a random variant form of Ph translocation, could be detected using different methods of clinical molecular genetics. (author)

Planned Pregnancy in a Chronic Myeloid Leukemia Patient in Molecular Remission

Science.gov (United States)

Pavlovsky, Carolina; Giere, Isabel; Van Thillo, Germán

2012-01-01

Excellent response rates and a good quality of life have been observed since the introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment. Consequently, some challenges began to appear in CML women in child-bearing age wishing to become pregnant. Currently, many women around the world are in stable major/complete molecular response MMR/CMR (MMR: <0.1% BCR-ABL/ABL and CMR: undetectable BCR-ABL mRNA by RQ-PCR transcript levels on the international scale). The condition of stable MMR/CMR is linked to a long-term virtual absence of progression to the accelerated and blastic phase and to the possibility of stopping the TKI treatment with the maintenance of a condition of CMR in a proportion of cases. Imatinib teratogenic and prescribing information prohibits the use of it during pregnancy. We describe the case of a 36-year-old female patient with CML in chronic phase who stopped imatinib after 2 years in major molecular response (MMR) to plan a pregnancy. Molecular monitoring by RQ-PCR was performed quarterly. She achieved a safe pregnancy and delivery maintaining an optimal molecular response throughout the pregnancy. Isolated literature reports have been described, but no formal advice has been described at present time. PMID:22928126

Pleural effusion as the initial manifestation of chronic myeloid leukemia: Report of a case with clinical and cytologic correlation

Directory of Open Access Journals (Sweden)

Paras Nuwal

2012-01-01

Full Text Available Pleural effusion in patients with chronic myeloid leukemia (CML is very rare and poorly understood. We report here a 26-year-old male patient having CML and presenting with pleural effusion as the first clinical sign. The possible mechanism of pleural effusion in CML, the cytological interpretive problem and the clinical significance of finding immature leucocytes in pleural fluid are also briefly discussed.

Turkish Chronic Myeloid Leukemia Study: Retrospective Sectional Analysis of CML Patients

Directory of Open Access Journals (Sweden)

Fahri Şahin

2013-12-01

Full Text Available OBJECTIVE: here have been tremendous changes in treatment and follow-up of patients with chronic myeloid leukemia (CML in the last decade. Especially, regular publication and updating of NCCN and ELN guidelines have provided enermous rationale and base for close monitorization of patients with CML. But, it is stil needed to have registry results retrospectively to evaluate daily CML practices. METHODS: In this article, we have evaluated 1133 patients’ results with CML in terms of demographical features, disease status, response, resistance and use of second-generation TKIs. RESULTS: The response rate has been found relatively high in comparison with previously published articles, and we detected that there was a lack of appropriate and adequate molecular response assessment. CONCLUSION: We concluded that we need to improve registry systems and increase the availability of molecular response assessment to provide high-quality patient care.

Prognostic value of regulatory T cells in newly diagnosed chronic myeloid leukemia patients.

Science.gov (United States)

Zahran, Asmaa M; Badrawy, Hosny; Ibrahim, Abeer

2014-08-01

Chronic myeloid leukemia (CML) is a clonal disease, characterized by a reciprocal t(9, 22) that results in a chimeric BCR/ABL fusion gene. Regulatory T cells (Tregs) constitute the main cell population that enables cancer cells to evade immune surveillance. The purpose of our study was to investigate the level of Tregs in newly diagnosed CML patients and to correlate it with the patients' clinical, laboratory and molecular data. We also aimed to assess the effect of treatment using tyrosine kinase inhibitor (TKI) on Treg levels. Tregs were characterized and quantified by flow cytometry in 63 newly diagnosed CML patients and 40 healthy controls. TKI was used in 45 patients with chronic phase CML, and the response to therapy was correlated with baseline Treg levels. The percentages of Tregs were significantly increased in CML patients compared to the controls. Treg numbers were significantly lower in patients with chronic phase CML versus the accelerated and blast phases, and were significantly lower in patients with complete molecular remission (CMR) compared to those patients without CMR. Tregs may play a role in the maintenance of CML. Moreover, the decrease of their levels in patients with CMR suggests that Tregs might have a clinical value in evaluating the effects of therapy.

Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec®, Gleevec™

Directory of Open Access Journals (Sweden)

Martin Henkes

2008-03-01

Full Text Available 1Martin Henkes, 2Heiko van der Kuip, 1Walter E Aulitzky12nd Department of Internal Medicine, Oncology and Hematology, Robert Bosch Hospital, Auerbachstr. 110, Stuttgart, Germany; 2Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, Stuttgart, and University of Tuebingen, GermanyAbstract: Treatment options for chronic myeloid leukemia (CML have changed dramatically during the last decades. Interferon-α treatment and stem cell transplantation (SCT clearly improved survival over conventional chemotherapy and offered the possibility of complete and durable responses. With the advent of the small molecule inhibitor imatinib mesylate (Glivec®, GleevecTM targeting the causative Bcr-Abl oncoprotein, the era of molecular cancer therapy began with remarkable success especially in chronic phase patients. Today, imatinib is the first-line treatment for CML. However, imatinib does not appear to be capable to eliminate all leukemia cells in the patients and pre-existing as well as acquired resistance to the drug has been increasingly recognized. To overcome these problems, several strategies involving dose escalation, combinations with other agents, and novel Bcr-Abl inhibitors have been developed.Keywords: CML therapy, imatinib, SCT, novel kinase inhibitors

Indoor radon and childhood leukaemia

International Nuclear Information System (INIS)

Raaschou-Nielsen, O.

2008-01-01

This paper summarises the epidemiological literature on domestic exposure to radon and risk for childhood leukaemia. The results of 12 ecological studies show a consistent pattern of higher incidence and mortality rates for childhood leukaemia in areas with higher average indoor radon concentrations. Although the results of such studies are useful to generate hypotheses, they must be interpreted with caution, as the data were aggregated and analysed for geographical areas and not for individuals. The seven available case - control studies of childhood leukaemia with measurement of radon concentrations in the residences of cases and controls gave mixed results, however, with some indication of a weak (relative risk < 2) association with acute lymphoblastic leukaemia. The epidemiological evidence to date suggests that an association between indoor exposure to radon and childhood leukaemia might exist, but is weak. More case - control studies are needed, with sufficient statistical power to detect weak associations and based on designs and methods that minimise misclassification of exposure and provide a high participation rate and low potential selection bias. (authors)

Recurrent SETBP1 mutations in atypical chronic myeloid leukemia

Science.gov (United States)

Piazza, Rocco; Valletta, Simona; Winkelmann, Nils; Redaelli, Sara; Spinelli, Roberta; Pirola, Alessandra; Antolini, Laura; Mologni, Luca; Donadoni, Carla; Papaemmanuil, Elli; Schnittger, Susanne; Kim, Dong-Wook; Boultwood, Jacqueline; Rossi, Fabio; Gaipa, Giuseppe; De Martini, Greta P; di Celle, Paola Francia; Jang, Hyun Gyung; Fantin, Valeria; Bignell, Graham R; Magistroni, Vera; Haferlach, Torsten; Pogliani, Enrico Maria; Campbell, Peter J; Chase, Andrew J; Tapper, William J; Cross, Nicholas C P; Gambacorti-Passerini, Carlo

2013-01-01

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases. PMID:23222956

[Management of the cardiovascular disease risk during nilotinib treatment in chronic myeloid leukemia: 2015 recommendations from the France Intergroupe des Leucémies Myéloïdes Chroniques].

Science.gov (United States)

Rea, Delphine; Ame, Shanti; Charbonnier, Aude; Coiteux, Valérie; Cony-Makhoul, Pascale; Escoffre-Barbe, Martine; Etienne, Gabriel; Gardembas, Martine; Guerci-Bresler, Agnès; Legros, Laurence; Nicolini, Franck; Tulliez, Michel; Hermet, Eric; Huguet, Françoise; Johnson-Ansah, Hyacinthe; Lapusan, Simona; Quittet, Philippe; Rousselot, Philippe; Mahon, François-Xavier; Messas, Emmanuel

2016-02-01

Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 2nd generation tyrosine kinase inhibitor nilotinib is licensed for the treatment of chronic myeloid leukemia with resistance or intolerance to imatinib and newly diagnosed chronic phase-chronic myeloid leukemia. Nilotinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucémies Myéloïdes Chroniques is to provide an overview of nilotinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in nilotinib-treated patients. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Azacitidine in the 'real-world': an evaluation of 1101 higher-risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario, Canada.

Science.gov (United States)

Mozessohn, Lee; Cheung, Matthew C; Fallahpour, Saber; Gill, Tripat; Maloul, Asmaa; Zhang, Liying; Lau, Olivia; Buckstein, Rena

2018-06-01

The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher-risk disease treated with azacitidine (AZA) in the 'real-world' remains largely unknown. We evaluated 1101 consecutive higher-risk MDS patients (International Prognostic Scoring System intermediate-2/high) and low-blast count acute myeloid leukaemia (AML; 21-30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5-2-2. Overall, median number of cycles was 6 (range 1-67) and 8 (range 6-14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7-12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6-19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML. © 2018 John Wiley & Sons Ltd.

International development of an EORTC questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients : The EORTC QLQ-CML24

NARCIS (Netherlands)

Efficace, Fabio; Baccarani, Michele; Breccia, Massimo; Saussele, Susanne; Abel, Gregory; Caocci, Giovanni; Guilhot, Francois; Cocks, Kim; Naeem, Adel; Sprangers, Mirjam; Oerlemans, Simone; Chie, Weichu; Castagnetti, Fausto; Bombaci, Felice; Sharf, Giora; Cardoni, Annarita; Noens, Lucien; Pallua, Stephan; Salvucci, Marzia; Nicolatou-Galitis, Ourania; Rosti, Gianantonio; Mandelli, Franco

Background Health-related quality of life (HRQOL) is a key aspect for chronic myeloid leukemia (CML) patients. The aim of this study was to develop a disease-specific HRQOL questionnaire for patients with CML to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ

International development of an EORTC questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients: the EORTC QLQ-CML24

NARCIS (Netherlands)

Efficace, Fabio; Baccarani, Michele; Breccia, Massimo; Saussele, Susanne; Abel, Gregory; Caocci, Giovanni; Guilhot, Francois; Cocks, Kim; Naeem, Adel; Sprangers, Mirjam; Oerlemans, Simone; Chie, Weichu; Castagnetti, Fausto; Bombaci, Felice; Sharf, Giora; Cardoni, Annarita; Noens, Lucien; Pallua, Stephan; Salvucci, Marzia; Nicolatou-Galitis, Ourania; Rosti, Gianantonio; Mandelli, Franco

2014-01-01

Background Health-related quality of life (HRQOL) is a key aspect for chronic myeloid leukemia (CML) patients. The aim of this study was to develop a disease-specific HRQOL questionnaire for patients with CML to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ

[Molecular genetics in chronic myeloid leukemia with variant Ph translocation].

Science.gov (United States)

Wu, Wei; Li, Jian-yong; Zhu, Yu; Qiu, Hai-rong; Pan, Jin-lan; Xu, Wei; Chen, Li-juan; Shen, Yun-feng; Xue, Yong-quan

2007-08-01

To explore the value of fluorescence in situ hybridization (FISH) and multiplex fluorescence in situ hybridization (M-FISH) techniques in the detection of genetic changes in chronic myeloid leukemia (CML) with variant Philadelphia translocation (vPh). Cytogenetic preparations from 10 CML patients with vPh confirmed by R banding were assayed with dual color dual fusion FISH technique. If only one fusion signal was detected in interphase cells, metaphase cells were observed to determine if there were derivative chromosome 9[der (9)] deletions. Meanwhile, the same cytogenetic preparations were assayed with M-FISH technique. Of the 10 CML patients with vPh, 5 were detected with der (9) deletions by FISH technique. M-FISH technique revealed that besides the chromosome 22, chromosomes 1, 3, 5, 6, 8, 10, 11 and 17 were also involved in the vPh. M-FISH technique also detected the abnormalities which were not found with conventional cytogenetics (CC), including two never reported abnormalities. The combination of CC, FISH and M-FISH technique could refine the genetic diagnosis of CML with vPh.

[Myeloid sarcoma of the small bowel with inversion of chromosome 16: a description of 3 clinical cases].

Science.gov (United States)

Gavrilina, O A; Bariakh, E A; Parovichnikova, E N; Troitskaia, V V; Zvonkov, E E; Kravchenko, S K; Sinitsyna, M N; Obukhova, T N; Gitis, M K; Savchenko, V G

2014-01-01

Myeloid sarcoma (MS) is a rare malignant solid tumor presented with myeloid blast cells showing varying degrees of maturation. MS may have an extramedullary site, precede, or develop simultaneously with the clinical manifestations of acute myeloid leukemia (AML); it may also occur as an AML relapse. Besides AML, MS may be a manifestation of chronic myeloid leukemia or other chronic myeloproliferative diseases. Due to the fact that this disease is rare, the bulk of the literature on MS is presented with single descriptions of retrospective studies and clinical cases. The paper describes 3 cases of MS with inversion of chromosome 16 and small bowel lesion.

Epidemiologic study on survival of chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation

DEFF Research Database (Denmark)

Nicolini, Franck E; Mauro, Michael J; Martinelli, Giovanni

2009-01-01

The BCR-ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP......), or blastic-phase (BP) and Philadelphia chromosome-positive (Ph)(+) acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation...

Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib

Directory of Open Access Journals (Sweden)

Ronan Swords

2009-03-01

Full Text Available Ronan Swords, Devalingam Mahalingam, Swaminathan Padmanabhan, Jennifer Carew, Francis GilesInstitute for Drug Development, Cancer Therapy and Research Centre, University of Texas Health Science Centre at San Antonio, USAAbstract: Chronic myeloid leukemia (CML is the consequence of a single balanced translocation that produces the BCR-ABL fusion oncogene which is detectable in over 90% of patients at presentation. The BCR-ABL inhibitor imatinib mesylate (IM has improved survival in all phases of CML and is the standard of care for newly diagnosed patients in chronic phase. Despite the very significant therapeutic benefits of IM, a small minority of patients with early stage disease do not benefit optimally while IM therapy in patients with advanced disease is of modest benefit in many. Diverse mechanisms may be responsible for IM failures, with point mutations within the Bcr-Abl kinase domain being amongst the most common resistance mechanisms described in patients with advanced CML. The development of novel agents designed to overcome IM resistance, while still primarily targeted on BCR-ABL, led to the creation of the high affinity aminopyrimidine inhibitor, nilotinib. Nilotinib is much more potent as a BCR-ABL inhibitor than IM and inhibits both wild type and IM-resistant BCR-ABL with significant clinical activity across the entire spectrum of BCR-ABL mutants with the exception of T315I. The selection of a second generation tyrosine kinase inhibitor to rescue patients with imatinib failure will be based on several factors including age, co-morbid medical problems and ABL kinase mutational profile. It should be noted that while the use of targeted BCR-ABL kinase inhibitors in CML represents a paradigm shift in CML management these agents are not likely to have activity against the quiescent CML stem cell pool. The purpose of this review is to summarize the pre-clinical and clinical data on nilotinib in patients with CML who have failed prior

Bilateral Proliferative Retinopathy as the Initial Presentation of Chronic Myeloid Leukemia

Science.gov (United States)

Macedo, Mafalda S. F.; Figueiredo, Ana R. M.; Ferreira, Natália N.; Barbosa, Irene M. A.; Furtado, Maria João F. B. S.; Correia, Nuno F. C. B. A.; Gomes, Miguel P.; Lume, Miguel R. B.; Menéres, Maria João S.; Santos, Marinho M. N.; Meireles S., M. Angelina C.

2013-01-01

The authors report a rare case of a 48-year-old male with chronic myeloid leukemia (CML) who initially presented with a bilateral proliferative retinopathy. The patient complained of recent visual loss and floaters in both eyes (BE). Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 20/50 in the right eye and 20/200 in the left eye (LE). Fundoscopy showed the presence of bilateral peripheral capillary dropout with multiple retinal sea fan neovascularisations, which were confirmed on fluorescein angiography. Full blood count revealed hyperleukocytosis, thrombocytosis, anemia, and hyperuricemia. Bone marrow aspiration and biopsy showed the reciprocal chromosomal translocation t (9;22), diagnostic of CML. The patient was started on hydroxyurea, allopurinol and imatinib mesylate. He received bilateral panretinal laser photocoagulation and a vitrectomy was performed in the LE. The patient has been in complete hematologic, cytogenetic, and major molecular remission while on imatinib and his BCVA is 20/25 in BE. PMID:24339689

Hoxa9 and Hoxa10 induce CML myeloid blast crisis development through activation of Myb expression.

Science.gov (United States)

Negi, Vijay; Vishwakarma, Bandana A; Chu, Su; Oakley, Kevin; Han, Yufen; Bhatia, Ravi; Du, Yang

2017-11-17

Mechanisms underlying the progression of Chronic Myeloid Leukemia (CML) from chronic phase to myeloid blast crisis are poorly understood. Our previous studies have suggested that overexpression of SETBP1 can drive this progression by conferring unlimited self-renewal capability to granulocyte macrophage progenitors (GMPs). Here we show that overexpression of Hoxa9 or Hoxa10 , both transcriptional targets of Setbp1 , is also sufficient to induce self-renewal of primary myeloid progenitors, causing their immortalization in culture. More importantly, both are able to cooperate with BCR/ABL to consistently induce transformation of mouse GMPs and development of aggressive leukemias resembling CML myeloid blast crisis, suggesting that either gene can drive CML progression by promoting the self-renewal of GMPs. We further identify Myb as a common critical target for Hoxa9 and Hoxa10 in inducing self-renewal of myeloid progenitors as Myb knockdown significantly reduced colony-forming potential of myeloid progenitors immortalized by the expression of either gene. Interestingly, Myb is also capable of immortalizing primary myeloid progenitors in culture and cooperating with BCR/ABL to induce leukemic transformation of mouse GMPs. Significantly increased levels of MYB transcript also were detected in all human CML blast crisis samples examined over chronic phase samples, further suggesting the possibility that MYB overexpression may play a prevalent role in driving human CML myeloid blast crisis development. In summary, our results identify overexpression of HOXA9 , HOXA10 , and MYB as critical drivers of CML progression, and suggest MYB as a key therapeutic target for inhibiting the self-renewal of leukemia-initiating cells in CML myeloid blast crisis patients.

Quantitative multiplex quantum dot in-situ hybridisation based gene expression profiling in tissue microarrays identifies prognostic genes in acute myeloid leukaemia

Energy Technology Data Exchange (ETDEWEB)

Tholouli, Eleni [Department of Haematology, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL (United Kingdom); MacDermott, Sarah [The Medical School, The University of Manchester, Oxford Road, M13 9PT Manchester (United Kingdom); Hoyland, Judith [School of Biomedicine, Faculty of Medical and Human Sciences, The University of Manchester, Oxford Road, M13 9PT Manchester (United Kingdom); Yin, John Liu [Department of Haematology, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL (United Kingdom); Byers, Richard, E-mail: richard.byers@cmft.nhs.uk [School of Cancer and Enabling Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Stopford Building, Oxford Road, M13 9PT Manchester (United Kingdom)

2012-08-24

Highlights: Black-Right-Pointing-Pointer Development of a quantitative high throughput in situ expression profiling method. Black-Right-Pointing-Pointer Application to a tissue microarray of 242 AML bone marrow samples. Black-Right-Pointing-Pointer Identification of HOXA4, HOXA9, Meis1 and DNMT3A as prognostic markers in AML. -- Abstract: Measurement and validation of microarray gene signatures in routine clinical samples is problematic and a rate limiting step in translational research. In order to facilitate measurement of microarray identified gene signatures in routine clinical tissue a novel method combining quantum dot based oligonucleotide in situ hybridisation (QD-ISH) and post-hybridisation spectral image analysis was used for multiplex in-situ transcript detection in archival bone marrow trephine samples from patients with acute myeloid leukaemia (AML). Tissue-microarrays were prepared into which white cell pellets were spiked as a standard. Tissue microarrays were made using routinely processed bone marrow trephines from 242 patients with AML. QD-ISH was performed for six candidate prognostic genes using triplex QD-ISH for DNMT1, DNMT3A, DNMT3B, and for HOXA4, HOXA9, Meis1. Scrambled oligonucleotides were used to correct for background staining followed by normalisation of expression against the expression values for the white cell pellet standard. Survival analysis demonstrated that low expression of HOXA4 was associated with poorer overall survival (p = 0.009), whilst high expression of HOXA9 (p < 0.0001), Meis1 (p = 0.005) and DNMT3A (p = 0.04) were associated with early treatment failure. These results demonstrate application of a standardised, quantitative multiplex QD-ISH method for identification of prognostic markers in formalin-fixed paraffin-embedded clinical samples, facilitating measurement of gene expression signatures in routine clinical samples.

Dipeptide species regulate p38MAPK–Smad3 signalling to maintain chronic myelogenous leukaemia stem cells

Science.gov (United States)

Naka, Kazuhito; Jomen, Yoshie; Ishihara, Kaori; Kim, Junil; Ishimoto, Takahiro; Bae, Eun-Jin; Mohney, Robert P.; Stirdivant, Steven M.; Oshima, Hiroko; Oshima, Masanobu; Kim, Dong-Wook; Nakauchi, Hiromitsu; Takihara, Yoshihiro; Kato, Yukio; Ooshima, Akira; Kim, Seong-Jin

2015-01-01

Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques. Strikingly, we show that CML stem cells accumulate significantly higher levels of certain dipeptide species than normal HSCs. Once internalized, these dipeptide species activate amino-acid signalling via a pathway involving p38MAPK and the stemness transcription factor Smad3, which promotes CML stem cell maintenance. Importantly, pharmacological inhibition of dipeptide uptake inhibits CML stem cell activity in vivo. Our results demonstrate that dipeptide species support CML stem cell maintenance by activating p38MAPK–Smad3 signalling in vivo, and thus point towards a potential therapeutic target for CML treatment. PMID:26289811

Considering baseline factors and early response rates to optimize therapy for chronic myeloid leukemia in chronic phase.

