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Clofarabine ± Fludarabine with IV Busulfan and Allogeneic Stem Cell Transplantation for Advanced Myeloid Leukemia (ML) and MDS
Clofarabine ± Fludarabine with IV Busulfan and allogeneic stem cell transplantation for advanced myeloid leukemia (ML) and MDS
Diem Chu, Ben C. Valdez, Patricia Fox, Peter F. Thall, Laura L. Worth, Uday Popat, Roy B. Jones, Elizabeth J. Shpall, Chitra Hosing, Amin Alousi, Gabriela Rondon, Partow Kebriaei, Richard E. Champlin and Borje S. Andersson
The nucleoside analog (NA) clofarabine (Clo) has improved antileukemic efficacy compared with fludarabine (Flu), commonly used with IV busulfan (Bu) in pretransplant conditioning. In vitro studies of [Clo+Flu] with Bu in AML cells showed higher synergistic cytotoxicity compared with [Clo+Bu] or [Flu+Bu] combination. We studied [Clo±Flu] with IV Bu in pretransplant conditioning for ML and MDS.
Methods: Patients were adaptively randomized (AR), based on day +30- and chimerism-status: Arm I Clo:Flu 10:30 mg/m2, Arm II 20:20 mg/m2, Arm III 30:10 mg/m2, and Arm IV Clo only at 40 mg/m2. The NA were/was infused over 60 min once daily for 4 days, on each day followed by Bu over 3 hours to an average daily AUC of 6,000 mM-min. GVHD-prophylaxis was tacrolimus and mini‑MTX. Recipients of unrelated (MUD) or one antigen-mismatched related donor cells received rabbit-ATG infused over 3 days for a total dose of 4 mg/kg.
Results: 70 patients were treated, M:F 39:31, median age 46 years (6-59). 49 patients had AML, 8 had MDS and 13 had CML. 29 patients had related donors while 41 had MUDs; marrow was used in 24, blood progenitor cells in 46. Only 13 of 57 AML/MDS patients were in cytological CR, 44 had active disease; all CML patients had advanced disease.
All evaluable patients engrafted and there were no secondary graft failures. Due to the AR, 25 patients were allocated to arms I and II (lower Clo doses), and 45 to Arms III and IV (higher Clo doses). Safety was acceptable with 100-day non-relapse mortality of 4%. Grade 2-3 mucositis occurred in half of the patients and there were no serious hepatic or neurologic events. The minimum follow-up of surviving patients was 26 months and there was no difference in overall or progression-free survival based on CR-status at SCT or whether patients had a MUD- or related donor graft.
We conclude that (1) [Clo±Flu] +IV Bu-based conditioning therapy is safe and efficacious in high-risk patients with ML/MDS, (2) Clo is sufficiently immunosuppressive to be used in pretransplant conditioning, and (3) the in vitro studies which showed a superior cytotoxic synergy of [Clo+Flu+Bu] compared with either [Clo+Bu] or [Flu+Bu] were supported clinically by a trend for improved overall and progression-free survival in patients treated in Arms III and IV (higher Clo doses) versus that of Arms I+II (lower Clo doses). Additional studies of Clo by itself or in combination with a second NA together with Bu in pretransplant conditioning are warranted.
Overall Survival in ML/MDS