Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: The long-term efficacy of a combination of chemotherapy and dasatinib in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is not well established. METHODS: Patients received dasatinib with 8 cycles of alternating hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and high-dose cytarabine and methotrexate. Patients in complete remission (CR) continued maintenance dasatinib, vincristine, and prednisone for 2 years, which was followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplantation (SCT) received it during their first CR. RESULTS: Seventy-two patients with a median age of 55 years (range, 21-80 years) were treated; 69 (96%) achieved CR. Among them, 57 (83%) achieved cytogenetic CR after 1 cycle, and 64 (93%) achieved a major molecular response at a median of 4 weeks (range, 2-38 weeks). Sixty-five patients (94%) were negative for minimal residual disease assessed by flow cytometry at a median of 3 weeks (range, 2-37 weeks). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. With a median follow-up of 67 months (range, 33-97 months), 33 patients (46%) were alive, and 30 (43%) were in CR; 12 underwent allogeneic SCT. Thirty-nine patients died (3 at induction, 19 after relapse, 7 after SCT performed during first CR, and 10 during CR). The median disease-free survival and overall survival were 31 (range, 0.3-97 months) and 47 months (range, 0.2-97 months), respectively. Seven relapsed patients had BCR-ABL kinase domain mutations, including 4 with T315I. CONCLUSIONS: A combination of chemotherapy with dasatinib is effective in achieving long-term remission for patients with newly diagnosed Ph + ALL.

The ever-evolving landscape of candidaemia in patients with acute leukaemia: non-susceptibility to caspofungin and multidrug resistance are associated with increased mortality.

OBJECTIVES: The epidemiology and clinical course of candidaemia in patients with acute leukaemia, a population frequently exposed to antifungals, have not been extensively studied. In the present contemporary series of acute leukaemia patients, we describe patient characteristics, Candida species and MIC distributions and investigate the association between antifungal resistance and all-cause mortality. METHODS: We performed a retrospective review of medical records and microbiological data of adult patients with acute leukaemia or high-risk myelodysplastic syndrome with at least one positive blood culture for Candida species at the MD Anderson Cancer Center between January 2008 and October 2012. Susceptibility was defined according to the 2012 epidemiological cut-off values and clinical breakpoints. RESULTS: We identified 67 episodes of candidaemia in 65 patients. Almost all episodes (94%) occurred in patients who were receiving antifungal agents, 71% in patients receiving an echinocandin. Almost all isolates (99%) were of non-albicans Candida species [most frequently Candida parapsilosis (32%), Candida tropicalis (23%) and Candida glabrata (20%)]. Caspofungin non-susceptibility was significantly associated with fluconazole resistance (P < 0.001). Non-susceptibility to caspofungin and multidrug resistance were associated with excess 14 day [adjusted HR (aHR) 3.02 (95% CI 1.28-7.09), P = 0.011 and aHR 3.02 (95% CI 1.27-7.14), P = 0.012, respectively] and 30 day [aHR 2.96 (95% CI 1.38-6.37), P = 0.005 and aHR 2.86 (95% CI 1.31-6.21), P = 0.008, respectively] all-cause mortality. CONCLUSIONS: In patients with acute leukaemia, a shift in candidaemia epidemiology was noted with a 99% predominance of non-albicans species. Non-susceptibility of Candida strains to caspofungin or multidrug resistance were independent markers of poor outcome in this patient population.