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..Myelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML) in approximately 30% of patients. Identification of risk factors for progression to AML and overall survival (OS) would help guide treatment decisions...

..001). These results would suggest that prospective studies are needed to delineate the timing and efficacy of allo-SCT in the HMA era...

..Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc...

..The overall 4-week mortality rate was 9%. In conclusion, BIDFA is active and safe in heavily pretreated patients with myeloid malignancies...

..To maximize adherence, CML treatment should be individualized to the patient and simplified as appropriate...

..In conclusion, 8% of patients with chronic phase chronic myeloid leukemia treated at our institution are in the high EUTOS score; in this population, the EUTOS score was not predictive for outcome...

..Controlling risk factors for poor adherence in combination with patient education that includes direct communication between the health care team and the patient are essential components for maximizing the benefits of TKI therapy...

..FLT-3 inhibition is of particular interest in AML patients with FLT-3 internal tandem duplication mutations; this type of targeted therapy continues to be studied...

..This article guides the treating physician with a rational approach in the management of patients with chronic myeloid leukemia who fail initial treatment with imatinib or lose response while on therapy with imatinib...

..Identification of suboptimal responders or patients failing treatment using hematologic, cytogenetic, and molecular techniques allows physicians to alter therapy earlier in the treatment course to improve long-term outcomes...

..To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse-event tolerance level, and risk factors...

..Herein, we review some of these targeted therapies, particularly those for which clinical data are already available...

..We also describe how common side effects can be effectively managed and offer a working definition of intolerance that may be useful to clinicians when they consider switching between TKIs...

..The choice of therapy should be guided by multiple factors, including mutational analysis, disease phase, patient characteristics, and the safety profile of the agents...

..Although molecular monitoring has a clear role in assessing residual disease and determining the risk of disease progression in patients with CML, the importance of cytogenetic monitoring should not be ignored...

..Future CML treatment may involve combination strategies. Overall, targeted agents have significantly improved the prognosis of patients diagnosed with CML...

..Preclinical and clinical investigations demonstrate that nilotinib effectively overcomes imatinib resistance, and has induced high rates of hematologic and cytogenetic responses in CML post imatinib failure...

..The prognosis of patients with myelodysplastic syndrome (MDS) after decitabine failure is not known...

..Combination therapies that augment the epigenetic effect of decitabine will likely improve responses and extend its use for the treatment of other malignancies...

..To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse-event tolerance, and risk factors...

..This scoring system could serve to advise patients of their prognosis and treatment options, as well as to evaluate the benefit of newer alternate options...

..Here, we propose a treatment algorithm for imatinib-resistant patients based on BCR-ABL mutation status and patient history...

..Successful treatment of patients with disease harboring T315I might lie in the effective combination or sequencing of these new agents with existing TKI therapies...

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..As experience with these agents continues to mature, we might optimize the treatment efficacy and safety profiles by altering dose regimens...

..To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse event tolerance level, and risk factors...

..The disease and patient characteristics at the time of imatinib failure should be evaluated before choosing second-line therapy to optimize the therapeutic benefit without unnecessary delay...

..It is unknown whether these definitions apply to patients treated with second-generation tyrosine kinase inhibitors (TKIs)...

..The achievement of early CCyR remains a major determinant of chronic myeloid leukemia outcome regardless of whether MMR is achieved or not...

..Patient and disease characteristics should be carefully considered to optimize treatment strategy for CML...

..Clinical trial data from an evaluation of the response of specific mutant BCR-ABL clones to TKIs is needed to establish the role of mutation testing in the management of CML...

..Seven patients are alive (6 in CMR) for a median of 19 months. Allo-SCT remains an important salvage option for patients who develop resistance to imatinib through Bcr-Abl mutations...

..Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TKIs and can help in therapy selection. More complex prognostic models will be required for advanced stages of disease...

..Median follow-up was 37 months. Median event-free and overall survival was 6 and 11 months. GO 2 mg m(-2) can be safely added to fludarabine/melphalan, and this regimen merits further evaluation...

..Dasatinib was recently approved by the FDA for use in Philadelphia-positive leukaemias in patients who are resistant or intolerant to imatinib...

..Combination strategies are currently being investigated in preliminary clinical studies and may prove to be useful. Overall, there are an increasing number of treatment options now available for patients with CML...

..SBT is still a rare event, probably less common than that observed with IFN-alpha therapy. Continuous monitoring of patients treated with imatinib is mandatory...

..Liposomal cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and cytarabine can result in significant neurotoxicity...

..The authors hypothesized that low doses of the hypomethylating agent 5-azacitidine may maximize the graft-versus-leukemia effect and may be tolerated well after allogeneic transplantation (HSCT)...

..These results suggest that achievement of a MCyR without concomitant CHR is associated with poor outcome...

..In conclusion, P-loop mutations were not associated with poor outcome, suggesting that the prognosis of patients who fail imatinib is multifactorial...

..Although the T315I mutation is resistant to currently available TKIs, survival of patients with T315I remains mostly dependent on the stage of the disease, with many CP patients having an indolent course...

