Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia

Overview

The ALL SCTped 2012 FORUM is a multinational, multi-centre, controlled, prospective phase III study for the therapy and therapy optimisation for children and adolescents with ALL in complete morphological remission (CR, less than 5% bone marrow blasts, no blasts in cerebrospinal fluid, no other extramedullary leukemia), who have an indication for HSCT with a myeloablative conditioning regimen. The stratification of patients in first and following remissions according to the individual transplantation modalities rests upon an indication for allogeneic HSCT and the availability of a suitable donor within the individual transplantation groups.

Detailed description

Acute and late side effects of TBI in combination with other chemotherapeutic are manifold to the growing organism and include severe organ dysfunction/failure due to toxicity. Although transplant associated mortality was reduced after HSCT in the last decade due to better HLA matching, infection prevention and control, the burden of late complications is still a matter of concern. Growth retardation, hormonal dysfunction, sterility and the risk of secondary cancer are the late consequences of TBI in children. However, so far no prospective study has demonstrated similar outcomes in paediatric ALL using chemo-conditioning regimen before HSCT. The reason for that is manifold: only a minority of children with ALL qualifies for allogeneic HSCT as most patients are cured with sole modern chemotherapy approaches. Those with dismal prognosis are treated in HSCT centres offering a care to patients with different diseases. Therefore it is nearly impossible to answer the complex outcome questions in single centres or even in single countries. International cooperation is essential to allow prospective investigation within comparable patient cohorts.

The trial was initiated to investigate whether chemotherapy based conditioning could replace TBI in pediatric patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). It was registered and approved as a prospective, randomized, controlled, open-label, international, multicenter, phase III, non-inferiority trial. Pediatric patients with acute lymphoblastic leukemia (ALL) aged ≤18 years at diagnosis and 4-21 years at HSCT in complete remission pre-HSCT, and with an HLA-compatible related (MSD) or unrelated donor (MD) were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo). The decision to use the irradiation-free conditioning or Flu/Thio/Treo or Flu/Thio/ivBu was country specific. Patients aged \< 4 years received irradiation-free conditioning. Patients with a mismatched donor (MMD) were stratified according to the donor's stem cell source (cordblood, haploidentical tx or bone marrow/peripheral blood stem cells).

The stopping rule was applied on March 31, 2019 following a suspension of random assignment in December 2018 after the chemoconditioning was proven to be significantly inferior to TBI. As a result, TBI/VP16 conditioning remains the standard for patients older than 4 years with MSD/MD, but the age limit for TBI/VP16-based conditioning may be optionally lowered to 2 years.The use of Flu/Thio/Treo or Flu/Thio/ivBu conditioning in this age group is made at centre level based on individual patient assessment. Alternatively, patients aged 0-2 years may receive Bu/VP16/Cy at the discretion of the treating physician.

The MSD/MD randomised patients remain in a follow-up to explore the impact of risk factors on the incidence of Adverse Events of Special Interest (AESIs) and on overall survival and event free survival in the entire MSD/MD cohort.

In MMD patients, event free survival (EFS) after HSCT from HLA mismatched donors using mismatched unrelated donors (MMD), mismatched cord blood or HLA haplo-identical family members is observed

Interventions

• Drug VP16
  60 mg/kg BW,1 day in TBI/VP16 conditioning; 40 mg/kg BW in Bu/VP16/Cy conditioning
• Radiation TBI
  2 x 2Gy/day , 3 days (total 12Gy)
• Drug Thiotepa
  2x5 mg/kg BW, 1 day
• Drug Treosulfan
  14g/m² BS, 3 days
• Drug Fludarabine
  30 mg/m² BS, 5 days
• Drug Busulfan
  iV, dosage according therapeutic drug monitoring, 4 days
• Drug ATG Thymoglobulin
  MD: ATG Thymo: 2,5mg/kg BW/d 3 days.
• Drug Cyclophosphamide
  as part of conditioning 60 mg/kg BW 2 days or as GvHD Prophylaxis 50mg/kg BW/d 2 days with Mesna
• Drug Grafalon
  MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days

Primary outcome measures

• Overall Survival (OS) Stratum 1a (randomisation TBI+ chemo-conditioning vs. chemo-conditioning only) [Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years]
• Event free survival (EFS) Stratum 2 (mismatched donor transplantation) [Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years]
• Overall Survival (OS), Stratum 1b: MSD/MD without randomisation [Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years]

Secondary outcome measures (5)

• EFS (Stratum 1a and 1b) [Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years]
• TRM [Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years]
• Relapse/progression [Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years]
• Acute and late toxicity for Stratum 1a, 1b and 2 [Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years]
• OS (Stratum 2) [Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years]