Science.gov (United States)

Akard, Luke P; Bixby, Dale

2016-05-01

Multiple BCR-ABL tyrosine kinase inhibitors (TKIs) are available for the treatment of chronic myeloid leukemia in chronic phase (CML-CP), and several baseline and on-treatment predictive factors have been identified that can be used to help guide TKI selection for individual patients. In particular, early molecular response (EMR; BCR-ABL ≤10% on the International Scale at 3 months) has become an accepted benchmark for evaluating whether patients with CML-CP are responding optimally to frontline TKI therapy. Failure to achieve EMR is considered an inadequate initial response according to the National Comprehensive Cancer Network guidelines and a warning response according to the European LeukemiaNet recommendations. Here we review data supporting the importance of achieving EMR for improving patients' long-term outcomes and discuss key considerations for selecting a frontline TKI in light of these data. Because a higher proportion of patients achieve EMR with second-generation TKIs such as nilotinib and dasatinib than with imatinib, these TKIs may be preferable for many patients, particularly those with known negative prognostic factors at baseline. We also discuss other considerations for frontline TKI choice, including toxicities, cost-effectiveness, and the emerging goals of deep molecular response and treatment-free remission.

224Ra: Risk to bone and haematopoietic tissue in ankylosing spondylitis patients

International Nuclear Information System (INIS)

Wick, R.R.; Goessner, W.; Chmelevsky, D.

1986-01-01

This follow-up study includes 1501 adult patients, who received repeated intraveneous injections of 224 Ra as a treatment for ankylosing spondylitis (a.sp), and a control group of 1557 a.sp. patients not treated with radioactive drugs or X-rays. The average total injected activity for the patients of the exposure group was 4.8 μCi of 224 Ra per kg body weight; the resulting average skeletal dose of α-rays has been 0.65 Gy. The mean duration of the 224 Ra treatment was 12 weeks with the mode at 10 weeks. At present, the mean follow-up time in the group of exposed patients is 16 years, and three cases of malignant skeletal tumours have been observed in patients with α-doses to the skeleton below 0.9 Gy (the lowest skeletal dose found to be associated with a bone tumour in the high dose group followed by Spiess and Mays). Based on general population statistics the expected number of bone tumours (ICD 170) was 0.4-0.7 . A recent risk estimate from data of Spiess and Mays suggests 5.8 radiation induced bone tumours for the present follow-up time. It is, furthermore, notable that 2 of the 3 observed skeletal tumours are tumours of the bone marrow; in the high dose group of Spiess and Mays there has been only 1 bone marrow tumour among 55 bone tumours. No malignant bone tumours have occurred, until now, in the control group. In the 224 Ra-group and the control group there have been 6 and 5 leukaemias, respectively,. Among the 6 leukaemias in the 224 R group 3 were chronic myeloid leukaemias while among the 5 leukaemias in the control group there was no chronic myeloid leukaemia. (orig.)

[Transient myeloproliferation and acute myeloid leukemia in infants with Down's syndrome].

Science.gov (United States)

Creutzig, U; Ritter, J; Vormoor, J; Eschenbach, C; Dickerhoff, R; Burdach, S; Scheel-Walter, H G; Kühl, J; Schellong, G

1990-01-01

Transient neonatal myeloproliferative disorders (TMD's) indistinguishable from acute leukaemia by clinical and morphological criteria have been described in neonates with Down's syndrome. To analyse its clinical significance, 10 infants under 1 year of age presenting with Down's syndrome and the morphological picture of acute myelogenous leukaemia were reviewed. 3 of these children had true AML leading to death after 2, 8 and 11 months. In the other 7 children the diagnosis TMD was suggested as spontaneous or in one case interferon-induced remission occurred within 4 to 25 weeks after diagnosis. The interferon-treated patient died of SIDS at the age of 11 months. Another one of the TMD children developed fatal erythroleukaemia at the age of 2 years. Regarding initial clinical and haematological parameters, TMD was indistinguishable from true congenital leukaemie. In all patients classification according to the FAB criteria was difficult, as mainly undifferentiated or poorly differentiated myeloid blasts were seen, sometimes with erythro- or megakaryocytic features. Because of the difficulties in the differential diagnosis of TMD and true AML it is recommended to delay specific cytostatic therapy in neonates with Down's syndrome, until definite progression of the leukaemic process is observed or cytogenetic analyses suggesting true AML are available.

Expression of interferon regulatory factor 4 in chronic myeloid leukemia: correlation with response to interferon alfa therapy.

Science.gov (United States)

Schmidt, M; Hochhaus, A; König-Merediz, S A; Brendel, C; Proba, J; Hoppe, G J; Wittig, B; Ehninger, G; Hehlmann, R; Neubauer, A

2000-10-01

Mice experiments have established an important role for interferon regulatory factor (IRF) family members in hematopoiesis. We wanted to study the expression of interferon regulatory factor 4 (IRF4) in various hematologic disorders, especially chronic myeloid leukemia (CML), and its association with response to interferon alfa (IFN-alpha) treatment in CML. Blood samples from various hematopoietic cell lines, different leukemia patients (70 CML, 29 acute myeloid leukemia [AML], 10 chronic myelomonocytic leukemia [CMMoL], 10 acute lymphoblastic leukemia, and 10 chronic lymphoid leukemia patients), and 33 healthy volunteers were monitored for IRF4 expression by reverse transcriptase polymerase chain reaction. Then, with a focus on CML, the IRF4 level was determined in sorted cell subpopulations from CML patients and healthy volunteers and in in vitro-stimulated CML cells. Furthermore, IRF4 expression was compared in the CML samples taken before IFN-alpha therapy and in 47 additional CML samples taken during IFN-alpha therapy. IRF4 expression was then correlated with cytogenetic response to IFN-alpha. IRF4 expression was significantly impaired in CML, AML, and CMMoL samples. The downregulation of IRF4 in CML samples was predominantly found in T cells. In CML patients during IFN-alpha therapy, a significant increase in IRF4 levels was detected, and this was also observed in sorted T cells from CML patients. The increase seen during IFN-alpha therapy was not due to different blood counts. In regard to the cytogenetic response with IFN-alpha, a good response was associated with high IRF4 expression. IRF4 expression is downregulated in T cells of CML patients, and its increase is associated with a good response to IFN-alpha therapy. These data suggest IRF4 expression as a useful marker to monitor, if not predict, response to IFN-alpha in CML.

Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.

Science.gov (United States)

Law, Philip J; Berndt, Sonja I; Speedy, Helen E; Camp, Nicola J; Sava, Georgina P; Skibola, Christine F; Holroyd, Amy; Joseph, Vijai; Sunter, Nicola J; Nieters, Alexandra; Bea, Silvia; Monnereau, Alain; Martin-Garcia, David; Goldin, Lynn R; Clot, Guillem; Teras, Lauren R; Quintela, Inés; Birmann, Brenda M; Jayne, Sandrine; Cozen, Wendy; Majid, Aneela; Smedby, Karin E; Lan, Qing; Dearden, Claire; Brooks-Wilson, Angela R; Hall, Andrew G; Purdue, Mark P; Mainou-Fowler, Tryfonia; Vajdic, Claire M; Jackson, Graham H; Cocco, Pierluigi; Marr, Helen; Zhang, Yawei; Zheng, Tongzhang; Giles, Graham G; Lawrence, Charles; Call, Timothy G; Liebow, Mark; Melbye, Mads; Glimelius, Bengt; Mansouri, Larry; Glenn, Martha; Curtin, Karen; Diver, W Ryan; Link, Brian K; Conde, Lucia; Bracci, Paige M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Albanes, Demetrius; Weinstein, Stephanie; Wang, Zhaoming; Caporaso, Neil E; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Vermeulen, Roel C H; Southey, Melissa C; Milne, Roger L; Clavel, Jacqueline; Topka, Sabine; Spinelli, John J; Kraft, Peter; Ennas, Maria Grazia; Summerfield, Geoffrey; Ferri, Giovanni M; Harris, Robert J; Miligi, Lucia; Pettitt, Andrew R; North, Kari E; Allsup, David J; Fraumeni, Joseph F; Bailey, James R; Offit, Kenneth; Pratt, Guy; Hjalgrim, Henrik; Pepper, Chris; Chanock, Stephen J; Fegan, Chris; Rosenquist, Richard; de Sanjose, Silvia; Carracedo, Angel; Dyer, Martin J S; Catovsky, Daniel; Campo, Elias; Cerhan, James R; Allan, James M; Rothman, Nathanial; Houlston, Richard; Slager, Susan

2017-02-06

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10 -13 ), 1q42.13 (rs41271473, P=1.06 × 10 -10 ), 4q24 (rs71597109, P=1.37 × 10 -10 ), 4q35.1 (rs57214277, P=3.69 × 10 -8 ), 6p21.31 (rs3800461, P=1.97 × 10 -8 ), 11q23.2 (rs61904987, P=2.64 × 10 -11 ), 18q21.1 (rs1036935, P=3.27 × 10 -8 ), 19p13.3 (rs7254272, P=4.67 × 10 -8 ) and 22q13.33 (rs140522, P=2.70 × 10 -9 ). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.

Treatment of chronic myeloid leukemia: assessing risk, monitoring response, and optimizing outcome.

Science.gov (United States)

Shanmuganathan, Naranie; Hiwase, Devendra Keshaorao; Ross, David Morrall

2017-12-01

Over the past two decades, tyrosine kinase inhibitors have become the foundation of chronic myeloid leukemia (CML) treatment. The choice between imatinib and newer tyrosine kinase inhibitors (TKIs) needs to be balanced against the known toxicity and efficacy data for each drug, the therapeutic goal being to maximize molecular response assessed by BCR-ABL RQ-PCR assay. There is accumulating evidence that the early achievement of molecular targets is a strong predictor of superior long-term outcomes. Early response assessment provides the opportunity to intervene early with the aim of ensuring an optimal response. Failure to achieve milestones or loss of response can have diverse causes. We describe how clinical and laboratory monitoring can be used to ensure that each patient is achieving an optimal response and, in patients who do not reach optimal response milestones, how the monitoring results can be used to detect resistance and understand its origins.

Leukaemia and nuclear installations

International Nuclear Information System (INIS)

Beral, V.

1990-01-01

The editorial comments on the paper by Gardner et al (BMJ 17 February 1990) which suggests a link between leukaemia and the occupational exposure of fathers to radiation and draws attention to the very small numbers involved and the only other relevant data available from the children of A-bomb survivors which do not show evidence of increased risk of leukaemia in the offspring. (author)

Leukaemia and nuclear installations

International Nuclear Information System (INIS)

Beral, V.

1991-01-01

The editorial comments on the paper by Gardner et al (BMJ 17 Feb 1990) which suggests a link between leukaemia and the occupational exposure of father to radiation and draws attention to the very small numbers involved and the only other relevant data available from the children of A-bomb survivors which do not show evidence of increased risk of leukaemia in the offspring. (author). 10 refs

Chronic myeloid leukaemia presenting with priapism as the only ...

African Journals Online (AJOL)

Objective: There have been few reports of priapism as complications of various haematological malignancies. Delays in establishing the cause and late institution of appropriate intervention in patients suffering from priapism could result in long-term complications, especially erectile dysfunction. We present here a case of ...

Translocation of BCR to chromosome 9: A new cytogenetic variant detected by FISH in two Ph-negative, BCR-positive patients with chronic myeloid leukemia

NARCIS (Netherlands)

A. Hagemeijer (Anne); A. Buijs (Arjan); E.M.E. Smit (Elisabeth); L.A.J. Janssen (Bart); G.J.M. Creemers (Geert-Jan); D. van der Plas (D.); G.C. Grosveld (Gerard)

1993-01-01

textabstractLeukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: I) Cytogenetics showed a normal 46.XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2

Causes of childhood leukaemia and lymphoma

International Nuclear Information System (INIS)

Lightfoot, Tracy J.; Roman, Eve

2004-01-01

Childhood cancer is rare comprising less than 1% of all malignancies diagnosed each year in developed countries. Leukaemia is the commonest form of cancer in children accounting for around a third of all childhood cancer, with acute lymphoblastic leukaemia (ALL) being the most prevalent. Biologically specific subtypes of ALL and acute myeloblastic leukaemia (AML), the other major morphological type of childhood leukaemia, are characterised by chromosomal changes. Whilst over 200 genes have been associated with chromosomal translocations, to date, only MLL, TEL, and AML1 have been linked with childhood leukaemia. Interestingly, there is increasing evidence to support the theory that gene rearrangements such as these may originate in utero. As with many other human diseases, both genetic and environmental factors have been implicated in the aetiology of the disease. Although much has been documented with regard to diet, smoking, alcohol consumption and recreational and prescription drug use during pregnancy, there is no consistent evidence to support a link with any of these factors and childhood leukaemia. However, findings from studies investigating prenatal and early life exposures are often based on small numbers of cases as both the type of cancer and exposure are rare. Furthermore, accurate information relating to past exposures can be difficult to obtain and is often reliant on self-reporting. To further our understanding of the aetiology of childhood leukaemia and lymphoma, there are areas which clearly warrant investigation. These include collection of parental dietary folate data combined with genetic analysis of the folate related genes, in utero exposure to DNA topoisomerase II inhibitors, and the possible effects of assisted reproduction technology on disease susceptibility

Leukaemia in East Suffolk

International Nuclear Information System (INIS)

Bush, M.F.H.

1983-09-01

An investigation was conducted by the East Suffolk Health Authority to determine whether there were any geographical variations in the incidence of leukaemia over the last fifteen years in East Suffolk suggesting an environmental hazard, e.g. Sizewell Power Station. No areas were found to have a statistically significant increased incidence of leukaemia cases although there did appear to be a cluster of cases in the Leiston area. (U.K.)

Chronic myelocytic leukaemia with unusual (27 years) complete remission terminating in acute undifferentiated leukaemia: a clinical and karyotypic study.

Science.gov (United States)

Najean, Y; Miclea, M; Tanzer, J; Lessard, M; Sigaux, F

1991-07-01

A case of clinically typical CML (300 x 10(6)/l leukocytes, 400 x 10(6)/l platelets, splenomegaly) is presented. After complete remission induced by busulphan, no clinical or haematological abnormalities were observed for 27 years until the development of acute leukaemia (type M1), which was rapidly fatal after a brief chemotherapy-induced remission. The cytogenetic findings were also original: no chromosome Ph1 (during remission 3 years after the onset of the disease), no translocation (banding study 5 years later), and no bcr/abl rearrangement (during the terminal phase).

Chronic myelogenous leukemia (CML)

Science.gov (United States)

CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... nuclear disaster. It takes many years to develop leukemia from radiation exposure. Most people treated for cancer ...

Imatinib mesylate in chronic myelogenous leukemia: a Congolese ...

African Journals Online (AJOL)

Major cytogenetic response was noticed in 87.18%. After a median follow up of 12 months, chronic myeloid leukemia had not progressed to the accelerated or blastic phase in an estimated 91.8% of patients and 86.6% were alive. Conclusion: Imatinib is effective in newly chronic phase chronic myeloid leukemia patient ...

Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric acute leukaemia patients receiving bortezomib-containing chemotherapy

Directory of Open Access Journals (Sweden)

Denise Niewerth

2016-09-01

Full Text Available Abstract Background Drug combinations of the proteasome inhibitor bortezomib with cytotoxic chemotherapy are currently evaluated in phase 2 and 3 trials for the treatment of paediatric acute myeloid leukaemia (AML and acute lymphocytic leukaemia (ALL. Methods We investigated whether expression ratios of immunoproteasome to constitutive proteasome in leukaemic cells correlated with response to bortezomib-containing re-induction chemotherapy in patients with relapsed and refractory acute leukaemia, enrolled in two Children’s Oncology Group phase 2 trials of bortezomib for ALL (COG-AALL07P1 and AML (COG-AAML07P1. Expression of proteasome subunits was examined in 72 patient samples (ALL n = 60, AML n = 12 obtained before start of therapy. Statistical significance between groups was determined by Mann-Whitney U test. Results Ratios of immunoproteasome to constitutive proteasome subunit expression were significantly higher in pre-B ALL cells than in AML cells for both β5i/β5 and β1i/β1 subunits (p = 0.004 and p < 0.001. These ratios correlated with therapy response in AML patients; β1i/β1 ratios were significantly higher (p = 0.028 between patients who did (n = 4 and did not reach complete remission (CR (n = 8, although for β5i/β5 ratios, this did not reach significance. For ALL patients, the subunit ratios were also higher for patients who showed a good early response to therapy but this relation was not statistically significant. Overall, for this study, the patients were treated with combination therapy, so response was not only attributed to proteasome inhibition. Moreover, the leukaemic blast cells were not purified for these samples. Conclusions These first ex vivo results encourage further studies into relative proteasome subunit expression to improve proteasome inhibition-containing therapy and as a potential indicator of bortezomib response in acute leukaemia.

Dose-adjusted arsenic trioxide for acute promyelocytic leukaemia in chronic renal failure.

Science.gov (United States)

Firkin, Frank; Roncolato, Fernando; Ho, Wai Khoon

2015-10-01

To determine the potential for arsenic trioxide (ATO) to be safely and effectively incorporated into induction therapy of newly diagnosed acute promyelocytic leukaemia (APL) in patients with severe chronic renal failure (CRF) by reduction of the ATO dosage to compensate for reduced renal elimination of arsenic in CRF. Two of the four CRF patients with APL in the study were dialysis-dependent, and two had eGFRs of 18 and 19 mL/min/1.73 m(2) . ATO dosage schedules were adjusted to obtain comparable whole-blood arsenic levels to those in APL patients with normal renal function who achieved molecular remission (MR) while receiving 10 mg ATO daily for 28 d. Average ATO administered per day in CRF patients ranged from 36 to 50% of the ATO administered to APL patients with normal renal function. No clinically significant cardiac, hepatic or other toxicities were detected. RT-PCR-negative MR was achieved after one treatment course in two patients and after two courses in the others. Relapse-free survival is 155, 60, 43 and 5 months. The observations in this pilot study have demonstrated whole-blood arsenic levels can provide a guide to adjustments of ATO dosage schedules that permit safe and effective therapeutic outcomes in APL patients with severely compromised renal function. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical relevance of the breakpoint sites within the M-BCR in 50 patients from Argentina with chronic myeloid leukemia.

Science.gov (United States)

Giere, I A; Larripa, I B

1996-08-01

Fifty patients from Argentina with chronic myeloid leukemia (CML) were studied in order to characterize the breakpoint site within the major breakpoint cluster region (M-BCR) and its relationship with the duration of the chronic phase (CP). The DNA digestion with the restriction enzymes: Bgl II, BAM HI and Hind III and hybridization with the 1.2Kb Hind III-Bgl II bcr probe showed that 56% of cases had the breakpoint in 5'M-bcr region and the remaining 44% in 3'M-bcr region. The duration of chronic phase from diagnosis to the onset of the blast crisis (BC) was correlated with the location of the breakpoint within the M-bcr and no statistical differences were observed between the 5' and the 3' groups. These data indicate that the breakpoint site within the bcr gene is not a prognostic indicator of the duration of CP of the disease.

Aberrant DNA Methylation in Chronic Myeloid Leukemia: Cell Fate Control, Prognosis, and Therapeutic Response.

Science.gov (United States)

Behzad, Masumeh Maleki; Shahrabi, Saeid; Jaseb, Kaveh; Bertacchini, Jessika; Ketabchi, Neda; Saki, Najmaldin

2018-01-31

Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy characterized by the expression of the BCR-ABL1 fusion gene with different chimeric transcripts. Despite the crucial impact of constitutively active tyrosine kinase in CML pathogenesis, aberrant DNA methylation of certain genes plays an important role in disease progression and the development of drug resistance. This article reviews recent findings relevant to the effect of DNA methylation pattern of regulatory genes on various cellular activities such as cell proliferation and survival, as well as cell-signaling molecules in CML. These data might contribute to defining the role of aberrant DNA methylation in disease initiation and progression. However, further studies are needed on the validation of specific aberrant methylation markers regarding the prognosis and prediction of response among the CML patients.

Managing chronic myeloid leukemia: a coordinated team care perspective.

Science.gov (United States)

Holloway, Stacie; Lord, Katharine; Bethelmie-Bryan, Beverly; Shepard, Marian W; Neely, Jessica; McLemore, Morgan; Reddy, Satyanarayan K; Montero, Aldemar; Jonas, William S; Gladney, Sara Pierson; Khanwani, Shyam L; Reddy, Silpa C; Lahiry, Anup K; Heffner, Leonard T; Winton, Elliott; Arellano, Martha; Khoury, Hanna Jean

2012-04-01

Treatment of chronic myeloid leukemia (CML) has seen dramatic progress in recent years with the development of tyrosine kinase inhibitors (TKIs). To take maximum advantage of therapy with TKIs, compliance and good understanding of monitoring response to therapy are essential. We established a team that included a hematologist, a physician assistant (PA), and a nurse who work closely with a social worker, a pharmacist, and a research coordinator to assist patients throughout their journey with CML. The patient and the referring community oncologist were incorporated into this team. This coordinated team care approach takes advantage of each member's specific skills to provide patients with education about CML, encourage patients' strong involvement in tracking/monitoring results/response to therapy, and support patients with issues that arise throughout the long course of the disease. A low rate of noncompliance with clinic visits (3%) was an indirect measure of the impact of this approach. The inclusion of the referring oncologist in the team extended the tracking of monitoring results to the community practice. We conclude that a coordinated team care approach is feasible in the management of patients with CML. This approach provided patients with education and a good understanding of response to therapy and improved relations with the health care team. Copyright © 2012 Elsevier Inc. All rights reserved.

IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia.

Science.gov (United States)

Bagnara, Davide; Callea, Vincenzo; Stelitano, Caterina; Morabito, Fortunato; Fabris, Sonia; Neri, Antonino; Zanardi, Sabrina; Ghiotto, Fabio; Ciccone, Ermanno; Grossi, Carlo Enrico; Fais, Franco

2006-04-01

Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented V(H)DJ(H) clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one V(L)J(L) rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s).

