Posted by rob on November 10, 2009 under Uncategorized | 
Impact of declining fertility rates in Canada on donor options in blood and marrow transplantation.
Biol Blood Marrow Transplant. 2009 Dec;15(12):1634-7
Authors: Allan DS, Takach S, Smith S, Goldman M
An HLA-matched sibling remains the optimal donor for most patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Marked declines in total fertility rates in Canada over the past 50 years will lead to increasing numbers of patients without sibling donors well into the future. We retrieved transplantation data from a Canadian center and the Canadian Blood and Marrow Transplant Group and total fertility data from the United Nations Department of Economic and Social Affairs. The mean age of adults with acute myelogenous leukemia (AML), who underwent transplantation at The Ottawa Hospital between 1995 and 2004, was 41 +/- 12 years (n = 87). The chance of finding 1 or more HLA-matched sibling donors for a patient with AML treated in 2002 is reflected by the total fertility rate in 1961 (average birth year for patients and sibling donors). The sibling rate for 1961 is the total fertility rate-1.0, or 2.68. The chance of having 1 or more HLA-matched sibling is 53.7% (1-chances of no matched sibling, or 1 – 0.75(2.68)). In 2009, the chance of identifying a matched sibling is only 37.1%, because of declining total fertility rates. Following this trend, this chance will be 24.6% in 2014 and 16.6% in 2024. Greater reliance on alternative donors, such as umbilical cord blood (UCB) and HLA-mismatched donors, can be anticipated. The issue of declining fertility rates appears to be regional, and the impact on transplantation will be more pronounced in Canada than in other developed nations.
PMID: 19896088 [PubMed - in process]
More
Posted by rob on under Uncategorized |
Impact of conditioning regimen in allogeneic hematopoetic stem cell transplantation for children with acute myelogenous leukemia beyond first complete remission: a pediatric blood and marrow transplant consortium (PBMTC) study.
Biol Blood Marrow Transplant. 2009 Dec;15(12):1620-7
Authors: Sisler IY, Koehler E, Koyama T, Domm JA, Ryan R, Levine JE, Pulsipher MA, Haut PR, Schultz KR, Taylor DS, Frangoul HA
Total body irradiation (TBI)-based conditioning regimens for pediatric patients with acute myelogenous leukemia (AML) beyond first complete remission (CR1) are controversial. Because the long-term morbidity of busulfan (Bu)-based regimens appears to be lower, determining efficacy is critical. We retrospectively evaluated 151 pediatric patients with AML beyond CR1, comparing outcomes in 90 patients who received a TBI-based conditioning regimen and 61 patients who received a Bu-based conditioning regimen. There were no differences between the 2 groups with respect to age, sex, duration of CR1, time from most recent remission to transplantation, or donor source. The probability of relapse at 2 years also did not differ between the 2 groups (26% and 27%, respectively; P=.93). No significant difference in event-free survival (EFS) (P=.29) or overall survival (OS) (P=.11) was noted between the 2 groups. These findings were supported by a multivariate analysis in which TBI was not associated with improved EFS (hazard ratio [HR]=1.17; 95% confidence interval [CI]=0.66-2.10; P=.58) or OS (HR=1.42; 95% CI=0.76-2.64; P=.27). Shorter CR1 and receiving an HLA-mismatched transplant adversely affected EFS and OS in this cohort. Our study provides no evidence of an advantage to using TBI in children with AML beyond CR1. A prospective, randomized study is needed to confirm these results.
PMID: 19896086 [PubMed - in process]
More
Posted by rob on under Uncategorized |
Myeloid leukaemia in systemic lupus erythematosus–a nested case-control study based on Swedish registers.
