In relapsed or refractory AML allogeneic transplantation (HCT) is considered to be the only chance to achieve long-term disease-free survival. However, only about 40% of younger patients with relapsed AML receive allogeneic HCT. A number of factors contribute to this low rate. Among them, a moderate activity of currently available salvage regimens and accumulating toxicity of chemotherapy may prevent from transplantation. Clofarabine is considered to have a favorable risk-benefit ratio in this indication. Therefore, our goal was to study the safety and efficacy of a clofarabine salvage therapy prior to allogeneic HCT (NCT 1295307). Here, we report data from patients of stage I of a two-stage phase II study.
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. Patients without a donor should receive consolidation therapy with CLARA. The conditioning regimen started earliest on day 15 after CLARA and consisted of clofarabine 30 mg/m2 on days -6 to -3 and melphalan 140 mg/m2 on day -2 prior to HCT. GvHD prophylaxis consisted of cyclosporine in combination with MMF. In patients with partially matched unrelated donors the administration of a cumulative dose of 4.5 mg/kg ATG (Genzyme) was recommended. Primary endpoint was treatment success defined as a complete remission (CR, CR(i)) six weeks after completion of therapy. Toxicities were graded according to CTCAE Version 3.0.
Twenty-six patients were enrolled into stage I of this trial. Median age was 60 years (range, 40 to 74 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 respond to CLARA and were subsequently treated off study. One patient died on day 18 after the first cycle 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 partially matched unrelated donors with one mismatch 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, all after allogeneic HCT. One patient responded to chemotherapy but needed surgical intervention due to a pulmonary aspergillosis and could not proceed with therapy within the projected timelines and was therefore considered as treatment failure. Liver toxicity was the most frequent adverse event. Seventeen patients (65%) developed grade III liver enzyme elevation considered to be at least possible related to the study drug. Grade IV liver toxicity was observed in 1 patient. Liver injury indicated by elevated transaminases was transient and did not lead to persistent liver damage or hepatic sinusoidal obstruction syndrome. Due to frequently required per-protocol dose reductions of clofarabine prompted by grade III elevations of transaminases the study protocol was amended to a reduced dose of clofarabine 30 mg/m2 in CLARA chemotherapy. Five patients developed grade I/II elevation of creatinine and 2 patients developed renal failure (grade IV) in the context of septic organ failure. Grade I/II hand-foot syndrome occurred in 5 patients. With a maximum follow up of 17 months 14 patients have died (5 patients died after relapse). At present 12 patients are alive, 7 of these are relapse-free, 3 patients are alive with relapse and 2 patients are currently receiving hypomethylating agents for molecular relapse.
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 complete remission rate of the first 26 patients was evaluated favorably and the trial is currently recruiting to reach the total number of 82 patients. Longer follow up is needed to evaluate relapse-free survival.
Middeke:Genzyme: Honoraria. Off Label Use: Clofarabine, not approved for AML. Bornhäuser:Genzyme: Honoraria. Schetelig:Genzyme/Sanofi: Honoraria, Research Funding.
Asterisk with author names denotes non-ASH members.