Whitlock James A, Malvar Jemily, Dalla-Pozza Luciano, Goldberg John M, Silverman Lewis B, Ziegler David S, Attarbaschi Andishe, Brown Patrick A, Gardner Rebecca A, Gaynon Paul S, Hutchinson Raymond, Huynh Van T, Jeha Sima, Marcus Leigh, Messinger Yoav, Schultz Kirk R, Cassar Jeannette, Locatelli Franco, Zwaan C Michel, Wood Brent L, Sposto Richard, Gore Lia
Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Pediatr Blood Cancer. 2022 Nov;69(11):e29901. doi: 10.1002/pbc.29901. Epub 2022 Aug 21.
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 /day and cyclophosphamide at 330-400 mg/m /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 ×5 every 3 weeks, were nelarabine 650 mg/m /day, etoposide 100 mg/m /day, and cyclophosphamide 400 mg/m /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.
T细胞急性淋巴细胞白血病（T-ALL）或淋巴细胞淋巴瘤（T-LBL）复发的儿童预后不佳，这在很大程度上是由于难以实现第二次缓解。我们假设，在核苷类似物奈拉滨的基础上加用依托泊苷和环磷酰胺，相对于单药奈拉滨，可提高复发T-ALL和T-LBL的缓解率。这项I期剂量递增试验的主要目的是评估奈拉滨与依托泊苷（100mg/m²/天）和环磷酰胺（330 - 400mg/m²/天）联合使用的剂量和安全性，二者均连续5天给药，用于治疗T-ALL患儿（13例）或T-LBL患儿（10例）。23例患者在三个剂量水平接受治疗；21例可评估剂量限制性毒性（DLT）和缓解情况。该方案每3周每日×5给药时的推荐II期剂量（RP2D）为奈拉滨650mg/m²/天、依托泊苷100mg/m²/天和环磷酰胺400mg/m²/天。DLT包括周围运动和感觉神经病变。由于入组缓慢，评估RP2D缓解情况的扩大队列提前终止。总体最佳缓解率为38%（8/21），T-ALL队列的缓解率为33%（4/12），T-LBL队列的缓解率为44%（4/9）。这些缓解率与单药奈拉滨在此情况下的缓解率相当。这些数据表明，在奈拉滨基础上加用环磷酰胺和依托泊苷，对于首次复发的T-ALL和T-LBL患儿，并不会增加神经毒性的发生率，也不会提高缓解率超过单药奈拉滨。