Rheumatology (Oxford). 2009 Oct;48(10):1222-6
Authors: Löfström B, Backlin C, Sundström C, Hellström-Lindberg E, Ekbom A, Lundberg IE
OBJECTIVE: To assess the risk factors for leukaemic transformation and myeloid leukaemia in patients with SLE. METHODS: A national SLE cohort identified through SLE discharge diagnoses in the Swedish hospital discharge register during 1964 to 1995 (n = 6438) was linked to the national cancer register. A nested case-control study in SLE patients who developed acute or chronic myeloid leukaemia was performed with SLE patients without malignancy as controls. Medical records from cases and controls were reviewed and bone marrow specimens were re-evaluated. A Medline search of previously published cases of SLE and myeloid leukaemia was performed. RESULTS: After confirmation of SLE diagnosis according to the ACR criteria, eight patients with SLE and myeloid leukaemia and 18 SLE controls were included in the study. Preceding leucopenia was significantly associated with leukaemia development, whereas other SLE manifestations were not. Two cases had a preceding bone marrow confirming myelodysplastic syndrome (MDS). Only two cases were significantly treated with cyclophosphamide or AZA. A Medline search resulted in only 15 previously published cases of coincident SLE and myeloid leukaemia. Preceding MDS was reported in five of these, whereas only eight had been treated with cytotoxic drugs. CONCLUSION: Low-dose chemotherapy was not a major cause of myeloid malignancy in our population-based cohort of SLE patients nor in the reported cases from literature. Leucopenia was a risk factor for myeloid leukaemia development and an MDS was frequently seen. Therefore bone marrow investigation should be considered in SLE patients with long-standing leucopenia and anaemia.
PMID: 19608725 [PubMed - indexed for MEDLINE]
More
Posted by rob on November 7, 2009 under Uncategorized |
Chronic myeloid leukemia with p190BCR-ABL: prevalence, morphology, tyrosine kinase inhibitor response, and kinase domain mutation analysis.
Blood. 2009 Oct 15;114(16):3502-3
Authors: Pardanani A, Tefferi A, Litzow MR, Zent C, Hogan WJ, McClure RF, Viswanatha D
PMID: 19833856 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis.
Blood. 2009 Oct 15;114(16):3459-63
Authors: Snead JL, O’Hare T, Adrian LT, Eide CA, Lange T, Druker BJ, Deininger MW
Pioneering work with the Bcr-Abl inhibitor, imatinib, demonstrated a requirement for constant Bcr-Abl inhibition to achieve maximal therapeutic benefit in treating chronic myeloid leukemia (CML), establishing a paradigm that has guided further drug development for this disease. Surprisingly, the second-generation Bcr-Abl inhibitor, dasatinib, was reported to be clinically effective with once-daily dosing, despite a short (3- to 5-hour) plasma half-life. Consistent with this observation, dasatinib treatment of progenitor cells from chronic-phase CML patients for 4 hours, followed by washout, or continuously for 72 hours both resulted in an induction of apoptosis and a reduction in the number of clonogenic cells. Such acute treatments with clinically achievable dasatinib concentrations also irreversibly committed Bcr-Abl+ CML cell lines to apoptotic cell death. Potent transient Bcr-Abl inhibition using the alternative inhibitor, nilotinib, also resulted in cell death. These findings demonstrate that in vitro assays designed to model in vivo pharmacokinetics can predict clinical efficacy. Furthermore, they challenge the widely held notion that continuous target inhibition is required for optimal efficacy of kinase inhibitors.
PMID: 19706883 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
How I monitor residual disease in chronic myeloid leukemia.
Blood. 2009 Oct 15;114(16):3376-81
Authors: Radich JP
Molecular monitoring in chronic myeloid leukemia (CML) is a powerful tool to document treatment responses and predict relapse. Nonetheless, the proliferation of clinical trials and “guidelines” using the molecular endpoints of CML has outpaced practice norms, commercial laboratory application, and reimbursement practices, leaving some anxiety (if not confusion and despair) about molecular monitoring in the day-to-day treatment of CML. This article will try to address these issues by describing how I monitor CML, which, in summary, is with interest and without panic.
PMID: 19661271 [PubMed - indexed for MEDLINE]
More
Posted by rob on November 5, 2009 under Uncategorized |
Molecular monitoring of residual disease in chronic myeloid leukemia by genomic DNA compared with conventional mRNA analysis.
