J E Cortes

..The continued study of these phenomena will help us to understand better the pathogenesis of CML and improve the long-term treatment of patients with CML...

..Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat...

..We concluded that HUM-195/rGel can be safely administered in a multi-dose cycle to patients with advanced myeloid malignancies and warrants further investigation...

..Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors...

..Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219...

..In this manuscript, we discuss the treatment approach that has helped us manage successfully a large CML population...

..The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML)...

..Outcomes in chronic myeloid leukemia have improved with tyrosine kinase inhibitor treatment. However, little is known about outcomes of chronic myeloid leukemia in adolescent and young adult patients...

..We herein summarize the preclinical and clinical experience of bosutinib in CML...

..Thus there is a need for developing approaches to overcome and prevent resistance to imatinib...

..R115777 showed clinical activity in patients with CML and MF. The effect on VEGF needs to be further investigated to determine whether this might be a possible mechanism of action of R115777...

..The 3-month cytogenetic response to imatinib mesylate refined the prognostic relevance of such studies in patients on imatinib mesylate therapy...

..Many of these agents are already showing promising results in the clinic. This manuscript reviews some of these agents, particularly those for which clinical data are already available...

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..These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015...

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

..The in vitro evidence of antileukemia and transient hematological improvements observed in some patients warrants further investigation of bortezomib in acute leukemias, probably in combination with other agents...

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

..Emerging CML therapies, some of which have different mechanisms of action from those of tyrosine kinase inhibitors, have shown promising results and could offer an alternative to these patients as monotherapy or in combination...

..Three of 4 nonresponders failed to respond to an increase in dose. Toxicity was minimal. We conclude that imatinib therapy is effective for HES...

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..Future studies should consider CMML as a separate entity to promote a better understanding and identify more effective therapy for patients with this disease...

..This article describes the natural history of CML and its prognostic factors,with emphasis on changes due to the emergence of imatinib...

..c-kit is expressed in most patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and PDGF has been implicated in the pathogenesis of myeloproliferative disorders (MPD)...

..Myelosuppression occurs in up to 50% of patients with chronic myeloid leukemia (CML) who are treated with imatinib and > or = Grade 3 myelosuppression is reported in approximately 10% of patients...

..The continued understanding of the biology of CML and mechanisms of resistance to imatinib and the ability to develop target-specific therapies should lead to the increased probability of cure for most patients who have CML...

..It is very possible that these agents will soon find their way to the ranks of established agents for the management of myeloid malignancies..

..In conclusion, high-dose imatinib induces complete cytogenetic responses in most patients with chronic-phase CML after interferon failure. This is accompanied by a high rate of molecular remission...

..To determine the clinical significance of molecular response and relapse among patients with chronic myelogenous leukemia (CML) treated with imatinib...

..To investigate the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of BMS-214662, a farnesyl transferase (FTase) inhibitor, in patients with acute leukemias and high-risk myelodysplastic syndromes (MDS)...

..However, based on the current data, imatinib blood-level testing seems to be a useful aid when making clinical decisions in CML...

..Some of these approaches are expected to improve the outcomes of patients with CML...

..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)...

..In this review, we analyze the current status of therapy of CML, and we discuss some of the most relevant clinical questions that we face today...

..The implications of rising BCR-ABL1 transcript levels and caveats of molecular monitoring are also described...

..This study is registered at http://www.clinicaltrials.gov as NCT00471497...

..The p53 antisense oligonucleotide cenersen has been shown to sensitize acute myeloid leukemia (AML) stem cells to DNA damaging agents...

..Patients with less than complete cytogenetic response to second -line therapy or beyond should be considered to have benefit from therapy and the value of this considered in the context of which alternative options are available...

..These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846...

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..Cytopenias were noted in the majority of patients, and were manageable with dose interruptions/reductions. Dasatinib is associated with a promising rate of response in this high-risk population...

..This study in adults evaluated safety of and compared efficacy of rasburicase alone with rasburicase followed by oral allopurinol and with allopurinol alone in controlling plasma uric acid...

..In the current study, the authors investigated the use of CsA in the management of anemia or thrombocytopenia of presumed autoimmune etiology associated with CLL...

..Long-term clinical outcome data have established imatinib 400 mg/d as standard front-line treatment for newly diagnosed patients with chronic myeloid leukemia (CML)...

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..If this is successful, complete eradication of disease may become a reality for the majority of patients with CML...

..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...

..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...

..To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase...

..Treatment recommendations have been developed for management of patients with chronic myeloid leukemia (CML)...

..It is unlikely that, as given here, either FA or TA is, in general, superior to IA, highlighting the need for new treatments...

..0017). In conclusion the hyper CVXD regimen has a relatively high response rate, significant toxicity and a moderate impact on survival in RS...

..To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia...

..We conclude that addition of ATRA +/- G-CSF to FAI had no effect on CR rate, survival, EFS, or EFS in CR in poor prognosis, newly diagnosed AML or high-risk MDS...