..45). Patients in CP had better outcome, with a 2-year survival of 75%. F317L mutation is resistant to dasatinib but sensitive to other TKIs. The prognosis is dependent mostly on the disease stage...

..Herein, we review some of these strategies, particularly those for which clinical data are currently available...

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..001) and relapse-free survival (P<0.001) in patients with AML and 11q23 abnormalities...

..5 g/m2 IV on Days 1 and 2) to the standard hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and cytarabine) would improve outcome...

..In summary, the prognosis of most patients (72%) ≥ 70 years of age with AML is poor with intensive chemotherapy (8-week mortality ≥ 30%; median survival < 6 months)...

..The objectives of this study were to define the prognosis for adult patients with ALL after first salvage through multivariate analyses of patient and disease characteristics...

..Dasatinib is effective therapy for chronic myeloid leukemia (CML) after imatinib failure. In this study, we investigate the efficacy of dasatinib as initial therapy for patients with CML in early chronic phase...

..This review focuses on supportive care modalities, the approved agents indicated for the treatment of MDS and future directions for the treatment of MDS, including agents under clinical investigation...

..Although most patients with chronic myeloid leukemia (CML) in chronic phase respond well to front-line therapy with imatinib, some patients do not achieve the desirable end point, and others may eventually lose response or are intolerant...

..Rapid reselection of TKI-resistant clones occurs following therapy switch in CML...

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..Herein, we review some of these targeted therapies, particularly those for which clinical data are already available...

..This approach, including posttransplantation treatment with TKIs and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions...

..The clinical significance of increasing levels of QPCR in patients in CGCR is uncertain...

..A phase I study of cloretazine combined with cytarabine (1-beta-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease...

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..In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks...

..In this study, the authors update their experience with decitabine in patients with MDS and analyze the cytogenetic response patterns and prognostic factors associated with decitabine therapy...

..The outlook today for patients with CML is much brighter than that of a few years ago...

..Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients...

..CAs occur in Ph-negative cells in a small percentage of patients with newly diagnosed CML treated with IM. In rare instances, these could reflect the emergence of a new malignant clone...

..Nilotinib is undergoing clinical trials in patients with newly diagnosed CML, acute lymphoblastic leukemia and gastrointestinal stromal tumors, among other indications...

..In this study, there was no marked increase in development of T315I...

..Patterns of KD mutations in Philadelphia chromosome (Ph)-positive acute lympho- blastic leukemia (ALL) are less well studied...

..In conclusion, imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic failure and a previous cytogenetic response to standard-dose imatinib...

..Collection of autologous stem cells prior to high-risk allografting can salvage a fraction of patients and lead to prolonged survivals...

..Even in the presence of poor disease characteristics, nilotinib provided significant clinical benefit in patients with imatinib-resistant or -intolerant CML. This system may yield insight on the prognosis of patients...

..Overall, we found that fludarabine and ATG conditioning before a second SCT allows engraftment of donor hematopoiesis. Future studies should include more intense GVHD prophylaxis...

..The median time to recovery from neutropenia and thrombocytopenia was 17 days and 39 days, respectively. CONCLUSIONS: The combined 2-CdA and ara-C chemotherapy regimen had activity in patients with HES...

..68, P= .003) and overall survival (hazard ratio=2.69, P= .002). In conclusion, detection of epigenetic alterations allows the identification of patients with ALL with standard risk but with poor prognosis...

..The EPI is reproducible and useful...

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..51, P = .049). These results confirm the poor prognosis of M7 AML and indicate that other biologic characteristics beyond cytogenetic abnormalities likely play a role in this disease...

..Stem cell transplantation remains a useful option, although it is not generally used as first-line treatment. Overall, there are an increasing number of treatment options available for patients with CML...

..Efforts to optimize therapy in CML have resulted in new and revised treatment guidelines or algorithms, which are reviewed here...

..It is unknown whether the use of these NTKIs before HSCT increases transplant-related toxicity...

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..Approximately 15,000 new cases of myelodysplastic syndromes (MDS) are expected in the United States each year...

..Randomized trials designed according to the new biologic prognostic parameters described in chronic lymphocytic leukemia are required to better define the role of NMA SCT in the near future...

..Ongoing studies will better determine their mechanism of action and the role of combination with other agents, defining their place in the therapeutic arsenal of hematologic disorders...

..Ongoing studies will better determine the mechanism of action of tipifarnib and the role of combination with other agents, defining its place in the therapeutic arsenal of hematologic disorders...

..CONCLUSIONS: 9-NC is active in MDS and CMML. The paucity of available therapies in CMML makes 9-NC a good candidate for further studies as a single agent, or in combination with decitabine, 5-azacitidine or cytarabine...

..PEG-IFN-alpha-2b is a pegylated IFN-alpha-2b with a significant advantage over nonpegylated form in that it is administered once a week...

..SUMMARY: Novel tyrosine kinase inhibitors with more potent and selective Bcr-Abl inhibition and with multitargeted inhibition of Bcr-Abl and Src family kinases are promising and may further improve prognosis in chronic myeloid leukemia...