Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma (study T2008-002 NECTAR)

James A. Whitlock, Jemily Malvar, Luciano Dalla-Pozza, John M. Goldberg, Lewis B. Silverman, David S. Ziegler, Andishe Attarbaschi, Patrick A. Brown, Rebecca A. Gardner, Paul S. Gaynon, Raymond Hutchinson, Van T. Huynh, Sima Jeha, Leigh Marcus, Yoav Messinger, Kirk R. Schultz, Jeannette Cassar, Franco Locatelli, C. Michel Zwaan, Brent L. WoodRichard Sposto, Lia Gore*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)

Abstract

Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have a dismal prognosis, largely due to difficulty attaining second remission. We hypothesized that adding etoposide and cyclophosphamide to the nucleoside analog nelarabine could improve response rates over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trial's primary objective was to evaluate the dose and safety of nelarabine given in combination with etoposide at 100 mg/m(2)/day and cyclophosphamide at 330-400 mg/m(2)/day, each for 5 consecutive days in children with either T-ALL (13 patients) or T-LBL (10 patients). Twenty-three patients were treated at three dose levels; 21 were evaluable for dose-limiting toxicities (DLT) and response. The recommended phase II doses (RP2D) for this regimen, when given daily x5 every 3 weeks, were nelarabine 650 mg/m(2)/day, etoposide 100 mg/m(2)/day, and cyclophosphamide 400 mg/m(2)/day. DLTs included peripheral motor and sensory neuropathies. An expansion cohort to evaluate responses at the RP2D was terminated early due to slow accrual. The overall best response rate was 38% (8/21), with 33% (4/12) responses in the T-ALL cohort and 44% (4/9) responses in the T-LBL cohort. These response rates are comparable to those seen with single-agent nelarabine in this setting. These data suggest that the addition of cyclophosphamide and etoposide to nelarabine does not increase the incidence of neurologic toxicities or the response rate beyond that obtained with single-agent nelarabine in children with first relapse of T-ALL and T-LBL.

Original languageEnglish
Article numbere29901
Number of pages9
JournalPediatric Blood & Cancer
Volume69
Issue number11
Early online date21 Aug 2022
DOIs
Publication statusPublished - Nov 2022

Bibliographical note

Funding Information:
The authors would like to acknowledge the TACL consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. This trial was supported by partial funding from the Higgins Family Foundation, and the Women's Auxiliary Millennium Chair in Haematology/Oncology at The Hospital for Sick Children (JW), and Alex's Lemonade Stand Foundation (LG). We thank Dr. Sally Stabler at the University of Colorado School of Medicine for her support of the vitamin B pathway analyses and helpful discussions of those results. We also thank Ingrid Argiropoulos for assistance in manuscript preparation, the staff of the TACL Operations office, and Elena Eckroth for assistance in study development and conduct, and the many patients, families, and healthcare providers who participated in this study.

Funding Information:
The authors would like to acknowledge the TACL consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. This trial was supported by partial funding from the Higgins Family Foundation, and the Women's Auxiliary Millennium Chair in Haematology/Oncology at The Hospital for Sick Children (JW), and Alex's Lemonade Stand Foundation (LG). We thank Dr. Sally Stabler at the University of Colorado School of Medicine for her support of the vitamin B pathway analyses and helpful discussions of those results. We also thank Ingrid Argiropoulos for assistance in manuscript preparation, the staff of the TACL Operations office, and Elena Eckroth for assistance in study development and conduct, and the many patients, families, and healthcare providers who participated in this study.

Publisher Copyright:
© 2022 Wiley Periodicals LLC.

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