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Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study
NKA. van Eijkelenburg, M. Rasche, E. Ghazaly, MN. Dworzak, T. Klingebiel, C. Rossig, G. Leverger, J. Stary, ESJM. De Bont, DA. Chitu, Y. Bertrand, B. Brethon, B. Strahm, IM. van der Sluis, GJL. Kaspers, D. Reinhardt, CM. Zwaan,
Language English Country Italy
Document type Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't
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- MeSH
- Leukemia, Myeloid, Acute diagnosis drug therapy mortality MeSH
- Survival Analysis MeSH
- Drug Resistance, Neoplasm MeSH
- Cytarabine administration & dosage pharmacokinetics MeSH
- Daunorubicin administration & dosage pharmacokinetics MeSH
- Child MeSH
- Remission Induction MeSH
- Clofarabine administration & dosage pharmacokinetics MeSH
- Infant MeSH
- Humans MeSH
- Liposomes MeSH
- Adolescent MeSH
- Young Adult MeSH
- Retreatment MeSH
- Child, Preschool MeSH
- Antineoplastic Combined Chemotherapy Protocols adverse effects therapeutic use MeSH
- Recurrence MeSH
- Drug Administration Schedule MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase I MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
Centre for Haemato Oncology Barts Cancer Institute Queen Mary University of London UK
Clinical Trial Center Department of Hematology Erasmus Medical Center Rotterdam the Netherlands
Department of Pediatric Hematology and Oncology AP HP GH HUEP Trousseau Hospital Paris France
Department of Pediatric Hematology Robert Debré Hospital Paris France
Department of Pediatric Oncology University Children's Hospital Essen Germany
Pediatric Hematology and Oncology University Children's Hospital Münster Germany
Pediatric Hematology Department IHOP and Claude Bernard University Lyon France
Pediatric Hematology Oncology Johann Wolfgang Goethe University Frankfurt Germany
References provided by Crossref.org
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