title: 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.
abstract: 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.
authors: Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA. usg2001@med.cornell.edu
authors: Usama
authors: U
authors: Gergis
authors: Gail
authors: G
authors: Roboz
authors: Tsiporah
authors: T
authors: Shore
authors: Ellen
authors: E
authors: Ritchie
authors: Sebastian
authors: S
authors: Mayer
authors: Usama
authors: U
authors: Wissa
authors: Marshall
authors: M
authors: McKenna
authors: Paul
authors: P
authors: Christos
authors: Roger
authors: R
authors: Pearse
authors: Tomer
authors: T
authors: Mark
authors: Joseph
authors: J
authors: Scandura
authors: Koen
authors: K
authors: van Besien
authors: Eric
authors: E
authors: Feldman
mesh_terms: D000328:Adult; D000368:Aged; D002066:Busulfan / Q000627:therapeutic use*; D016022:Case-Control Studies; D003561:Cytarabine / Q000627:therapeutic use*; D003630:Daunorubicin / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011379:Prognosis; D012008:Recurrence; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D019653:Myeloablative Agonists; D003561:Cytarabine; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D003630:Daunorubicin