Risk of leukaemia following intravenous treatment with {sup 224}Ra - results of a long term follow-up study of ankylosing spondylitis patients; Leukaemierisiko nach intravenoeser {sup 224}Ra-Behandlung - Ergebnisse einer Langzeitstudie an Bechterew-Patienten

Energy Technology Data Exchange (ETDEWEB)

Wick, R.R. [GSF - Forschungszentrum fuer Umwelt und Gesundheit Neuherberg GmbH, Oberschleissheim (Germany). Inst. fuer Strahlenbiologie; Chmelevsky, D. [GSF - Forschungszentrum fuer Umwelt und Gesundheit Neuherberg GmbH, Oberschleissheim (Germany). Inst. fuer Strahlenschutz; Goessner, W. [GSF - Forschungszentrum fuer Umwelt und Gesundheit Neuherberg GmbH, Oberschleissheim (Germany). Inst. fuer Pathologie

1993-12-31

In an epidemiological study of the somatic late effects risk following incorporation of a short lived {alpha}-emitter, 1473 ankylosing spondylitis patients treated with repeated intravenous injections of {sup 224}Ra in the years 1948 - 75, have been observed in the GSF. The usual therapeutic plan consisted of a total of 10 - 12 injections of 1.036 MBq (28 {mu}Ci) of {sup 224}Ra each, given at weekly intervals; this would result in an cumulative {alpha}-dose of 0.56 - 0.67 Gy to the marrow-free skeleton of a 70-kg-man (standard man). These patients have been followed together with a control group of ankylosing spondylitis patients not treated with radioactive drugs and/or X-rays. Until May 1993 (mean follow-up time 19.9 yr), 595 patients of the exposure group and 722 patients of the control group have died, causes of death have been ascertained for 578, resp. 668 patients. Among others we observed in the exposure group 10 cases of leukaemia (vs. 2.7 - 2.8 cases expected, p < 0.001) and 6 cases of leukaemia in the control group (vs. 3.3 - 3.5 exp., p = 0.14). Subclassification of the leukaemias shows a clear preference for chronic myeloid leukaemia (CML) in the exposure group (4 cases obs. vs. 0.8 cases exp., p = 0.009), whereas in the control group the observed cases of CML are within the range of expectancy. Similar observations have not been made in another group of patients, now observed by Spiess and co-workers, who have been treated at a higher dose/dose rate range. This increased incidence of leukaemias in our exposure group is in one line with results from animal experiments with bone seeking {alpha}-emitters given at low dose rates. The induction of myeloid leukaemia has been demonstrated in mice down to dose rates of only a few mGy/day also for {sup 239}Pu, an {alpha}-emitter which like {sup 224}Ra deposits preferentially on the bone surface. (orig.) [Deutsch] Im Rahmen einer epidemiologischen Studie zum somatischen Strahlenspaetschadenrisiko nach

Cranial irradiation of leukaemia in childhood

International Nuclear Information System (INIS)

Gyenes, Gy.; Sator, G.; Varjas, G.

1979-01-01

The fundamental combined cytostatic treatment, initiated immediatly after the diagnosis, of the acute lymphoid leukaemia in the childhood is the method of choice. The haematologic remission, however, does not signify recovery, the starting-place of the relapse is mostly in the central nervous system. Telecobalt irradiation of the neurocranium using the known ray-physical and ray-biological advantages regularly distroys the leukaemia cells hidden in this region. In the paper the experiences gained with the irradiation of 151 children are reported. Further ulterior informations could be obtained by the authors only from 66 patients, out of them meningeosis leukaemia developed in 12%. (author)

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Directory of Open Access Journals (Sweden)

Agnes S. M. Yong

2017-04-01

Full Text Available Chronic myeloid leukemia (CML is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01% in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR, which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important

Immune Effector Recovery in Chronic Myeloid Leukemia and Treatment-Free Remission

Science.gov (United States)

Hughes, Amy; Yong, Agnes S. M.

2017-01-01

Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl oncogene. Tyrosine kinase inhibitors (TKIs) represent the standard of care for CML patients and exert a dual mode of action: direct oncokinase inhibition and restoration of effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%) in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a durable DMR as a prelude to successful treatment-free remission (TFR), which occurs in approximately half of all CML patients who cease TKI therapy. The lack of overt relapse in such patients has been attributed to immunological control of CML. In this review, we discuss an immunological timeline to successful TFR, focusing on the immunology of CML during TKI treatment; an initial period of immune suppression, limiting antitumor immune effector responses in newly diagnosed CML patients, linked to an expansion of immature myeloid-derived suppressor cells and regulatory T cells and aberrant expression of immune checkpoint signaling pathways, including programmed death-1/programmed death ligand-1. Commencement of TKI treatment is associated with immune system re-activation and restoration of effector-mediated [natural killer (NK) cell and T cell] immune surveillance in CML patients, albeit with differing frequencies in concert with differing levels of molecular response achieved on TKI. DMR is associated with maximal restoration of immune recovery in CML patients on TKI. Current data suggest a net balance between both the effector and suppressor arms of the immune system, at a minimum involving mature, cytotoxic CD56dim NK cells may be important in mediating

Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study

DEFF Research Database (Denmark)

Baccarani, Michele; Rosti, Gianantonio; Castagnetti, Fausto

2009-01-01

Imatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic...

Low educational level but not low income impairs the achievement of cytogenetic remission in chronic myeloid leukemia patients treated with imatinib in Brazil

Directory of Open Access Journals (Sweden)

Monica Napoleão Fortes Rego

2015-05-01

Full Text Available OBJECTIVES: In Brazil, imatinib mesylate is supplied as the first-line therapy for chronic myeloid leukemia in the chronic phase through the public universal healthcare program, Sistema Único de Saúde (SUS. We studied the socio-demographic factors that influenced therapy success in a population in the northeast region of Brazil. METHODS: Patients with chronic myeloid leukemia from the state of Piauí were treated in only one reference center. Diagnosis was based on WHO 2008 criteria. Risk was assessed by Sokal, Hasford and EUTOS scores. Patients received 400 mg imatinib daily. We studied the influence of the following factors on the achievement of complete cytogenetic response within one year of treatment: age, clinical risk category, time interval between diagnosis and the start of imatinib treatment, geographic distance from the patient's home to the hospital, years of formal education and monthly income. RESULTS: Among 103 patients studied, the median age was 42 years; 65% of the patients had 2-9 years of formal education, and the median monthly income was approximately 100 US$. Imatinib was started in the first year after diagnosis (early chronic phase in 69 patients. After 12 months of treatment, 68 patients had a complete cytogenetic response. The Hasford score, delay to start imatinib and years of formal education influenced the attainment of a complete cytogenetic response, whereas income and the distance from the home to the healthcare facility did not. CONCLUSION: Patients require additional healthcare information to better understand the importance of long-term oral anticancer treatment and to improve their compliance with the treatment.

Cytogenetics of Post-Irradiation Mouse Leukaemia

Energy Technology Data Exchange (ETDEWEB)

Wald, N.; Pan, S.; Upton, A.; Brown, R. [Graduate School of Public Health, University of Pittsburgh, PA (United States); Oak Ridge National Laboratory, Oak Ridge, TN (United States)

1969-11-15

The interrelationship between radiation, cytogenetic abnormalities, and viruses in leukaemogenesis has been studied in the RF/Un mouse which develops a high incidence of granulocytic leukaemia on radiation exposure. A virus-like agent has been demonstrated in such leukaemic animals and the disease has been transmitted by passage of apparently acellular materials from irradiated primary animals to normal recipients. Pilot cytogenetic studies revealed consistent abnormal chromosome markers and modal shifts in both irradiated leukaemic animals and in non-irradiated animals developing leukaemia after passage injection. To define better the relationship between consistent bone-marrow chromosome aberrations and postirradiation primary and passaged leukaemia, 100 RF/Un mice were studied which were irradiated with 300 R of 250-kVp X-rays at 100 weeks of age and subsequently developed leukaemia. Eighty-seven had granulocytic leukaemia and in 72 of these, bone-marrow cytogenetic abnormalities were found. The distribution of-numerical and structural chromosome aberrations in 3225 cells studied are reviewed in derail. The correlation of specific aberrations to clinical and histopathologic findings has been attempted: Sequential passages of apparently cell-free material from the post-irradiation leukaemic mice into unirradiated RE/Un recipients and subsequent passages from leukaemic recipients were performed to observe the evolution of any initial chromosome markers and shifts in modal chromosome number in the passage generations. Two-hundred-thirty-six mice were inoculated with the material obtained either from primary post-irradiation leukaemic mice or from serially-passaged leukaemia cases. In the most extensive passaged line, 22 transfer generations containing 129 leukaemic mice were examined by clinical, histopathologic, -haematologic and cytogenetic procedures. Evolution of abnormal chromosome modes from 41 in the early passages to 39 chromosomes consistently after the 4

A new Leukemia Prognostic Scoring System for refractory/relapsed adult acute myelogeneous leukaemia patients: a GOELAMS study.

Science.gov (United States)

Chevallier, P; Labopin, M; Turlure, P; Prebet, T; Pigneux, A; Hunault, M; Filanovsky, K; Cornillet-Lefebvre, P; Luquet, I; Lode, L; Richebourg, S; Blanchet, O; Gachard, N; Vey, N; Ifrah, N; Milpied, N; Harousseau, J-L; Bene, M-C; Mohty, M; Delaunay, J

2011-06-01

A simplified prognostic score is presented based on the multivariate analysis of 138 refractory/relapsed acute myeloid leukaemia (AML) patients (median age 55 years, range: 19-70) receiving a combination of intensive chemotherapy+Gemtuzumab as salvage regimen. Overall, 2-year event-free survival (EFS) and overall survival (OS) were 29±4% and 36±4%, respectively. Disease status (relapse Leukemia Prognostic Scoring System was then validated on an independent cohort of 111 refractory/relapsed AML patients. This new simplified prognostic score, using three clinical and biological parameters routinely applied, allow to discriminate around two third of the patients who should benefit from a salvage intensive regimen in the setting of refractory/relapsed AML patients. The other one third of the patients should receive investigational therapy.

Leukaemia: some unsolved problems

International Nuclear Information System (INIS)

Doll, Richard; Darby, Sarah

1991-01-01

The objectives of this session of the Human Radiation Research workshop were to review knowledge of radiation-induced leukaemia and identify major uncertainties and areas for future research. It is concluded that some of the most outstanding problems are to determine the risk of childhood leukaemia produced by parental gonad exposure, the relative risks produced by exposure of the embryo and fetus at different stages of intra-uterine life, how long the effect of intra-uterine radiation persists, and the leukaemogenic effects of radon. (UK)

Achieving deeper molecular response is associated with a better clinical outcome in chronic myeloid leukemia patients on imatinib front-line therapy

Science.gov (United States)

Etienne, Gabriel; Dulucq, Stéphanie; Nicolini, Franck-Emmanuel; Morisset, Stéphane; Fort, Marie-Pierre; Schmitt, Anna; Etienne, Madeleine; Hayette, Sandrine; Lippert, Eric; Bureau, Caroline; Tigaud, Isabelle; Adiko, Didier; Marit, Gérald; Reiffers, Josy; Mahon, François-Xavier

2014-01-01

Sustained imatinib treatment in chronic myeloid leukemia patients can result in complete molecular response allowing discontinuation without relapse. We set out to evaluate the frequency of complete molecular response in imatinib de novo chronic phase chronic myeloid leukemia patients, to identify base-line and under-treatment predictive factors of complete molecular response in patients achieving complete cytogenetic response, and to assess if complete molecular response is associated with a better outcome. A random selection of patients on front-line imatinib therapy (n=266) were considered for inclusion. Complete molecular response was confirmed and defined as MR 4.5 with undetectable BCR-ABL transcript levels. Median follow up was 4.43 years (range 0.79–10.8 years). Sixty-five patients (24%) achieved complete molecular response within a median time of 32.7 months. Absence of spleen enlargement at diagnosis, achieving complete cytogenetic response before 12 months of therapy, and major molecular response during the year following complete cytogenetic response was predictive of achieving further complete molecular response. Patients who achieved complete molecular response had better event-free and failure-free survivals than those with complete cytogenetic response irrespective of major molecular response status (95.2% vs. 64.7% vs. 27.7%, P=0.00124; 98.4% vs. 82.3% vs. 56%, P=0.0335), respectively. Overall survival was identical in the 3 groups. In addition to complete cytogenetic response and major molecular response, further deeper molecular response is associated with better event-free and failure-free survivals, and complete molecular response confers the best outcome. PMID:24362549

An investigation into childhood leukaemia in Northamptonshire

International Nuclear Information System (INIS)

1996-01-01

This report has been written specifically for the families of children who have had leukaemia in Northamptonshire. It gives the Health Authority's answers to the questions and worries that they raised at a meeting we had on 22nd September 1995. The report will also be circulated to other people who have been concerned by this problem and will, therefore, include some background information as well. The report thus has several different purposes: to give a brief summary of what is known about leukaemia and its causes; to explain the implications of having five cases of childhood leukaemia in a small area over a number of years; to let people know what Northamptonshire Health Authority has done in response to their concerns; to explain why a local epidemiological study of these cases could not tell us what caused leukaemia in the affected children; to reassure residents in the Pembroke Road area that we have found no reason to be concerned that their children are at an increased risk of developing leukaemia; to give information to the families about the current scientific evidence on the relationship between several potential environmental hazards they have identified and childhood leukaemia; to let people know that the important questions about what causes leukaemia in children are being addressed in several important and well-designed scientific studies. We hope that this report can be understood by people who are not familiar with medical jargon. Sometimes it has been necessary to use medical and technical terms, so at the back of this report there is a glossary which gives the meaning of any medical terms used

Complex Variant t(9;22 Chromosome Translocations in Five Cases of Chronic Myeloid Leukemia

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Ana Valencia

2009-01-01

Full Text Available The Philadelphia (Ph1 chromosome arising from the reciprocal t(9;22 translocation is found in more than 90% of chronic myeloid leukemia (CML patients and results in the formation of the chimeric fusion gene BCR-ABL. However, a small proportion of patients with CML have simple or complex variants of this translocation, involving various breakpoints in addition to 9q34 and 22q11. We report five CML cases carrying variant Ph translocations involving both chromosomes 9 and 22 as well as chromosomes 3, 5, 7, 8, or 10. G-banding showed a reciprocal three-way translocation involving 3q21, 5q31, 7q32, 8q24, and 10q22 bands. BCR-ABL fusion signal on der(22 was found in all of the cases by FISH.

[Modern therapy of chronic myeloid leukemia: an example for paradigma shift in hemato-oncology].

Science.gov (United States)

Leitner, A A; Hehlmann, R

2011-02-01

Chronic myeloid leukemia (CML) is exceptional amongst neoplasias since its underlying pathomechanism has been elucidated, and potent well tolerated targeted drugs, the tyrosine kinase inhibitors (TKI), are available for treatment. They convincingly improve prognosis while retaining good quality of life. Aims of therapy are complete remissions as well as prolongation of life and cure. Imatinib 400 mg per day is current standard therapy. There are hints for a better outcome with a higher initial imatinib dose or with combination therapy. Even after achievement of complete molecular response continuous therapy might be necessary in most cases. In case of imatinib intolerance or failure, the second generation TKI dasatinib and nilotinib and allogeneic stem cell transplantation are available. The use of second generation TKI as first line treatment might further improve prognosis. The therapeutic response should be regularly monitored according to international recommendations.

Efficacy of DSP30-IL2/TPA for detection of cytogenetic abnormalities in chronic lymphocytic leukaemia/small lymphocytic lymphoma.

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Holmes, P J; Peiper, S C; Uppal, G K; Gong, J Z; Wang, Z-X; Bajaj, R

2016-10-01

Chronic lymphocytic leukaemia (CLL) is the most prevalent leukaemia in the Western Hemisphere. Cytogenetic abnormalities in CLL are used for diagnosis, prognosis and treatment. However, detecting these is difficult because mature B cells do not readily divide in culture. Here, we present data on two mitogen cocktails: CpG-oligonucleotide DSP30/Interleukin-2 (IL-2) and DSP30/IL-2 in combination with 12-O-tetradecanoylphorbol-13-acetate (TPA). We analysed 165 cases of CLL with FISH and cytogenetics from January 2011 to June 2013. In 2011, three cultures were set-up: unstimulated, DSP30/IL-2-stimulated and TPA-stimulated. In 2012-2013, two cultures were set-up: unstimulated and stimulated with TPA/DSP30/IL-2. In 2011, FISH had a detection rate of 91% and cytogenetics using DSP30/IL2 had a detection rate of 91% (n = 22). In 2012-2013, FISH had a detection rate of 79% and cytogenetics using TPA/DSP30/IL-2 had a detection rate of 98% (n = 40). The percentage of cases with normal FISH but abnormal cytogenetics increased from 9% in 2011 to 21% in 2012-2013. The TPA/DSP30/IL-2 cultures in 2012-2013 detected more novel abnormalities (n = 5) as compared to DSP30/IL-2 alone (n = 3). TPA/DSP30/IL2 was as good as or better than DSP30/IL2 alone. TPA/DSP30/IL-2 offers a high detection rate for CLL abnormalities with a single stimulated culture and may increase detection of clinically significant abnormalities. © 2016 John Wiley & Sons Ltd.

Trace elements in scalp hair of leukaemia patients

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Khuder Ali

2014-08-01

Full Text Available The aim of this study was to determine the concentration of Fe, Ni, Cu, Zn and Pb in scalp hair of leukaemia patients and healthy volunteers, using the optimised XRF method. Leukaemia hair samples were classifi ed corresponding to type, growth and age of the participants. The results showed that the studied trace elements (TEs in both of leukaemia and control groups were positively skewed. In comparison with the control group, lower Fe, Cu, Zn and Pb and higher of Ni medians were found in all studied leukaemia patients. The median rank obtained by Mann-Whitney U-test revealed insignifi cant differences between the leukaemia patients subgroups and the controls. An exact probability (α 0.70 in the scalp hair of control group were observed between Ni/Fe-Ni, Cu/Fe-Cu, Zn/Fe-Zn, Pb/Fe-Pb, Cu/Ni-Zn/Ni, Cu/Ni-Pb/Ni, Zn/Ni-Pb/Ni, Zn/Fe-Zn/Cu, Pb/Ni-Ni and Ni/Fe-Pb/Ni, whereas only very strong positive ratios in the scalp hair of leukaemia patients group were observed between Ni/Fe-Ni, Cu/Fe-Cu, Zn/Fe-Zn and Pb/Fe-Pb, all correlations were signifi cant at p < 0.05. Other strong and signifi cant correlations were also observed in scalp hair of both groups. Signifi cant differences between grouping of studied TEs in all classifi ed leukaemia groups and controls were found using principal component analysis (PCA. The results of PCA confi rmed that the type and the growth of leukaemia factors were more important in element loading than the age factor.

Aetiology of childhood acute leukaemias: Current status of knowledge

International Nuclear Information System (INIS)

Rossig, C.; Juergens, H.

2008-01-01

Acute leukaemia is a consequence of malignant transformation of a haematopoietic progenitor cell. Molecular studies have revealed a prenatal origin of many childhood leukaemias. According to current models, a pre-leukaemic stem cell clone is generated by a first mutation in utero which, in a minority of children, progresses to leukaemia after receiving further postnatal genetic hits. The nature of pre- and postnatal events involved in leukemogenesis in children is not well understood. Although genetic predisposition and specific environmental exposures may account for individual cases, the bulk of childhood leukaemia cannot be explained by any of these factors. The higher incidence of the most common leukaemia subtype in affluent societies, as well as the age peak between 2-5 y, suggest a contributory role of socioeconomic factors. An abnormal immune response during delayed exposure to common infections provides a plausible mechanism for malignant progression of pre-leukaemic clones in a subgroup of children. As highlighted in this review, a common cause for all types and subtypes of childhood leukaemia is highly unlikely. Deeper insights into the pathogenesis of childhood leukaemia will rely on large-scale and combined epidemiological and bio-molecular studies. (authors)

Fallout, radiation doses near Dounreay, and childhood leukaemia

International Nuclear Information System (INIS)

Darby, S.C.; Doll, Richard

1987-01-01

Possible explanations for the recently reported increased incidence of childhood leukaemia around Dounreay were examined in the light of changes in the national incidence of leukaemia that occurred during the period of exposure to fallout from international testing of nuclear weapons in the atmosphere. It was concluded that the increase could not be accounted for by underestimate of the risk of leukaemia per unit dose of radiation at low doses and low dose rates, nor by underestimate of the relative biological efficiency of high compared with low linear energy transfer radiation. One possible explanation was underestimation of doses to the red bone marrow due to the discharges at Dounreay relative to dose from fallout, though investigation of ways in which this might have occurred did not suggest anything definite. Other explanations included a misconception of the site of origin of childhood leukaemia, outbreaks of an infectious disease and exposure to other, unidentified environmental agents. These findings weigh against the hypothesis that the recent increase in childhood leukaemia near Dounreay might be accounted for by radioactive discharges from nuclear plants, unless the doses to the stem cells from which childhood leukaemia originates have been grossly underestimated. (author)

Risk analysis of leukaemia incidence among people living along the Techa River: a nested case-control study

International Nuclear Information System (INIS)

Ostroumova, E; Gagniere, B; Laurier, D; Gudkova, N; Krestinina, L; Verger, P; Hubert, P; Bard, D; Akleyev, A; Tirmarche, M; Kossenko, M

2006-01-01

Large quantities of radioactive materials released over time from the Mayak nuclear weapons facility caused significant internal and external exposure for people living along the banks of the Techa River (Southern Urals, Russia). We conducted a nested case-control study in the Extended Techa River Cohort to determine whether the risk of leukaemia incidence increased with protracted exposure to ionising radiation or with other non-radiation risk factors. The study included 83 cases identified over 47 years of follow-up and 415 controls matched for sex, age at diagnosis, age (within a 5 year age group), and date of initial residence in the riverside area. External and internal doses have been calculated using the Techa River Dosimetry System 1996 (TRDS96). Conditional logistic regression was used to calculate odds ratios per Gray (OR/Gy) and 95% confidence intervals (95% CI). After excluding cases of chronic lymphoid leukaemia, the OR/Gy of total, external, and internal doses were 4.6 (95% CI: 1.7-12.3), 7.2 (95%CI: 1.7-30.0) and 5.4 (95%CI: 1.1-27.2), respectively. A history of solid tumour, either malignant or benign, before the leukaemia diagnosis was associated with a 2.5-fold increase in the leukaemia risk (95% CI: 1.1-5.9). Even though the analysis of confounders was less useful than expected because of missing data, multivariate analyses that took the exposure dose into account confirmed the association between leukaemia incidence and tumour history

Supplementary oxygen and risk of childhood lymphatic leukaemia.

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Naumburg, E; Bellocco, R; Cnattingius, S; Jonzon, A; Ekbom, A

2002-01-01

Childhood leukaemia has been linked to several factors, such as asphyxia and birthweight, which in turn are related to newborn resuscitation. Based on the findings from a previous study a population-based case-control study was performed to investigate the association between childhood leukaemia and exposure to supplementary oxygen and other birth-related factors. Children born in Sweden and diagnosed with lymphatic leukaemia between 1973 and 1989 (578 cases) were individually matched by gender and date of birth to a randomly selected control. Children with Down's syndrome were excluded. Exposure data were blindly gathered from antenatal, obstetric and other standardized medical records. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated by conditional logistic regression. Resuscitation with 100% oxygen with a facemask and bag immediately postpartum was significantly associated with an increased risk of childhood lymphatic leukaemia (OR = 2.57, 95% Cl 1.21-6.82). The oxygen-related risk further increased if the manual ventilation lasted for 3 min or more (OR = 3.54, 95% CI 1.16-10.80). Low Apgar scores at 1 and 5 min were associated with a non-significantly increased risk of lymphatic leukaemia. There were no associations between lymphatic leukaemia and supplementary oxygen later in the neonatal period or other birth-related factors. Resuscitation with 100% oxygen immediately postpartum is associated with childhood lymphatic leukaemia, but further studies are warranted to confirm the findings.

