肿瘤细胞治疗研究
英文原题：Framework for Optimizing, Refining, and Unifying Management of HSCT in Pediatric ALL
这是一项 II/III 期注册临床试验，评估 T 细胞治疗急性淋巴细胞白血病、移植物抗宿主病的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 1000 例。试验地点：欧洲 · 维也纳、布拉格、哥本哈根、赫尔辛基（共 9 个中心）。登记号：NCT07297914。
不限性别 · ≥ 3 Months 且 ≤ 25 Years
适用于所有子研究的纳入标准： • 按国家一线治疗方案判定有ALL异基因移植指征的男性或女性患者。HSCT时年龄≥3个月且≤25岁。移植前须完全缓解（原始细胞<5%，且髓外部位无白血病细胞）。 • 供者为相合供者（包括9/10相合亲属供者、10/10或9/10 HLA相合无关供者）或不相合亲属供者（HLA相合≤8/10）。可使用骨髓或外周血干细胞；脐带血需至少6/8 HLA相合，且冷冻保存有核细胞数≥3×10⁷/kg受者体重。 • 有生育能力女性筛选时妊娠试验阴性；所有患者同意研究期间采取有效避孕。患者及/或父母、监护人提供书面知情同意和/或儿童同意。 适用于所有子研究的排除标准： • HSCT时年龄<3个月或>25岁；入组时未达到形态学完全缓解；初诊为非霍奇金淋巴瘤；ALL为继发恶性肿瘤。既往自体或异基因HSCT史排除；但接受移植后干预的R2/P1子研究受试者，若本次为首次异基因移植，则允许既往异基因移植。 • 妊娠或哺乳；有生育能力者不同意禁欲或在有性生活时避孕。 • 活动性、临床未控制的细菌、真菌、寄生虫或病毒感染。已开始适当治疗且筛选时无体格或影像学进展证据者视为已控制。需要治疗的活动性HBV/HCV感染或有HBV再激活风险（如HBsAg阳性）。HBsAg阴性但总HBc抗体阳性者，如筛选时HBV DNA不可检出，可入组；HCV抗体阳性者须PCR检测HCV RNA阴性。免疫状态未知/不确定者须入组前确认，既往血清学结果可用于判定。已知HIV感染。 • 严重呼吸系统疾病，包括机械通气或室内空气静息血氧<90%。治疗前72小时内确认严重肾功能损害：按更新的床旁Schwartz或Cockcroft-Gault公式估算GFR<30 mL/min/1.73m²，或需要肾透析。 • 临床显著或未控制心脏病，包括未控制高血压、NYHA III/IV级心衰或临床显著心律失常。严重肝功能不全：Child-Pugh C级；AST/ALT>ULN的5倍（GVHD所致除外）；总胆红素>3.0 mg/dL（GVHD所致除外）；INR≥1.7；或有肝性脑病/腹水临床证据。 • 研究者判断严重合并疾病导致无法按方案治疗（如严重合并症的唐氏综合征、重大心脏畸形、影响治疗可行性的代谢疾病）；会妨碍参与、显著增加风险或影响数据解释的躯体/精神疾病。Karnofsky或Lansky评分<50；不愿或不能遵守程序、随访和治疗安排。
Inclusion criteria applicable to all substudies * Male and female patients with allogenic transplant indication for ALL, as determined by national frontline protocols * Age ≥3 months to ≤25 years at the time of HSCT. * Patients must be in complete remission (with \<5% blasts and absence of leukemia cells in extramedullary sites) prior to undergoing HSCT. * Selected donor must be either a matched donor (matched donor category includes 9/10 identical siblings and 10/10 or 9/10 HLA-matched unrelated donors) or a mismatched family donor (≤8/10 HLA match). Either bone marrow or peripheral blood stem cell grafts are permitted. Cord blood is permitted, as well, provided that the unit is at least 6/8 HLA matched and with a cryopreserved cellularity of at least 3x107 nucleated cells/Kg recipient body weight. * Female patients of childbearing potential must have a negative pregnancy test at screening, and all patients must agree to adhere to effective contraception during the study period. * Written study informed consent and/or assent from the patient and/or the parent, or guardian Exclusion criteria applicable to all substudies * Patients \< 3 months and \> 25 years of age at the time of HSCT. * Patients not in complete morphological remission at the time of enrollment. * Patients with an initial diagnosis of Non-Hodgkin Lymphoma (NHL). * Patients with ALL as a secondary malignancy. * Patients with a history of previous autologous or allogeneic HSCT (prior allogeneic transplantation is permitted for subjects receiving post-transplant interventions, such as those enrolled in the R2 and P1 substudies, provided that this is their first allogeneic HSCT). * Female patients who are pregnant or breast feeding. * Fertile male or female patients of childbearing potential who do not agree to abstinence or, if sexually active, do not agree to the use of contraception. * Active clinically uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no physical or radiographic signs of infection progression are present. * Active HBV or HCV infection that requires treatment, or at risk for HBV reactivation (e.g. positive HBsAg). Subjects with negative HbsAg and positive total HB core antibody may be included if HBV DNA is undetectable at the time of screening. Subjects who are positive for HCV antibody are eligible only if polymerase chain reaction test is negative for HCV RNA. Subjects whose immune status is unknown or uncertain must have results confirming immune status before enrollment. Prior serology results are acceptable for determining eligibility. * Known human immunodeficiency virus infection (HIV). * Significant respiratory disease including patients who are on mechanical ventilation or who have resting O2 saturation \<90% by pulse-oximetry on room-air. * Presence of severely impaired renal function (confirmed within 72 hours prior to study treatment start) defined by: * Glomerular Filtration Rate (GFR) \< 30 mL/min/1.73 m2 using estimated creatinine clearance calculated by updated bedside Schwartz equation or Cockcroft Gault equation OR * Renal dialysis requirement * Clinically significant or uncontrolled cardiac disease including any of the following: * Uncontrolled hypertension * New York Heart Association Class III or IV congestive heart failure * Clinically