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Cardiotoxicity of tyrosine kinase inhibitors in chronic myelogenous leukemia therapy
Zhenshu Xu,Shundong Cang,Ting Yang,Delong Liu
Hematology Reports , 2009, DOI: 10.4081/hr.2009.e4
Abstract: Emerging evidence suggests that the three tyrosine kinase inhibitors currently approved for the treatment of patients with chronic myelogenous leukemia (CML) – imatinib, dasatinib, and nilotinib – have potential cardiotoxic effects. The mechanisms behind these events, and the relations between them, are largely unclear. For example, relative to dasatinib and nilotinib, severe congestive heart failure and left ventricular dysfunction are rare but prominent with imatinib treatment, particularly in patients receiving higher doses (>600 mg/day). In comparison with imatinib, prolongation of the QT interval is relatively common in patients treated with either dasatinib or nilotinib. In contrast to nilotinib, pericardial effusions are observed with both imatinib and dasatinib. It is suggested that these data, an evaluation of cardiac status, use of concomitant medications, and potential risk factors should be considered in the management of CML.
Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors
Michael G. Martin,John F. DiPersio,Geoffrey L. Uy
Oncology Reviews , 2011, DOI: 10.4081/78
Abstract: Tyrosine kinase inhibitors (TKIs) are the mainstay for treatment of chronic myelogenous leukemia (CML). Imatinib was the first TKI approved for use in CML, but resistance to this therapy has emerged as a significant issue, and second-line options are often necessary. Increased-dose imatinib may elicit responses in some patients, but clinical evidence suggests only a minority experience sustained benefit. The second-generation TKIs, dasatinib and nilotinib, have demonstrated efficacy in patients resistant or intolerant to imatinib. Changes in therapy, with the aim of inducing durable response, should occur promptly after imatinib failure is identified as all agents are more effective in chronic phase disease than in later stages. Selection of second-line agents should be driven by efficacy and safety: dasatinib may be more effective in patients with P-loop or F359C mutations; nilotinib may be more effective in those with F317L mutations.
The role of Lyn kinase in the development of imatinib resistance in chronic myelogenous leukemia  [cached]
Camillo Porta,Federica Tagliani
Oncology Reviews , 2011, DOI: 10.4081/111
Abstract: Imatinib mesylate, a small-molecule inhibitor of BCRABL tyrosine kinase activity, has emerged as the well-recognized standard of treatment for chronic myelogenous leukemia (CML). Indeed, both its efficacy, tolerability, as well as cost-effectiveness have been clearly proven...
Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia?
Avital F. Barak,Lilach Bonstein,Roy Lauterbach,Elizabeth Naparstek
Hematology Reports , 2011, DOI: 10.4081/hr.2011.e29
Abstract: 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.
Aurora kinase inhibitors: which role in the treatment of chronic myelogenous leukemia patients resistant to imatinib?
Giovanni Martinelli,Simona Soverini,Ilaria Iacobucci,Cristina Papayannidis
Hematology Reports , 2009, DOI: 10.4081/hr.2009.e1
Abstract: At present, there are no compounds in clinical development in the field of chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) that have been documented to harbor significant activity against the imatinib-resistant T315I mutation. Recent reports on the pre-clinical activity of some emerging tyrosine kinase inhibitors such as ON012380, VX-680 and PHA-739358 promise possible clinical efficacy against this specific Bcr-Abl mutant form. Here, we focus on the role of aurora kinase inhibitor VX-680 and PHA-739358 in blocking the leukemogenic pathways driven by wild-type and T315I-Bcr-Abl in CML or Ph+ ALL by reviewing recent research evidence. We also discuss the possibility of employing aurora kinase inhibitors as a promising new therapeutic approach in the treatment of CML and Ph+ ALL patients resistant to first and second generation TK inhibitors.