Ibrutinib versus previous standard of care: an adjusted comparison in patients with relapsed/refractory chronic lymphocytic leukaemia.

Science.gov (United States)

Hansson, Lotta; Asklid, Anna; Diels, Joris; Eketorp-Sylvan, Sandra; Repits, Johanna; Søltoft, Frans; Jäger, Ulrich; Österborg, Anders

2017-10-01

This study explored the relative efficacy of ibrutinib versus previous standard-of-care treatments in relapsed/refractory patients with chronic lymphocytic leukaemia (CLL), using multivariate regression modelling to adjust for baseline prognostic factors. Individual patient data were collected from an observational Stockholm cohort of consecutive patients (n = 144) diagnosed with CLL between 2002 and 2013 who had received at least second-line treatment. Data were compared with results of the RESONATE clinical trial. A multivariate Cox proportional hazards regression model was used which estimated the hazard ratio (HR) of ibrutinib versus previous standard of care. The adjusted HR of ibrutinib versus the previous standard-of-care cohort was 0.15 (p ibrutinib in the RESONATE study were significantly longer than with previous standard-of-care regimens used in second or later lines in routine healthcare. The approach used, which must be interpreted with caution, compares patient-level data from a clinical trial with outcomes observed in a daily clinical practice and may complement results from randomised trials or provide preliminary wider comparative information until phase 3 data exist.

BCR translocation to derivative chromosome 2, a new case of chronic myeloid leukemia with complex variant translocation and Philadelphia chromosome

International Nuclear Information System (INIS)

Al-Achkar, W.; Wafa, A.; Al-Medani, S.

2011-01-01

The well-known typical fusion gene BCR/ABL can be observed in connection with a complex translocation event in only 5-8% of cases with chronic myeloid leukemia (CML). Herein we report an exceptional CML case with complex chromosomal aberrations not observed before, translocated BCR to the derivative chromosome 2 [der(2)], additional to involving a four chromosomes translocation implying chromosomal regions such as 1p32 and 2q21 besides 9q34 and 22q11.2. Which were characterized by molecular cytogenetics. (author)

Study on the risk of late damage in humans after incorporation of the short-lived alpha emitter Ra-224

International Nuclear Information System (INIS)

Wick, R.R.; Nekolla, E.A.; Kellerer, A.M.; Goessner, W.

2003-01-01

An epidemiological study has been carried out at the GSF - National Research Center for Environment and Health - between 1948 and 1975, on 1460 ankylosing spondylitis (AS) patients. The aim of the study was to ascertain the late health effects suffered by these patients who had received repeated intravenous injections of the short lived α-emitter 224 Ra. These patients have been followed together with a control group of 1323 ankylosing spondylitis patients not treated with radioactive drugs and/or X-rays. Causes of death have been ascertained for 842 exposed patients and 861 controls by the end of 2002. In the exposed group there has been a total of 219 malignant diseases and 206 cases among the controls. In particular, we observed 15 cases of leukaemia in the exposure group and 8 cases of leukaemia in the control group. Further subclassification of the leukaemias demonstrated a high increase of myeloid leukaemia in the exposure group (9 cases obs. vs. 2.5 cases exp.), and out of these especially the acute myeloid leukaemias (6 cases observed vs. 1.6 expected), whereas in the control group the observed cases are within the expected range (3 myeloid leukaemias vs. 2.6 cases). Out of these 6 cases of myeloid leukaemia, 3 cases have been observed at doses comparable to those of the currently applied 224 Ra treatment with the preparation SpondylAT registered , in one case the 224 Ra-dose was the 0.6fold, in another case 1.6fold, whereas in one case the total dose could not be verified exactly. The enhanced leukaemia incidence in our exposed group is in line with results from animal experiments in mice having been injected with bone seeking α-emitters given at low dose rates. (orig.) [de

Pneumocystis carinii Pneumonia in Acute Lymphatic Leukaemia ...

African Journals Online (AJOL)

A case report of a patient who developed fatal pneumocystis pneumonia while in remission from acute lymphatic leukaemia is presented. Clinical and aetiological aspects of this rare infection are discussed. Attention is drawn to diagnostic pitfalls encountered in leukaemia.

Expression, prognostic significance and mutational analysis of protein tyrosine phosphatase SHP-1 in chronic myeloid leukemia.

Science.gov (United States)

Papadopoulou, Vasiliki; Kontandreopoulou, Elina; Panayiotidis, Panayiotis; Roumelioti, Maria; Angelopoulou, Maria; Kyriazopoulou, Lydia; Diamantopoulos, Panagiotis T; Vaiopoulos, George; Variami, Eleni; Kotsianidis, Ioannis; Athina Viniou, Nora

2016-05-01

The protein tyrosine phosphatase SHP-1 dephosphorylates BCR-ABL1, thereby serving as a potential control mechanism of BCR-ABL1 kinase activity. Pathways regulating SHP-1 expression, which could be exploited in the therapeutics of TKI-resistant chronic myeloid leukemia (CML), remain unknown. Moreover, the questions of whether there is any kind of SHP-1 deregulation in CML, contributing to disease initiation or evolution, as well as the question of prognostic significance of SHP-1, have not been definitively answered. This study shows moderately lower SHP-1 mRNA expression in chronic phase CML patients in comparison to healthy individuals and no change in SHP-1 mRNA levels after successful TKI treatment. Mutational analysis of the aminoterminal and phosphatase domains of SHP-1 in patients did not reveal genetic lesions. This study also found no correlation of SHP-1 expression at diagnosis with response to treatment, although a trend for lower SHP-1 expression was noted in the very small non-responders' group of the 3-month therapeutic milestone.

Childhood leukaemia around Canadian nuclear facilities. Phase 1

International Nuclear Information System (INIS)

Clarke, E.A.; McLaughlin, J.; Anderson, T.W.

1989-05-01

A ninefold excess risk of leukaemia, as observed in vicinity of the Sellafield facility, was not observed amongst children born to mothers residing in the areas around nuclear research facilities and uranium mining, milling and refining facilities in Ontario. In the vicinity of nuclear research facilities, the rate of leukaemia was, in fact, less than expected. In the areas around the uranium mining, milling and refining facilities; leukaemia occurred slightly more frequently than expected; however, due to small frequencies these results may have risen by chance. A slightly greater than expected occurrence of leukaemia was also detected, which may well have been due to chance, in an exploratory study of the areas around nuclear power generating stations in Ontario

B-Cell Chronic Lymphocytic Leukemia with 11q22.3 Rearrangement in Patient with Chronic Myeloid Leukemia Treated with Imatinib

Directory of Open Access Journals (Sweden)

Krzysztof Lewandowski

2016-01-01

Full Text Available The coexistence of two diseases chronic myeloid leukemia (CML and B-cell chronic lymphocytic leukemia (B-CLL is a rare phenomenon. Both neoplastic disorders have several common epidemiological denominators (they occur more often in men over 50 years of age but different origin and long term prognosis. In this paper we described the clinical and pathological findings in patient with CML in major molecular response who developed B-CLL with 11q22.3 rearrangement and Coombs positive hemolytic anemia during the imatinib treatment. Due to the presence of the symptoms of autoimmune hemolytic anemia and optimal CML response to the imatinib treatment, the decision about combined therapy with prednisone and imatinib was made. During the follow-up, the normalization of complete blood count and resolution of peripheral lymphadenopathy were noted. The hematologic response of B-CLL was diagnosed. The repeated FISH analysis of cultured peripheral blood lymphocytes showed 2% of cells carrying 11q22.3 rearrangement. At the same time, molecular monitoring confirmed the deep molecular response of CML. The effectiveness of such combination in the described case raises the question about the best therapeutic option in such situation, especially in patients with good imatinib tolerance and optimal response.

BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase.

Science.gov (United States)

Hughes, T P; Saglio, G; Quintás-Cardama, A; Mauro, M J; Kim, D-W; Lipton, J H; Bradley-Garelik, M B; Ukropec, J; Hochhaus, A

2015-09-01

BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.

Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia.

Science.gov (United States)

Giustacchini, Alice; Thongjuea, Supat; Barkas, Nikolaos; Woll, Petter S; Povinelli, Benjamin J; Booth, Christopher A G; Sopp, Paul; Norfo, Ruggiero; Rodriguez-Meira, Alba; Ashley, Neil; Jamieson, Lauren; Vyas, Paresh; Anderson, Kristina; Segerstolpe, Åsa; Qian, Hong; Olsson-Strömberg, Ulla; Mustjoki, Satu; Sandberg, Rickard; Jacobsen, Sten Eirik W; Mead, Adam J

2017-06-01

Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.

Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia

Science.gov (United States)

Laidlaw, Kamilla M.E.; Berhan, Samuel; Liu, Suhu; Silvestri, Giovannino; Holyoake, Tessa L.; Frank, David A.; Aggarwal, Bharat; Bonner, Michael Y.; Perrotti, Danilo

2016-01-01

The use of tyrosine kinase inhibitors (TKI), including nilotinib, has revolutionized the treatment of chronic myeloid leukemia (CML). However current unmet clinical needs include combating activation of additional survival signaling pathways in persistent leukemia stem cells after long-term TKI therapy. A ubiquitous signaling alteration in cancer, including CML, is activation of reactive oxygen species (ROS) signaling, which may potentiate stem cell activity and mediate resistance to both conventional chemotherapy and targeted inhibitors. We have developed a novel nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, imipramine blue (IB) that targets ROS generation. ROS levels are known to be elevated in CML with respect to normal hematopoietic stem/progenitor cells and not corrected by TKI. We demonstrate that IB has additive benefit with nilotinib in inhibiting proliferation, viability, and clonogenic function of TKI-insensitive quiescent CD34+ CML chronic phase (CP) cells while normal CD34+ cells retained their clonogenic capacity in response to this combination therapy in vitro. Mechanistically, the pro-apoptotic activity of IB likely resides in part through its dual ability to block NF-κB and re-activate the tumor suppressor protein phosphatase 2A (PP2A). Combining BCR-ABL1 kinase inhibition with NADPH oxidase blockade may be beneficial in eradication of CML and worthy of further investigation. PMID:27438151

Insights into the management of chronic myeloid leukemia in resource-poor settings: a Mexican perspective.

Science.gov (United States)

Gomez-de-León, Andrés; Gómez-Almaguer, David; Ruiz-Delgado, Guillermo J; Ruiz-Arguelles, Guillermo J

2017-09-01

The arrival of targeted therapy for chronic myeloid leukemia (CML) was revolutionary. However, due to the high cost of tyrosine kinase inhibitors, access to this highly effective therapy with strict monitoring strategies is limited in low to middle-income countries. In this context, following standard recommendations proposed by experts in developed countries is difficult. Areas covered: This review aims to provide an insight into the management of patients with CML living in a resource-limited setting. It addresses several issues: diagnosis, initial treatment, disease monitoring, and additional treatment alternatives including allogeneic hematopoietic stem cell transplantation. Expert commentary: Imatinib is probably the most cost-effective TKI for initial treatment in developing and underdeveloped countries. Generic imatinib preparations should be evaluated before considering their widespread use. Adherence to treatment should be emphasized. Adequate monitoring can be performed through several methods successfully and is important for predicting outcomes, particularly early in the first year, and if treatment suspension is being considered. Access to further therapeutic alternatives should define our actions after failure or intolerance to imatinib, preferring additional TKIs if possible. Allogeneic transplantation in chronic phase is a viable option in this context.

Dose Dependent Survival Response in Chronic Myeloid Leukemia under Continuous and Pulsed Targeted Therapy

International Nuclear Information System (INIS)

Pizzolato, N.; Valenti, D.; Spagnolo, B.; Persano Adorno, D.

2010-01-01

A simulative study of cancer growth dynamics in patients affected by Chronic Myeloid Leukemia (CML), under the effect of a targeted dose dependent continuous or pulsed therapy, is presented. We have developed a model for the dynamics of CML in which the stochastic evolution of white blood cell populations are simulated by adopting a Monte Carlo approach. Several scenarios in the evolutionary dynamics of white blood cells, as a consequence of the efficacy of the different modelled therapies, pulsed or continuous, are described. The best results, in terms of a permanent disappearance of the leukemic phenotype, are achieved with a continuous therapy and higher dosage. However, our findings demonstrate that an intermittent therapy could represent a valid choice in patients with high risk of toxicity, when a long-term therapy is considered. A suitably tuned pulsed therapy can enhance the treatment efficacy and reduce the percentage of patients developing resistance. (authors)

Monoclonal Antibody Therapy in Treating Patients With Ovarian Epithelial Cancer, Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Non-Small Cell Lung Cancer

Science.gov (United States)

2013-01-09

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer

[State of the art molecular diagnostics and therapy of chronic lymphocytic leukaemia in the era of new targeted therapies].

Science.gov (United States)

Gurbity Pálfi, Tímea; Fésüs, Viktória; Bödör, Csaba; Borbényi, Zita

2017-10-01

Chronic lymphoid leukaemia (CLL) has a heterogeneous clinical course depending on many clinical and molecular prognostic markers, which play an important role in the selection of the best treatment option. So far, TP53 disruption is the key prognostic and predictive factor assisting treatment decisions, especially in the era of novel therapies. Asymptomatic patients in early stages of the disease will still benefit from watchful waiting. In the frontline setting, chemoimmunotherapy is still the standard care in the majority of standard risk CLL patients. New classes of drugs like kinase inhibitors and BCL-2 inhibitors (ibrutinib, idelalisib and venetoclax) are the treatment of choice in CLL patients with relapsed/refractory disease, with the exception of high risk disease, where the optimal treatment is frontline ibrutinib monotherapy. In the near future, integrating next generation sequencing into the routine diagnostics would help the development of individual CLL patient management and to choose an optimal treatment strategy. Orv Hetil. 2017; 158(41): 1620-1629.

Analysis of images of acute human and animal leukaemia

International Nuclear Information System (INIS)

Feinermann, Emmanuel

1981-01-01

This research thesis first proposes a review of the development of stereology: historical backgrounds, basic principles. It discusses the choices regarding instrumentation: Coulter counter (principle and theory), quantitative analysis of particles, image analyser (optical microscope, epidiascope, scanners, detection, electronic pencil, computers, programming and data processing system), and stereo-logical parameters. The author then reports the stereo-logical study of acute human leukaemia: definition, classification, determination of spherical particle size distribution, lympho-blast size distributions. He reports the comparative study of rat L 5222 leukaemia and Brown Norway rat acute myelocytic leukaemia, and discusses their relationship with acute human leukaemia

Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

Science.gov (United States)

2014-08-26

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Secondary Acute Myeloid Leukemia; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma

Diagnosis and Treatment of Chronic Myeloid Leukemia (CML) in 2015

Science.gov (United States)

Thompson, Philip A; Kantarjian, Hagop; Cortes, Jorge E

2017-01-01

Few neoplastic diseases have undergone a transformation in a relatively short period of time like chronic myeloid leukemia (CML) has in the last few years. In 1960, CML was the first cancer where a unique chromosomal abnormality, “a minute chromosome”,1 was identified and a pathophysiologic correlation suggested. Landmark work followed, recognizing the underlying translocation between chromosomes 9 and 22 that gave rise to this abnormality2 and shortly afterward, the specific genes involved3,4 and the pathophysiologic implications of this novel rearrangement.5–7 Fast-forward a few years, this knowledge has given us the most remarkable example of a specific therapy targeting the dysregulated kinase activity represented by this molecular change. The broad use of tyrosine kinase inhibitors has resulted in an improvement in the overall survival to the point where the life expectancy of patients today is nearly equal to that of the general population.8 Still, there are challenges and unanswered questions that define the reasons why the progress still escapes many patients, and the details that separate patients from ultimate “cure”. In this manuscript we review our current understanding of CML in 2015, present recommendations for optimal management, and discuss the unanswered questions and what could be done to answer them in the near future. PMID:26434969

Chronic myeloid leukemia with variation of translocation at (Ph) [ins (22;9) (q11;q21q34)]: a case report.

Science.gov (United States)

Wang, Zhiqiong; Zen, Wen; Meng, Fankai; Xin, Xing; Luo, Li; Sun, Hanying; Zhou, Jianfeng; Huang, Lifang

2015-01-01

Chronic myeloid leukemia (CML) is most frequently observed in middle-aged individuals. In most patients, normal marrow cells are replaced by cells with an abnormal G-group chromosome, the Philadelphia (Ph) chromosome. The Ph chromosome that is characterized by the translocation (9;22) (q34;q11) is noted in 90-95% of patients diagnosed with CML. Studies have also shown that CML can be associated with various other cytogenetic abnormalities, with 5-10% of these cases showing complex translocation involving another chromosome in addition to the Ph chromosome. Here, we report the case of a Ph(+) CML patient with an inserted karyotype who presented clinically in the chronic phase but with atypical features. This case highlights the significance of cytogenetic abnormalities on the prognosis in CML.

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein

DEFF Research Database (Denmark)

Järås, Marcus; Johnels, Petra; Hansen, Nils Gunder

2010-01-01

Chronic myeloid leukemia (CML) is genetically characterized by the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between chromosomes 9 and 22 and giving rise to the constitutively active tyrosine kinase P210 BCR/ABL1. Therapeutic strategies aiming for a cure of CML...... will require full eradication of Ph chromosome-positive (Ph(+)) CML stem cells. Here we used gene-expression profiling to identify IL-1 receptor accessory protein (IL1RAP) as up-regulated in CML CD34(+) cells and also in cord blood CD34(+) cells as a consequence of retroviral BCR/ABL1 expression. To test...

Clinicopathological features of transient myeloproliferative syndrome and congenital leukaemia

International Nuclear Information System (INIS)

Sajid, N.; Ahmed, N.; Mahmood, S.

2010-01-01

The objectives of the study were to determine the spectrum of the clinical and pathological findings, the management and prognosis of patients of transient myeloproliferative syndrome (TMS) and congenital leukaemia. Study Design: Case series. Place and Duration of Study: The study was conducted over a period of 8 years, from January 2000 to December 2007, at the Children's Hospital and the Institute of Child Health, Lahore. Methodology: Suspected patients presenting with fever, pallor, bruises and hepatosplenomegaly and diagnosed as either transient myeloproliferative disorder or congenital leukaemia were studied. The complete blood count, reticulocyte count, leukocyte alkaline phosphatase score, liver function tests, karyotyping studies and bone marrow aspiration biopsy were performed in all of those patients. Management and out come was noted. Results were described as frequency percentages. Results: Out of 10,000 patients presenting during this period, 24 patients were diagnosed as either of transient myeloproliferative syndrome or congenital leukaemia. Fifteen of these were diagnosed as patients of TMS and 9 as patients of congenital leukaemia. Down syndrome (DS) was diagnosed in 75% of these patients. TMS patients were put on supportive treatment and recovered spontaneously. One DS patient with congenital leukaemia went into spontaneous remission and 2 of DS patients with congenital leukaemia responded to chemotherapy while rest of them either died or lost to follow-up. Conclusion: TMS and congenital leukaemia were not very uncommon in the studied population. Majority had Down syndrome. It is important to differentiate their clinical and pathological presentations for proper management. TMS may resolve with supportive treatment while congenital leukaemia is a fatal condition requiring chemotherapy. (author)

Prognostic significance of flow-cytometry evaluation of minimal residual disease in children with acute myeloid leukaemia treated according to the AIEOP-AML 2002/01 study protocol.

Science.gov (United States)

Buldini, Barbara; Rizzati, Frida; Masetti, Riccardo; Fagioli, Franca; Menna, Giuseppe; Micalizzi, Concetta; Putti, Maria Caterina; Rizzari, Carmelo; Santoro, Nicola; Zecca, Marco; Disarò, Silvia; Rondelli, Roberto; Merli, Pietro; Pigazzi, Martina; Pession, Andrea; Locatelli, Franco; Basso, Giuseppe

2017-04-01

In children with acute myeloid leukaemia (AML), assessment of initial treatment response is an essential prognostic factor; methods more sensitive than morphology are still under evaluation. We report on the measurement of minimal residual disease (MRD), by multicolour flow-cytometry in one centralized laboratory, in 142 children with newly diagnosed AML enrolled in the Associazione Italiana di EmatoOncologia Pediatrica-AML 2002/01 trial. At the end of the first induction course, MRD was 1% in 51 patients. The 8-year disease-free survival (DFS) of 125 children in morphological complete remission and with MRD <0·1%, 0·1-1% and ≥1% was 73·1 ± 5·6%, 37·8 ± 12·1% and 34·1 ± 8·8%, respectively (P < 0·01). MRD was also available after the second induction course in 92/142 patients. MRD was ≥0·1% at the end of the first induction course in 36 patients; 13 reached an MRD <0·1% after the second one and their DFS was 45·4 ± 16·7% vs. 22·8 ± 8·9% in patients with persisting MRD ≥0·1% (P = 0·037). Multivariate analysis demonstrated that MRD ≥0·1% after first induction course was, together with a monosomal karyotype, an independent adverse prognostic factor for DFS. Our results show that MRD detected by flow-cytometry after induction therapy predicts outcome in patients with childhood AML and can help stratifying post-remission treatment. © 2017 John Wiley & Sons Ltd.

Childhood leukaemia and socioeconomic status: What is the evidence?

International Nuclear Information System (INIS)

Adam, M.; Rebholz, C. E.; Egger, M.; Zwahlen, M.; Kuehni, C. E.