Eligibility criteria

Inclusion criteria

Patients with ALL (except for patients with B-ALL) who fulfil the following criteria:

• age at diagnosis ≤ 18 years. Age at HSCT ≤ 21 years
• indication for allogeneic HSCT
• complete remission (CR) before HSCT
• written consent of the parents (legal guardian) and, if necessary, the minor patient via "Informed Consent Form"
• no pregnancy
• no secondary malignancy
• no previous HSCT
• HSCT is performed in a study participating centre

Exclusion criteria

• patients who do not fulfil the inclusion criteria
• Non Hodgkin-Lymphoma
• the whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
• no consent is given for saving and propagation of anonymous medical data for study reasons
• severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion (e.g. malformation syndromes, cardiac malformations, metabolic disorders)
• Karnofsky / Lansky score < 50%
• subjects unwilling or unable to comply with the study procedures

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 24 centers

• Uniklinik RWTH Aachen, Kinder- und Jugendmedizin — Aachen
• Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum — Berlin
• Universitätsklinikum Bonn, Abteilung für Pädiatrische Hämatologie und Onkologie — Bonn
• Universitätsklinikum Düsseldorf, Klinik für Kinder-Onkologie, -Hämatologie und Klinische I — Düsseldorf
• Universitätsklinikum Erlangen, Kinder- und Jugendklinik — Erlangen
• Universitätsklinikum Essen, Klinik für Kinderheilkunde III — Essen
• Klinikum der Johann Wolfgang Goethe-Universität, Klinik für Kinder- und Jugendmedizin (KKJ — Frankfurt am Main
• Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin — Freiburg im Breisgau
• … and 16 more centers

France · 13 centers

• CHU Bordeaux — Bordeaux
• CHU Clermont-Ferrand — Clermont-Ferrand
• CHU Grenoble - Clinique Universitaire de Pédiatrie, Hôpital Couple Enfant — Grenoble
• CHRU Lille, Service d'Hématologie Pédiatrique — Lille
• IHOP / Lyon, Service Hématologie et d'Oncologie pédiatrique — Lyon
• Hopital la Timone Adulte — Marseille
• Hopital Arnaud de Villeneuve — Montpellier
• CHU Nancy - Hopital d'Enfants — Nancy
• … and 5 more centers

Turkey (Türkiye) · 12 centers

Center list to be confirmed — check the primary protocol.

Italy · 10 centers

• Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi di Bologna — Bologna
• Ospedale Mayer di Firenze SODc Tumori Pediatrici e TMO — Florence
• Istituto Gaslini Genova Oncoematologia Pediatrica- — Genoa
• A.O. San Gerardo di Monza Clinica Pediatrica — Monza
• A.O.R.N. Santobono Pausilipon, Dipartimento di Oncoematologia — Naples
• Azienda Ospedaliera di Padova Oncoematologia Pediatrica — Padova
• Fondazione IRCCS Policlinico San Matteo — Pavia
• Azienda Ospedaliero Universitaria Pisana U.O. di Oncoematologia Pediatrica A.O. — Pisa
• … and 2 more centers

Canada · 6 centers

• Alberta Children's Hospital Division of Pediatric Oncology — Calgary
• Montreal Children's Hospital — Montral
• CHU Sainte-Justine Hematology-Oncology Division — Montreal
• Hospital for Sick Children University of Toronto Division of Haematology/Oncology — Toronto
• BC Children's Hospital — Vancouver
• CancerCare Manitoba/University of Manitoba — Winnipeg

Australia · 5 centers

• Children's Cancer Centre The Royal Children's Hospital — Melbourne
• Princess Margaret Hospital for Children — Perth
• Sydney Children's Hospital — Randwick
• Lady Cilento Children's Hospital — South Brisbane
• The Children's Hospital at Westmead Oncology Unit — Sydney

Belgium · 5 centers

• Hôpital Universitaire des Enfants Reine Fabiola (HUDERF) — Brussels
• Cliniques Universitaires Saint-Luc (UCL) Hématologie et oncologie pédiatrique — Brussels
• University Hospital Gent Pediatrische hemato-oncologie — Ghent
• University Hospitals Leuven Kinderhemato-oncologie — Leuven
• Centre Hospitalier Universitaire de Liège Domaine Universitaire du Sart Tilman — Liège

Poland · 5 centers

Center list to be confirmed — check the primary protocol.

Spain · 5 centers

Center list to be confirmed — check the primary protocol.

Sweden · 4 centers

Center list to be confirmed — check the primary protocol.

