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

Haematologica. 2018 Sep;103(9):1484-1492. doi: 10.3324/haematol.2017.187153. Epub 2018 May 17.

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 1st (n=11), early 1st (n=15), ≥2nd 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Child
  • Child, Preschool
  • Clofarabine / administration & dosage
  • Clofarabine / pharmacokinetics
  • Cytarabine / administration & dosage
  • Cytarabine / pharmacokinetics
  • Daunorubicin / administration & dosage
  • Daunorubicin / pharmacokinetics
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Infant
  • Leukemia, Myeloid, Acute / diagnosis
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / mortality
  • Liposomes
  • Male
  • Recurrence
  • Remission Induction
  • Retreatment
  • Survival Analysis
  • Treatment Outcome
  • Young Adult

Substances

  • Liposomes
  • Cytarabine
  • Clofarabine
  • Daunorubicin

Associated data

  • EudraCT/2009-009457-13
  • NTR/1880