2008-01-01

The objectives of this systematic review are to summarise the current literature on socioeconomic status (SES) and the risk of childhood leukaemia, to highlight methodological problems and formulate recommendations for future research. Starting from the systematic review of Poole et al. (Socioeconomic status and childhood leukaemia: a review. Int. J. Epidemiol. 2006;35(2):370-384.), an electronic literature search was performed covering August 2002-April 2008. It showed that (1) the results are heterogeneous, with no clear evidence to support a relation between SES and childhood leukaemia; (2) a number of factors, most importantly selection bias, might explain inconsistencies between studies; (3) there is some support for an association between SES at birth (rather than later in childhood) and childhood leukaemia and (4) if there are any associations, these are weak, limited to the most extreme SES groups (the 10-20% most or least deprived). This makes it unlikely that they would act as strong confounders in research addressing associations between other exposures and childhood leukaemia. Future research should minimise case and control selection bias, distinguish between different SES measures and leukaemia subtypes and consider timing of exposures and cancer outcomes. (authors)

Childhood leukaemia, fallout and radiation doses near Dounreay

International Nuclear Information System (INIS)

Darby, S.C.; Doll, Richard

1987-01-01

The possible explanations of the recently reported increase in the incidence of childhood leukaemia around Dounreay are examined in the light of the changes in national leukaemia incidence that occurred during the period of exposure to fallout from international atmospheric testing of nuclear weapons. It is concluded that the increase cannot be due to underestimation of the risk of leukaemia per unit dose of radiation, nor to an underestimate of the relative biological efficiency of high as compared with low LET radiation. Possible explanations of the increase include an underestimate of the red bone marrow doses due to the Dounreay discharges relative to those from fallout, a misconception of the site of origin of childhood leukaemia, epidemics of infectious disease and exposure to some other unidentified environmental agent. (author)

Selecting the Best Frontline Treatment in Chronic Myeloid Leukemia

Science.gov (United States)

Yilmaz, Musa; Abaza, Yasmin; Jabbour, Elias

2017-01-01

With the discovery of Philadelphia chromosome, understanding of chronic myeloid leukemia (CML) pathobiology has tremendously increased. Development of tyrosine kinase inhibitors (TKI) targeting the BCR/ABL1 oncoprotein has changed the landscape of the disease. Today, the expected survival of CML patients, if properly managed, is likely to be similar to the general population. Imatinib is the first approved TKI in CML treatment, and for several years, it was the only option in the frontline setting. Four years ago, second generation TKIs (nilotinib and dasatinib) were approved as alternative frontline options. Now, clinicians are faced the challenge of making decision for which TKI to chose upfront. Second generation TKIs have been demonstrated to induce deeper and faster responses compared to imatinib, however, none of 3 TKIs have been shown to have a clear survival advantage, they all are reasonable options. In contrast, when considering therapy in individual patients, the case may be stronger for a specific TKI. Co-morbidities of the patient and side effect profile of the TKI of interest should be an important consideration in decision making. At present, the cost nilotinib or dasatinib is not remarkably different from imatinib. However, patent for imatinib is expected to expire soon, and it will be available as a generic. Clinicians, then, need to weigh the advantages some patients gain with nilotinib or dasatinib in the frontline setting against the difference in cost. Whatever TKI is chosen as frontline, intolerance, non-compliance or treatment failure should be recognized early as a prompt intervention increases the chance of achieving best possible response. PMID:25921387

Leukaemia and occupation: a New Zealand Cancer Registry-based case-control Study.

Science.gov (United States)

McLean, David; Mannetje, Andrea 't; Dryson, Evan; Walls, Chris; McKenzie, Fiona; Maule, Milena; Cheng, Soo; Cunningham, Chris; Kromhout, Hans; Boffetta, Paolo; Blair, Aaron; Pearce, Neil

2009-04-01

To examine the association between occupation and leukaemia. We interviewed 225 cases (aged 20-75 years) notified to the New Zealand Cancer Registry during 2003-04, and 471 controls randomly selected from the Electoral Roll collecting demographic details, information on potential confounders and a comprehensive employment history. Associations between occupation and leukaemia were analysed using logistic regression adjusted for gender, age, ethnicity and smoking. Elevated odds ratios (ORs) were observed in agricultural sectors including horticulture/fruit growing (OR: 2.62, 95% confidence interval (CI): 1.51, 4.55), plant nurseries (OR: 7.51, 95% CI: 1.85, 30.38) and vegetable growing (OR: 3.14, 95% CI: 1.18, 8.40); and appeared greater in women (ORs: 4.71, 7.75 and 7.98, respectively). Elevated ORs were also observed in market farmers/crop growers (OR: 1.84, 95% CI: 1.12, 3.02), field crop/vegetable growers (OR: 3.98, 95% CI: 1.46, 10.85), market gardeners (OR: 5.50, 95% CI: 1.59, 19.02), and nursery growers/workers (OR: 4.23, 95% CI: 1.34, 13.35); also greater in women (ORs: 3.48, 7.62, 15.74 and 11.70, respectively). These elevated ORs were predominantly for chronic lymphocytic leukaemia (CLL). Several associations persisted after semi-Bayes adjustment. Elevated ORs were observed in rubber/plastics products machine operators (OR: 3.76, 95% CI: 1.08, 13.08), predominantly in plastic product manufacturing. CLL was also elevated in tailors and dressmakers (OR: 7.01, 95% CI: 1.78, 27.68), cleaners (OR: 2.04, 95% CI: 1.00, 4.14) and builder's labourers (OR: 4.03, 95% CI: 1.30, 12.53). These findings suggest increased leukaemia risks associated with certain agricultural, manufacturing, construction and service occupations in New Zealand.

An economic analysis of high-dose imatinib, dasatinib, and nilotinib for imatinib-resistant chronic phase chronic myeloid leukemia in China: A CHEERS-compliant article.

Science.gov (United States)

Wu, Bin; Liu, Maobai; Li, Te; Lin, Houwen; Zhong, Hua

2017-07-01

The aim of the study was to test the cost-effectiveness of dasatinib compared to high-dose imatinib and nilotinib in Chinese patients who were diagnosed with imatinib-resistant chronic myeloid leukemia in the chronic phase (CML-CP). A Markov model combined with clinical effectiveness, utility, and cost data was used. The sensitivity analyses were conducted to determine the robustness of the model outcomes. The impact of patient assistance programs (PAPs) was assessed. Treatment with dasatinib is expected to produce 3.65, 0.59, and 0.15 more quality-adjusted life years (QALYs) in comparison with high-dose imatinib (600 and 800 mg) and nilotinib, respectively. When a PAP was available, dasatinib yielded an incremental cost of $16,417 per QALY compared to imatinib (600 mg) and was cost-saving compared to imatinib (800 mg) and nilotinib. When PAP is available in the Chinese setting, dasatinib is likely to be a cost-effective strategy for patients with CML-CP standard-dose imatinib resistance. The results should be carefully explained due to the assumptions and limitations used in the study.

Childhood leukaemia around Canadian nuclear facilities. Phase 2

International Nuclear Information System (INIS)

Clarke, E.A.; McLaughlin, J.; Anderson, T.W.

1991-06-01

Prompted by findings of increased occurrence of childhood leukaemia in the vicinity of some nuclear facilities in the United Kingdom, this study aimed to investigate whether the frequency of leukaemia among children born to mothers living near nuclear facilities in Ontario differed from the provincial average. The Ontario Cancer Registry was used to identify 1894 children aged 0 to 14 years who died from leukaemia between 1950 and 1987, and 1814 children who were diagnosed with leukaemia between 1964 and 1986. Residence at birth and death was obtained from birth and death certificates. Analyses were performed separately for nuclear research and development facilities; uranium mining, milling and refining facilities; and, nuclear generating stations; and for areas within the same county as the facility and 'nearby' - within a 25-km radius of the facility. Risk estimates were calculated as the ratio of the observed (O) number of events over the expected (E) number. In the vicinity of nuclear research and development facilities the rate of leukaemia was less than expected and within the bound of chance variation. In the areas around the uranium mining, milling and refining facilities and nuclear power plants leukaemia occurred slightly more frequently than expected, but due to small frequencies these differences may have arisen due to chance. Large differences between observed and expected rates were not detected around any of the Ontario facilities. This study was large enough to detect excess risks of the magnitude reported in the United Kingdom, but it was not large enough to discriminate between the observed relative risks and a chance finding. Levels of leukaemia detected near nuclear generating stations indicate the need for further investigation. (20 tabs., 15 figs., 32 refs.)

Re-emergence of interferon-α in the treatment of chronic myeloid leukemia

Science.gov (United States)

Talpaz, M; Hehlmann, R; Quintás-Cardama, A; Mercer, J; Cortes, J

2013-01-01

Treatment for chronic myeloid leukemia (CML) has evolved from chemotherapy (busulfan, hydroxyurea) to interferon-α (IFNα), and finally to tyrosine kinase inhibitors such as imatinib. Although imatinib has profoundly improved outcomes for patients with CML, it has limitations. Most significantly, imatinib cannot eradicate CML primitive progenitors, which likely accounts for the high relapse rate when imatinib is discontinued. IFNα, unlike imatinib, preferentially targets CML stem cells. Early studies with IFNα in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFNα were able to sustain durable remissions after discontinuing therapy and were probably cured. The mechanisms by which IFNα exerts its antitumor activity in CML are not well understood; however, activation of leukemia-specific immunity may have a role. Some clinical studies have demonstrated that the combination of imatinib and IFNα is superior to either therapy alone, perhaps because of their different mechanisms of action. Nonetheless, the side effects of IFNα often impede its administration, especially in combination therapy. Here, we review the role of IFNα in CML treatment and the recent developments that have renewed interest in this once standard therapy for patients with CML. PMID:23238589

Overexpression of Hiwi Inhibits the Growth and Migration of Chronic Myeloid Leukemia Cells.

Science.gov (United States)

Wang, Yalin; Jiang, Yan; Ma, Ning; Sang, Bailu; Hu, Xiaolin; Cong, Xiaofeng; Liu, Ziling

2015-09-01

Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by dysregulated growth and proliferation of hematopoietic stem/progenitor cells in bone marrow and excessive expansion of hematopoietic compartments in peripheral blood. Expression deletion of Hiwi, a human Piwi homolog, has been reported to be implicated in leukemogenesis. We here explored Hiwi's role in CML pathogenesis by determining how and whether its forced overexpression could affect CML cell growth and migration. The present results showed that lentivirus-mediated overexpression of Hiwi significantly suppressed cell proliferation and induced obvious apoptosis in K562 cells, a CML line cell line. Tumors in BALB/c nude mice generated by the K562 cells expressing Hiwi were much smaller than those formed by the control cells. Like in vitro, Hiwi upregulation induced cell apoptosis in the tumor tissues in vivo. Additionally, Hiwi elevation suppressed K562 cell migration and inhibited the activity and expression of matrix metalloproteinase-2 and -9. In summary, our study demonstrates that Hiwi overexpression inhibits CML cell growth and migration, providing insights into its role in CML pathogenesis.

Pharmacogenetics of tyrosine kinase inhibitors in gastrointestinal stromal tumor and chronic myeloid leukemia.

Science.gov (United States)

Ravegnini, Gloria; Sammarini, Giulia; Angelini, Sabrina; Hrelia, Patrizia

2016-07-01

Gastrointestinal stromal tumors (GIST) and chronic myeloid leukemia (CML) are two tumor types deeply different from each other. Despite the differences, these disorders share treatment with tyrosine kinase inhibitor imatinib. Despite the success of imatinib, the response rates vary among different individuals and pharmacogenetics may play an important role in the final clinical outcome. In this review, the authors provide an overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST and CML treatment efficacy and toxicity. So far, several polymorphisms influencing the pharmacokinetic determinants of imatinib have been identified. However, the data are not yet conclusive enough to translate pharmacogenetic tests in clinical practice. In this context, the major obstacles to pharmacogenetic test validation are represented by the small sample size of most studies, ethnicity and population admixture as confounding source, and uncertainty related to genetic variants analyzed. In conclusion, a combination of different theoretical approaches, experimental model systems and statistical methods is clearly needed, in order to appreciate pharmacogenetics applied to clinical practice in the near future.

Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.

Science.gov (United States)

Hochhaus, A; Masszi, T; Giles, F J; Radich, J P; Ross, D M; Gómez Casares, M T; Hellmann, A; Stentoft, J; Conneally, E; García-Gutiérrez, V; Gattermann, N; Wiktor-Jedrzejczak, W; le Coutre, P D; Martino, B; Saussele, S; Menssen, H D; Deng, W; Krunic, N; Bedoucha, V; Saglio, G

2017-07-01

The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR 4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1 IS )) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1 IS ⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR 4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).

Proximity to overhead power lines and childhood leukaemia

DEFF Research Database (Denmark)

Amoon, Aryana T; Crespi, Catherine M; Ahlbom, Anders

2018-01-01

BACKGROUND: Although studies have consistently found an association between childhood leukaemia risk and magnetic fields, the associations between childhood leukaemia and distance to overhead power lines have been inconsistent. We pooled data from multiple studies to assess the association with d...

New leukaemia link

International Nuclear Information System (INIS)

Roche, P.

1993-01-01

A new study around the Aldermaston and Burghfield nuclear weapons establishments published in the British Medical Journal has found a similar association between the risk of childhood leukaemia and employment in the nuclear industry to that found by Professor Gardner in 1990 at Sellafield. It suggests that occupational exposure to radiation prior to conception increases the risk of a subsequent child developing leukaemia by 9 times. It is clear that working at Aldermaston or Burghfield does not explain the entire excess of cancers -there must be another factor at work. The one factor that Aldermaston, Burghfield, Sellafield and Dounreay where a similar pattern is found, have in common is plutonium. Whilst further studies are important to determine the role played by plutonium, it should be declared 'guilty until proven innocent'. The production and use of plutonium should cease immediately. (author)

Attentional ability among survivors of leukaemia.

Science.gov (United States)

Rodgers, J; Horrocks, J; Britton, P G; Kernahan, J

1999-04-01

Attentional ability in 19 survivors of acute lymphoblastic leukaemia and 19 sibling controls was assessed using a neuropsychological model of attention. Analysis revealed that children who had received treatment for leukaemia exhibited significantly poorer performance on measures of the "focus encode" and "focus execute" elements of attention and on measures of the ability to respond to external cues and feedback. No significant differences in performance were found for measures of sustained attention and the ability to shift attention. These results indicate that children who have received treatment for leukaemia may experience highly specific attentional deficits that could have an impact on academic performance, particularly mathematical and reading skills. It is suggested that this underlying attentional deficit might be the source of the neuropsychological sequelae associated with the disease. Future attempts at remediation should incorporate activities specifically designed to ameliorate focusing difficulties.

Child leukaemia and low frequency electromagnetic fields

International Nuclear Information System (INIS)

Clavel, J.

2009-01-01

The author discusses the possible causes of child leukaemia: exposure to natural ionizing radiation (notably radon), to pesticides, and to hydrocarbons emitted by road traffic. Some studies suggested that an inadequate reaction of the immune system to an ordinary infection could result in leukaemia. Other factors are suspected, notably extremely low frequency electromagnetic fields, the influence of which is then discussed by the author. She evokes and discusses results of different investigations on this topic which have been published since the end of the 1970's. It appears that a distance less than 50 meters from high voltage lines or the vicinity of transformation stations may double the risk of child leukaemia

Persistence of chromosomal abnormalities additional to the Philadelphia chromosome after Philadelphia chromosome disappearance during imatinib therapy for chronic myeloid leukemia.

Science.gov (United States)

Zaccaria, Alfonso; Valenti, Anna Maria; Donti, Emilio; Gozzetti, Alessandro; Ronconi, Sonia; Spedicato, Francesco

2007-04-01

Five Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) patients with additional chromosome abnormalities at diagnosis have been followed during Imatinib therapy. In all, the Ph chromosome disappeared, while the 5 cases, additional abnormalities [dup(1); del(5), +8 (2 patients) and +14] persisted in the subsequent studies, performed over a period of 11 to 49 months, either alone or together with a karyotypically normal cell population. This finding is consistent with a secondary origin of the Ph chromosome in these patients. It is still to early to evaluate the possible prognostic value of these additional abnormalities.

Identification of de Novo Fanconi Anemia in Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

Science.gov (United States)

2016-05-13

Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Fanconi Anemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Report of chronic myeloid leukemia SMS Medical College Hospital, Jaipur.

Science.gov (United States)

Malhotra, Hemant; Sharma, Rajesh; Singh, Yogender; Chaturvedi, Hemant

2013-07-01

This is a retrospective analysis of patients of chronic myeloid leukemia (CML) registered and under treatment at the Leukemia Lymphoma Clinic at the Birla Cancer Center, SMS Medical College Hospital, Jaipur. Approximately, two-thirds of the patients are getting imatinib mesylate (IM) through the Glivec International Patient Assistance Program while the rest are on generic IM. In addition to comparison of hematological and molecular responses in the Glivec versus the genetic group, in this analysis, an attempt is also made to assess the socio-economic (SE) status of the patients and its effect on the response rates. Of the 213 patients studied, most (28.6%) are in the age group between 30 years and 40 years and the mean age of the patients in 39 years, a good decade younger that in the west. There is a suggestion that patients in lower SE class present with higher Sokal scores and with more disease burden. Possibly hematological responses are similar with both Glivec and generic IM. No comment can be made with regards to molecular response between the two groups as a significant number of patients in the Glivec arm (42%) do not have molecular assessment because of economic reasons. CML is a common and challenging disease in the developing world with patients presenting at an earlier age with more advanced disease. SE factors play a significant role in therapy and disease monitoring decision making and may impact on response rates and prognosis.

Orlando Magic: report from the 57th meeting of the American Society of Haematology, 5–7 December 2015, Orlando, USA

Science.gov (United States)

Mazzarella, Luca

2016-01-01

The 57th American Society of Haematology (ASH) meeting held in Orlando, FL was certainly the year when myeloma management changed for good, with a plethora of newly Food and Drug Administration (FDA)-approved drugs showing impressive outcome improvements and the introduction of new techniques for disease monitoring. Also, chimeric antigen receptor (CAR) T cells continued their triumphal march, consolidating their success in lymphoma and chronic lymhocytic leukaemia (CLL) and venturing into new fields such as again multiple myeloma. Some experimental drugs showed long-awaited results (midostaurin in FLT3-mutated acute myeloid leukaemia (AML)) and some brand new drugs showed promising results in the clinic after extensive preclinical studies, such as those targeting new epigenetic factors (histone methyltransferases) and apoptosis. PMID:26823681

Orlando Magic: report from the 57th meeting of the American Society of Haematology, 5-7 December 2015, Orlando, USA.

Science.gov (United States)

Mazzarella, Luca

2016-01-01

The 57th American Society of Haematology (ASH) meeting held in Orlando, FL was certainly the year when myeloma management changed for good, with a plethora of newly Food and Drug Administration (FDA)-approved drugs showing impressive outcome improvements and the introduction of new techniques for disease monitoring. Also, chimeric antigen receptor (CAR) T cells continued their triumphal march, consolidating their success in lymphoma and chronic lymhocytic leukaemia (CLL) and venturing into new fields such as again multiple myeloma. Some experimental drugs showed long-awaited results (midostaurin in FLT3-mutated acute myeloid leukaemia (AML)) and some brand new drugs showed promising results in the clinic after extensive preclinical studies, such as those targeting new epigenetic factors (histone methyltransferases) and apoptosis.

Heme oxygenase-1: A new druggable target in the management of chronic and acute myeloid leukemia.

Science.gov (United States)

Salerno, Loredana; Romeo, Giuseppe; Modica, Maria N; Amata, Emanuele; Sorrenti, Valeria; Barbagallo, Ignazio; Pittalà, Valeria

2017-12-15

Heme oxygenase-1 (HO-1) is the enzyme catalyzing the rate-limiting oxidative degradation of cellular heme into free iron, carbon monoxide (CO), and biliverdin, which is then rapidly converted into bilirubin. By means of these catabolic end-products and by removal of pro-oxidant heme, HO-1 exerts antioxidant, antiapoptotic, and immune-modulating effects, leading to overall cytoprotective and beneficial functions in mammalian cells. Therefore, HO-1 is considered a survival molecule in various stress-related conditions. By contrast, growing evidence suggests that HO-1 is a survival-enhancing molecule also in various solid and blood cancers, such as various types of leukemia, promoting carcinogenesis, tumor progression, and chemo-resistance. Among leukemias, chronic myeloid leukemia (CML) is currently therapeutically well treated with tyrosine kinase inhibitors (TKIs) such as Imatinib (IM) and its congeners; nevertheless, resistance to all kinds of current drugs persist in a number of patients. Moreover, treatment outcomes for acute myeloid leukemia (AML) remain unsatisfactory, despite progress in chemotherapy and hematopoietic stem cell transplantation. Therefore, identification of new eligible targets that may improve leukemias therapy is of general interest. Several recent papers prove that inhibition of HO-1 through HO-1 inhibitors as well as modulation of other pathways involving HO-1 by a number of different new or known molecules, are critical for leukemia treatment. This review summarizes the current understanding of the pro-tumorigenic role of HO-1 and its potential as a molecular target for the treatment of leukemias. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Women Administered Standard Dose Imatinib for Chronic Myeloid Leukemia Have Higher Dose-Adjusted Plasma Imatinib and Norimatinib Concentrations Than Men.

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Belsey, Sarah L; Ireland, Robin; Lang, Kathryn; Kizilors, Aytug; Ho, Aloysius; Mufti, Ghulam J; Bisquera, Alessandra; De Lavallade, Hugues; Flanagan, Robert J

2017-10-01

The standard dose of imatinib for the treatment of chronic-phase chronic myeloid leukemia (CML) is 400 mg·d. A predose plasma imatinib concentration of >1 mg·L is associated with improved clinical response. This study aimed to assess the plasma imatinib and norimatinib concentrations attained in patients with chronic myeloid leukemia administered standard doses of imatinib adjusted for dose, age, sex, body weight, and response. We evaluated data from a cohort of patients treated between 2008 and 2014 with respect to dose, age, sex, body weight, and response. The study comprised 438 samples from 93 patients (54 male, 39 female). The median imatinib dose was 400 mg·d in men and in women. The plasma imatinib concentration ranged 0.1-5.0 mg·L and was below 1 mg·L in 20% and 16% of samples from men and women, respectively. The mean dose normalized plasma imatinib and norimatinib concentrations were significantly higher in women in comparison with men. This was partially related to body weight. Mixed effects ordinal logistic regression showed no evidence of an association between sex and plasma imatinib (P = 0.13). However, there was evidence of an association between sex and plasma norimatinib, with higher norimatinib concentrations more likely in women than in men (P = 0.02). Imatinib therapeutic drug monitoring only provides information on dosage adequacy and on short-term adherence; longer-term adherence cannot be assessed. However, this analysis revealed that approximately 1 in 5 samples had a plasma imatinib concentration <1 mg·L, which was suggestive of inadequate dosage and/or poor adherence and posed a risk of treatment failure. Higher imatinib exposure in women may be a factor in the increased rate of long-term, stable, deep molecular response (undetectable breakpoint cluster-Abelson (BCR-ABL) transcript levels with a PCR sensitivity of 4.5 log, MR4.5) reported in women.

Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib

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Hochhaus, Andreas; le Coutre, Philipp D.; Rosti, Gianantonio; Pinilla-Ibarz, Javier; Jabbour, Elias; Gillis, Kathryn; Woodman, Richard C.; Blakesley, Rick E.; Giles, Francis J.; Kantarjian, Hagop M.; Baccarani, Michele

2011-01-01

Nilotinib has significant efficacy in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) and in patients with CML-CP or CML in accelerated phase (CML-AP) after imatinib failure. We investigated the occurrence of cross-intolerance to nilotinib in imatinib-intolerant patients with CML. Only 1/75 (1%) patients with nonhematologic imatinib intolerance experienced a similar grade 3/4 adverse event (AE), and 3/75 (4%) experienced a similar persistent grade 2 nonhematologic AE on nilotinib. Only 7/40 (18%) patients with hematologic imatinib intolerance discontinued nilotinib, all because of grade 3/4 thrombocytopenia. Ninety percent of imatinib-intolerant patients with CML-CP who did not have complete hematologic response (CHR) at baseline (n = 52) achieved CHR on nilotinib. Nilotinib induced a major cytogenetic response in 66% and 41% of patients with imatinib-intolerant CML-CP and CML-AP (complete cytogenetic response in 51% and 30%), respectively. Minimal cross-intolerance was confirmed in patients with imatinib-intolerant CML. The favorable tolerability of nilotinib in patients with imatinib intolerance leads to alleviation of AE-related symptoms and significant and durable responses. In addition to its established clinical benefit in patients with newly diagnosed CML and those resistant to imatinib, nilotinib is effective and well-tolerated for long-term use in patients with imatinib intolerance. This study is registered at http://www.clinicaltrials.gov as NCT00471497 PMID:21467546

Acute lymphocytic leukaemia in children in the Netherlands

International Nuclear Information System (INIS)

Does-van den Berg, A. van der.

1980-01-01

Some features, present at diagnosis in children with acute lymphocytic leukaemia, investigated during the period 1973-1975, and the results of treatment according to protocol AL II of the Dutch Childhood Leukaemia Study Group (SNWLK), are described. This report concerns the results of induction treatment, elective treatment of the central nervous system, and also of the prospective comparative study on the influence of the addition of cyclophosphamide to maintenance treatment with 6-mercaptopurine and methotrextate. In the context of the investigation of long-term side effects of disease and treatment, the immunocompetence of children with acute lymphocytic leukaemia in continuous remission after cessation of therapy was studied. (Auth.)

Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial.

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Gore, Lia; Kearns, Pamela R; de Martino, Maria Lucia; Lee; De Souza, Carmino Antonio; Bertrand, Yves; Hijiya, Nobuko; Stork, Linda C; Chung, Nack-Gyun; Cardos, Rocio Cardenas; Saikia, Tapan; Fagioli, Franca; Seo, Jong Jin; Landman-Parker, Judith; Lancaster, Donna; Place, Andrew E; Rabin, Karen R; Sacchi, Mariana; Swanink, Rene; Zwaan, C Michel

2018-05-01

Purpose Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias. Methods CA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest. Results Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients. Conclusion In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported.

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

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Deininger, Michael W.; Rosti, Gianantonio; Hochhaus, Andreas; Soverini, Simona; Apperley, Jane F.; Cervantes, Francisco; Clark, Richard E.; Cortes, Jorge E.; Guilhot, François; Hjorth-Hansen, Henrik; Hughes, Timothy P.; Kantarjian, Hagop M.; Kim, Dong-Wook; Larson, Richard A.; Lipton, Jeffrey H.; Mahon, François-Xavier; Martinelli, Giovanni; Mayer, Jiri; Müller, Martin C.; Niederwieser, Dietger; Pane, Fabrizio; Radich, Jerald P.; Rousselot, Philippe; Saglio, Giuseppe; Saußele, Susanne; Schiffer, Charles; Silver, Richard; Simonsson, Bengt; Steegmann, Juan-Luis; Goldman, John M.; Hehlmann, Rüdiger

2013-01-01

Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome–positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved. PMID:23803709

Managing inadequate responses to frontline treatment of chronic myeloid leukemia: a case-based review.

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Bixby, Dale L

2013-05-01

The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib are the standard of care for treating patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML). Compared with interferon-based treatment, the previous standard of care, imatinib is associated with significantly higher cytogenetic response rates and prolonged overall survival. Nilotinib and dasatinib, both newer and more potent TKIs, significantly improve cytogenetic and molecular response rates compared with imatinib. Despite significant advances in CML treatment enabled by the TKIs, a fraction of patients who receive frontline treatment with a TKI demonstrate inadequate response. The reasons for this vary, but in many cases, inadequate response can be attributed to non-adherence to the treatment regimen, intolerance to the drug, intrinsic or acquired resistance to the drug, or a combination of reasons. More often than not, strategies to improve response necessitate a change in treatment plan, either a dose adjustment or a switch to an alternate drug, particularly in the case of drug intolerance or drug resistance. Improved physician-patient communication and patient education are effective strategies to address issues relating to adherence and intolerance. Because inadequate response to TKI treatment correlates with poor long-term outcomes, it is imperative that patients who experience intolerance or who fail to achieve appropriate responses are carefully evaluated so that appropriate treatment modifications can be made to maximize the likelihood of positive long-term outcome. Copyright © 2012. Published by Elsevier Ltd.

Long-term safety and efficacy of dasatinib in the treatment of chronic-phase chronic myeloid leukemia patients resistant or intolerant to imatinib

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Shoumariyeh K

2014-09-01

Full Text Available Khalid Shoumariyeh, Nikolas von BubnoffDepartment of Hematology, Oncology and Stem Cell Transplantation, University Hospital Freiburg, Freiburg, Germany Abstract: Treatment of chronic myeloid leukemia (CML has undergone dramatic changes in the last decade. Dissecting the molecular pathways that lead to the development of this disease resulted in the development of targeted therapy against the molecular driver of CML, namely the aberrantly activated tyrosine kinase BCR-ABL1. By introducing the tyrosine kinase inhibitor imatinib to the treatment repertoire, the natural course of the disease has been dramatically altered and overall survival of patients with CML prolonged substantially. Nevertheless, a significant number of patients are primarily resistant, acquire resistance during the course of their disease, or do not tolerate the intake of imatinib due to adverse effects. Second-generation tyrosine kinase inhibitors were developed in an attempt to overcome these problems. Dasatinib is a potent oral kinase inhibitor that was originally developed as an Src-kinase inhibitor but exhibited promising potency against BCR-ABL1 as well. Phase I and II trials demonstrated efficacy in patients failing imatinib, and thus dasatanib was approved in 2006 for the treatment of imatinib-resistant or -intolerant patients with chronic-phase CML harboring the BCR-ABL1 fusion protein. It has since shown promising efficacy and good overall tolerability in subsequent clinical trials, including the Phase III first-line DASISION trial that led to the extension of its approval for first-line treatment of chronic-phase CML. The following review summarizes the available data on the long-term efficacy and safety of dasatinib as a second-line therapy in chronic-phase CML. Keywords: BCR-ABL1, TKI, CML-CP, second-line treatment

Successful treatment of follicular lymphoma with second-generation tyrosine kinase inhibitors administered for coexisting chronic myeloid leukemia.

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Fujiwara, Shin-Ichiro; Shirato, Yuya; Ikeda, Takashi; Kawaguchi, Shin-Ichiro; Toda, Yumiko; Ito, Shoko; Ochi, Shin-Ichi; Nagayama, Takashi; Mashima, Kiyomi; Umino, Kento; Minakata, Daisuke; Nakano, Hirofumi; Morita, Kaoru; Yamasaki, Ryoko; Kawasaki, Yasufumi; Sugimoto, Miyuki; Ashizawa, Masahiro; Yamamoto, Chihiro; Hatano, Kaoru; Sato, Kazuya; Oh, Iekuni; Ohmine, Ken; Muroi, Kazuo; Kanda, Yoshinobu

2018-06-01

Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic myeloid leukemia (CML). However, the effects of these agents on mature B cell lymphoma are not well known. We describe a 50-year-old man who was diagnosed with CML in the chronic phase and treated with imatinib. After 3 years of imatinib therapy that achieved a complete cytogenetic response of CML, he developed Philadelphia-negative follicular lymphoma (FL). Rituximab monotherapy induced a partial response of FL, and he subsequently achieved a major molecular response (MMR) of CML. Three years later, however, the MMR was lost, followed by the progression of FL. Imatinib was switched to nilotinib for the treatment of CML, while we chose watchful waiting for FL. He achieved MMR again under treatment with nilotinib for 8 months including one month of substitutional use of dasatinib due to adverse events, but thereafter nilotinib was switched to bosutinib due to hyperbilirubinemia. With the administration of second-generation TKIs (2G-TKIs) for a total of 18 months, he achieved a complete response to FL without antilymphoma treatment. This is the first report to suggest that 2G-TKIs may have direct or indirect effects on FL.

Early Complete Molecular Response to First-Line Nilotinib in Two Patients with Chronic Myeloid Leukemia Carrying the p230 Transcript

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Marianna Greco

2013-01-01

Full Text Available Chronic myeloid leukemia (CML with the rare fusion gene e19a2, encoding a p230 protein, has been described in patients with typical or rather aggressive clinical course. Although tyrosine kinase inhibitors (TKIs induce a substantial cytogenetic and molecular response in all phases of CML, a minority of p230 positive patients have been treated with TKIs. We report two cases of CML patients carrying the p230 transcript, who achieved fast and deep complete molecular response (CMR after frontline treatment with nilotinib. Our results suggest the use of nilotinib as frontline agent for the treatment of this CML variant.

Laboratory tools for diagnosis and monitoring response in patients with chronic myeloid leukemia.

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Tohami, Tali; Nagler, Arnon; Amariglio, Ninette

2012-08-01

Chronic myeloid leukemia (CML) is a clonal hematological disease that represents 15-20% of all adult leukemia cases. The study and treatment of CML has contributed pivotal advances to translational medicine and cancer therapy. The discovery that a single chromosomal abnormality, the Philadelphia (Ph) chromosome, is responsible for the etiology of this disease was a milestone for treating and understanding CML. Subsequently, CML became the first disease for which allogeneic bone marrow transplantation is the treatment of choice. Currently, CML is one of the few diseases where treatment targeted against the chromosomal abnormality is the sole frontline therapy for newly diagnosed patients. The use of directed therapy for CML challenged disease monitoring during treatment and led to the development of definitions that document response and predict relapse sooner than the former routine methods. These methods relied on classical cytogenetics through molecular cytogenetics (FISH) and, finally, on molecular monitoring assays. This review discusses the laboratory tools used for diagnosing CML, for monitoring during treatment, and for assessing remission or relapse. The advantages and disadvantages of each test, the common definition of response levels, and the efforts to standardize molecular monitoring for CML patient management are discussed.

Heterogeneity of BCR-ABL rearrangement in patients with chronic myeloid leukemia in Pakistan.

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Tabassum, Najia; Saboor, Mohammad; Ghani, Rubina; Moinuddin, Moinuddin

2014-07-01

Breakpoint cluster region-Abelson (BCR-ABL) rearrangement or Philadelphia (Ph) chromosome in Chronic Myeloid Leukemia (CML) is derived from a reciprocal chromosomal translocation between ABL gene on chromosome 9 and BCR gene on chromosome 22. This chimeric protein has various sizes and therefore different clinical behaviour. The purpose of this study was to determine the heterogeneity of BCR-ABL rearrangement in patients with Ph(+)CML in Pakistan. The study was conducted at Civil Hospital and Baqai Institute of Hematology (BIH) Karachi. Blood samples from 25 patients with CML were collected. Multiplex reverse transcription polymerase chain reaction (RT-PCR) was performed to identify various BCR-ABL transcripts. All 25 samples showed BCR-ABL rearrangements. Out of these, 24 (96%) patients expressed p210 BCR-ABL rearrangements i.e. 60% (n=15) had b3a2 and 32% (n=8) had b2a2 rearrangements. Co-expression of b3a2 /b2a2 rearrangement and p190 (e1a3) rearrangement was also identified in two patients. It is apparent that majority of the patients had p210 BCR-ABL rearrangements. Frequency of co-expression and rare fusion transcripts was very low.

Oral chronic graft-versus-host disease: analysis of dendritic cells subpopulations*

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Botari, Clara Marino Espricigo; Nunes, Adauto José Ferreira; de Souza, Mair Pedro; Orti-Raduan, Érica Sinara Lenharo; Salvio, Ana Gabriela

2014-01-01

The graft-versus-host disease is the major cause of morbidity and mortality in patients who have undergone hematopoietic stem cell transplantation. Aiming at contributing to the understanding of the role of myeloid and plasmacytoid dendritic cells, and natural killer cells in chronic graft-versus-host disease, we examined biopsies of jugal mucosa of 26 patients with acute myeloid leukemia who had undergone allogenic hematopoietic stem cell transplantation. Half of these patients developed oral chronic graft-versus-host disease. Microscopic sections were immunohistochemically stained for anti-CD1a, anti-CD123 and anti-CD56. We calculated the number of immunostained cells in the corium per square millimeter and applied the Mann-Whitney test. Results showed a statistically significant increase of myeloid dendritic cells (CD1a+; p=0,02) and natural killer cells (CD56; p=0,04) in patients with oral chronic graft-versus-host disease. CD123 immunostaining showed no statistical difference between groups. It was concluded that myeloid dendritic cells and natural killer cells participate in the development of oral chronic graft-versus-host disease. PMID:25054751

Oral chronic graft-versus-host disease: analysis of dendritic cells subpopulations.

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Botari, Clara Marino Espricigo; Nunes, Adauto José Ferreira; Souza, Mair Pedro de; Orti-Raduan, Erica Sinara Lenharo; Salvio, Ana Gabriela

2014-01-01

The graft-versus-host disease is the major cause of morbidity and mortality in patients who have undergone hematopoietic stem cell transplantation. Aiming at contributing to the understanding of the role of myeloid and plasmacytoid dendritic cells, and natural killer cells in chronic graft-versus-host disease, we examined biopsies of jugal mucosa of 26 patients with acute myeloid leukemia who had undergone allogenic hematopoietic stem cell transplantation. Half of these patients developed oral chronic graft-versus-host disease. Microscopic sections were immunohistochemically stained for anti-CD1a, anti-CD123 and anti-CD56. We calculated the number of immunostained cells in the corium per square millimeter and applied the Mann-Whitney test. Results showed a statistically significant increase of myeloid dendritic cells (CD1a+; p=0,02) and natural killer cells (CD56; p=0,04) in patients with oral chronic graft-versus-host disease. CD123 immunostaining showed no statistical difference between groups. It was concluded that myeloid dendritic cells and natural killer cells participate in the development of oral chronic graft-versus-host disease.

Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

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Burchert, A; Saussele, S; Eigendorff, E; Müller, M C; Sohlbach, K; Inselmann, S; Schütz, C; Metzelder, S K; Ziermann, J; Kostrewa, P; Hoffmann, J; Hehlmann, R; Neubauer, A; Hochhaus, A

2015-06-01

A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

Combined Targeting of BCL-2 and BCR-ABL Tyrosine Kinase Eradicates Chronic Myeloid Leukemia Stem Cells

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Mak, Po Yee; Mu, Hong; Zhou, Hongsheng; Mak, Duncan H.; Schober, Wendy; Leverson, Joel D.; Zhang, Bin; Bhatia, Ravi; Huang, Xuelin; Cortes, Jorge; Kantarjian, Hagop; Konopleva, Marina

2016-01-01

BCR-ABL tyrosine kinase inhibitors (TKIs) are effective against chronic myeloid leukemia (CML), but they rarely eliminate CML stem cells. Disease relapse is common upon therapy cessation, even in patients with complete molecular responses. Furthermore, once CML progresses to blast crisis (BC), treatment outcomes are dismal. We hypothesized that concomitant targeting of BCL-2 and BCR-ABL tyrosine kinase could overcome these limitations. We demonstrate increased BCL-2 expression at the protein level in bone marrow cells, particularly in Lin−Sca-1+cKit+ cells of inducible CML in mice as determined by CyTOF mass cytometry. Further, selective inhibition of BCL-2, aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly decreased leukemic Lin−Sca-1+cKit+ cell numbers and long-term stem cell frequency, and prolonged survival in a murine CML model. Additionally, this combination effectively eradicated CD34+CD38−, CD34+CD38+, and quiescent stem/progenitor CD34+ cells from BC CML patient samples. Our results suggest that BCL-2 is a key survival factor for CML stem/progenitor cells and that combined inhibition of BCL-2 and BCR-ABL tyrosine kinase has the potential to significantly improve depth of response and cure rates of chronic phase and BC CML. PMID:27605552

Chromosomal mechanisms in murine radiation acute myeloid leukemogenesis

International Nuclear Information System (INIS)

Bouffler, S.D.; Breckon, G.; Cox, R.

1996-01-01

Chromosome 2 abnormalities, particularly interstitial deletions, characterize murine radiation-induced acute myeloid leukaemias (AMLs). Here, G-band analyses in CBA/H mice of early (1-6 month) post 3 Gy X-radiation events in bone marrow cells in vivo and karyotype evolution in one unusual AML are presented. The early event analysis showed that all irradiated animals carry chromosome 2 abnormalities, that chromosome 2 abnormalities are more frequent than expected and that interstitial deletions are more common in chromosome 2 than in the remainder of the genome. On presentation AML case N122 carried a t(2; 11) terminal translocation which, with passaging, evolved into a del2(C3F3). Therefore two pathways in leukaemogenesis might exist, one deletion-driven, the other terminal tranlocation-driven involving interstitial genes and terminal genes respectively of chromosome 2. As all irradiated individuals carried chromosome 2 abnormalities, the formation of these aberrations does not determine individual leukaemogenic sensitivity as only 20-25% of animals would be expected to develop AML. Similar lines of argument suggest that chromosome 2 abnormalities are necessary but not sufficient for radiation leukaemogenesis in CBA/H nor are they rate limiting in leukaemogenesis. (Author)

A Novel Three-Colour Fluorescence in Situ Hybridization Approach for the Detection of t(7;12)(q36;p13) in Acute Myeloid Leukaemia Reveals New Cryptic Three Way Translocation t(7;12;16)

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Naiel, Abdulbasit [Leukaemia and Chromosome Research Laboratory, Division of Biosciences, Brunel University, London, Middlesex UB8 3PH (United Kingdom); Vetter, Michael [MetaSystems, Altlussheim 68804 (Germany); Plekhanova, Olga [Regional Children’s Hospital N 1, Ekaterinburg 620149 (Russian Federation); Fleischman, Elena; Sokova, Olga [N.N. Blokhin Russian Cancer Research Center Russian Academy of Medical Science, Moscow 115478 (Russian Federation); Tsaur, Grigory [Regional Children’s Hospital N 1, Ekaterinburg 620149 (Russian Federation); Research Institute of Medical Cell Technologies, Ekaterinburg 620149 (Russian Federation); Harbott, Jochen [Oncogenetic Laboratory, Department of Paediatric Haematology and Oncology, Justus Liebig University, Giessen 35392 (Germany); Tosi, Sabrina, E-mail: sabrina.tosi@brunel.ac.uk [Leukaemia and Chromosome Research Laboratory, Division of Biosciences, Brunel University, London, Middlesex UB8 3PH (United Kingdom)

2013-03-11

The t(7;12)(q36;p13) translocation is a recurrent chromosome abnormality that involves the ETV6 gene on chromosome 12 and has been identified in 20–30% of infant patients with acute myeloid leukaemia (AML). The detection of t(7;12) rearrangements relies on the use of fluorescence in situ hybridization (FISH) because this translocation is hardly visible by chromosome banding methods. Furthermore, a fusion transcript HLXB9-ETV6 is found in approximately 50% of t(7;12) cases, making the reverse transcription PCR approach not an ideal screening method. Considering the report of few cases of variant translocations harbouring a cryptic t(7;12) rearrangement, we believe that the actual incidence of this abnormality is higher than reported to date. The clinical outcome of t(7;12) patients is believed to be poor, therefore an early and accurate diagnosis is important in the clinical management and treatment. In this study, we have designed and tested a novel three-colour FISH approach that enabled us not only to confirm the presence of the t(7;12) in a number of patients studied previously, but also to identify a cryptic t(7;12) as part of a complex rearrangement. This new approach has proven to be an efficient and reliable method to be used in the diagnostic setting.

Some implications of current therapy in leukaemia | Jacobs | South ...

African Journals Online (AJOL)

Improved survival in acute leukaemia follows aggressive combination chemotherapy based on a proper understanding of tumour cell kinetics and principles of modern pharmacology. Such cytoreduction ... Logically, patients with acute leukaemia should have the benefit of management in these units. S. Afr. Med. J., 48 ...

Central nervous system leukemia in a patient with concurrent nasopharyngeal carcinoma and acute myeloid leukaemia: A case report.

Science.gov (United States)

Liu, Jun-Qing; Mai, Wen-Yuan; Wang, Si-Ben; Lou, Yin-Jun; Yan, Sen-Xiang; Jin, Jie; Xu, Wei-Lai

2017-12-01

Concurrent case of nasopharyngeal carcinoma (NPC) and acute myeloid leukemia (AML) has not been reported. Here, we report a case of NPC, who was concurrently suffered from AML one mother after the NPC diagnosis. The patient was a 45-year-old male who presented with a mass on his right side neck. The patient was diagnosed with Epstein-Barr virus negative type-2 non-keratinizing carcinoma with clivus involvement and unilateral metastasis to the cervical lymph node. He was treated with one cycle of cisplatin and 69.76 Gy of concurrent external-beam radiation. Three months after completion of chemo-radiotherapy, the patient was diagnosed as acute myeloid leukemia, which achieved complete remission after one course induction chemotherapy. Two months later, however, the patient was diagnosed as central nervous system leukemia. He ultimately died of relapsed leukemia. The overall survival of the patient was 10 months. The co-occurrence of NPC and AML is rare and prognosis is poor. Radiotherapy in NPC can disrupt the blood-brain barrier, which may contribute to the pathogenesis of central nervous system leukemia. Early alert and prevention of central nervous system leukemia following radiotherapy in NPC patient is recommended. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Active caspase-3 detection to evaluate apoptosis induced by Verbena officinalis essential oil and citral in chronic lymphocytic leukaemia cells

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Laura De Martino

2011-10-01

Full Text Available Verbena officinalis L., Verbenaceae, commonly known as vervain, is a plant widely used in medicine. Despite of its widespread use in different traditional practices, the mechanisms of pharmacological actions of the plant and its volatile oil are still unclear. We evaluated the pro-apoptotic activity of V. officinalis essential oil and of its main component, citral, on lymphocytes collected from ten patients with chronic lymphocytic leukaemia (CLL, a disease in which a faulty apoptotic mechanism is still retained one of the primary pathogenic events, by adding to treated mononuclear cells, annexin-V, propidium iodide, and CD19. Apoptosis was also evaluated using anti-active-caspase-3 monoclonal antibody after permeabilization of the cells. Both V. officinalis essential oil and citral were found able to induce apoptosis in CLL cells and to activate caspase-3, which is considered the way by means they active apoptosis in B neoplastic cells. This data further support evidences that indicate natural compounds as possible lead structure to develop new therapeutic agents for CLL.

