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

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• Exclusion Criteria applicable to all the patients • 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 study, 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 (ie, 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 hrs prior to study treatment start) defined by: o Glomerular Filtration Rate (GFR) < 30 mL/min/1.73 m2 using estimated creatinine clearance calculated by updated bedside Schwartz equation or Cockroft Gault equation • Or o Renal dialysis requirement • Clinically significant or uncontrolled cardiac disease including any of the following: o - Uncontrolled hypertension o - New York Heart Association Class III or IV congestive heart failure o - Clinically significant cardiac arrhythmias • Severe hepatic insufficiency, defined by any of the following: o Child-Pugh Class C liver disease o AST (aspartate aminotransferase) or ALT (alanine aminotransferase) levels > 5 times the upper limit of normal (ULN), unless attributable to GvHD o Total bilirubin > 3.0 mg/dL, unless attributable to GvHD o INR (International Normalized Ratio) ≥ 1.7 o 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, 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.
• R1 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason). • Patients <2 years or > 25 years of age at the time of informed consent. • Use of an unrelated cord blood unit or a mismatched family donor as the stem cell source • Patients who received CNS irradiation at a dose of 18 Gy within 12 months prior to HSCT, if the combined total dose from prior CNS irradiation and planned TBI conditioning will exceed 24 Gy. • Patient meets one or more of the exclusion criteria defined in the FORUM 2 platform trial
• R2 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason) • Patients <3 months of age or ≥ 18 years. • Patients transplanted from mismatched family donor (≤8/10 HLA match) or related/unrelated CB. • Patients having received any prior systemic treatment of aGvHD except for a maximum 72h of prior systemic corticosteroid therapy after the onset of acute GvHD. Patients are allowed to have received prior GvHD prophylaxis which is not counted as systemic treatment (as long as the prophylaxis was started prior to the diagnosis of aGvHD) • Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features • Failed prior allogeneic HSCT, including previous primary or secondary graft failure • Acute GvHD occurring after non-scheduled donor leukocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. • Presence of overt relapse of primary malignancy, requiring either additional treatment after allogeneic HSCT or rapid immune suppression tapering/withdrawal • Any corticosteroid therapy for indications other than GVHD at doses > 1 mg/kg per day methylprednisolone (or prednisone equivalent) within 7 days of randomization. • Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to aGvHD and ongoing organ dysfunction). • Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.
• S1 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason) • Patients <3 months or > 25 years of age at the time of informed consent. • Any type of GvHD prophylaxis other than in-vivo PTCy or ex vivo αβ T-Cell depletion
• P1 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason) • Patients ≥ 2 years of age at HSCT • Patients not in complete remission at the time of enrollment • Presence of transplant-associated thrombotic microangiopathy • Previous diagnosis of SOS/VOD not resolved since at least 3 weeks before study inclusion • Presence of idiopathic pneumonia syndrome • Ongoing immunosuppression for reasons other than standard GVHD prophylaxis • Patients who received TBI as part of their conditioning regimen or a chemotherapy-based conditioning regimen other than busulfan, thiotepa and fludarabine or treosulfan, thiotepa and fludarabine or busulfan and cyclophosphamide (±VP16). • Presence of active grade III-IV acute GVHD at the time of enrollment. • Presence of grade II acute GVHD with either gastrointestinal or liver involvement. • Clinically relevant active infections, including unresolved bacterial, fungal, or parasitic infections or active uncontrolled viral reactivations (e.g., CMV, EBV, or adenovirus). • ANC <0.5 × 109/L or self-sustained platelet count <30 x 109/L at time of study enrolment, • Creatinine clearance lower than 30 ml/min or serum bilirubin > 3 x ULN prior to start of treatment (unless related to Gilbert’s or Meulengracht disease). • Lansky performance status < 50. • Patients transplanted from related/unrelated CB.
• O1 Sub-Study Exclusion Criteria • Patients not enrolled in the FORUM 2 platform trial (independently of the reason) • Patients <3 months or > 26 years of age at the time of informed consent.