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Haematologica 2018 Volume 103(9):1484-1492
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Gertjan J.L. Kaspers,2,16,17 Dirk Reinhardt3,17 and C. Michel Zwaan1,2,3
Ferrata Storti Foundation
Acute Myeloid Leukemia
Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study
Natasha K.A. van Eijkelenburg,1,2,3* Mareike Rasche,4* Essam Ghazaly,5 Michael N. Dworzak,6 Thomas Klingebiel,7 Claudia Rossig,8 Guy Leverger,9 Jan Stary,10 Eveline S.J.M. De Bont,11 Dana A. Chitu,12 Yves Bertrand,13
Benoit Brethon,
Brigitte Strahm,
15 1,3 Inge M. van der Sluis,
1Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; 2Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; 3European Consortium for Innovative Therapies for Children with Cancer (ITCC), Villejuif, France; 4Department of Pediatric Oncology, University Children's Hospital, Essen, Germany; 5Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK; 6Children’s Cancer Research Institute and St. Anna Children’s Hospital, Department of Pediatrics, Medical University of Vienna, Austria; 7Pediatric Hematology/Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany; 8Pediatric Hematology and Oncology, University Children’s Hospital, Münster, Germany; 9Department of Pediatric Hematology and Oncology, AP-HP, GH HUEP, Trousseau Hospital, Paris, France; 10Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University Prague, University Hospital Motol, Czech Republic; 11Department of Pediatric Oncology, University Medical Center Groningen, University of Groningen, the Netherlands; 12Clinical Trial Center, Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands; 13Pediatric Hematology Department, IHOP and Claude Bernard University, Lyon, France; 14Department of Pediatric Hematology, Robert Debré Hospital, Paris, France; 15Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Germany; 16Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands and 17I-BFM-AML committee, Kiel, Germany
*NKAE and MR contributed equally to this work as first authors.
ABSTRACT
Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course of flu- darabine, cytarabine and liposomal daunorubicin, followed by flu- darabine 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 combina- tion 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 recommend- ed 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 clo- farabine; 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 proba- bility 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-
Correspondence:
c.m.zwaan@erasmusmc.nl
Received: December 24, 2017. Accepted: May 16, 2018. Pre-published: May 17, 2018.
doi:10.3324/haematol.2017.187153
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/9/1484
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