Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study

Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m(2)/day x 5 dys) and liposomal daunorubicin (40-80 mg/m(2)/day) were administered with cytarabine (2 g/m(2)/day x 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), >= 2nd relapse (n=8). Dose level 3 (30 mg/m(2) clofarabine; 60 mg/m(2) liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m(2) clofarabine with 60 mg/m(2) liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5 +/- 7.6 and probability of survival (pOS) 32.4 +/- 8.0%. In the 21 responding patients, the 2-year pEFS was 42.9 +/- 10.8 and pOS 47.6 +/- 10.9%. Clofarabine exposure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub)clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Munster study for newly diagnosed acute myeloid leukemia