1,721,850 research outputs found
From FAB to 2008 WHO classification: the wide heterogeneity of refractory anemia subtype among different countries
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Efficacy and safety of deferasirox in myelodysplastic syndromes.
No full textTransfusion dependence in myelodysplastic syndrome (MDS) patients may lead to organ damage due to accumulation of non-transferrin-bound iron with consequent increased oxidative stress. Iron chelation has been reported in retrospective studies to improve overall survival in low-risk MDS patients, but this information needs to be validated in prospective trials. The oral iron chelator, deferasirox, has been shown to reduce serum ferritin levels in chelation naïve and pre-treated patients and to reduce labile plasma iron, independently from the efficacy on iron overload. Deferasirox is a potent NF-kB inhibitor, tested in vivo and on acute myeloid leukemia and MDS cell lines, and this effect may explain in part the phenomenon of hematological improvements reported in case reports and in different clinical trials. The drug has an acceptable safety profile, with the most common side effects reported being non-progressive change in serum creatinine level, gastrointestinal disturbances, and skin rash. In this review, we report the results of different studies testing safety and efficacy of deferasirox in MDS patients, side effects associated with the drug, and suggested management of iron overload
Suboptimal response in chronic myeloid leukemia patients treated with imatinib: Early identification and new therapeutic challenges.
No full textIn 2006 European LeukemiaNet proposed recommendations to define several categories of chronic myeloid leukemia patients treated front-line with imatinib. In 2009 an update of these recommendations was published: whereas it is clear how important is to switch rapidly to a second line of treatment in failure patients, the correct treatment of patients with sub-optimal response is still a matter of debate. Several groups have indeed shown that prognosis of patients with sub-optimal cytogenetic response is similar to that of failure patients, whereas lack of data exists for patients with sub-optimal molecular response at 18months. In this article, we overview studies demonstrating prognostic implications of being suboptimal responders to imatinib as well as results of recent clinical trials testing new generation tyrosine kinase inhibitors in this setting
Resistance to imatimib in chronic myeloid leukemia and therapeutic approaches to circumvent the problem.
No full textThe majority of patients with chronic phase chronic myeloid leukaemia (CP-CML) treated with imatinib achieves cytogenetic disease remission. Molecular monitoring for residual disease has prognostic significance: rising BCR-ABL levels may provide earliest indication that a patient has become resistant to treatment. The emergence of resistance to imatinib has dampened the enthusiasm for this drug. The most common cause of resistance is the selection of leukemic clones mutated in ABL kinase domain due to amino acid substitutions with prevention of appropriate binding of the drug. Amplification and over-expression of BCR-ABL, acquired cytogenetic aberrations and modulation of drug efflux or influx transporters have been reported. These observations have established the rationale for the creation of new compounds that have been explored in clinical trials. This review will discuss the underlying mechanisms of imatinib-resistance and new strategies to avoid and overcome this phenomenon
Discontinuation of tyrosine kinase inhibitors and new approaches to target leukemic stem cells: Treatment-free remission as a new goal in chronic myeloid leukemia.
No full textOnly a small fraction of chronic phase chronic myeloid leukemia patients (CP-CML) achieves a very deep reduction of residual disease with imatinib. Second-generation tyrosine kinase inhibitors administered as front-line therapy for CP-CML have improved the rates and degree of deeper molecular responses. Owing to this improvement, new standardized definition of complete molecular remission has been provided, which allowed plan of prospective strategies to definitively discontinue therapy in the long-term. In this review, we report the results of several published discontinuation studies and critically discuss the new approaches and tools to monitor residual disease during treatment and new strategies to target leukemic stem cells to reach a potential "operational" cure and persistent long-term leukemia-free survival
Refining targeted therapies in chronic myeloid leukemia: development and application of nilotinib, a step beyond imatinib.
No full textThe BCR-ABL kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia (CML). Despite the remarkable results achieved with imatinib for the treatment of CML, the emergence of resistance to this drug has become a significant problem. Mutations within the ABL kinase domain have been identified as the main mechanism of resistance to imatinib. Other mechanisms include genomic amplification of BCR-ABL and modulation of drug efflux or influx transporters. Several strategies have been developed to overcome the problem of imatinib resistance, including dose escalation of imatinib, combination treatments, or novel targeted agents. Nilotinib is a tyrosine kinase inhibitor 30-fold more potent than imatinib, active against a wide range of mutant clones, except T315I. Phase I-II trials of nilotinib showed high activity in imatinib-resistant CML and Ph+ acute lymphoblastic leukemia. We here review the development of nilotinib and the activity of this agent in CML patients and in other forms of sensitive neoplasms
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