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In relapsed or refractory AML allogeneic transplantation (HCT) is considered to be the only chance to achieve long-term survival but still only about 40% of younger patients receive allogeneic HCT. Moderate activity of salvage regimens and accumulating toxicity of chemotherapy are reasons that may prevent from transplantation. Our goal was to study the safety and efficacy of a clofarabine salvage therapy prior to allogeneic HCT. Here, we report data from patients of stage I of a two-stage phase II study.
Patients and Methods
Patients above the age of 40 with relapsed or refractory AML who were fit for allogeneic HCT were eligible to participate in this multicenter, single-arm study. All patients received at least one cycle of clofarabine 40 mg/m² followed by intermediate dose cytarabine 1 g/m² days 1-5 (CLARA). Patients with a donor who exposed at least a reduction of leukemic blasts were scheduled for allogeneic HCT in aplasia after CLARA. The conditioning regimen consisted of clofarabine 30 mg/m² on days -6 to -3 and melphalan 140 mg/m² on day -2. Cyclosporine in combination with MMF was used for GvHD prophylaxis. In patients with partially matched unrelated donors the administration of ATG was recommended. Primary endpoint was treatment success defined as a complete remission (CR, CR(i)) six weeks after completion of therapy.
Results
Twenty-six patients were enrolled into stage I of this trial. Median age was 60 years. Fifty percent of the patients each had refractory or relapsed AML. At early response assessment on day 15 after CLARA-1 13 patients (50%) had less than 10% marrow blasts. Ten patients (38%) showed a reduction in marrow cellularity or blast percentage. Two patients did not have a significant marrow blast reduction. One patient died after the first cycle CLARA from septic multi-organ failure. Twenty-two patients (85%) received allogeneic HCT within this trial. Donors were HLA-identical siblings in 5 patients (23%), HLA-compatible unrelated donors in 11 patients (50%) and unrelated donors with one mismatch in 6 patients (27%). Liver toxicity was the most frequent adverse event. Seventeen patients (65%) developed grade III liver enzyme elevation while Grade IV was observed in 1 patient. Grad III/IV GvHD occurred in 6 patients (27%). All 26 patients have been evaluated for the primary endpoint. Sixteen patients had a CR (62%) and 6 patients a CRi (23%) at final response evaluation.
With a maximum follow up of 19 months 16 patients have died (7 patients died after relapse). At present 10 patients are alive, 6 of them had refractory disease.
Conclusion
Salvage therapy with CLARA and subsequent conditioning with clofarabine and melphalan prior to allogeneic HCT provides good anti-leukemic activity in patients with relapsed or refractory AML. The CR rate of the first 26 patients was evaluated favorably and the trial is currently recruiting into stage 2.