Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University, Palo Alto, CA.
Hematology Division, Department of Pediatrics, University of California San Francisco, San Francisco, CA.
Blood Adv. 2024 Dec 10;8(23):6055-6063. doi: 10.1182/bloodadvances.2024014078.
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507 leadership and the data safety monitoring board (DSMB) established incremental entry criteria for children aged 5 to 14.99 years with sickle cell disease (SCD) enrolling in a phase 2 trial of HLA-haploidentical hematopoietic stem cell transplantation. First, the enrollment was limited to overt stroke in the first 10 participants (stage 4). Subsequently, the DSMB reviewed the interim results and expanded the eligibility to include children with silent cerebral infarcts or abnormal transcranial Doppler velocities with magnetic resonance angiography-defined cerebral vasculopathy (stage 3). A third cohort was enrolled after the DSMB reviewed the clinical outcomes in these cumulative initial enrollments (n = 18) and additions were made to the entry criteria that included nonneurologic morbidities (stage 2). Added eligibility criteria included the following: (1) life-threatening acute chest syndrome requiring exchange transfusion; (2) right heart catheterization confirmed pulmonary hypertension; (3) persistent systemic hypertension despite maximum medical therapy; (4) acute pain despite maximum medical therapy in the absence of psychosocial factors and unmanaged asthma after adjudication; and (5) 2 major priapism episodes in 12 months or 3 in 24 months. Children with SCD who did not meet the criteria for stages 4, 3, and 2 were not eligible. To our knowledge, for the first time, we introduce a staged strategy for eligibility in a curative therapy trial for children with SCD concordant with 45 Code of Federal Regulations § 46.405(b). The research governance-mandated eligibility strategy used within the BMT CTN 1507 phase 2 study may apply to future pediatric SCD curative therapy trials. This trial was registered at www.ClinicalTrials.gov as #NCT032635590.
血液和骨髓移植临床试验网络（BMT CTN）1507 领导团队和数据安全监测委员会（DSMB）为年龄在 5 至 14.99 岁患有镰状细胞病（SCD）的儿童制定了增量入组标准，这些儿童参与 HLA 单倍体不相合造血干细胞移植的 2 期试验。首先，将入组人数限制在前 10 名参与者（第 4 阶段）中出现显性中风的患者。随后，DSMB 审查了中期结果，并扩大了入组标准，将有沉默性脑梗死或磁共振血管造影定义的脑血管病变伴经颅多普勒超声异常流速的儿童纳入其中（第 3 阶段）。在 DSMB 审查了这些累积初始入组（n=18）的临床结果后，第三个队列被招募，并且在入组标准中增加了包括非神经学合并症的内容（第 2 阶段）。增加的入组标准包括以下内容：（1）需要换血的危及生命的急性胸部综合征；（2）右心导管术证实的肺动脉高压；（3）尽管接受最大药物治疗，但持续存在系统性高血压；（4）在没有精神社会因素和未控制的哮喘的情况下，经过裁决后仍存在急性疼痛，且最大药物治疗无效；（5）12 个月内 2 次或 24 个月内 3 次大阴茎异常勃起。不符合第 4、3 和 2 阶段标准的 SCD 儿童不符合入组条件。据我们所知，这是首次在与 45 联邦法规§ 46.405(b)一致的 SCD 儿童根治性治疗试验中引入了分级入组策略。BMT CTN 1507 2 期研究中使用的研究治理授权入组策略可能适用于未来的儿科 SCD 根治性治疗试验。该试验在 www.ClinicalTrials.gov 上注册为 #NCT032635590。
