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Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study.
- Source :
-
Haematologica [Haematologica] 2018 Sep; Vol. 103 (9), pp. 1484-1492. Date of Electronic Publication: 2018 May 17. - Publication Year :
- 2018
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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/m <superscript>2</superscript> /day × 5 days) and liposomal daunorubicin (40-80 mg/m <superscript>2</superscript> /day) were administered with cytarabine (2 g/m <superscript>2</superscript> /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 1 <superscript>st</superscript> (n=11), early 1st (n=15), ≥2 <superscript>nd</superscript> relapse (n=8). Dose level 3 (30 mg/m <superscript>2</superscript> clofarabine; 60 mg/m <superscript>2</superscript> 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/m <superscript>2</superscript> clofarabine with 60 mg/m <superscript>2</superscript> 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.<br /> (Copyright© 2018 Ferrata Storti Foundation.)
- Subjects :
- Adolescent
Antineoplastic Combined Chemotherapy Protocols adverse effects
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 mortality
Liposomes
Male
Recurrence
Remission Induction
Retreatment
Survival Analysis
Treatment Outcome
Young Adult
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Leukemia, Myeloid, Acute drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1592-8721
- Volume :
- 103
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- 29773602
- Full Text :
- https://doi.org/10.3324/haematol.2017.187153