J Mol Diagn. 2009 Sep;11(5):482-7
Authors: Mattarucchi E, Spinelli O, Rambaldi A, Pasquali F, Lo Curto F, Campiotti L, Porta G
Translocation t(9;22), which produces the BCR-ABL gene, is pathognomonic of chronic myeloid leukemia. For clinical purposes, the amount of chimeric transcript is considered proportional to the leukemic clone; thus, mRNA is commonly used for molecular monitoring of patients. However, there is no consensus regarding the degree of increase in mRNA that should cause concern or whether the absence of transcript indicates a “cure.” In this study, we analyzed 57 samples from 10 chronic myeloid leukemia patients undergoing imatinib treatment. For each sample, we compared BCR-ABL mRNA levels with the actual proportion of leukemic cells, which were measured through a novel genomic approach based on the quantitative amplification of DNA breakpoints. The two approaches gave similar patterns of residual disease, and the majority of patients were still positive after an average treatment period of 2 years. Nevertheless, in one of two patients with confirmed undetectable levels of chimeric transcript, DNA still revealed the persistence of leukemic cells at 42 months. These findings appear to justify the clinical practice of maintaining imatinib treatment indefinitely. However, the absence of leukemic DNA (observed in 1 of 10 patients) could be used to identify possible candidates for drug discontinuation. In conclusion, DNA analysis proved to be a reliable index of residual disease with potential applications in the field of clinical diagnostics and research.
PMID: 19710400 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Imatinib and beyond–exploring the full potential of targeted therapy for CML.
Nat Rev Clin Oncol. 2009 Sep;6(9):535-43
Authors: Quintás-Cardama A, Kantarjian H, Cortes J
A subset of patients with chronic myeloid leukemia (CML) who receive imatinib therapy will require alternative therapy at some point owing to safety reasons or lack of efficacy. Achieving an early response with imatinib is protective against treatment failure; second-generation tyrosine kinase inhibitors (TKIs; for example, nilotinib, dasatinib, bosutinib), however, have proven to be efficacious at restoring cytogenetic responses in patients who require subsequent therapy. Response duration, however, is yet to be established and a considerable proportion of patients fail to achieve a clinically meaningful response. A third generation of TKIs is currently undergoing clinical testing for use in patients who fail imatinib and a second-generation TKI. Most of these agents are multikinase inhibitors with activity against a wide variety of BCR-ABL1 mutations, including the highly resistant T315I. The use of second-generation TKIs in the frontline setting seems to provide higher rates of early response compared with imatinib. If these results are confirmed in randomized studies, nilotinib and dasatinib could replace imatinib as standard frontline therapy in CML. Despite the activity of all of the above mentioned agents, curing CML will ultimately depend on the development of agents capable of vanquishing BCR-ABL1-positive CML stem cells. Efforts aimed at achieving this goal are ongoing.
PMID: 19652654 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Interferon-alpha may restore sensitivity to tyrosine-kinase inhibitors in Philadelphia chromosome positive acute lymphoblastic leukaemia with F317L mutation.
Br J Haematol. 2009 Jul;146(2):227-30
Authors: Potenza L, Volzone F, Riva G, Soverini S, Martinelli S, Iacobucci I, Gnani A, Barozzi P, Forghieri F, Morselli M, Zanetti E, Maccaferri M, Baccarani M, Martinelli G, Torelli G, Luppi M
PMID: 19545285 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Dasatinib-induced response in a rare case of chronic lymphocytic leukaemia associated with chronic myeloid leukaemia.
Br J Haematol. 2009 Jul;146(2):222-3
Authors: Tecchio C, Nichele I, Todeschini G, Pizzolo G, Ambrosetti A
PMID: 19466973 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Platelets and thrombosis in myeloproliferative diseases.
Hematology Am Soc Hematol Educ Program. 2005;:409-15
Authors: Harrison CN
The myeloproliferative disorders have been the “poor cousins” in the family of hematological malignancies for some time. Recently this field has advanced considerably with the description of a mutation in the JAK2 kinase detectable in the majority of patients and the publication of two landmark clinical trials–ECLAP and MRC PT1. But although both ECLAP and MRC PT1 inform clinical management and allude to the complexities of thrombosis we still lack fundamental knowledge, and our understanding of thrombosis in these conditions has not paralleled advances in the field of thrombosis and vascular biology. The predominant clinical complications of essential thrombocythemia and polycythemia vera are thrombotic and hemorrhagic; these significantly impact upon prognosis and quality of life. Here the current status of our knowledge is reviewed with specific emphasis upon the role of the platelet in the pathogenesis of thrombosis as well as the impact of recent data from ECLAP and MRC PT1.
PMID: 16304412 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases.
