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

NCT07297914 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: FORUM22025-522052-13-00
• Study Type: interventional
• Target: 1,000
• Locations: 9 countries
• Sites: 9

Brief Summary

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.

Conditions

Stem Cell Transplant; Graft -Versus-host-disease; Acute Lymphoblastic Leukemia (ALL)

Outcome Measures

Primary Outcomes (4)

• Event Free Survival (EFS)

  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

  at year 4

• Overall response rate (ORR) at 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.

  day 28

• Event Free Survival (EFS)

  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

  at year 4

• Cumulative incidence of relapse (CIR) at 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)

  2 years after HSCT

Study Arms (4)

R1 substudy

EXPERIMENTAL

A phase III, randomized, multi-center study comparing TBI 8 Gy versus TBI 12 Gy in children and young adults with ALL for conditioning of allogeneic HSCT

Radiation: Total Body Irradiation 8 Gy; Radiation: Total Body Irradiation 12 Gy

R2 substudy

EXPERIMENTAL

A phase III, randomized, open-label multi-center study comparing ruxolitinib plus corticosteroids versus corticosteroids alone in children with ALL and treatment-naïve grade II-IV aGvHD following allogeneic HSCT

Combination Product: Ruxolitinib; Drug: Corticosteroids

S1 substudy

EXPERIMENTAL

A prospective stratified cohort study comparing between in vivo PT-Cy and ex vivo αβ T-cell depletion in mismatched donor transplantation for pediatric and young adult ALL.

Drug: Cyclophosphamide; Other: αβ T-cells depletion

P1 substudy

ACTIVE COMPARATOR

A phase II, open-label, multi-center study of blinatumomab following allogeneic HSCT for B-lineage ALL in children younger than 2 years not receiving TBI as part of the conditioning regimen

Drug: Blinatumomab

Interventions

Ruxolitinib COMBINATION_PRODUCT

Ruxolitinib plus corticosteroids in treatment-naïve acute graft-versus-host disease

R2 substudy

Blinatumomab DRUG

Up to four cycles of blinatumomab as post-HSCT maintenance therapy

P1 substudy

Cyclophosphamide DRUG

In vivo T-cells depletion/modulation with post-transplant cyclophosphamide

S1 substudy

Total Body Irradiation 12 Gy RADIATION

Total Body Irradiation 12 Gy administered in combination with VP16 as part of the conditioning regimen

R1 substudy

Corticosteroids DRUG

Corticosteroids alone in treatment-naïve acute graft-versus-host disease

R2 substudy

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)

S1 substudy

Total Body Irradiation 8 Gy RADIATION

Total Body Irradiation 8 Gy administered in combination with VP16 as part of the conditioning regimen

R1 substudy

Eligibility Criteria

• Age: 3 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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:

Sponsors & Collaborators

• Bambino Gesù Hospital and Research Institute: lead

Study Sites (9)

St'Anna Children Hospital

Vienna, Austria

Location

University Hospital Motol

Prague, Czechia

Location

Rigshopsitalet, University Hospital

Copenhagen, Denmark

Location

HUS-Yhtymae (HUS Helsinki University Hospital)

Helsinki, Finland

Location

Robert- Debré Academic Hospital

Paris, France

Location

Goethe-Universität

Frankfurt, Germany

Location

IRCCS Ospedale Pediatrico Bambino Gesù

Roma, RM, 00165, Italy

Location

University Hospital

Oslo, Norway

Location

University of Medical Sciences

Poznan, Poland

Location

Related Publications (4)

• 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 BACKGROUND

• 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 BACKGROUND

• Bader P, Potschger U, Dalle JH, Moser LM, Balduzzi A, Ansari M, Buechner J, Gungor T, Ifversen M, Krivan G, Pichler H, Renard M, Staciuk R, Sedlacek P, Stein J, Heusel JR, Truong T, Wachowiak J, Yesilipek A, Locatelli F, Peters C. Low rate of nonrelapse mortality in under-4-year-olds with ALL given chemotherapeutic conditioning for HSCT: a phase 3 FORUM study. Blood Adv. 2024 Jan 23;8(2):416-428. doi: 10.1182/bloodadvances.2023010591.

  PMID: 37738088 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Graft vs Host Disease

Interventions

ruxolitinib; blinatumomab; Cyclophosphamide; Adrenal Cortex Hormones

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Franco Locatelli, Professor

  IRCSS Ospedale Pediatrico Bambino Gesù

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Franco Locatelli, Professor

CONTACT

+39 06 6859 3697; franco.locatelli@opbg.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The FORUM2 study has a flexible design which consists of: * Two randomized comparison groups (R1 SUBSTUDY and R2 SUBSTUDY), * One stratified cohort (S1 SUBSTUDY), * One pilot cohort (P1 SUBSTUDY).

Study Record Dates

• First Submitted: November 25, 2025
• First Posted: December 22, 2025
• Study Start: January 15, 2026
• Primary Completion (Estimated): November 30, 2032
• Study Completion (Estimated): December 1, 2032
• Last Updated: December 22, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

FI (1); NO (1); DE (1); IT (1); PL (1); CZ (1); DK (1); FR (1); AU (1)