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.

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 \ 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 \ 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 \