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

Natasha K. A. van Eijkelenburg, Mareike Rasche, Essam Ghazaly, Michael N. Dworzak, Thomas Klingebiel, Claudia Rossig, Guy Leverger, Jan Stary, Eveline S. J. M. de Bont, Dana A. Chitu, Yves Bertrand, Benoit Brethon, Brigitte Strahm, Inge M. van der Sluis, Gertjan J. L. Kaspers, Dirk Reinhardt, C. Michel Zwaan

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Abstract

Survival in children with relapsed/refractory a cute 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 x 5 days) and liposomal daunorubicin (40-80 mg/m2/day) were administered with cytarabine (2 g/m2/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/m2 clofarabine; 60 mg/m2 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/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 expo-sure 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.
Original languageEnglish
Pages (from-to)1484-1492
JournalHaematologica
Volume103
Issue number9
DOIs
Publication statusPublished - 2018

Cite this

van Eijkelenburg, N. K. A., Rasche, M., Ghazaly, E., Dworzak, M. N., Klingebiel, T., Rossig, C., ... Zwaan, C. M. (2018). Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: A phase IB study. Haematologica, 103(9), 1484-1492. https://doi.org/10.3324/haematol.2017.187153