Immunological implications of the use of tyrosine kinase inhibitors in chronic myeloid leukemia
Camila de Souza Rodrigues,Larine Miranda Mendon?a,Jhony Robison de Oliveira,Marcelo Henrique Napimoga
Journal of Hematological Malignancies , 2012, DOI: 10.5430/jhm.v2n3p45
Abstract: Background: The treatment of chronic myeloid leukemia (CML) employs drugs known as tyrosine kinase inhibitors (TKIs). Comparative analyses of the effects of different TKIs has shown that these substances can reduce the immunogenicity of leukemic cells, and prejudice anti-tumoral immunity. Once the TKIs differ in terms of their direct influence on cells of the immunological system, the objective of this work was therefore to analyze alterations in the immunological systems of CML patients using different TKI drugs. Methodology/Principal findings: A review of the literature revealed that imatinib is considered to be the new paradigm for treatment of CML; however, use of this drug can result in inhibition of activation of immune system cells and development of resistance. Second and third generation TKIs can be used in the treatment of patients resistant to imatinib, but can have immunosuppressor effects. Nilotinib is more effective than imatinib in recently-diagnosed patients, however at high doses can induce myelosuppression and diminish cytokine production. Dasatinib was found to induce a rapid full cytogenetic response, with heightened in vivo immune-stimulation, in contrast to an immunosuppression observed in vitro. The mutated T315I phenotype of CML only shows a response to treatment with inhibitors that do not compete with ATP, involving aurora kinases that control mitosis, progression of the cellular cycle, and apoptosis induction. MK0457, which is able to act in the presence of the mutation, presents important bone marrow toxicity, while in small doses danusertib has shown anti-proliferative and pro-apoptotic activity against a wide spectrum of BCR-ABL-positive cells. Conclusions/Significance: Selection of the most suitable tyrosine kinase inhibitor in patients showing positive to the BCR-ABL mutation requires previous analysis of the phenotype and the influence of the TKI on the immunological system.
Indirect comparisons of second-generation tyrosine kinase inhibitors in CML: case study using baseline population characteristics
Kimbach Tran Carpiuc,Gianantonio Rosti,Fausto Castagnetti,et al
OncoTargets and Therapy , 2010,
Abstract: Kimbach Tran Carpiuc1, Gianantonio Rosti2, Fausto Castagnetti2, Maarten Treur3, Jennifer Stephens11Pharmerit North America LLC, Bethesda, MD, USA; 2Department of Hematology and Oncology, S Orsola-Malpighi University Hospital, Bologna, Italy; 3Pharmerit Europe, Rotterdam, The NetherlandsAbstract: The use of indirect comparisons to evaluate the relative effectiveness between two or more treatments is widespread in the literature and continues to grow each year. Appropriate methodologies will be essential for integrating data from various published clinical trials into a systematic framework as part of the increasing emphasis on comparative effectiveness research. This article provides a case study example for clinicians using the baseline study population characteristics and response rates of the tyrosine kinase inhibitors in imatinib-resistant or imatinib-intolerant chronic myelogenous leukemia followed by a discussion of indirect comparison methods that are being increasingly implemented to address challenges with these types of comparisons.Keywords: comparative effectiveness research, meta-analysis, BCR–ABL-positive chronic myelogenous leukemia, imatinib mesylate, nilotinib, dasatinib
Importance of monitoring and early switch to second generation tyrosine kinase inhibitors for the prognosis of patients with chronic myeloid leukemia with imatinib resistance or intolerance
Sim?es, Belinda Pinto;Braga Junior, José Wilson Ramos;Rego, Maria Aparecida do Carmo;Souza, Cármino Ant?nio de;
Revista Brasileira de Hematologia e Hemoterapia , 2011, DOI: 10.5581/1516-8484.20110017
Abstract: imatinib mesylate was the first bcr-abl-target agent approved for the treatment of chronic myeloid leukemia. although most patients respond well to imatinib therapy, the literature shows that one third develops resistance or intolerance. the timing of second-line treatment after failure of initial treatment may have a significant impact on long-term outcome. thus, appropriate monitoring to identify resistance and/or intolerance is crucial to early intervention with second generation tyrosine kinase inhibitors and attainment of better results
