Posted by rob on December 31, 2009 under Uncategorized | 
Authors: Goldstein BD
There is a long standing issue concerning the strength of evidence relating benzene to lymphocytic neoplasms. Because benzene is a known cause of human acute myelogenous leukemia there has been little reason for organizations such as the International Agency for Research on Cancer (IARC) or the US National Toxicology Program (NTP) to perform standard hazard identification reviews of benzene as a possible cause of other cancers such as lymphomas. Increased understanding of underlying mechanisms of carcinogenesis, as is reflected in the greater scope given to mechanistic evidence in assigning overall sufficiency of evidence for carcinogenicity by both IARC and NTP, suggests that the evidence supporting benzene as a cause of lymphoma likely has passed the threshold r…
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Detection of Drug-Resistant Clones in Chronic Myelogenous Leukemia Patients during Dasatinib and Nilotinib Treatment.
Clin Chem. 2009 Dec 29;
Authors: Gruber FX, Ernst T, Kiselev Y, Hochhaus A, Mikkola I
BACKGROUND: Imatinib effectively inhibits the tyrosine kinase activity conferred by the BCR-ABL gene [fusion gene of BCR (breakpoint cluster region) and ABL1 (c-abl oncogene 1, receptor tyrosine kinase)] and thereby appreciably improves outcomes for chronic myelogenous leukemia (CML). A small percentage of patients relapse because of the proliferation of escape clones; such relapses can be treated with second-generation drugs. Early detection and monitoring of resistant clones may provide clinical benefit. We describe the development and testing of a new approach for quantitative monitoring of CML resistance. METHODS: We designed mutation-specific assays that use hydrolysis probes and an array of allele-specific primers containing nucleotides mismatched at various positions. All assays were tested with plasmids containing corresponding mutant or wild-type sequences, allowing identification of optimal assays for specific and effective amplification of the target template. Clinical samples were then used to compare the results of selected assays with those of standard genotyping. RESULTS: We used a modified amplification refractory mutational system approach and testing with plasmid constructs to design assays that allowed highly selective detection of resistance for all target mutations. By taking advantage of single-step performance and high PCR efficiency, we were able to quantitatively track the absolute amount of resistance conferred by a specific mutation over 4 orders of magnitude. Moreover, we designed an integrated test for dasatinib resistance that uses multiple primers simultaneously. CONCLUSIONS: These single-step, closed-tube assays specifically target mutations associated with resistance to dasatinib or nilotinib. Compared with standard genotyping, such biased genotyping improves the detection of resistance or alternative features via quantitative analysis of the absolute amount of resistance.
PMID: 20040619 [PubMed - as supplied by publisher]
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Posted by rob on December 21, 2009 under Uncategorized |
Conclusion
Mutations in the Cbl family RING finger domain or linker sequence constitute important pathogenic lesions associated with not only preleukemic CMML, JMML, and other MPN, but also progression to AML, suggesting that impairment of degradation of activated tyrosine kinases constitutes an important cancer mechanism. (Source: Journal of Clinical Oncology)
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Report of a phase 1/2 study of a combination of azacitidine and cytarabine in acute myelogenous leukemia and high-risk myelodysplastic syndromes.
Leuk Lymphoma. 2009 Dec 17;
Authors: Borthakur G, Huang X, Kantarjian H, Faderl S, Ravandi F, Ferrajoli A, Torma R, Morris G, Berry D, Issa JP
Cytarabine resistance characterizes relapsed and refractory acute myelogenous leukemia (AML). Restoration of cytarabine sensitivity can potentially improve treatment outcome in this setting. Acquired hypermethylation of gene promoters and associated silencing of gene expression has been implicated in chemo resistance, and drug-induced hypomethylation can improve sensitivity to cytarabine in vitro. We conducted an adaptively randomized study of a combination of azacitidine, a hypomethylating agent, and cytarabine in 34 patients with AML. The combination administered in a concomitant fashion is safe at full doses of azacitidine and cytarabine, without unexpected toxicities. However, in this advanced AML population, it was difficult to deliver more than one cycle of therapy, and minimal anti-leukemia activity was seen in patients with relapsed/refractory disease. Complete remission was achieved in 2 of 6 minimally pre-treated patients. We conclude that the combination of azacitidine and cytarabine is feasible but has limited activity in relapsed/refractory AML.
