Hochberg Jessica, Oesterheld Javier, Gardenswartz Aliza, Flower Allyson, Klejmont Liana, Basso Jackie, Shi Qiuhu, Harrison Lauren, Borowitz Michael J, Loken Michael R, Cairo Mitchell S
Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
Department of Pediatrics, Levine Children's Hospital, Charlotte, NC, USA.
EClinicalMedicine. 2025 Apr 28;83:103211. doi: 10.1016/j.eclinm.2025.103211. eCollection 2025 May.
Children with relapsed/refractory acute leukaemias have lower response rates to reinduction and decreased overall survival. Mitoxantrone and clofarabine both have proven efficacy in acute leukaemia. We present our final results utilising this novel reinduction platform as a bridge to haematopoietic stem cell transplantation (HSCT) in children with high-risk pediatric leukaemias.
From 2013 to 2021, patients 0-30.99 yr old with acute lymphoblastic leukaemia (ALL) or acute myelogenous leukaemia (AML) with relapse/refractory disease were given 1 to 3 cycles of clofarabine (escalating doses 20, 30, 35 and 40 mg/m/day to establish the maximal tolerated dose [MTD]) days 1-5, in combination with mitoxantrone 12 mg/m/day on days 3-6. The primary objective was to determine the maximal tolerated dose (MTD) or maximal acceptable dose of clofarabine in combination with mitoxantrone 12 mg/m/day. The key secondary objective was to determine the overall response rate of the combination of mitoxantrone and clofarabine. The protocol was registered with clinicaltrials.gov (NCT01842672).
Forty patients enrolled (18 phase I, 22 phase II) with median age 13 yrs (8 months-23 yrs). Demographics: 22 ALL (10 = induction failure [IF]/minimal residual disease [MRD], 9 = Relapse 1, 3 = Relapse 2), 17 AML (9 = IF/MRD, 6 = Relapse 1, 2 = Relapse 2). During phase I, there were 2 dose-limiting toxicities (DLTs) at dose level 4 requiring de-escalation to dose level 3. The phase I MTD was established at 35 mg/m/dose clofarabine and continued in phase II. One patient with Burkitt Lymphoma was not included in this efficacy analysis. Thirty-three of 39 (85%) leukaemia patients achieved a complete response (CR). Of these, 88% achieved MRD negativity. Thirty-two of 33 patients went on to allogeneic HSCT. The event free survival/overall survival (EFS/OS) at 1 year was 74% for the entire cohort and 85% for responding/bridging patients at a median follow-up time of >75 months (range 30-120).
The MTD of clofarabine in combination with mitoxantrone reinduction therapy was 35 mg/m/dose x 5 days and was safe, well-tolerated and resulted in an 85% CR rate with 88% MRD negativity and, following HSCT, a 1 yr EFS/OS of 85%.
Pediatric Cancer Research Foundation, Pediatric Cancer Foundation, Children's Cancer Fund, St. Baldrick's Foundation, Carolinas Healthcare, and NCCF subcontract #16252.
复发/难治性急性白血病患儿再诱导缓解率较低，总生存率降低。米托蒽醌和氯法拉滨在急性白血病治疗中均已证实具有疗效。我们展示了利用这种新型再诱导方案作为高危儿童白血病患儿造血干细胞移植（HSCT）桥梁的最终结果。
2013年至2021年，年龄在0至30.99岁之间、患有复发/难治性疾病的急性淋巴细胞白血病（ALL）或急性髓细胞白血病（AML）患者，在第1至5天接受1至3个周期的氯法拉滨治疗（剂量递增为20、30、35和40mg/m²/天以确定最大耐受剂量[MTD]），并在第3至6天联合使用米托蒽醌12mg/m²/天。主要目标是确定氯法拉滨与12mg/m²/天米托蒽醌联合使用时的最大耐受剂量（MTD）或最大可接受剂量。关键次要目标是确定米托蒽醌与氯法拉滨联合治疗的总缓解率。该方案已在clinicaltrials.gov（NCT01842672）注册。
40名患者入组（18名I期，22名II期），中位年龄13岁（8个月至23岁）。人口统计学特征：22例ALL（10例诱导失败[IF]/微小残留病[MRD]，9例首次复发，3例第二次复发），17例AML（9例IF/MRD，6例首次复发，2例第二次复发）。在I期，剂量水平4出现2例剂量限制性毒性（DLT），需要降至剂量水平3。I期MTD确定为氯法拉滨35mg/m²/剂量，II期继续使用。1例伯基特淋巴瘤患者未纳入本疗效分析。39例白血病患者中有33例（85%）达到完全缓解（CR）。其中，88%达到MRD阴性。33例患者中有32例继续接受异基因HSCT。整个队列1年无事件生存率/总生存率（EFS/OS）为74%，缓解/过渡患者为85%，中位随访时间>75个月（范围30 - 120个月）。
氯法拉滨与米托蒽醌再诱导治疗的MTD为35mg/m²/剂量×5天，安全、耐受性良好，CR率达85%，MRD阴性率达88%，HSCT后1年EFS/OS为85%。
儿童癌症研究基金会、儿童癌症基金会、儿童癌症基金、圣巴德里克基金会、卡罗莱纳医疗保健公司以及NCCF分包合同#16252。
