Thrombocytopenia, common in leukemias and myelodysplastic syndromes (MDS), is responsible for increased risk of bleeding and delay of therapy. Platelet transfusions, although effective in increasing platelet counts, are limited by supply, are associated with risks, and result in limited and transient benefits. Successful development of an alternative treatment approach with thrombopoietin agonists was nearly thwarted when early formulations of recombinant thrombopoietin agonists elicited antibodies that cross-reacted with and neutralized endogenous thrombopoietin. The effectiveness of these recombinant agents led to the development of second generation thrombopoietin receptor agonists that do not induce cross-reacting neutralizing antibodies against thrombopoietin. Two of the novel thrombopoietin receptor agonists, romiplostim (Nplate™, Amgen, Thousand Oaks, CA) and eltrombopag (Promacta™, GlaxoSmithKline, London UK & Philadelphia, US), have established clinical activity in chronic immune (idiopathic) thrombocytopenic purpura (ITP), and are being explored for the treatment of thrombocytopenia in MDS.

The management of the myelodysplastic syndromes (MDS) requires insight into the complex biology of the disease. Despite this challenge, two recent developments have contributed significantly to advancements in the treatment of MDS: (i) improvements in classification systems and prognostic models; and (ii) the emergence of US FDA-approved agents such as lenalidomide, azacitidine and decitabine. Prior to these developments, supportive care measures consisting of blood and platelet transfusions, haematopoietic growth factors and antimicrobials remained standard of care for the treatment of MDS. As a result of these developments, clinicians are able to provide patient-tailored therapy for specific MDS subgroups. Clinical trials addressing combination therapies with multiple investigational agents as well as novel combination regimens are ongoing. 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.

Bosutinib is a safe and effective second-line treatment option for select patients with Ph-positive CML who were intolerant or resistant to prior TKI therapy.

Background Combination of cytotoxic chemotherapy with imatinib or dasatinib is effective in the treatment of Ph+ ALL. Ponatinib is a more potent BCR-ABL inhibitor. It also suppresses the T315I clones, a common cause of relapse in pts with Ph+ ALL. Clinical trials of ponatinib have demonstrated its high activity and limited toxicity in Ph+ leukemias. The complete cytogenetic response (CCyR) rate is 40% to 50% in patients failing 2-3 TKIs and in those with a T315I mutation. The combinations of chemotherapy and ponatinib may be associated with better response rates and higher likelihood of eradication of minimal residual disease (MRD) than those reported with imatinib or dasatinib. Methods In this phase II trial, pts with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Rituximab was administered during the first 4 cycles in pts with CD20 expression ≥20%. Pts in CR received maintenance with ponatinib 45 mg po daily and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring was conducted. Results To date 28 pts with untreated Ph+ ALL and 2 pts previously treated (1 with prior cycle of chemotherapy before Ph+/BCR-ABL status was known not in CR, and 1 post HCVAD-dasatinib in CR) have received a median of 6 cycles (1-8) of therapy; 10 pts are receiving maintenance in CR. Median age was 55 years (28–75). Median WBC at diagnosis was 3.55 x 109/L (1.6 -629 x 109/L). CD20 expression was reported positive in 11 pts (37%). 2 (7%) had concomitant CNS disease at diagnosis. All pts were in CR after cycle 1. 24 of the 26 pts (92%) with Ph+ metaphases (at least 20 metaphases analyzed) by cytogenetic analysis at baseline achieved a CCyR after 1 cycle; 1 had a minor cytogenetic response only and one had no cytogenetic analysis at CR, both of them achieved a CCyR after cycle 2; 4 had a diploid karyotype at the start of therapy (one in CCyR post previous chemotherapy and 3 diploid by standard G-banding technique and positive by FISH and PCR). To date, 26 pts (93%) have achieved a MMR, of whom 19 (70%) have achieved a CMR at a median of 10 weeks from initiation of treatment (2 -28). MRD assessment by flow cytometry is negative in 26 (90%) pts at a median of 3 weeks (3-14). Median time to neutrophil and platelet recovery for cycle 1 was 18 and 23 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥ 3 toxicity included increase of LFT’s in 11 pts (37%), thrombotic events in 3 (10%, 1 renal vein thrombosis and 2 pulmonary emboli), myocardial infarction (MI) in 3 (10%, 1 unexplained, 1 with history of cardiomyopathy, and 1 in the context of sepsis ), skin rash in 3 (15%), and pancreatitis in 2 (7%). 11 pts (37%) had their dose reduced to 30 mg and 2 pts (10%) switched to dasatinib (n=1) or imatinib (n=1). With a median follow up of 7 months (1-20), 21 pts are alive and in CR; 1 pt died in CR from an unrelated cardiac event after being taken off therapy and placed on imatinib, 1 pt died from multiple organ failure post sepsis (C2D13), and 1 from non ST elevation MI (NSTEMI) post cycle 2 (C2D41). 6 pts have undergone an allogeneic stem cell transplant. The 1-year progression-free and overall survival rates were 100% and 88% respectively. Conclusion The combination of hyperCVAD with ponatinib is safe and highly effective in achieving molecular remissions in pts with Ph+ ALL. Disclosures: Jabbour: Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Cortes:Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Research Funding; BMS: Research Funding. Faderl:Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Introduction The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in acute leukemias. Mutations involving FLT3 are among the most common molecular abnormalities in acute myelogenous leukemia (AML). Available evidence suggests that these molecular lesions confer a shorter disease-free survival and overall survival in patients with intermediate-risk cytogenetics. Therefore, substantial interest in FLT3 as a therapeutic target has led to the development of several promising inhibitors that target this tyrosine kinase. Areas covered This review covers the molecular pathways associated with FLT3 activation in patients with AML, the biological rationale for inhibiting FLT3 and recent clinical progress with FLT3 inhibitors for the treatment of AML. Six FLT3 inhibitors undergoing clinical evaluation are discussed. A review of selected published manuscripts on the subject of FLT3 inhibition in AML and a search of the English language manuscripts in PubMed using the index words FLT3 and AML were conducted and articles of interest selected. Expert opinion Mutated forms of FLT3, specifically FLT3-internal tandem duplication, have a significant impact on the prognosis of AML patients, particularly those with a normal karyotype. 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.