F Ravandi

..With further refinement and standardization of the assays, and the development of novel, effective, and molecularly targeted agents, monitoring of minimal residual disease is likely to be incorporated into AML guidelines...

..We conclude that FLT3-ITD mutations are unstable at follow up and may occur for the first time at relapse. Therefore, FLT3-ITD is not a reliable marker for minimal residual disease in acute myeloid leukemia...

..IDH1 and IDH2 gene mutations are novel, recurring molecular aberrations among patients with normal karyotype acute myeloid leukemia (AML)...

..The data available to date is analyzed and future perspectives regarding the development of this agent is discussed...

....

..Whether such strategies of chemoimmunotherapy would lead to further improvements in the outcome of patients with HCL needs to be further investigated...

..The combination of chemotherapy with dasatinib is effective in achieving long-term remissions in patients with newly diagnosed Ph(+) ALL. This study was registered at www.ClinicalTrials.gov as NCT00390793...

..In this review, we summarize the clinical experience with these growth factors in treating acute leukemias...

..Disease characteristics may potentially be used to identify patients that are more likely to benefit from such additional therapy...

..Ongoing research is likely to reveal the molecular mechanisms responsible for LSC characteristics and lead to novel strategies for eradicating leukemia...

..Outcome of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) with chromosome 5 and 7 abnormalities (excluding del 5[q]) has been poor, with <10% of patients alive at 2 years...

..04). Other mechanisms may be responsible for abnormal phosphorylation of FLT3 and inhibitors of FLT3 should also be investigated in patients without mutations...

..It is likely that we will further refine therapeutic approaches and improve patient outcome through the translation of biologic and molecular discoveries into effective and risk-adapted strategies...

..Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. CONCLUSION Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling...

..017). Overall, patients with mutated FLT3 had a shorter survival from the time of relapse compared to those with FLT3-WT (P<0.001). The adverse prognostic impact of FLT3 mutations appears to persist beyond the initial treatment...

..The introduction of effective TKIs in the treatment of Ph+ ALL has introduced several avenues of research in a disease that was hitherto difficult to treat...

..Effective antibiotic prophylaxis can limit the incidence of infections, which are the major side effect associated with the profound lymphopenia occurring as a result of treatment with this agent...

..This review summarises the preclinical, clinical and pharmacokinetic investigations with these novel agents...

..Alternative strategies are needed for these patients...

..The recent availability of modern immunophenotypic and molecular tools has allowed a better distinction of this disorder from its B-cell counterpart and other mature T-cell leukemias...

....

..Rational design and conduct of clinical trials is necessary to ensure that the full potential of these new agents is realized...

..Furthermore, the understanding of the mechanisms of immune dysfunction in CLL is of pivotal importance in the novel immune-based therapeutic strategies currently under development...

..Novel strategies and new agents directed at the biology of the disease and the mechanisms of resistance are needed...

..Despite this, and with appropriate and more effective antibiotic prophylaxis, it is likely that we will witness an expansion of the role of alemtuzumab in the future...

..Furthermore, risk-based strategies to decrease the incidence of these infectious complications have been proposed...

..Alemtuzumab with or without nucleoside analogs such as pentostatin may provide a role in this setting. However, the associated immunosuppression is a concern in patients with viral-mediated disease...

..Median survival duration has not been reached (range, 2+-64+ months). Treatment with cladribine followed by rituximab is effective tk;4and may increase CR rate. This study was registered at www.clinicaltrials.gov as NCT00412594...

..Herein, we review the clinical and pathological features of mature T-cell leukemias...

..Patients who relapse during treatment with dasatinib frequently carry the T315I mutation of BCR-ABL. Future regimens combining dasatinib with an agent able to inhibit this mutation may further improve outcome...

..Alternatively, it may be possible to identify patients who are more likely to relapse using pretreatment characteristics such as the mutational status of IGHV and apply these strategies solely to them...

