FLEND (nelarabine, fludarabine, and etoposide) for relapsed T-cell acute lymphoblastic leukemia in children: a report fr

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FLEND (nelarabine, fludarabine, and etoposide) for relapsed T‑cell acute lymphoblastic leukemia in children: a report from Japan Children’s Cancer Group Tadashi Kumamoto1 · Hiroaki Goto2 · Chitose Ogawa1 · Toshinori Hori3 · Takao Deguchi4 · Takuya Araki5 · Akiko M. Saito6 · Atsushi Manabe7 · Keizo Horibe6 · Hidemi Toyoda8 Received: 18 May 2020 / Revised: 6 July 2020 / Accepted: 28 July 2020 © Japanese Society of Hematology 2020

Abstract Nelarabine is a key drug for T-cell acute lymphoblastic leukemia (T-ALL). Fludarabine and etoposide might have synergistic effect with nelarabine by inhibiting ribonucleotide reductase and by preparing cell cycle for G1/S phase, respectively. We had started phase 1/2 multicenter clinical trial of combination chemotherapy consisted of nelarabine, fludarabine, and etoposide (FLEND therapy) for children with relapsed/refractory T-ALL which has been conducted since October 2011. Although we could not complete this trial because of recruitment difficulties, we treated five children with first-relapsed T-ALL which were enrolled in the phase 1 dose escalation study of fludarabine and etoposide with nelarabine. No dose-limiting toxicity occurred, and frequent grade 3–4 toxicity was hematological toxicity and febrile neutropenia, as expected. There was no neurotoxicity. All 2 patients who received the target dose of FLEND, in which nelarabine (650 mg/m2), fludarabine (30 mg/ m2), and etoposide (100 mg/m2) were administered for 5 consecutive days, were induced to complete remission. We concluded that FLEND might be safe and one of the promising combination chemotherapies to relapsed/refractory T-ALL. Keywords  FLEND · T-ALL · Nelarabine · Fludarabine · Etoposide

Introduction * Tadashi Kumamoto [email protected] 1



Department of Pediatric Oncology, National Cancer Center Hospital, 5‑1‑1 Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan

2



Department of Hematology and Oncology, Children’s Cancer Center, Kanagawa Children’s Medical Center, Yokohama, Japan

3

Department of Pediatrics, Aich Medical University Hospital, Nagoya, Japan

4

Division of Cancer Immunodiagnostics, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan

5

Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

6

Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

7

Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan

8

Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan







Nelarabine is an effective anti-leukemic agent for T-cell acute lymphoblastic leukemia (T-ALL) [1, 2]. Recently, nelarabine has been used for high-risk T-ALL as one of the agents during the frontline chemotherapy [3, 4], and has been used in combination with other anti-leukemic agents, such as etoposide and cyclophosphamide [5], methotrexate [3], or hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and de