Active caspase-3 detection to evaluate apoptosis induced by Verbena officinalis essential oil and citral in chronic lymphocytic leukaemia cells

Directory of Open Access Journals (Sweden)

Laura De Martino

2011-05-01

Full Text Available Verbena officinalis L., Verbenaceae, commonly known as vervain, is a plant widely used in medicine. Despite of its widespread use in different traditional practices, the mechanisms of pharmacological actions of the plant and its volatile oil are still unclear. We evaluated the pro-apoptotic activity of V. officinalis essential oil and of its main component, citral, on lymphocytes collected from ten patients with chronic lymphocytic leukaemia (CLL, a disease in which a faulty apoptotic mechanism is still retained one of the primary pathogenic events, by adding to treated mononuclear cells, annexin-V, propidium iodide, and CD19. Apoptosis was also evaluated using anti-active-caspase-3 monoclonal antibody after permeabilization of the cells. Both V. officinalis essential oil and citral were found able to induce apoptosis in CLL cells and to activate caspase-3, which is considered the way by means they active apoptosis in B neoplastic cells. This data further support evidences that indicate natural compounds as possible lead structure to develop new therapeutic agents for CLL.

Autoradiography at Cell and Chromosome Level in the Study of Multiplication and Cytodifferentiation of Haematopoietic Tissue

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Gavosto, F. [Instituto di Clinica Medica, University of Turin (Italy)

1967-07-15

Haematopoietic tissue proliferates by the mitotic activity of the youngest cells. The first data on the proliferation of blood cells recorded by use of the stathmokinetic technique was followed by more detailed information obtained with autoradiographic studies and by using special precursors of DNA such as thymidine. It has been observed that in the bone marrow in progressive myeloid and erythroid maturation, proliferative capacity decreases progressively until it stops altogether at the myelocytic and polychromatic erythroblastic stage. For chronic myeloid leukaemia the labelling index of each proliferating cell type is similar to the values of the corresponding normal cells. In 1958 we used tritiated thymidine to study many cases of acute leukaemia, that is those with a complete differentiation block and a very high blast content, and we found a clear fall in proliferative capacity of these blast cells. The same results have been obtained in other laboratories and now, quite the contrary to what was thought a few years ago, namely that leukaemic cells grew faster than normal cells, we know that the rate of growth of these cells is often much slower than the corresponding normal cells.

Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC).

Science.gov (United States)

Marcotte, Erin L; Thomopoulos, Thomas P; Infante-Rivard, Claire; Clavel, Jacqueline; Petridou, Eleni Th; Schüz, Joachim; Ezzat, Sameera; Dockerty, John D; Metayer, Catherine; Magnani, Corrado; Scheurer, Michael E; Mueller, Beth A; Mora, Ana M; Wesseling, Catharina; Skalkidou, Alkistis; Rashed, Wafaa M; Francis, Stephen S; Ajrouche, Roula; Erdmann, Friederike; Orsi, Laurent; Spector, Logan G

2016-04-01

Results from case-control studies have shown an increased risk of acute lymphoblastic leukaemia (ALL) in young children born by caesarean delivery, and prelabour caesarean delivery in particular; however, an association of method of delivery with childhood leukaemia subtypes has yet to be established. We therefore did a pooled analysis of data to investigate the association between childhood leukaemia and caesarean delivery. We pooled data from 13 case-control studies from the Childhood Leukemia International Consortium done in nine countries (Canada, Costa Rica, Egypt, France, Germany, Greece, Italy, New Zealand, and the USA) for births from 1970-2013. We analysed caesarean delivery overall and by indications that probably resulted in prelabour caesarean delivery or emergency caesarean delivery. We used multivariable logistic regression models, adjusted for child's birthweight, sex, age, ethnic origin, parental education, maternal age, and study, to estimate odds ratios (ORs) and 95% CIs for the risk of ALL and acute myeloid leukaemia (AML) in children aged 0-14 years at diagnosis. The studies provided data for 8780 ALL cases, 1332 AML cases, and 23 459 controls, of which the birth delivery method was known for 8655 (99%) ALL cases, 1292 (97%) AML cases, and 23 351 (>99%) controls. Indications for caesarean delivery were available in four studies (there were caesarean deliveries for 1061 of 4313 ALL cases, 138 of 664 AML cases, and 1401 of 5884 controls). The OR for all indications of caesarean delivery and ALL was 1·06 (95% CI 0·99-1·13), and was significant for prelabour caesarean delivery and ALL (1·23 [1·04-1·47]; p=0·018). Emergency caesarean delivery was not associated with ALL (OR 1·02 [95% CI 0·81-1·30]). AML was not associated with caesarean delivery (all indications OR 0·99 [95% CI 0·84-1·17]; prelabour caesarean delivery 0·83 [0·54-1·26]; and emergency caesarean delivery 1·05 [0·63-1·77]). Our results suggest an increased risk of

Direct conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue.

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Sinha, Mithun; Sen, Chandan K; Singh, Kanhaiya; Das, Amitava; Ghatak, Subhadip; Rhea, Brian; Blackstone, Britani; Powell, Heather M; Khanna, Savita; Roy, Sashwati

2018-03-05

Inflammation, following injury, induces cellular plasticity as an inherent component of physiological tissue repair. The dominant fate of wound macrophages is unclear and debated. Here we show that two-thirds of all granulation tissue fibroblasts, otherwise known to be of mesenchymal origin, are derived from myeloid cells which are likely to be wound macrophages. Conversion of myeloid to fibroblast-like cells is impaired in diabetic wounds. In cross-talk between keratinocytes and myeloid cells, miR-21 packaged in extracellular vesicles (EV) is required for cell conversion. EV from wound fluid of healing chronic wound patients is rich in miR-21 and causes cell conversion more effectively compared to that by fluid from non-healing patients. Impaired conversion in diabetic wound tissue is rescued by targeted nanoparticle-based delivery of miR-21 to macrophages. This work introduces a paradigm wherein myeloid cells are recognized as a major source of fibroblast-like cells in the granulation tissue.

Childhood leukaemia around nuclear facilities

International Nuclear Information System (INIS)

Wojcik, Andrzej; Feychting, Maria

2010-06-01

In December 2007 the German Federal Office for Radiation Protection (BfS) published a report on the incidence of childhood cancers among children living in the vicinity of 16 German nuclear power plants. The results show a significantly enhanced risk of leukaemia in children aged below 5 years, who live within 5 km from a nuclear power plant. The study is known as KiKK (Epidemiologische Studie zu Kinderkrebs in der Umgebung von Kernkraftwerken) and stirred considerable concern about the safety of nuclear installations. In this review we summarise the present state-of-the art regarding childhood leukaemia in the vicinity of nuclear installations and present the main results of the KiKK study with a critical evaluation

Childhood leukaemia around nuclear facilities

Energy Technology Data Exchange (ETDEWEB)

Wojcik, Andrzej (Centre for Radiation Protection Research, GMT Dept., Stockholm Univ., Stockholm (Sweden)); Feychting, Maria (Inst. of Environmental Medicine, Karolinska Inst., Stockholm (Sweden))

2010-06-15

In December 2007 the German Federal Office for Radiation Protection (BfS) published a report on the incidence of childhood cancers among children living in the vicinity of 16 German nuclear power plants. The results show a significantly enhanced risk of leukaemia in children aged below 5 years, who live within 5 km from a nuclear power plant. The study is known as KiKK (Epidemiologische Studie zu Kinderkrebs in der Umgebung von Kernkraftwerken) and stirred considerable concern about the safety of nuclear installations. In this review we summarise the present state-of-the art regarding childhood leukaemia in the vicinity of nuclear installations and present the main results of the KiKK study with a critical evaluation

Late effects of treatment in survivors of childhood acute lymphoblastic leukaemia

International Nuclear Information System (INIS)

Roux, P.

1987-01-01

The overall aim of this study was a comprehensive assessment of the nature and severity of the late effects of treatment in a group of children surviving acute lymphoblastic leukaemia. In the absence of damage preceding treatment, late effects could be ascribed to treatment. Cranial irradiation, methotrexate, L-asparaginase and cytosine arabinoside are therapeutic modalities most likely to cause injury to the central nervous system. Survivors of childhood leukaemia also showed an increase in weight-for-height during and after therapy which appeared to be the consequence of a loss in statural growth as well as increasing weight-for-age. Assessment of endocrine function in leukaemia survivors indicated abnormalities in the regulation of growth hormone and thyroid stimulating hormone in some patients. Survivors of childhood leukaemia were shown to have an intellectual deficit compared with their siblings and a high incidence of visual-perceptual defects. The intellectual effects of lower doses of cranial irradiation are as yet unknown. A variety of minor neurological abnormalities were detected among leukaemia survivors and thought to be related to preceding central nervous system 'prophylactic' chemotherapy and irradiation. A new instrument, the functional deficit score, was derived to reflect overall outcome in survivors of childhood leukaemia. With few exceptions, leukaemia survivors in this study had received 2400 rads of deep x-ray therapy as cranial irradiation. This dosage has since been reduced world-wide. Current cranial irradiation 'prophylaxis' consists of 1800 rad of megavoltage radiotherapy

Late effects of treatment in survivors of childhood acute lymphoblastic leukaemia

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Roux, P

1987-01-01

The overall aim of this study was a comprehensive assessment of the nature and severity of the late effects of treatment in a group of children surviving acute lymphoblastic leukaemia. In the absence of damage preceding treatment, late effects could be ascribed to treatment. Cranial irradiation, methotrexate, L-asparaginase and cytosine arabinoside are therapeutic modalities most likely to cause injury to the central nervous system. Survivors of childhood leukaemia also showed an increase in weight-for-height during and after therapy which appeared to be the consequence of a loss in statural growth as well as increasing weight-for-age. Assessment of endocrine function in leukaemia survivors indicated abnormalities in the regulation of growth hormone and thyroid stimulating hormone in some patients. Survivors of childhood leukaemia were shown to have an intellectual deficit compared with their siblings and a high incidence of visual-perceptual defects. The intellectual effects of lower doses of cranial irradiation are as yet unknown. A variety of minor neurological abnormalities were detected among leukaemia survivors and thought to be related to preceding central nervous system 'prophylactic' chemotherapy and irradiation. A new instrument, the functional deficit score, was derived to reflect overall outcome in survivors of childhood leukaemia. With few exceptions, leukaemia survivors in this study had received 2400 rads of deep x-ray therapy as cranial irradiation. This dosage has since been reduced world-wide. Current cranial irradiation 'prophylaxis' consists of 1800 rad of megavoltage radiotherapy.

Testicular myeloid sarcoma: case report.

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Zago, Luzia Beatriz Ribeiro; Ladeia, Antônio Alexandre Lisbôa; Etchebehere, Renata Margarida; de Oliveira, Leonardo Rodrigues

2013-01-01

Myeloid sarcomas are extramedullary solid tumors composed of immature granulocytic precursor cells. In association with acute myeloid leukemia and other myeloproliferative disorders, they may arise concurrently with compromised bone marrow related to acute myeloid leukemia, as a relapsed presentation, or occur as the first manifestation. The testicles are considered to be an uncommon site for myeloid sarcomas. No therapeutic strategy has been defined as best but may include chemotherapy, radiotherapy and/or hematopoietic stem cell transplantation. This study reports the evolution of a patient with testicular myeloid sarcoma as the first manifestation of acute myeloid leukemia. The patient initially refused medical treatment and died five months after the clinical condition started.

Relapse risk assessment of transplantation for patients with chronic myeloid leukaemia

Institute of Scientific and Technical Information of China (English)

无

2003-01-01

Objective To analyse the risk factors of relapse before bone marrow transplantation (BMT) and to present the prognostic information as good as possible.Methods A total of 3142 patients, who underwent the allogeneic blood or bone marrow tran splantation between 1989 and 1997 and were documented in the European Group for Blood and Marrow transplantation (EBMT), were included. Six possible risk factors including type of donor, stage of disease, age, gender, donor@#-recipient sex co mbination and the waiting time from diagnosis to transplation of relapse were co nsidered. The time to relapse was analysed by Kaplan-Meier curves and Coxregre ssion with stratification on prognostic factors that did not satisfy the Proport ional Hazard Assumption.Results An amount of 447 patients relapsed out of all 3142 patients. The relapse rate was 14.2%. Type of donor and stage of disease showed a clear prognostic effect, but failed the proportional hazard assumption. Therefore, the data were stratified on the combination of type of donor and stage of disease. Within these strata a n additional significant effect of age could be observed. Relative risk of age ≥40 vs age <40 was 1.32 (95% confidence interval 1.09-1.59). The prognostic model is summarized graphically.Conclusions The combination of type of donor, stage of disease and age of recipient at transplantation are important prognostic factors for relapse after BMT.

SB-715992 in Treating Patients With Acute Leukemia, Chronic Myelogenous Leukemia, or Advanced Myelodysplastic Syndromes

Science.gov (United States)

2013-01-10

Acute Undifferentiated Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

Lack of Association of Multidrug Resistance Gene-1 Polymorphisms with Treatment Outcome in Chronic Myeloid Leukemia Patients Treated with Imatinib

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Yaya Kassogue

2015-10-01

Full Text Available Background: Despite the impressive results obtained with imatinib, inadequate response or resistance are observed in certain patients. It is known that imatinib is a substrate of a multidrug resistance gene (MDR1. Thus, interindividual genetic differences linked to single nucleotide polymorphisms in MDR1 may influence the metabolism of imatinib. The present study has aimed to examine the impact of MDR1 polymorphisms on the hematologic and cytogenetic responses in 70 chronic myeloid leukemia patients who received imatinib. Methods: We used a polymerase chain reaction followed by restriction fragment length polymorphism to identify different profiles of 1236C>T, 2677G>T and 3435C>T in MDR1. Results: The distribution of the three SNPs in responders and poor responders did not show any particular trend (P>0.05. The T allele was slightly higher in responders, but not significantly regardless of the type of SNP (40.3% vs. 33.8% for 1236C>T; 25% vs. 14.7% for 2677G>T and 33.3% vs. 22% for 3435C>T. The dominant model showed a similar trend (P>0.05. Diplotypes composed by the T allele in different exons were frequent in responders. Haplotype analysis showed that 1236C-2677G-3435C was slightly higher in poor responders (60.02% compared to responders (50.42%. However, 1236T-2677T-3435T was frequent in responders (16.98% compared to poor responders (13.1%. Overall, none of the haplotypes were associated with IM response in our cohort (global haplotype association test, P=0.39. Conclusion: The identification of 1236C>T, 2677G>T and 3435C>T polymorphisms may not be advantageous to predict imatinib response for our chronic myeloid leukemia patients.

Childhood leukaemia and low-level radiation - are we underestimating the risk?

International Nuclear Information System (INIS)

Wakeford, R.

1996-01-01

The Seascale childhood leukaemia 'cluster' can be interpreted as indicating that the risk of childhood leukaemia arising from low-level exposure to ionising radiation has been underestimated. Indeed, several variants of such an interpretation have been advanced. These include exposure to particular radionuclides, an underestimation of the radiation risk coefficient for childhood leukaemia, and the existence of a previously unrecognized risk of childhood leukaemia from the preconceptional irradiation of fathers. However, the scientific assessment of epidemiological associations is a complex matter, and such associations must be interpreted with caution. It would now seem most likely that the Seascale 'cluster' does not represent an unanticipated effect of the exposure to ionising radiation, but rather the effect of unusual population mixing generated by the Sellafield site which has produced an increase in the infection-based risk of childhood leukaemia. This episode in the history of epidemiological research provides a timely reminder of the need for great care in the interpretation-of novel statistical associations. (author)

PTCH1 is a reliable marker for predicting imatinib response in chronic myeloid leukemia patients in chronic phase.

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Juan M Alonso-Dominguez

Full Text Available Patched homolog 1 gene (PTCH1 expression and the ratio of PTCH1 to Smoothened (SMO expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72. In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF, which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013, probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02, and proportions of early molecular failure (14% vs. 43%, P = 0.015. Every progression to an advanced phase (n = 3 and CML-related death (n = 2 occurred in the low PTCH1 group (P<0.001 for both comparisons. PTCH1 was an independent prognostic factor for the prediction of IF. We also validated previously published thresholds for PTCH1 expression. Therefore, we confirmed that PTCH1 expression can predict the imatinib response in CML patients in CP by applying a more rigorous statistical analysis. Thus, PTCH1 expression is a promising molecular marker for predicting the imatinib response in CML patients in CP.

Attempted treatment of meningeosis leucaemica by intrathecal application of 90-silicate and 90Y-citrate colloid in a case of chronic myleoic leukaemia; Behandlungsversuch einer Meningeosis leucaemica durch intrathekale Applikation von {sup 90}Y-Silikat- und {sup 90}Y-Zitrat-Kolloid bei chronisch-myleoischer Leukaemie

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Kittner, C.; Schuemichen, C. [Rostock Univ. (Germany). Klinik und Poliklinik fuer Nuklearmedizin; Steiner, B.; Kahl, C.; Wolff, D.; Freund, M. [Rostock Univ. (Germany). Klinik fuer Innere Medizin, Abt. fuer Haematologie; Putzar, H.; Roesler, K.; Hauenstein, K.H. [Rostock Univ. (Germany). Inst. fuer Diagnostische und Interventionalle Radiologie

2003-12-01

A 41-year-old man with chronic myeoloic leukaemia was treated for Meningeosis leucaemica by intrathecal application of yttrium-90-citrate colloide as palliative therapy. (orig.) [German] Wir berichten ueber einen 41-jaehrigen Mann mit chronisch-myeloischer Leukaemie bei dem eine Meningeosis leucaemica durch eine intrathekale Applikation von Yttrium-90-Zitrat-Kolloid palliativ therapiert wurde. (orig.)

Mutations of NPM1 gene in de novo acute myeloid leukaemia: determination of incidence, distribution pattern and identification of two novel mutations in Indian population.

Science.gov (United States)

Ahmad, Firoz; Mandava, Swarna; Das, Bibhu Ranjan

2009-06-01

Mutations in the nucleophosmin (NPM1) gene have been recently described to occur in about one-third of acute myeloid leukaemias (AMLs) and represent the most frequent genetic alteration currently known in this subset, specially in those with normal karyotype. This study explored the prevalence and clinical profile of NPM1 mutations in a cohort of 200 Indian adult and children with AML. NPM1 mutations were observed in 19.5% of all population and 34.2% of those with normal karyotype. Adults had a significantly higher incidence of NPM1 mutations than children [38 of 161 (23.6%) vs. 1 of 39 (2.5%), p = 0.002]. NPM1 mutations were significantly associated with normal karyotype (p = 0.001), high WBC count (p = 0.034), AML-M4 subtype (p = 0.039) and a gradient increase of mutation rate with the increase in age groups. Sequence analysis of 39 mutated cases revealed typical mutations (types A, B, D, Nm and H*) as well as two novel variations (types F1 and F2). Majority of the patients had mutation type A (69.2%), followed by B (5.1%), D (15.3%), H* (2.5%) and Nm (2.5%) all involving COOH terminal of the NPM1 protein. In conclusion, this study represents the first report of NPM1 mutation from Indian population and confirms that the incidence of NPM1 mutations varies considerably globally, with slightly lower incidence in Indian population compared to western countries. The current study also served to identify two novel NPM1 mutants that add new insights into the heterogeneity of genomic insertions at exon 12. More ongoing larger studies are warranted to elucidate the molecular pathogenesis of AML that arises in this part of the world. Furthermore, we believe that in light of its high prevalence worldwide, inclusion of NPM1 mutation detection assay in diagnostic evaluations of AML may improve the efficacy of routine genetic characterization and allow assignment of patients to better-defined risk categories.

Leukaemia and lymphoma among Czech uranium miners

International Nuclear Information System (INIS)

Tomasek, L.; Malatova, I.

2006-01-01

Leukaemia is one of the most sensitive cancers in relation to ionizing radiation. It is surprising that in studies of uranium miners, no risk of leukaemia in relation to cumulated radon exposure was observed (Darby et al, 1995). However, when the risk among Czech uranium miners was analyzed in dependence on duration of exposure, the trend was significant. These results were based on 10 cases (Tomasek, 1993). Since then the original cohort of 4320 miners has been extended by another cohort, now including nearly 10 000 uranium miners and the follow-up is longer by 10 years. The present report aims to analyze the risk of haemopoietic cancers in the Czech cohort accounting for both external and internal doses, similarly as reported by Jacobi and Roth (1995), and using available data on metal content and airborne particulates for dose estimates.The present results of follow-up show that increased risk of leukaemia among uranium miners is significantly associated with cumulated equivalent red bone marrow doses which is dominated by exposures to long lived alpha radionuclides in airborne particulates. The increased mortality is mainly observed decades after exposure and is consistent with estimated internal dose to red bone marrow. The estimated risk coefficient for leukaemia is consistent with results from other studies, however, further studies are needed to reduce uncertainty in the risk estimates. (N.C.)

Leukaemia and lymphoma among Czech uranium miners

Energy Technology Data Exchange (ETDEWEB)

Tomasek, L.; Malatova, I. [National Radiation Protection Institute, Prague (Czech Republic)

2006-07-01

Leukaemia is one of the most sensitive cancers in relation to ionizing radiation. It is surprising that in studies of uranium miners, no risk of leukaemia in relation to cumulated radon exposure was observed (Darby et al, 1995). However, when the risk among Czech uranium miners was analyzed in dependence on duration of exposure, the trend was significant. These results were based on 10 cases (Tomasek, 1993). Since then the original cohort of 4320 miners has been extended by another cohort, now including nearly 10 000 uranium miners and the follow-up is longer by 10 years. The present report aims to analyze the risk of haemopoietic cancers in the Czech cohort accounting for both external and internal doses, similarly as reported by Jacobi and Roth (1995), and using available data on metal content and airborne particulates for dose estimates.The present results of follow-up show that increased risk of leukaemia among uranium miners is significantly associated with cumulated equivalent red bone marrow doses which is dominated by exposures to long lived alpha radionuclides in airborne particulates. The increased mortality is mainly observed decades after exposure and is consistent with estimated internal dose to red bone marrow. The estimated risk coefficient for leukaemia is consistent with results from other studies, however, further studies are needed to reduce uncertainty in the risk estimates. (N.C.)

