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

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.