A phase I study of CPX-351 in combination with busulfan and fludarabine conditioning and allogeneic stem cell transplantation in adult patients with refractory acute leukemia.

This phase I study evaluated the maximal tolerated dose of CPX-351 when administered sequentially with allogeneic hematopoietic stem cell transplantation (HSCT) in patients with refractory acute leukemia. CPX-351 is a novel liposomal formulation that combines cytosine arabinoside (ara-c) and daunorubicin in a fixed molar ratio of 5:1. Patients in cohorts of 3 were treated with CPX-351 followed by fludarabine and busulfan (Bu/Flu) conditioning at 4-week (schedule A) or 3-week (schedule B) intervals. CPX-351 doses were escalated in 20-U/m(2) increments starting at 60 U/m(2) for 3 doses. Of the 36 patients enrolled, 29 were able to undergo HSCT, and the other 7 (the majority on schedule A) did not proceed to HSCT because of rapid disease progression. The maximal tolerated dose of CPX-351 was not reached at the 120 U/m(2) × 3 dose level. All 29 patients who proceeded to HSCT demonstrated adequate neutrophil and platelet engraftment. The median follow-up on the study for all 36 patients was 205 days (range, 20 to 996 days). The 1-year cumulative incidence of relapse for the 36 patients was 60.1% (95% confidence interval [CI], 43.4% to 77.3%), and that of nonrelapse mortality was 23.8% (95% CI, 10.9% to 47.4%). The 1-year overall survival and leukemia-free survival were 37% (95% CI, 21% to 53%) and 27% (95% CI, 13% to 43%), respectively. Our data suggest that a phase II trial should incorporate CPX-351 120 U/m(2) × 3 dosing on schedule B. Patients with good performance status and those who achieve effective cytoreduction from CPX-351 derived the greatest benefit.

Are low-intensity induction strategies better for older patients with acute myeloid leukemia?

This study compares outcomes of low-intensity versus standard-intensity induction strategies for older patients with acute myeloid leukemia at the Weill Cornell Leukemia Program. From 1999 to 2009, 298 adults ≥ 60 years with AML underwent induction chemotherapy with low-intensity and standard-intensity regimens, based on physician and patient preferences and investigational protocol availability. Overall, 33% of the cohort achieved complete remission with initial treatment, 23% with low-intensity induction and 53% with standard-intensity induction (P<0.0001). The median overall survival was 6.5 months and there was no significant difference in overall survival between patients initially treated with a low-intensity regimen compared to those receiving standard-intensity induction. There were no differences in 30- or 60-day mortality between the two groups.

High-risk myelodysplastic syndromes: chemotherapy, transplantation, and beyond.

Allogeneic hematopoietic cell transplantation (HCT) has curative potential for patients with myelodysplastic syndromes (MDS), though with considerable nonrelapse mortality and morbidity. The International Prognostic Scoring System, despite its confines, remains a widely used tool guiding treatment decisions in MDS. The two hypomethylating agents, 5-azacytidine (azacitidine) and 5-aza-2-deoxycytidine (decitabine), are both effective in high-risk MDS, but about 50% of high-risk MDS patients fail to achieve a meaningful response, and these agents offer only a modest survival benefit, with a median response duration of 13 months. The more recent proposed risk models of MDS, as well as modern transplant strategies and expanded alternative donor sources, have helped to increase the number of patients offered curative treatment. As both drug therapy and HCT modalities evolve, treatment decisions are certain to become more complex. Current therapeutic options should view the hypomethylating agents as a way to optimize disease response before (and possibly after) HCT.