Austria · 3 centers

• Universitätsklinik für Kinder- und Jugendheilkunde, Abt. f. Hämato-Onkologie — Graz
• Universitätsklinik für Kinder- und Jugendheilkunde — Innsbruck
• St. Anna Children's Hospital, Vienna, Austria — Vienna

Israel · 3 centers

• Rambam Medical Center — Haifa
• Schneider Children's Medical Center of Israel — Petah Tikva
• Dana Children's Hospital — Tel Aviv

Switzerland · 3 centers

Center list to be confirmed — check the primary protocol.

Argentina · 2 centers

• Hospital de Pediatria "Juan P. Garrahan" Combate de Los Pozos N°1800 CABA — Buenos Aires
• Hospital Sor Maria Ludovica, Department Hematology Stem Cell Transplant Unit — La Plata

Netherlands · 2 centers

Center list to be confirmed — check the primary protocol.

Romania · 2 centers

Center list to be confirmed — check the primary protocol.

Belarus · 1 center

• Belarusian Research Center for Pediatric Oncology, Hematology and Immunology — Minsk

Chile · 1 center

• Hospital Dr Luis Calvo Mackenna — Santiago

Croatia · 1 center

• Department of Pediatrics, UHC Zagreb — Zagreb

Czechia · 1 center

• Department of Pediatric Hematology and Oncology Teaching Hospital Motol, 2nd Medical Schoo — Prague

Denmark · 1 center

• Paediatric Stem Cell Transplant and Immune Deficiency, Dept. for children and adolescents — Copenhagen

Finland · 1 center

• Division of Hematology-Oncology and Stem Cell Transplantation, Hospital for Children and A — Helsinki

Greece · 1 center

• Saint Sophia Children's Hospital BMT Unit — Athens

Hungary · 1 center

• National Institute of Haematology and Infectious Disease, Hospital of Southern Pest, Paedi — Budapest

Malaysia · 1 center

• University of Malaya, Department of Paediatrics — Kuala Lumpur

Mexico · 1 center

Center list to be confirmed — check the primary protocol.

New Zealand · 1 center

Center list to be confirmed — check the primary protocol.

Norway · 1 center

Center list to be confirmed — check the primary protocol.

Saudi Arabia · 1 center

Center list to be confirmed — check the primary protocol.

Slovakia · 1 center

Center list to be confirmed — check the primary protocol.

Slovenia · 1 center

Center list to be confirmed — check the primary protocol.

Publications

• Ben Hassine K, Gloor Y, Dupanloup I, Uppugunduri CRS, Mlakar V, Gonzales F, Gungor T, Ifversen M, Shaw PJ, Buechner J, Truong TH, Bittencourt H, Teague L, Toporski J, Sedlacek P, Poetschger U, Krajinovic M, Kalwak K, Balduzzi A, Algeri M, Bader P, Peters C, Dalle JH, Ansari M. Refining busulfan exposure enhances pediatric ALL HSCT outcomes: insights from the International FORUM study. Blood Adv. 2 PMID 41779961
• Buechner J, Poetschger U, Bader P, Yesilipek A, Pichler H, Palma J, Staciuk R, Riha P, Krivan G, Ifversen M, Gungor T, Goussetis E, Kalwak K, Toporski J, Gabriel M, Renard M, Diaz-de-Heredia C, Matic T, Calkoen FG, Svec P, Meisel R, Balduzzi A, Locatelli F, Peters C, Dalle JH, Stein J. Outcomes of BCP-ALL with hypodiploidy or BCR::ABL1 fusion in children undergoing allogeneic HSCT: results from th PMID 41259231
• Greco R, Ruggeri A, McLornan DP, Snowden JA, Alexander T, Angelucci E, Averbuch D, Bazarbachi A, Hazenberg MD, Kalwak K, Kenyon M, Mekelenkamp H, Neven B, Pedrazzoli P, Peric Z, Risitano AM, Sanchez-Ortega I, Ciceri F, Sureda A. Indications for haematopoietic cell transplantation and CAR-T for haematological diseases, solid tumours and immune disorders: 2025 EBMT practice recommendations. Bone Mar PMID 40926035
• 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 PMID 39602342
• 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. PMID 37738088
• Gomez SM, Varela MA, Ruiz C, Sung L. Comparable Outcomes of Matched Sibling Donor and Matched Unrelated Donor Stem Cell Transplantation in Children With Acute Leukemia in Argentina. J Pediatr Hematol Oncol. 2021 Oct 1;43(7):e1020-e1024. doi: 10.1097/MPH.0000000000002174. PMID 33974585
• 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 PMID 33332189
• Tasian SK, Peters C. Targeted therapy or transplantation for paediatric ABL-class Ph-like acute lymphocytic leukaemia? Lancet Haematol. 2020 Dec;7(12):e858-e859. doi: 10.1016/S2352-3026(20)30369-0. No abstract available. PMID 33242441

Identifiers

NCT: NCT01949129 · ALL SCTped FORUM 2012

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