A Randomized Study of Fludarabine-Clofarabine Vs Fludarabine Alone Combined with Busulfan and Allogeneic Hematopoietic Transplantation for AML and MDS

Disease relapse remains the major cause of treatment failure following hematopoietic transplantation for AML/MDS. A major goal is to develop more effective antileukemic regimens without excessive toxicity. Busulfan (Bu)-fludarabine (Flu) is a widely used preparative regimen. We demonstrated that targeting a relatively high busulfan systemic exposure pharmacokinetic (PK) dose adjustment was superior to fixed busulfan dosing. Clofarabine (Clo) has improved antileukemic activity compared to fludarabine. We previously reported a phase I/II study of different dosing combinations of busulfan with Flu and Clo; the best results were obtained with Bu with Flu 10 mg/m2 and Clo 30 mg/m2 daily for four daily doses. We performed a phase III randomized controlled trial to determine if Flu/Clo/Bu improved progression free survival compared to the Flu/Bu regimen. Busulfan was given with PK dose adjustment AUC 6000 mM x min for age <=60 years or 4000 mM x min for older patients and those with performance status (PS) <80%. GVHD prophylaxis was tacrolimus-mini methotrexate. Unrelated donor recipients also received ATG.

Patients aged 3-70 with intermediate or high risk AML or MDS, with PS>60% and adequate organ function were eligible if they had an HLA identical related or 9/10 or 10/10 matched unrelated donor. Patients were randomized to receive either Flu/Bu or Flu/Clo/Bu as the preparative regimen and stratified based on disease status, in complete remission (CR) or not in CR (NCR).

250 patients were entered; 130 received Flu/Bu, 120 Flu/Clo/Bu. 95 had a matched sibling, 155 a matched unrelated donor. Median age was 51 yrs. 181 had AML, 69 MDS. Poor risk cytogenetics was present in 37%. 133 patients were in remission; 117 had active disease. Comorbidity index was <3 in 60%. Performance status was >90% in 88%.

249 patients achieved engraftment. 41% had grade 2 and 6% grade 3-4 acute GVHD. 93 patients developed chronic GVHD. The Kaplan Meier 3-year PFS was 0.52 (95%CI: 0.44 - 0.62) for Flu/Clo/Bu and 0.48 (95%CI: 0.41 - 0.58) for Flu/Bu (P=0.44). For the Flu Bu group, 52 patients progressed and 16 died with nonrelapse mortality (NRM). For the Flu/Clo Bu group, 32 progressed and 27 died with NRM. There was a significantly lower risk of progression with Flu/Clo/Bu (p=0.025), but a significantly higher risk of NRM (p=0.018). There was no difference in PFS for patients in CR, but there was a trend for improved PFS (p=0.17) with a significantly reduced risk of relapse (p=0.002) for patients over age 60 who were not in CR.

In conclusion, Flu/Clo/Bu reduced the risk of relapse but had greater NRM compared to Flu/Bu. In patients over age 60 who were not in remission at transplant, there was a reduced risk of relapse and a trend towards improved PFS.

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