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

Abstract

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/m²/day × 5 days) and liposomal daunorubicin (40-80 mg/m²/day) were administered with cytarabine (2 g/m²/day × 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 1^st (n=11), early 1st (n=15), ≥2^nd relapse (n=8). Dose level 3 (30 mg/m²clofarabine; 60 mg/m²liposomal 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/m² clofarabine with 60 mg/m² 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-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.

Figure 1.

Treatment schedule. Clofarabine was administered intravenously (IV) in 2 hours (h) (days 1-5); liposomal daunorubicin (DNX) in 1 h (days 1, 3, 5); DNX in 1 h (days 1, 3, 5), starting 30 minutes after the end of clofarabine; cytarabine was administered (IV) in 3 h (days 1-5), starting 3 h after the end of clofarabine. Intrathecal therapy was administered at day 6 with cytarabine for prophylaxis, or triple therapy (cytarabine and methotrexate and prednisolone) with age-adjusted dosages in case of central nervous system involvement. G-CSF: granulocyte-colony stimulating factor.

Figure 2.

Survival estimates after clofarabine combination chemotherapy reinduction. (A) Overall survival of all patients. (B) Event-free survival of all patients. (C) Cumulative Incidence of relapse of the 21 responding patients. (D) Overall survival of all patients at dose level (DL) 4. (E) Event-free survival of all patients at DL4. N: number; F: females; F: failure (event).

Figure 3.

Clofarabine pharmacokinetics and Ppasma concentrations. (A) Clofarabine plasma concentrations normalized to infused dose (ng/mL/mg of infused dose) as measured by liquid chromatography mass spectrometry (LC-MS)/MS. Each line represents plasma concentrations for a single patient before receiving clofarabine infusion (Pre-dose), 2 (T2), 5 (T5) and 24 (T24) hours (h) after starting of clofarabine infusion at day (d)1 and d5 of the first treatment cycle. Samples from 2 patients (ns. 0708 and 0717) were available from two different treatment cycles. (B) A scatter plot for clofarabine plasma concentrations as measured by LC-MS/MS (in color) overlaid on the pharmacokinetic model developed by Bonate et al. (in gray) for single agent clofarabine in 3 previous clinical studies (ID99-383, CLO-212 and CLO-222) fitted using non-parametric LOESS fit.