..The median survival of patients with chromosome 8 abnormalities was 12 months compared with 40 months of those without (P=0.17). Novel therapies for patients with GS are required...

..01). In conclusion, the addition of intensive chemotherapy may improve survival in patients with CML who have not obtained an adequate cytogenetic response on an IFN-alpha-based regimen...

..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...

..T-cell lymphoid blastic phase (BP) transformation is rare in chronic myelogenous leukemia (CML). 2-amino-9-beta-D-arabinosyl-6-methoxy-9H-guanine (GW506U78), a prodrug of arabinosylguanine (ara-G), is effective in T-cell leukemias...

..Nonetheless, the rates and duration of PCR negativity produced by lipoATRA monotherapy suggest that lipoATRA is a superior anti-APL agent than oral ATRA...

..In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation...

..Our data suggest that lipoATRA is an effective means of producing molecular CR in newly diagnosed APL...

..Myelosuppression and infection remain the most significant complications of therapy in CLL...

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

..These findings suggest that inhibition of ZAP70 signaling pathway and suppression of Th1 cytokine synthesis by CD4+ T cells required the presence of IM at the time of T-cell activation through the T-cell receptor...

..The role of angiogenesis in hematological malignancies, the rationale for the use of angiosuppressive therapy for these entities, and the status of novel antiangiogenic agents in clinical trials are discussed...

..Interleukin-11 (IL-11) is a thrombopoietic cytokine that attenuates postchemotherapy thrombocytopenia at doses of 50 microg/kg/d subcutaneously. Very little is known about the activity of IL-11 in patients with bone marrow failure states...

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

..The association of treatment response with survival was evaluated by multivariate and landmark analyses...

..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...

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..More research is needed to define the intensity and duration of treatment and the role of cranial irradiation in the treatment of isolated CNS relapses...

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..Because the results of standard regimens have been disappointing, high-dose chemotherapeutic regimens were investigated recently. In the absence of randomized trials, the relative merits of various treatment regimens are unknown...

..The efficacy of rasburicase, administered daily for 5 days, has been well established. However, the optimal duration of therapy is unknown in adults...

..Grade 3 toxicities included arrhythmia (n=1) and transient ischemic attack (n=1). Ten patients (30%) had no side-effects. CONCLUSIONS: Low-dose IL-11 has activity in patients with BMF and is generally well tolerated...

..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...

..On the basis of these results, ABL1 kinase inhibitors warrant clinical investigation in patients with NUP214-ABL1-positive T-cell malignancies...

..Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR-alpha-positive HES...

..AmBisome was better tolerated than ABLC but was associated with mild abnormalities in liver function tests at the end of therapy...

..To evaluate the efficacy and safety of the combination of topotecan and cytarabine in patients with myelodysplastic syndromes (MDSs) and chronic myelomonocytic leukemia (CMML)...

..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 results show that PEG IFN-alpha-2b is easier to deliver (once weekly), better tolerated, and perhaps more effective than IFN-alpha...

..Efficacy of rituximab was also significant in this group of patients...

..02), with overall survival rates of 91%, 69%, and 75%, respectively (P=0.13). In conclusion, patients with more than one BCR-ABL1 mutation fare worse than those with no or one mutation...

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

..1 microg/ml, with the lowest limit of quantitation being 0.2 microg/ml. This method is suitable for routine analysis of UCN-01 in human plasma at concentration from 0.2 to 30 microg/ml...

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

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..Thus, there is little evidence to suggest that GO with or without IL-11 should be used instead of IA in older patients with newly diagnosed AML or myelodysplastic syndrome...

..A median of 5 post-CR courses have been given to date with 3 patients having currently received 8 post-CR courses, and 4 patients receiving 7 post-CR courses. Mylotarg appears active in APL, and repeated administration is feasible...

..This phenomenon should be considered when evaluating toxicity from chemotherapy, particularly when using new and investigational agents...

..Pilot studies showed that alemtuzumab is active in lymphoproliferative disorders. The authors conducted a Phase II trial to evaluate the efficacy and safety of alemtuzumab in advanced or refractory chronic lymphoproliferative disorders...

..To investigate the activity of a novel dioxolane L-nucleoside analog, troxacitabine (L-(-)-OddC, BCH-4556), in patients with refractory leukemia...

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

..We report 16 patients with CML who developed VZV infection during imatinib mesylate therapy...

..Troxacitabine has significant single-agent activity. This study was conducted to define the dose-limiting toxicities (DLTs) of its combination with cytarabine (ara-C), idarubicin, or topotecan...

..Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS...

..A prospective, randomized study was conducted in patients aged 50 years or older with untreated, adverse karyotype, acute myeloid leukemia (AML) to assess troxacitabine-based regimes as induction therapy...

..CONCLUSIONS: The combination of imatinib mesylate and anagrelide was safe and was associated with an 89% CHR rate in patients with CML in chronic phase and persistent thrombocythemia...