Imatinib Treatment Induces CD5+ B Lymphocytes and IgM Natural Antibodies with Anti-Leukemic Reactivity in Patients with Chronic Myelogenous Leukemia  [PDF]
Silvia Catellani,Ivana Pierri,Marco Gobbi,Alessandro Poggi,Maria Raffaella Zocchi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018925
Abstract: Imatinib mesylate is a first line treatment of Chronic Myelogenous Leukemia and of a rare form of gastrointestinal stromal cancer, where the response to the drug is also linked to the immune system activation with production of antineoplastic cytokines. In this study, forty patients in the chronic phase of disease, treated with imatinib mesylate, were analyzed. Bone marrow aspirates were drawn at diagnosis, after 3, 6, 12, 18 months for haematological, cytofluorimetric, cytogenetic, biomolecular evaluation and cytokine measurement. Responder and non responder patients were defined according to the European LeukemiaNet recommendations. In responder patients (n = 32), the percentage of bone marrow CD20+CD5+sIgM+ lymphocytes, and the plasma levels of IgM, were significantly higher, at 3 months and up to 9 months, than in non responders. These IgM reacted with O-linked sugars expressed by leukemic cells and could induce tumor cell apoptosis. In responeìder patients the stromal-derived factor-1 and the B-lymphocyte-activating factor of the tumor necrosis factor family significantly raised in the bone marrow after imatinib administration, together with the bone morphogenetic proteins-2 and ?7. All patients with high number of CD20+CD5+sIgM+ cells and high stromal-derived factor-1 and B lymphocyte activating factor levels, underwent complete cytogenetic and/or molecular remission by 12 months. We propose that CD20+CD5+sIgM+ lymphocytes producing anti-carbohydrate antibodies with anti-tumor activity, might contribute to the response to imatinib treatment. As in multivariate analysis bone marrow CD20+CD5+sIgM+ cells and stromal-derived factor-1 and B-lymphocyte-activating factor levels were significantly related to cytogenetical and molecular changes, they might contribute to the definition of the pharmacological response.
Prognostic factors associated with complete cytogenetic response in patients with chronic myelogenous leukemia on imatinib mesylate therapy  [PDF]
?ojba?i? Irena,Ma?ukanovi?-Golubovi? Lana
Srpski Arhiv za Celokupno Lekarstvo , 2010, DOI: 10.2298/sarh1006305c
Abstract: Introduction Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor, has proved to be most effective therapy of Philadelphia chromosome-positive chronic myelogenous leukemia. Imatinib induces complete haematological and cytogenetic response in high percentage of patients. Objective The aim of this study was to identify potential prognostic factors before beginning treatment with imatinib associated with complete cytogenetic response. Methods We analyzed 20 patients with newly diagnosed Philadelphia positive chronic myelogenous leukemia treated at our institution from June 2006 until May 2009. These patients were treated with imatinib mesylate in oral dose of 400 to 800 mg daily. Complete blood counts were performed every month, while serum chemistry evaluations and bone marrow evaluations including morphology and cytogenetics were performed every 6 months. Results Of the 20 patients analyzed in this study, 19 (95%) achieved complete haematologic response within three months. In all patients cytogenetic analyses were done and all have achieved absolute cytogenetic response. The best cytogenetic response rate at any time during study treatment among 20 patients was: complete cytogenetic response in 15, partial cytogenetic response in three and minor cytogenetic response in two patients. Among 11 observed base-line patients' characteristics five were independent predictors of a high rate of complete cytogenetic response; the absence of blasts and basophils in peripheral blood, the presence of less than 5 percent of bone marrow blasts, white blood cell count less than 10x109/L and the absence of splenomegaly (p<0.01). Conclusion Our results showed that some pre-treatment characteristics of patients might be the cause of differences in treatment outcome. On the basis of this analysis, we identified several pre-treatment patients' characteristics to be independent prognostic factors for achievement of complete cytogenetic response. .
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