..In this article, we review the diagnostic and clinical features of mature B-cell and T-cell lymphoproliferative disorders that commonly have a leukemic presentation...

..To examine the efficacy and safety of the combination of alemtuzumab and pentostatin in patients with T-cell neoplasms...

..The diagnosis of AML-M6 does not impart by itself a worse prognosis, and treatment decisions on this disease should be guided by well known AML prognostic factors...

..The patient then developed myelodysplastic syndrome and solitary central nervous system relapse of ALL...

..Seven patients were treated with regimens designed for AML. Complete remission (CR) rates of 78% and 57% were noted respectively. The overall survival probability at 2 years was 60%...

..Significant responses were not seen with any of these treatment regimens. We conclude that cyclosporine therapy may be beneficial for T-LGL leukemia patients. New treatment modalities are needed for these patients...

..An evaluation in patients with a better prognosis, in combination with other agents or as part of consolidation therapy, is warranted...

....

..Current response data should encourage further study of this drug, either alone or in combination with other agents, for treatment of relapsed acute leukemia after an allogeneic transplant...

..Prior therapy with hypomethylating agents did not increase toxicity and may improve the outcome of allogeneic transplant in MDS and should be evaluated in a prospective trial...

..2 months (95% CI 13-18). In summary, this analysis indicates that it is possible to identify patients with lower risk MDS and poor prognosis who may benefit from early intervention...

..LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In this phase I study, LBH589 was administered i.v. as a 30-minute infusion on days 1 to 7 of a 21-day cycle...

..Forodesine has biologic activity in CLL; pharmacodynamic parameters suggest that an alternate dosing schedule and/or higher doses to achieve greater intracellular dGTP may be beneficial in this patient population...

..Targeted therapy has improved outcomes in some patients. Most of the new agents are less toxic then their predecessors, and they can be used in combination with the more intensive traditional regimens...

..Our data suggest that HSCT is preferable to chemotherapy alone in these patients with poor prognoses, with particular benefits noted in patients under age 50 years...

..VPA blood levels were higher in responders (P < .005). In conclusion, the combination studied is safe and has significant clinical activity. This clinical trial was registered at www.clinicaltrials.gov as no. NCT00326170...

..Median survival was 5 months (range, 2 - 20 months). This outpatient regimen is effective and well tolerated and perhaps superior to single-agent imatinib for patients in myeloid BP...

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

..The combination of vorinostat and idarubicin is generally tolerable and active in patients with advanced leukaemia and should be studied in the front-line setting...

....

..The influence of these cellular proteins and caspase-3 activity on apoptosis in CML is complex and merits further investigation...

..Secondary malignancies including myeloid neoplasms occur infrequently in acute lymphoblastic leukemia (ALL) and to the authors' knowledge have not been as well documented in adults as in children...

..These results suggest that patients receiving 2TKI with no cytogenetic response at 3 to 6 months should be considered for alternative therapies...

..Dasatinib is a 325-fold more potent inhibitor of Bcr-Abl than imatinib and has been associated with high rates of durable responses in patients with CML in chronic phase (CP) after imatinib failure...

..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...

..Based on these data, a phase 2 clinical trial of forodesine has been initiated for CLL patients...

..001) respectively; median OS was 45, 31 and 19 weeks (P = 0.04) respectively. The HCTCI score is predictive of early death rates and OS in older patients receiving AML induction therapy...

..The EPI is reproducible and useful...

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

..Grade III/IV toxicities were mainly cytopenias and neutropenic fever. Combination of rATG, cyclosporine and G-CSF is safe and effective as first-line treatment of AA and has significant activity in low-risk MDS...

..Further studies are required to determine whether there might be a minimum adequate dose of these agents...

..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...

..Resistance to multiple TKIs does occur, particularly in patients with the T315I mutation. Several new agents are in development including new TKIs, aurora kinase inhibitors and homoharringtonine...

