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

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.

• Total Body Irradiation 8 Gy (Radiation): Total Body Irradiation 8 Gy administered in combination with VP16 as part of the conditioning regimen
• Ruxolitinib (Combination product): Ruxolitinib plus corticosteroids in treatment-naïve acute graft-versus-host disease
• Blinatumomab (Drug): Up to four cycles of blinatumomab as post-HSCT maintenance therapy
• Cyclophosphamide (Drug): In vivo T-cells depletion/modulation with post-transplant cyclophosphamide
• Total Body Irradiation 12 Gy (Radiation): Total Body Irradiation 12 Gy administered in combination with VP16 as part of the conditioning regimen
• Corticosteroids (Drug): Corticosteroids alone in treatment-naïve acute graft-versus-host disease
• αβ T-cells depletion (Other): Ex vivo graft manipulation based on selective depletion of T-cell receptor αβ (TCR αβ+)/CD19+ lymphocytes from the graft (αβ T-cells depletion)

Primary outcomes

• Event Free Survival (EFS) [at year 4]: 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
• Overall response rate (ORR) at day 28 [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.
• Event Free Survival (EFS) [at year 4]: 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
• Cumulative incidence of relapse (CIR) at 2 years after HSCT [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)

Sex: All, ages: 3 Months to 25 Years

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.

• Oostenbrink LVE, Von Asmuth EGJ, Jol-van der Zijde CM, Jansen-Hoogendijk AM, Vervat C, Bredius RGM, Van Tol MJD, Schilham MW, Sedlacek P, Ifversen M, Balduzzi A, Bader P, Peters C, Moes DJAR, Lankester AC. Anti-T-lymphocyte globulin exposure is associated with acute graft-versus-host disease and relapse in pediatric acute lymphoblastic leukemia patients undergoing hematopoietic stem cell transplantation: a multinational prospective study. Haematologica. 2024 Sep 1;109(9):2854-2863. doi: 10.3324/haematol.2023.284632. PMID 38721739
• Peters C, Dalle JH, Locatelli F, Poetschger U, Sedlacek P, Buechner J, Shaw PJ, Staciuk R, Ifversen M, Pichler H, Vettenranta K, Svec P, Aleinikova O, Stein J, Gungor T, Toporski J, Truong TH, Diaz-de-Heredia C, Bierings M, Ariffin H, Essa M, Burkhardt B, Schultz K, Meisel R, Lankester A, Ansari M, Schrappe M; IBFM Study Group;; von Stackelberg A; IntReALL Study Group; Balduzzi A; I-BFM SCT Study Group; Corbacioglu S; EBMT Paediatric Diseases Working Party; Bader P. Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study. J Clin Oncol. 2021 Feb 1;39(4):295-307. doi: 10.1200/JCO.20.02529. Epub 2020 Dec 17. PMID 33332189
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• Kalwak K, Moser LM, Potschger U, Bader P, Kleinschmidt K, Meisel R, Dalle JH, Yesilipek A, Balduzzi A, Krivan G, Goussetis E, Staciuk R, Sedlacek P, Pichler H, Svec P, Gabriel M, Gungor T, Bilic E, Buechner J, Renard M, Vettenranta K, Ifversen M, Diaz-de-Heredia C, Stein J, Toporski J, Bierings M, Peters C, Ansari M, Locatelli F. Comparable outcomes after busulfan- or treosulfan-based conditioning for allo-HSCT in children with ALL: results of FORUM. Blood Adv. 2025 Feb 25;9(4):741-751. doi: 10.1182/bloodadvances.2024014548. PMID 39602342

• Franco Locatelli, Professor, Principal investigator, IRCSS Ospedale Pediatrico Bambino Gesù

NIH grants: 2025