Framework for Optimizing, Refining, and Unifying Management of HSCT in Pediatric ALL

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.

The key focus areas and objectives include: * Optimization of conditioning regimens * Advancements in GvHD prevention and treatment * Integration of novel immunotherapies * Improvement of long-term survivorship * Harmonization of supportive care and post-transplant monitoring * Expansion of donor availability The FORUM2 study comprises two randomized comparisons (R1 and R2 substudies), one stratified cohort (S1 substudy), and one pilot cohort (P1 substudy). The protocol is structured as a master protocol, with the R1 substudy serving as the central component because it represents the continuation of the FORUM1 study (which compared TBI-based and chemotherapy-based conditioning) and is expected to enroll the majority of patients. Patients ineligible for the R1 substudy-due to age (\<2 years), donor type, physician discretion, or personal preference-will still be included in the master protocol and monitored accordingly. Patients transplanted from a mismatched family donor will be stratified within the S1 substudy. Additionally, patients younger than 2 years of age with B-ALL are eligible for the P1 pilot substudy, which will investigate the use of post-HSCT blinatumomab to reduce relapse incidence in this high-risk population. Primary and secondary endpoints, general assessment timelines, and supportive care guidelines will remain consistent for both R1 substudy participants and patients included in the broader master protocol. Additional assessments, endpoints, and interventions specific to other study groups are outlined in their respective protocol sections (or appendices) and will be conducted exclusively for patients enrolled in those specific cohorts.