..Experimental introduction and knockdown of TCL1 influence the kinetics and strength of TCR-mediated AKT activation. We propose that in T-PLL, TCL1 represents a highly regulated, targetable modulator of TCR-mediated AKT growth signaling...

..AG-01736 had minimal biologic or clinical activity in this elderly patient population...

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

..0014) and returned to 50% at the end of the first 28-day cycle (P=0.016). 5-azacitidine is relatively well tolerated and results in induction of global hypomethylation in patients with MF, but results in limited clinical activity...

..ClinicalTrials.gov Identifier: NCT00217646)...

..4 months (range, 1-39). Late relapses in AML are infrequent, with poor response to therapy. Karyotype at relapse is frequently different, raising the question of second AML versus relapse with the original clone...

..We conclude that a low-dose, dose-intensity schedule of decitabine optimizes epigenetic modulation and clinical responses in MDS...

..Efficacy and toxicity profile of orally administered clofarabine were evaluated in patients with higher-risk myelodysplastic syndrome (MDS)...

..Future studies of purine analogues should evaluate patients who are less heavily pretreated and combination therapy with other agents such as alemtuzumab should be investigated in order to prolong the duration of disease remission...

..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...

..Interferon alpha (IFN α) is efficacious in CML likely due to its immunomodulatory properties, and is synergistic in vitro with imatinib and granulocyte macrophage-colony stimulating factor (GM-CSF)...

..Decitabine is a hypomethylating agent that has activity in patients with leukemia. The authors combined decitabine with busulfan and cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation...

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

....

..Potential cure of acute myeloid leukemia (AML) is now a widely accepted idea, but it is uncertain whether there is heterogeneity in the failure rate in patients once they have been in complete remission (CR) for various periods of time...

..The prognosis of patients with chronic myelogenous leukemia (CML) after failure of imatinib mesylate therapy is not well documented...

..Earlier reports suggested similar outcomes for patients with de novo and secondary AML associated with core-binding factor (CBF) abnormalities...

..These results could be used in assessing the efficacy of new treatments aimed at improving CR durations and survival post salvage therapy...

..This review describes the pathophysiological role of this pathway in hematological malignancies and the potential benefits of JAK-STAT inhibition...

..Inhibiting FLT3 may lead to clinical benefit for patients with AML. Newly developed FLT3 inhibitors have shown encouraging activity as monotherapy and in combination with other therapeutic agents...

..Further studies of ruxolitinib, in patients with acute and chronic leukemias, are now needed to establish the clinical usefulness of this promising drug...

....

..g. lactate dehydrogenase (LDH), S-phase fraction, mature B-cell phenotype) to design a risk-oriented approach to CNS prophylaxis...

..38, p=0.02), as was higher platelet count (hazard ratio 1.35, p=0.04). These findings suggest that blood counts at CR, information readily available, are useful in prognostication in AML...

..We conclude that clinically significant responses with decitabine can be seen in patients post-azacitidine failure without significant toxicity...

..The specific efficacy in CMML has not been detailed in a large number of patients. The aim of the study was to evaluate the activity and safety of decitabine in CMML...

..They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades...

..This review attempts to provide a practical introduction to the complex and growing field of targeted therapy in hematological malignancies...

..No correlation was observed between the development of DLT and pharmacokinetics. The RTPD is 1,750 mg. XK469R induced hematological responses in patients with refractory leukemia at tolerable doses...

..4 months vs 5.8 months; P = .1). Clofarabine plus low-dose cytarabine has a higher response rate than clofarabine alone with comparable toxicity. This trial is registered at www.clinicaltrials.gov as no. NCT00088218...

..Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway are warranted...

..This prognostic model may help patients and clinicians in clinical decision making as well as in clinical research and clinical trial design...

..The comparative efficacy of these 2 forms of treatment in MDS is unknown. The objective of the current study was to compare the efficacy and toxicity profiles of decitabine and intensive chemotherapy in MDS...