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
Affiliations
Natasha K.A. van Eijkelenburg
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands;Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands;European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France
Mareike Rasche
Department of Pediatric Oncology, University Children’s Hospital, Essen, Germany
Essam Ghazaly
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK
Michael N. Dworzak
Children’s Cancer Research Institute and St. Anna Children’s Hospital, Department of Pediatrics, Medical University of Vienna, Austria
Thomas Klingebiel
Pediatric Hematology/Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany
Claudia Rossig
Pediatric Hematology and Oncology, University Children’s Hospital, Münster, Germany
Guy Leverger
Department of Pediatric Hematology and Oncology, AP-HP, GH HUEP, Trousseau Hospital, Paris, France
Jan Stary
Department of Pediatric Hematology and Oncology, 2ndFaculty of Medicine, Charles University Prague, University Hospital Motol, Czech Republic
Eveline S.J.M. De Bont
Department of Pediatric Oncology, University Medical Center Groningen, University of Groningen, the Netherlands
Dana A. Chitu
Clinical Trial Center, Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands
Yves Bertrand
Pediatric Hematology Department, IHOP and Claude Bernard University, Lyon, France
Benoit Brethon
Department of Pediatric Hematology, Robert Debré Hospital, Paris, France
Brigitte Strahm
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Germany
Inge M. van der Sluis
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands;European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France
Gertjan J.L. Kaspers
Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands;Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands;I-BFM-AML committee, Kiel, Germany
Dirk Reinhardt
European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France;I-BFM-AML committee, Kiel, Germany
C. Michel Zwaan
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands;Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands;European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France
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.