PMID: 20017599 [PubMed - as supplied by publisher]
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Primary antifungal prophylaxis in acute myeloblastic leukemia and myelodysplastic syndrome – still an open question?
Leuk Lymphoma. 2009 Dec 17;
Authors: Rüping MJ, Vehreschild JJ, Cornely OA
In this review, we aim to compare different early treatment strategies of invasive fungal diseases in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Three treatment approaches – prophylactic, empiric, and pre-emptive treatment – are subject to continuous discussion among physicians treating patients at risk. Considering the available clinical basis of evidence, we opt for antifungal prophylaxis with posaconazole 200 mg tid po as our primary prophylactic strategy, while the employment of pre-emptive treatment should be delayed until more accurate diagnostic tools become available. In addition to antifungal prophylaxis, empiric treatment with caspofungin or L-AmB may be administered to patients with fever resistant to broad-spectrum antibiotic treatment and without radiographic findings typical of invasive fungal disease.
PMID: 20017598 [PubMed - as supplied by publisher]
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Posted by rob on December 18, 2009 under Uncategorized |
Imatinib is highly effective in inducing remission in chronic myelogenous leukemia (CML). However, complete eradication of the malignant clone by imatinib is rare. We investigated the efficacy of combining imatinib with cisplatin. Inhibition of Bcr-Abl by imatinib induced a hypersensitive phenotype both in Bcr-Abl+ cell lines and in CD34+ cells from CML patients. Importantly, cisplatin sensitivity of leukemic cells harboring an inactive Bcr-Abl greatly exceeded that of Bcr-Abl– parental cells. The cisplatin response of Bcr-Abl+ cells treated with imatinib was characterized by an impaired G2-M arrest and by rapid induction of mitochondrial cell death after the first passage through G2. Imatinib abrogated ATM activation on cisplatin selectively in Bcr-Abl+ cells. As a consequence, phos…
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Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently coexpressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary end point was 6-month progression-free survival (6M-PFS). Patients requiring enzyme-inducing antiepileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptabl…
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Childhood chronic myeloid leukemia with celiac disease.
Pediatr Blood Cancer. 2010 Jan;54(1):177
Authors: Singhal M, Makharia G, Bakhshi S
PMID: 19731332 [PubMed - indexed for MEDLINE]
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Posted by rob on December 14, 2009 under Uncategorized |
We show the molecular and functional characterization of a novel population of lineage-negative CD34-negative (Lin–CD34–) hematopoietic stem cells from chronic myelogenous leukemia (CML) patients at diagnosis. Molecular karyotyping and quantitative analysis of BCR-ABL transcript demonstrated that approximately one-third of CD34– cells are leukemic. CML Lin–CD34– cells showed kinetic quiescence and limited clonogenic capacity. However, stroma-dependent cultures induced CD34 expression on some cells and cell cycling, and increased clonogenic activity and expression of BCR-ABL transcript. Lin–CD34– cells showed hematopoietic cell engraftment rate in 2 immunodeficient mouse strains similar to Lin-CD34+ cells, whereas endothelial cell engraftment was si…
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Acute Myelogenous Leukemia and Myelodysplasia Secondary to Breast Cancer Treatment: Case Studies and Literature Review.
