AAML0523: A Report From the Children's Oncology Group On the Safety of Clofarabine in Combination with Cytarabine in Pediatric Patients with Relapsed Acute Leukemia.

Despite improvements in survival rates for pediatric ALL and AML, many children still relapse with dismal outcomes. It is critical to develop non-anthracycline containing salvage regimens that induce remission and allow for hematopoietic stem cell transplantation (HSCT). Clofarabine is a nucleoside analog that potently inhibits ribonucleotide reductase and DNA polymerase αa. The biochemical modulation of cytarabine by clofarabine via inhibition of ribonucleotide reductase is well established, and this combination has been studied in adults with relapsed AML.

The Children's Oncology Group instituted a Phase I/II study testing the combination of clofarabine and cytarabine in pediatric patients with AML in first relapse and ALL in second or subsequent relapse. We report on the toxicity profile in the Phase I portion of the study. Cytarabine was administered on days 1-5 at a dose of 1 gm/m² and clofarabine was administered on days 2-6 in varying doses. Cytarabine was given 4 hours after the start of clofarabine to optimize the biochemical modulation of ara-CTP. Patients could receive up to 2 cycles on study. The Phase I portion of the study consisted of a single dose escalation/de-escalation of clofarabine with a fixed dose of cytarabine. For each dose level, 10 patients were enrolled. The first cohort of patients received clofarabine at 40 mg/m²/day (the adult single-agent MTD). Based on safety data on the first cohort, the dose of clofarabine would either be escalated to 52 mg/m²/day (single-agent pediatric MTD) or deescalated to a dose of 30 mg/m²/day. The MTD determined in this dose finding phase would determine the dose for the Phase II efficacy portion of the study.

Of the 10 patients enrolled on the first cohort, 8 patients had ALL (6 in second relapse, 2 refractory to reinduction) and 2 had AML. Ten patients completed one cycle and 5 patients completed two cycles. In both cycles, the most common toxicities ≥ Grade 3 were fever/neutropenia (7/15 occurrences), infection (6/15), transaminitis (5/15), abdominal pain (3/15), and hypokalemia (4/15). Two ALL patients with prior HSCT had dose-limiting toxicities (DLT's): one with grade 4 fungal infection and pneumonitis and another with grade 4 fungal infection. Neither patient was on antifungal prophylaxis. The MTD was not met, and 10 patients were enrolled on the second cohort (52 mg/m²): 3 patients with ALL in second relapse and 7 with AML. Ten patients completed cycle 1 and 7 completed two cycles. In both cycles, the most common toxicities ≥Grade 3 were diarrhea (3/17), nausea (3/17), febrile neutropenia (5/17), infection (10/17), hyperglycemia (3/17), and hypokalemia (3/17). In this cohort, one AML patient experienced DLT's of prolonged bone marrow aplasia, Grade 4 hypokalemia, Grade 3 nausea, and Grade 3 dehydration. The table below summarizes count recovery data at both dose levels. The median cycle length for patients without ANC and platelet recovery at the 40 mg/m² level was 22 and 30 days respectively after one course and 19 and 17.5 days respectively after 2 courses. At the 52 mg/m² dose level, the median cycle length for patients without ANC and platelet recovery was 20 days for each after one course and 23 and 25 days respectively after 2 courses. These numbers suggest that patients without marrow recovery had progressive disease, received alternate chemotherapy, or proceeded to HSCT prior to count recovery, rather than drug-induced prolonged bone marrow aplasia.

The combination of clofarabine and cytarabine is safe and tolerable in pediatric patients with relapsed acute leukemia. The MTD of clofarabine in combination with cytarabine in pediatric patients with relapsed acute leukemia is 52 mg/m²/day.

Whitlock:Genzyme: Consultancy.