Hematology Am Soc Hematol Educ Program. 2005;:195-200
Authors: Vainchenker W, Constantinescu SN
Myeloproliferative disorders (MPDs) are heterogeneous diseases that occur at the level of a multipotent hematopoietic stem cell. They are characterized by increased blood cell production related to cytokine hypersensitivity and virtually normal cell maturation. The molecular pathogenesis of the MPDs has been poorly understood, except for chronic myeloid leukemia (CML), where the Bcr-Abl fusion protein exhibits constitutive kinase activity. Since some rare MPDs are also related to a dysregulated kinase activity, a similar mechanism was thought to be likely responsible for the more frequent MPDs. We investigated the mechanisms of endogenous erythroid colony formation (EEC) by polycythemia vera (PV) erythroid progenitor cells and found that EEC formation was abolished by a pharmacological inhibitor of JAK2 as well as an siRNA against JAK2. JAK2 sequencing revealed a unique mutation in the JH2 domain leading to a V617F substitution in more than 80% of the PV samples. This mutation in the pseudokinase autoinhibitory domain results in constitutive kinase activity and induces cytokine hypersensitivity or independence of factor-dependent cell lines. Retroviral transduction of the mutant JAK2 into murine HSC leads to the development of an MPD with polycythemia. The same mutation was found in about 50% of patients with idiopathic myelofibrosis (IMF) and 30% of patients with essential thrombocythemia (ET). Using different approaches, four other teams have obtained similar results. The identification of the JAK2 mutation represents a major advance in our understanding of the molecular pathogenesis of MPDs that will likely permit a new classification of these diseases and the development of novel therapeutic approaches.
PMID: 16304380 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Pathobiology of lymphoid and myeloid blast crisis and management issues.
Hematology Am Soc Hematol Educ Program. 2005;:188-94
Authors: Ilaria RL
Despite recent improvements in the treatment of early-stage disease, the blastic phase of chronic myeloid leukemia (CML) remains a therapeutic challenge. For imatinib-naïve patients, imatinib provided encouraging hematologic and cytogenetic benefits; however, the vast majority of CML blast crisis cases today arise in patients already on imatinib-based therapy. Clonal evolution and duplication of the Philadelphia chromosome continue to be associated with blastic phase transformation, but recent studies have identified BCR/ABL kinase domain mutations in 30%-40% of blast crisis patients. This implies that BCR-ABL-targeted therapy might have influenced the molecular road map to blastic transformation. In this review, we will examine the effect of imatinib on primitive CML progenitors and how this might influence the pathophysiology of blast crisis. A rational framework for deciding how best to integrate stem cell transplantation, traditional chemotherapy, imatinib, and other BCR-ABL kinase inhibitors in the care of blast crisis patients will also be discussed.
PMID: 16304379 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Loss of response to imatinib: mechanisms and management.
Hematology Am Soc Hematol Educ Program. 2005;:183-7
Authors: Shah NP
The treatment of chronic myeloid leukemia (CML) has been revolutionized by the small molecule BCR-ABL-selective kinase inhibitor imatinib. Although imatinib is highly effective initially and generally well-tolerated, relapse is increasingly encountered clinically. Until recently, for the majority of CML patients with disease no longer responsive to imatinib, as well as for patients with imatinib intolerance, few effective therapeutic options existed. Our understanding of the major mechanisms of imatinib resistance has led to the clinical development of two novel BCR-ABL inhibitors that harbor significant therapeutic promise in early clinical trial experience. These agents, dasatinib (BMS-354825) and AMN107, are more potent inhibitors of BCR-ABL than imatinib, and moreover, harbor activity against nearly all imatinib-resistant BCR-ABL kinase domain mutant forms tested in vitro. Notably, neither of these compounds is effective against the imatinib-resistant BCR-ABL/T315I mutation. The potential availability of highly effective medications for the treatment of imatinib-resistant and intolerant cases of CML is expected to further complicate the timing of other effective therapies, such as allogeneic stem cell transplantation. Additionally, periodic genotyping of the BCR-ABL kinase domain to screen for drug-resistant mutations may play an increasingly important role in the future management of CML cases.
PMID: 16304378 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Management of early stage disease.
