Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias Journal Article

Authors: Abd Elmoneim, A.; Gore, L.; Ricklis, R. M.; Boklan, J.; Cooper, T.; Narendran, A.; Rolla, K.; Scott, T.; Arceci, R. J.
Article Title: Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias
Abstract: Background: By inhibiting DNA repair, clofarabine (CLO) may augment cyclophosphamide (CY)-induced DNA damage and apoptosis. We performed a Phase I study for refractory and/or relapsed (R/R) leukemia in children to determine maximum-tolerated dose (MTD) of time-sequential CLO followed by CY. Procedure: Thirteen patients with (R/R) ALL (n=8) and AML (N=5), median age 9 years (range: 2-12 years), were treated with escalating doses of CLO on days 1, 2, 3 and 8, 9, 10 and CY 200mg/m 2/day on days 0 and 1 then 400mg/m 2/day on days 2, 3, 8, 9, and 10. Ten patients were treated at dose level 1 (DL1) (CLO 20mg/m 2/day) and three patients at DL2 (CLO 30mg/m 2/day). The average number of prior chemotherapies was 8.9. DNA damage testing was performed before treatment on day 0, and 2hours after CY on day 0, before sequential CLO, CY treatment on day 1, and 2hours after CLO followed by CY on day 1. Results: Two patients at DL2 had dose-limiting toxicities (DLTs) that included hypotension with cardio-respiratory failure (1) and hepato-renal failure (1). Complete remission (CR) was achieved in 2/11 (18.2%) and partial remission (PR) in 2/11 (18.2%) for an overall response (OR) of 36.4%. The use of CLO before CY augmented CY-induced DNA damage in leukemic blasts compared to CY alone. Conclusion: In pediatric patients with R/R leukemia, 20mg/m 2/day is the MTD for CLO in timed sequential combination with CY. Increased DNA damage with the use of this combination suggests a mechanism for the sequential timing of these two chemotherapeutic agents. © 2012 Wiley Periodicals, Inc.
Keywords: adolescent; adult; cancer chemotherapy; child; clinical article; preschool child; school child; treatment response; child, preschool; leukemia; cancer surgery; young adult; leukemia, myeloid, acute; neutropenia; hypertension; side effect; treatment duration; cancer radiotherapy; anorexia; dna damage; anemia; thrombocytopenia; antineoplastic combined chemotherapy protocols; peripheral neuropathy; drug administration schedule; recurrence; creatinine; cyclophosphamide; bradycardia; creatinine blood level; kidney failure; acute lymphoblastic leukemia; alanine aminotransferase blood level; aspartate aminotransferase blood level; coughing; drug dose escalation; hypoxia; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; confusion; hypotension; cancer regression; albumin; dna; paracetamol; acute myeloblastic leukemia; nausea and vomiting; precursor cell lymphoblastic leukemia-lymphoma; pleura effusion; hyperbilirubinemia; cardiopulmonary insufficiency; maximum tolerated dose; phase 1 clinical trial; hydrocortisone; corticosteroid; leukemia relapse; clofarabine; tachycardia; acute disease; sinus tachycardia; restrictive cardiomyopathy; phase i; allopurinol; hepatorenal syndrome; myositis; relapsed/refractory; adenine nucleotides; arabinonucleosides; pediatric leukemias
Journal Title: Pediatric Blood and Cancer
Volume: 59
Issue: 7
ISSN: 1545-5009
Publisher: Wiley Periodicals, Inc  
Date Published: 2012-12-15
Start Page: 1252
End Page: 1258
Language: English
DOI: 10.1002/pbc.24264
PROVIDER: scopus
PUBMED: 22887831
Notes: --- - "Export Date: 2 November 2012" - "CODEN: PBCEA" - "Source: Scopus"
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MSK Authors
  1. Katherine L Rolla
    4 Rolla