Leucemia mieloide crónica: Actualización en Citogenética y Biología Molecular Chronic myeloid leukemia: Updating in cytogenetics and molecular biology

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Valia Pavón Morán

2005-08-01

Full Text Available La leucemia mieloide crónica (LMC es un síndrome mieloproliferativo crónico de naturaleza clonal, originada en la célula madre, que resulta en un excesivo número de células mieloides en todos los estadios de maduración. Fue la primera enfermedad maligna en que se demostró una anomalía genética adquirida y es en la actualidad el modelo molecular de leucemia mejor estudiado. En la LMC se expresa la translocación cromosómica t (9; 22 (q34; q11 que da lugar a la formación del cromosoma Filadelfia (Ph. A causa de esta translocación se producen 2 nuevos genes híbridos: el BCR-ABL en el cromosoma 22q- o cromosoma Ph y el gen recíproco ABL-BCR en el cromosoma derivado 9q+, el cual, aunque transcripcionalmente activo, no parece desempeñar ninguna actividad funcional en la enfermedad. En la actualidad, la identificación de enfermedad mínima residual mediante métodos moleculares es de vital importancia para la evaluación precisa del estado evolutivo de la enfermedadChronic myeloid leukemia (CML is a a chronic myeloproliferative syndrome of clonal nature, originated in the stem cell, that results in an excessive number of myeloid cells in all the maturation stages. It was the first malignat disease in which an acquired genetic abnormality was proved, and it is at present the best studied molecular model of leukemia. In the chronic myeloid leukemia, it is expressed the chromosal translocation t (9;22 (q34;q11, giving rise to the formation of the Philadelphia (Ph chromosome. Due to this translocation, 2 new hybrid genes are produced: BCR-ABL in chromosome 22q- or Ph chromosome, and the reciprocal gene ABL-BCR in the derivative chromosome 9q+, which , although transcriptionally active, does not seem to play any functional activity in the disease. Nowadays, the identification of the minimal residual disease by molecular methods is very important for the exact evaluation of the evolutive state of the disease

Estimation of the target stem-cell population size in chronic myeloid leukemogenesis

International Nuclear Information System (INIS)

Radivoyevitch, T.; Ramsey, M.J.; Tucker, J.D.

1999-01-01

Estimation of the number of hematopoietic stem cells capable of causing chronic myeloid leukemia (CML) is relevant to the development of biologically based risk models of radiation-induced CML. Through a comparison of the age structure of CML incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program and the age structure of chromosomal translocations found in healthy subjects, the number of CML target stem cells is estimated for individuals above 20 years of age. The estimation involves three steps. First, CML incidence among adults is fit to an exponentially increasing function of age. Next, assuming a relatively short waiting time distribution between BCR-ABL induction and the appearance of CML, an exponential age function with rate constants fixed to the values found for CML is fitted to the translocation data. Finally, assuming that translocations are equally likely to occur between any two points in the genome, the parameter estimates found in the first two steps are used to estimate the number of target stem cells for CML. The population-averaged estimates of this number are found to be 1.86 x 10 8 for men and 1.21 x 10 8 for women; the 95% confidence intervals of these estimates are (1.34 x 10 8 , 2.50 x 10 8 ) and (0.84 x 10 8 , 1.83 x 10 8 ), respectively. (orig.)

Cutaneous myeloid sarcoma: natural history and biology of an uncommon manifestation of acute myeloid leukemia.

Science.gov (United States)

Hurley, M Yadira; Ghahramani, Grant K; Frisch, Stephanie; Armbrecht, Eric S; Lind, Anne C; Nguyen, Tudung T; Hassan, Anjum; Kreisel, Friederike H; Frater, John L

2013-05-01

We conducted a retrospective study of patients with cutaneous myeloid sarcoma, from 2 tertiary care institutions. Eighty-three patients presented, with a mean age of 52 years. Diagnosis of myeloid sarcoma in the skin was difficult due to the low frequency of myeloperoxidase and/or CD34+ cases (56% and 19% of tested cases, respectively). Seventy-one of the 83 patients (86%) had ≥ 1 bone marrow biopsy. Twenty-eight (39%) had acute myeloid leukemia with monocytic differentiation. Twenty-three had other de novo acute myeloid leukemia subtypes. Thirteen patients had other myeloid neoplasms, of which 4 ultimately progressed to an acute myeloid leukemia. Seven had no bone marrow malignancy. Ninety-eight percent of the patients received chemotherapy, and approximately 89% died of causes related to their disease. Cutaneous myeloid sarcoma in most cases represents an aggressive manifestation of acute myeloid leukemia. Diagnosis can be challenging due to lack of myeloblast-associated antigen expression in many cases, and difficulty in distinguishing monocyte-lineage blasts from neoplastic and non-neoplastic mature monocytes.

Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia

DEFF Research Database (Denmark)

Wolthers, Benjamin O.; Frandsen, Thomas L.; Baruchel, André

2017-01-01

BACKGROUND: Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re......-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study. METHODS: Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute...... lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal...

DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier.

Science.gov (United States)

Santos, Margarida A; Faryabi, Robert B; Ergen, Aysegul V; Day, Amanda M; Malhowski, Amy; Canela, Andres; Onozawa, Masahiro; Lee, Ji-Eun; Callen, Elsa; Gutierrez-Martinez, Paula; Chen, Hua-Tang; Wong, Nancy; Finkel, Nadia; Deshpande, Aniruddha; Sharrow, Susan; Rossi, Derrick J; Ito, Keisuke; Ge, Kai; Aplan, Peter D; Armstrong, Scott A; Nussenzweig, André

2014-10-02

Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks, we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma, is required for stem-cell activity and an aggressive form of acute myeloid leukaemia harbouring the MLL-AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukaemic blasts, which protects mice from death related to acute myeloid leukaemia. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 protects MLL4(-/-) MLL-AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM or BRCA1 sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. Indeed, we show that restriction-enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL-AF9 blasts, which requires cyclin-dependent kinase inhibitor p21(Cip1) (Cdkn1a) activity. In summary, we have uncovered an unexpected tumour-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in acute myeloid leukaemia.

Towards Comprehension of the ABCB1/P-Glycoprotein Role in Chronic Myeloid Leukemia

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Raquel C. Maia

2018-01-01

Full Text Available Abstract: The introduction of imatinib (IM, a BCR-ABL1 tyrosine kinase inhibitor (TKI, has represented a significant advance in the first-line treatment of chronic myeloid leukemia (CML. However, approximately 30% of patients need to discontinue IM due to resistance or intolerance to this drug. Both resistance and intolerance have also been observed in treatment with the second-generation TKIs—dasatinib, nilotinib, and bosutinib—and the third-generation TKI—ponatinib. The mechanisms of resistance to TKIs may be BCR-ABL1-dependent and/or BCR-ABL1-independent. Although the role of efflux pump P-glycoprotein (Pgp, codified by the ABCB1 gene, is unquestionable in drug resistance of many neoplasms, a longstanding question exists about whether Pgp has a firm implication in TKI resistance in the clinical scenario. The goal of this review is to offer an overview of ABCB1/Pgp expression/activity/polymorphisms in CML. Understanding how interactions, associations, or cooperation between Pgp and other molecules—such as inhibitor apoptosis proteins, microRNAs, or microvesicles—impact IM resistance risk may be critical in evaluating the response to TKIs in CML patients. In addition, new non-TKI compounds may be necessary in order to overcome the resistance mediated by Pgp in CML.

Intermittent targeted therapies and stochastic evolution in patients affected by chronic myeloid leukemia

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Pizzolato, N.; Persano Adorno, D.; Valenti, D.; Spagnolo, B.

2016-05-01

Front line therapy for the treatment of patients affected by chronic myeloid leukemia (CML) is based on the administration of tyrosine kinase inhibitors, namely imatinib or, more recently, axitinib. Although imatinib is highly effective and represents an example of a successful molecular targeted therapy, the appearance of resistance is observed in a proportion of patients, especially those in advanced stages. In this work, we investigate the appearance of resistance in patients affected by CML, by modeling the evolutionary dynamics of cancerous cell populations in a simulated patient treated by an intermittent targeted therapy. We simulate, with the Monte Carlo method, the stochastic evolution of initially healthy cells to leukemic clones, due to genetic mutations and changes in their reproductive behavior. We first present the model and its validation with experimental data by considering a continuous therapy. Then, we investigate how fluctuations in the number of leukemic cells affect patient response to the therapy when the drug is administered with an intermittent time scheduling. Here we show that an intermittent therapy (IT) represents a valid choice in patients with high risk of toxicity, despite an associated delay to the complete restoration of healthy cells. Moreover, a suitably tuned IT can reduce the probability of developing resistance.

Lck is a relevant target in chronic lymphocytic leukaemia cells whose expression variance is unrelated to disease outcome.

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Till, Kathleen J; Allen, John C; Talab, Fatima; Lin, Ke; Allsup, David; Cawkwell, Lynn; Bentley, Alison; Ringshausen, Ingo; Duckworth, Andrew D; Pettitt, Andrew R; Kalakonda, Nagesh; Slupsky, Joseph R

2017-12-01

Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement. This latter finding makes Lck similar to ZAP70, another T-cell kinase whose aberrant expression in CLL cells also associates with BCR signalling capacity, but also different because ZAP70 is not easily pharmacologically targetable. Here we describe a robust method of measuring Lck expression in CLL cells using flow cytometry. However, unlike ZAP70 whose expression in CLL cells predicts prognosis, we find Lck expression and disease outcome in CLL are unrelated despite observations that its inhibition produces effects that biologically resemble the egress phenotype taken on by CLL cells treated with idelalisib. Taken together, our findings provide insight into the pathobiology of CLL to suggest a more complex relationship between expression of molecules within the BCR signalling pathway and disease outcome.

Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial.

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Cortes, Jorge E; Saglio, Giuseppe; Kantarjian, Hagop M; Baccarani, Michele; Mayer, Jiří; Boqué, Concepción; Shah, Neil P; Chuah, Charles; Casanova, Luis; Bradley-Garelik, Brigid; Manos, George; Hochhaus, Andreas

2016-07-10

We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long

Quality of life in chronic myeloid leukaemia patients after haematopoietic cell transplantation pretreated with second-generation tyrosine kinase inhibitors

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Agnieszka Piekarska

2016-12-01

Full Text Available Aim of the study : To was to determine the impact of chronic obstructive pulmonary disease (COPD and active smoking on the efficacy of chemotherapy and complete blood count (CBC in patients with non-small cell lung cancer (NSCLC. Material and methods : The retrospective evaluation included 50 patients with stage IIIB–IV NSCLC, who started cisplatin-based chemotherapy. Peripheral blood CBC values were collected for testing before chemotherapy and after the first and third cycles. Results: COPD was diagnosed in 49% of patients, while 42% of those enrolled were current smokers. Current smoking (p = 0.92 and COPD (p = 0.91 status did not affect the response to treatment. The non-COPD population presented a significantly higher pretreatment absolute lymphocyte count (ALC than the COPD population (2.31 vs. 1.81 × 109/l; p = 0.0374. Also, only the non-COPD group demonstrated an elevated absolute monocyte count (AMC following the first and third cycles of chemotherapy (p = 0.004. In current smokers, pretreatment values for white blood cells (WBC, absolute neutrophil count (ANC, and platelets (PLT were higher than in the ex-smoker population (WBC 9.94 vs. 8.7 (× 109/l; p = 0.01; ANC 6.47 vs. 5.61 (× 109/l; p = 0.037; PLT 316 vs. 266 (× 109/l; p = 0.049. Ex-smokers demonstrated AMC level elevation after the first cycle of chemotherapy and PLT level elevation after the third cycle, while current smokers also demonstrated an early decrease in LMR. Conclusions : COPD and smoking induce chronic systemic inflammation and oxidative stress, which influence the results of standard laboratory tests, but do not change the response rate of lung cancer on chemotherapy.

Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era.

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Zafar Iqbal

Full Text Available BACKGROUND: BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. METHODS: We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. RESULTS: Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48, all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. CONCLUSION: Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid

The long-term clinical implications of clonal chromosomal abnormalities in newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib mesylate.

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Lee, Sung-Eun; Choi, Soo Young; Bang, Ju-Hee; Kim, Soo-Hyun; Jang, Eun-Jung; Byeun, Ji-Young; Park, Jin Eok; Jeon, Hye-Rim; Oh, Yun Jeong; Kim, Myungshin; Kim, Dong-Wook

2012-11-01

The aim of this study was to evaluate the long-term clinical significance of an additional chromosomal abnormality (ACA), variant Philadelphia chromosome (vPh) at diagnosis, and newly developed other chromosomal abnormalities (OCA) in patients with chronic myeloid leukemia (CML) on imatinib (IM) therapy. Sequential cytogenetic data from 281 consecutive new chronic phase CML patients were analyzed. With a median follow-up of 78.6 months, the 22 patients with vPh (P = 0.034) or ACA (P = 0.034) at diagnosis had more events of IM failure than did the patients with a standard Ph. The 5-year overall survival (OS), event-free survival (EFS), and failure-free survival (FFS) rates for patients with vPh at diagnosis were 77.8%, 75.0%, and 53.3%, respectively; for patients with ACA at diagnosis, 100%, 66.3%, and 52.1%, respectively; and for patients with a standard Ph, 96.0%, 91.3%, and 83.7%, respectively. During IM therapy, eight patients developed an OCA, which had no impact on outcomes as a time-dependent covariate in our Cox proportional hazards regression models. This study showed that vPh was associated with poor OS and FFS and that ACA had adverse effects on EFS and FFS. In addition, no OCA, except monosomy 7, had any prognostic impact, suggesting that the development of OCA may not require a change in treatment strategy. Copyright © 2012 Elsevier Inc. All rights reserved.

A propensity score matching analysis of dasatinib and nilotinib as a frontline therapy for patients with chronic myeloid leukemia in chronic phase.

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Takahashi, Koichi; Kantarjian, Hagop M; Yang, Yulong; Sasaki, Koji; Jain, Preetesh; DellaSala, Sara; Ravandi, Farhad; Kadia, Tapan; Pemmaraju, Naveen; Daver, Naval; Borthakur, Gautam; Garcia-Manero, Guillermo; Jabbour, Elias; Cortes, Jorge E

2016-11-15

Both dasatinib and nilotinib are approved frontline therapy for chronic myeloid leukemia in chronic phase (CML-CP) based on randomized trials compared with imatinib. However, no head-to-head comparison of dasatinib and nilotinib has been conducted in patients with newly diagnosed CML-CP. The authors conducted a propensity score (PS) matched comparison of patients with CML-CP who received frontline therapy with either dasatinib (N = 102) or nilotinib (N = 104) under the respective phase 2 trials conducted in parallel. PS matching resulted in 87 patients from each trial being matched for pretreatment characteristics. The 3-month BCR-ABL1/ABL1 ratio treatment cohorts. The 3-year probability of event-free survival was 89% among the patients who received dasatinib and 87% among those who received nilotinib (P = .99), and the corresponding 3-year overall survival probabilities were 99% and 93%, respectively (P = .95). No statistical difference was observed between the dasatinib and nilotinib groups in any of the other survival endpoints. The treatment discontinuation rate also was similar between the 2 cohorts (dasatinib group, 18%; nilotinib group, 19%; P = .82). In a PS-matched cohort of patients with newly diagnosed CML-CP, dasatinib and nilotinib offer similar response and survival outcomes. Both drugs can be considered reasonable standard-of-care options as first-line therapy for patients with CML-CP. Cancer 2016;122:3336-3343. © 2016 American Cancer Society. © 2016 American Cancer Society.

Population pharmacokinetics of cytarabine, etoposide and daunorubicin in the treatment of acute myeloid leukaemia

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Krogh-Madsen, Mikkel; Bender, B.; Jensen, M. K.

2012-01-01

PURPOSE: Interpatient variability in the pharmacokinetics (PK) of cytarabine, etoposide, and daunorubicin following body surface area-adjusted doses calls for studies that point to other covariates to explain this variability. The purpose of this study was to investigate such relationships and gi...... and the relationship between kidney function and etoposide clearance to clinical end points would support dose individualization. Patients with above-normal creatinine clearances and high bWBC may receive sub-optimal treatment due to elevated etoposide clearances....... insights into the PK of this combination treatment. METHODS: A prospective population PK study of twenty-three patients with acute myeloid leukemia was undertaken. Plasma concentrations of patients were determined by high-pressure liquid chromatography. PK models were developed with NONMEM...... in creatinine clearance of 60 mL/min resulted in a decrease in etoposide clearance of 32%. CONCLUSIONS: Population-based models characterized the PK for all three drugs. bWBC was a significant covariate for etoposide and cytarabine and showed a trend for daunorubicin. Linking the significant bWBC relationships...

Exposure to electromagnetic fields and the risk of childhood leukaemia: A review

International Nuclear Information System (INIS)

Schuez, J.; Ahlbom, A.

2008-01-01

Extremely low-frequency magnetic fields have been classified as possibly carcinogenic to humans, mainly based on epidemiological studies consistently showing an association between long-term average exposures to magnetic fields above 0.3/0.4 μT and the risk of childhood leukaemia. No mechanism to explain this finding has been established and no support for a causal link emerged from experimental studies. Chance or bias cannot be ruled out with reasonable confidence as an explanation for the observed association. If the association is causal, it explains only a small fraction of childhood leukaemia cases. There were some reports of childhood leukaemia clusters in the vicinity of high-power radio and television broadcast transmitters in studies in Australia and Italy. However, recent large-scale systematic studies in Korea and Germany show no association between exposure to radio frequency electromagnetic fields emitted from broadcast towers and childhood leukaemia risk. Studies on mobile phone use and leukaemia risk in adolescents and young adults may be indicated. (authors)

Single-centre experience of allogeneic haemopoietic stem cell ...

African Journals Online (AJOL)

Allogeneic haemopoietic stem cell transplant (Allo-HSCT) is used to treat a broad but well-defined range of paediatric conditions, most frequently in paediatric oncology for treatment intensification or salvage therapy for acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Allo-HSCT is also indicated in.

Long-term follow-up of patients receiving allogeneic stem cell transplant for chronic lymphocytic leukaemia: mixed T-cell chimerism is associated with high relapse risk and inferior survival.

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Thompson, Philip A; Stingo, Francesco; Keating, Michael J; Wierda, William G; O'Brien, Susan M; Estrov, Zeev; Ledesma, Celina; Rezvani, Katayoun; Qazilbash, Muzaffar; Shah, Nina; Parmar, Simrit; Popat, Uday; Anderlini, Paolo; Yago, Nieto; Ciurea, Stefan O; Kebriaei, Partow; Champlin, Richard; Shpall, Elizabeth J; Hosing, Chitra M

2017-05-01

There is limited information regarding the immunological predictors of post-allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T-cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post-alloSCT and the ability of post-transplant immunomodulation to treat relapse. Mixed T-cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post-alloSCT; upon 3- and 6-month landmark analysis, this was associated with inferior progression-free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P CLL. © 2017 John Wiley & Sons Ltd.

The risk of childhood leukaemia near nuclear establishments

International Nuclear Information System (INIS)

Stather, J.W.; Clarke, R.H.; Duncan, K.P.

1988-01-01

Childhood leukaemia has been reported to be increased in communities living near a number of nuclear sites in the United Kingdom. The National Radiological Protection Board has, over the last three and a half years, published the results of a series of studies giving radiation doses and risks calculated for some of these populations. The studies have all indicated that it is most unlikely that radiation doses arising from releases of radioactive materials into the environment could have contributed to any increase in the leukaemia incidence in local communities. In the absence of any other obvious causative agent, however, there remains some concern that the radiation doses and risks of leukaemia have been underestimated. This report, therefore, summarises the methods used in the analyses by the Board, examines possible sources of uncertainty in the calculations, and considers the extent to which more information is required. (author)

Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

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Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

2011-01-01

Biologic and clinical observations suggest that combining imatinib with IFN-a may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission......%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-a2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-a2b arm (82%) compared...... with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-a2b treatment ( 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-a2b to imatinib markedly increased the MMR rate at 12 months...

Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma

DEFF Research Database (Denmark)

Nysom, K; Holm, K; Hesse, B

1996-01-01

Longitudinal data were analysed on the lung function of 25 of 29 survivors of childhood leukaemia or lymphoma, who had been conditioned with cyclophosphamide and total body irradiation before allogeneic bone marrow transplantation, to test whether children are particularly vulnerable to pulmonary...... damage after transplantation. None developed chronic graft-versus-host disease. Transfer factor and lung volumes were reduced immediately after bone marrow transplantation, but increased during the following years. However, at the last follow up, 4-13 years (median 8) after transplantation, patients had...... to their age at bone marrow transplantation. In conclusion, patients had subclinical restrictive pulmonary disease at a median of eight years after total body irradiation and allogeneic bone marrow transplantation....

Are maternal fertility problems related to childhood leukaemia

International Nuclear Information System (INIS)

Steensel-Moll, H.A. van; Valkenburg, H.A.; Vandenbroucke, J.P.; Zanen, G.E. van

1985-01-01

A study was conducted in the Netherlands, from a nationwide register of childhood leukaemia (1973-1980). Controls were matched with cases for year of birth, sex and place of residence. Information about exposures of the mother to potential risk factors in the year before and during pregnancy was collected via mailed questionnaires. Analyses concerned data on 519 patients with acute lymphocytic leukaemia and 507 controls. An association between maternal subfertility and childhood leukaemia might be suggested by several findings. A history of two or more miscarriages (OR 1.6; 95% Cl 1.0-2.7) and fertility problems (OR 6.0; 95% Cl 0.9-38.2) were more frequently reported among mothers of cases. Use of oral contraceptives (OC) was significantly higher (OR 1.3; 95% Cl 1.0-1.8) and the duration between discontinuation of OC and the relevant pregnancy was significantly longer. The OR for threatened abortion during the relevant pregnancy was 1.6 (95% Cl 1.0-2.6) and the related use of 'drugs to maintain pregnancy' was 1.9; 95% Cl 1.0-3.5. Among known risk factors, an increased OR for diagnostic irradiation was confirmed (OR 2.2; 95% Cl 1.2-3.8). No association between childhood leukaemia and prenatal viral infections, smoking and alcohol was found. (author)