Hematology Am Soc Hematol Educ Program. 2005;:174-82
Authors: Deininger MW
More than 80% of newly diagnosed patients with chronic myeloid leukemia in chronic phase will achieve a complete cytogenetic response (CCR) with the standard dose of 400 mg imatinib daily. The probability of progression free survival is tightly correlated with the level of response, approaching 100% in those patients who achieve a reduction of BCR-ABL mRNA by at least 3-log at 12 months. High Sokal risk predicts poorer outcome, but on-treatment response parameters generally override pretherapeutic prognostic variables. Standard disease monitoring includes full blood counts, cytogenetics and quantitative RT-PCR for BCR-ABL mRNA but must be tailored to the level of response attained by a given patient. Conservative therapeutic milestones include a complete hematologic response at 3 months, a minor cytogenetic response at 6, a major cytogenetic response at 12 and CCR at 18, but a more aggressive approach may be justified in specific circumstances. Failure to achieve any of these milestones should trigger a re-assessment of the therapeutic strategy. Most patients with CCR remain positive by RT-PCR, and discontinuation of drug is usually followed by relapse, suggesting that imatinib fails to eradicate leukemic stem cells. The mechanisms underlying disease persistence are not well understood. Evidence is accumulating that early therapy intensification using high doses of imatinib (800 mg daily) or imatinib in combination with cytarabine or interferon-alpha may induce higher rates of RT-PCR negativity. Large studies will be required to determine whether this translates into improved progression free and overall survival.
PMID: 16304377 [PubMed - indexed for MEDLINE]
More
Posted by rob on November 3, 2009 under Uncategorized |
New agents in the treatment of chronic myelogenous leukemia.
J Natl Compr Canc Netw. 2009 Oct;7(9):1028-37
Authors: Pinilla-Ibarz J, Quintas-Cardama A
The discovery of molecularly targeted agents that selectively inhibit bcr-abl tyrosine kinase activity, such as imatinib, has revolutionized the treatment and natural history of chronic myelogenous leukemia (CML). Treatment of chronic-phase CML with imatinib showed complete cytogenetic response rates of more than 40% in patients after failure of interferon-alpha, and more than 80% in patients with newly diagnosed CML. Patients with CML can now expect excellent long-term survival, often without major side effects. In most patients, however, residual leukemic burden remains detectable using a sensitive reverse transcription-polymerase chain reaction method. In addition, many patients undergoing imatinib therapy will either not respond or lose their response over time because of resistance or intolerance. The introduction of second-generation tyrosine kinase inhibitors (TKIs) re-establishes response in approximately half of these patients. Several agents are being developed for treating patients who experience suboptimal response to second-generation TKIs and for those who develop resistance caused by the emergence of highly resistant BCR-ABL1 mutations. This article provides an overview of novel targeted agents available for CML.
PMID: 19878642 [PubMed - in process]
More
Posted by rob on under Uncategorized |
NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia.
J Natl Compr Canc Netw. 2009 Oct;7(9):984-1023
Authors: O’Brien S, Berman E, Borghaei H, Deangelo DJ, Devetten MP, Devine S, Erba HP, Gotlib J, Jagasia M, Moore JO, Mughal T, Pinilla-Ibarz J, Radich JP, Shah Md NP, Shami PJ, Smith BD, Snyder DS, Tallman MS, Talpaz M, Wetzler M
PMID: 19878641 [PubMed - in process]
More
Posted by rob on November 1, 2009 under Uncategorized |
Acta Haematol 2010;123:1-5 (DOI:10.1159/000253856) (Source: Karger Publishers)
More
Posted by rob on under Uncategorized |
TARGETS AND EFFECTORS OF THE CELLULAR RESPONSE TO AURORA KINASE INHIBITOR MK-0457 (VX-680) IN IMATINIB SENSITIVE AND RESISTANT CHRONIC MYELOGENOUS LEUKEMIA.
Biochem Pharmacol. 2009 Oct 26;
Authors: Donato NJ, Feng D, Sun H, Giannola D, Peterson LF, Talpaz M
MK-0457 inhibits aurora, BCR-ABL and other kinases and may be clinically active in imatinib resistant leukemia. To define mediators of MK-0457 responsiveness, kinase inhibitory profiles were examined in multiple cell models of imatinib sensitive and resistant disease. Aurora and BCR-ABL kinase inhibition were consistently measured at 20 – 100nM and 2 – 10muM MK-0457, respectively, but expression of T315I-BCR-ABL and overexpression of Lyn kinase reduced MK-0457 sensitivity. Aurora kinase inhibition was associated with cell cy…
More