significant cardiac arrhythmias * Severe hepatic insufficiency, defined by any of the following: * Child-Pugh Class C liver disease * AST (aspartate aminotransferase) or ALT (alanine aminotransferase) levels \> 5 times the upper limit of normal (ULN), unless attributable to GvHD * Total bilirubin \> 3.0 mg/dL, unless attributable to GvHD * INR (International Normalized Ratio) ≥ 1.7 * Clinical evidence of hepatic encephalopathy or ascites * Presence of severe concomitant constitutional disease that precludes treatment as per protocol, based on the investigator's judgment. Examples include but are not limited to: Down syndrome with severe comorbidities, significant cardiac malformations, and metabolic disorders affecting treatment feasibility. * Underlying or current medical or psychiatric condition that, in the opinion of the Investigator, would interfere participation in the study, pose a significant risk to the patient or interfere with interpretation of study data. * Karnofsky or Lansky performance score \<50%, indicating significant functional impairment. * Patients who are unwilling or unable to comply with study procedures, including follow-up requirements and treatment schedules.
以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Event Free Survival (EFS) · EFS is defined as the time from randomization (intention-to-treat analysis) or HSCT (per-protocol/as treated) to first failure event defined as follows: Failure events are: * Relapse * Graft failure * Death from any cause * Diagnosis of a second malignant neoplasm · at year 4；Overall response rate (ORR) at day 28 · Overall response rate (ORR) at day 28 after randomization, defined as the proportion of patients in each arm demonstrating a complete response (CR) or partial response (PR) without requirement for additional systemic therapies for earlier progression, mixed response or nonresponse. · day 28；Event Free Survival (EFS) · EFS is defined as the time from HSCT to first failure event defined as follows: Failure events are: * Relapse * Graft failure * Death from any cause * Diagnosis of a second malignant neoplasm · at year 4；Cumulative incidence of relapse (CIR) at 2 years after HSCT · CIR at 2 years after HSCT in blinatumomab-treated patents and historical controls. CIR is calculated from the time of study enrolment until the date of relapse (defined as either bone marrow aspirate or biopsy with ≥ 5% blasts or as appearance of leukemia cells in an extramedullary site) or last follow-up (death from any cause other than leukemia relapse and secondary malignancies will be considered a competing event) · 2 years after HSCT
Ⅲ期随机多中心研究，比较ALL儿童及青年异基因HSCT预处理使用8 Gy或12 Gy全身照射（TBI）。
Ⅲ期随机开放标签多中心研究，比较异基因HSCT后治疗初治II–IV级急性GVHD的ALL患儿使用芦可替尼联合糖皮质激素与单用糖皮质激素。
前瞻性分层队列研究，比较儿童/青年ALL不相合供者移植中体内PT-Cy与体外αβ T细胞去除。
Ⅱ期开放标签多中心研究：未将TBI纳入预处理、年龄<2岁的B系ALL儿童，在异基因HSCT后接受blinatumomab。
高危或复发ALL患者通常需要强化治疗，包括异基因造血干细胞移植（HSCT）。HSCT有治愈潜力，但伴随非复发死亡、显著发病率及长期并发症。FORUM协作组旨在改善接受HSCT儿童患者的结局、减少危及生命及终身并发症并提高生活质量。基于FORUM1证据，FORUM2在统一、国际协调的框架下进一步优化不同年龄和供者条件下ALL的HSCT。主方案包括多个假设驱动的子研究，分别评估影响移植结局的因素，统一治理、终点定义和数据质量标准；总体目标是在保留移植物抗白血病作用的同时降低治疗毒性。
Current therapeutic strategies for high-risk or relapsed ALL patients often involve intensive treatments, including allogeneic hematopoietic stem cell transplantation (HSCT). HSCT remains a cornerstone of therapy, offering curative potential; however, it is associated with considerable risks, including non-relapse mortality (NRM), significant morbidity, and long-term complications that continue to be major concerns. In response to these challenges, the FORUM consortium has made substantial progress in improving outcomes for children with ALL undergoing HSCT. The consortium focuses on reducing life-threatening and lifelong complications, ultimately aiming to enhance quality of life for these high-risk patients. Building on the robust evidence generated by FORUM1, the FORUM2 study has been designed to further optimize the role of HSCT in ALL across all age groups and donor settings within a harmonized and internationally coordinated framework. The FORUM2 study introduces a master protocol structure that encompasses multiple hypothesis-driven substudies, each addressing a specific determinant of HSCT outcomes. This design enables simultaneous or sequential evaluation of novel strategies while ensuring uniform governance, endpoint definitions, and data-quality standards. The overarching objective is to refine the role of HSCT in ALL by reducing treatment-related toxicity while preserving the essential graft-versus-leukemia effect.
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