Am J Med Sci. 2009 Dec 4;
Authors: Cole M, Strair R
Background and Purpose: Chemotherapy and radiation therapy for breast cancer are known to increase the risk of developing a myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML). Alkylating agents and topoisomerase II inhibitors, fundamental to the treatment of breast cancer, are the most likely contributors to this increase in risk. Radiation therapy adds to the risk, and there is speculation that granulocyte colony-stimulating factor (G-CSF) may also predispose to leukemia. The purpose of this systemic review is to bring to the attention of family physicians the unintended consequence of leukemia secondary to aggressively treated breast cancer. METHODS:: The medical records of several patients from Robert Wood Johnson University Hospital, with previously treated breast cancer admitted for therapy for AML or myelodysplasia, were reviewed. In addition, the recent literature on this topic was reviewed. RESULTS:: Cases of patients whose AML was likely secondary to their treatment for breast cancer were used to illustrate the role of chemotherapy, radiation therapy, and perhaps G-CSF in the development of leukemia. CONCLUSIONS:: Chemotherapy and radiation therapy administered for breast cancer predispose patients to the development of MDS or AML. We hypothesize that the breast cancer (BRCA) gene mutations might add to the risk and that primary care physicians must be aware of the long-term risks of cytotoxic therapy, including the development of MDS or AML.
PMID: 19996729 [PubMed - as supplied by publisher]
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Posted by rob on December 6, 2009 under Uncategorized |
Authors: Imamura M, Tanaka J
Nonmyeloablative stem cell transplantation (NST) is increasingly used with beneficial effects because it can be applied to older patients with hematological malignancies and those with various complications who are not suitable for conventional myeloablative stem cell transplantation (CST). Various conditioning regimens differ in their myeloablative and immunosuppressive intensity. Regardless of the type of conditioning regimen, graft-versus- host disease (GVHD) in NST occurs almost equally in CST, although a slightly delayed development of acute GVHD is observed in NST. Although graft-versus-hematological malignancy effects (i.e., graft-versus-leukemia effect, graft-versus-lymphoma effect, and graft-versus-myeloma effect) also occur in NST, completely erad…
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Advances in the biology and therapy of patients with chronic myeloid leukaemia.
Best Pract Res Clin Haematol. 2009 Sep;22(3):395-407
Authors: Jabbour E, Fava C, Kantarjian H
Chronic myelogenous leukaemia (CML) is a progressive and often fatal haematopoietic neoplasm. The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate represented a major therapeutic advance over conventional CML therapy, with more than 90% of patients obtaining complete haematologic response and 70-80% of patients achieving a complete cytogenetic response. Resistance to imatinib represents a clinical challenge and is often a result of point mutations causing a conformation change in Bcr-Abl, which impairs imatinib binding. Novel targeted agents designed to overcome imatinib resistance include dasatinib, nilotinib, bosutinib and others. Other approaches are exploring combination therapy, with agents affecting different oncogenic pathways and immune modulation. Herein, we review some of these targeted therapies, particularly those for which clinical data are already available.
PMID: 19959090 [PubMed - in process]
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Posted by rob on December 1, 2009 under Uncategorized |
This study shows that BCR-ABL1 RQ-PCR monitoring of CML patients after ASCT with PB is concordant with BM in 95.3% of cases, and thus may be used to monitor the disease. This may be relevant when discussing both quality of life issues and the need for post-transplant monitoring with the patient. (Source: Clinical and Laboratory Haematology)
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Acute myelogenous leukemia switch lineage upon relapse to acute lymphoblastic leukemia: a case report.
Cases J. 2009;2:154
Authors: Dorantes-Acosta E, Arreguin-Gonzalez F, Rodriguez-Osorio CA, Sadowinski S, Pelayo R, Medina-Sanson A
Acute leukemia, the most common form of cancer in children, accounts for approximately 30% of all childhood malignancies, with acute lymphoblastic leukemia being five times more frequent than acute myeloid leukemia. Lineage switch is the term that has been used to describe the phenomenon of acute leukemias that meet the standard French-American-British system criteria for a particular lineage (either lymphoid or myeloid) upon initial diagnosis, but meet the criteria for the opposite lineage at relapse. Many reports have documented conversions of acute lymphoblastic leukemia to acute myeloid leukemia.Here, we report the case of a 4-year-old child with acute myeloid leukemia, which upon relapse switched to acute lymphoblastic leukemia. The morphologic, phenotypic, and molecular features suggest the origin of a new leukemic clone.
PMID: 19946525 [PubMed - in process]
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