A Phase 2/3 interventional study of VP16 and TBI in Acute Lymphoblastic Leukaemia, sponsored by St. Anna Kinderkrebsforschung. Recruiting at 119 sites in 31 countries. Open to participants aged 1 Month to 18 Years. Per ClinicalTrials.gov, last updated 2026-09-04.
Sponsored by St. Anna Kinderkrebsforschung · Phase 2/3, Interventional, and Treatment
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.
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 as a prospective, randomised, global study 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 (cord blood, haploidentical HSCT 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. If TBI/VP16 was not the conditioning regimen, participating centres/treating physicians could choose either Flu/Thio/iv BU or Flu/Thio/Treo based on individual patient assessment.
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.
During the trial, new questions arise, such as new chemotherapy options for no-irradiation conditioning, individualised drug dosing, influence of pharmacogenomics, immune reconstitution, influence of different levels of MRD negativity, donor factors such as MSD vs. MD, HSCT in patients younger than 4 years and in infants, differences in outcome in a non-randomised cohort, factors influencing the development of acute and chronic GvHD, and many other questions that could be analysed and investigated based on the data collected in the trial. In addition, relapse remains the major cause of treatment failure in infants and young children with high-risk ALL undergoing HSCT.
To address this, the protocol was amended (version 7.0/29 October 2022) to allow a choice of conditioning between TBI/VP16 and chemo-conditioning Flu/Thio/Treo or Flu/Thio/Bu and optionally Bu/VP16/Cy for patients aged 0-2 years.
In countries that have stopped enrolling patients prior to the approval of protocol version 7.0/29 October 2022, or in countries where V7.0 was not approved at the time of the transition to the Clinical Trials Regulation, the choice of conditioning between TBI/VP16 and chemo-conditioning according to international protocol version 6.0/9 September 2019 is as follows:
In EU/EEA countries that have transitioned to the Clinical Trials Regulation, a consolidated version of the protocol (v8.0, effective 1 July 2024) is in use, reflecting the common core provisions of versions 6 and 7 that have been approved in the respective Member States.
Countries that are not subject to the CTR use versions that have been approved in their respective countries.
Patients with ALL (except for patients with B-ALL) who fulfil the following criteria:
Exclusion Criteria:
Fludarabine/Thiotepa/Treosulfan is used as conditioning regimen for haematopoietic stem cell transplantation (HSCT) in patients with: * MSD (matched sibling donors) or MD (matched related or unrelated donors). In addition, patients undergoing MD HSCT will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) with CB (Cord blood) or TCD (T-Cell depletion) or CD34+ selection. In addition, these patients will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) patients receiving Post TX-Cyclophosphamide
Drug: Thiotepa · Drug: Treosulfan · Drug: Fludarabine · Drug: ATG Thymoglobulin · Drug: Grafalon
TBI (Total Body Irradiation) / VP16 is used as conditioning regimen for haematopoietic stem cell transplantation (HSCT) in patients older than 48 months with: * MSD (matched sibling donors) or MD (matched related or unrelated donors). In addition, patients undergoing MD HSCT will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) with CB (Cord blood) or TCD (T-Cell depletion) or CD34+ selection. In addition, these patients will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) patients receiving Post TX-Cyclophosphamide. Patients aged 24-48 months may optionally receive Total Body Irradiation (TBI).
Drug: VP16 · Radiation: TBI · Drug: ATG Thymoglobulin · Drug: Grafalon
Fludarabine/Thiotepa/iV Busulfan is used as conditioning regimen for haematopoietic stem cell transplantation (HSCT) in patients with: * MSD (matched sibling donors) or MD (matched related or unrelated donors). In addition, patients undergoing MD HSCT will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) with CB (Cord blood) or TCD (T-Cell depletion) or CD34+ selection. In addition, these patients will receive ATG Thymo- or Grafalon. * MMD (mismatched donors) patients receiving Post TX-Cyclophosphamide
Drug: Thiotepa · Drug: Fludarabine · Drug: Busulfan · Drug: ATG Thymoglobulin · Drug: Cyclophosphamide · Drug: Grafalon
Busulfan/VP16/Cyclophosphamide is an alternative conditioning arm that may optionally be used for HSCT with MSD/MD and MMD graft in patients aged 0-24 months. Patients undergoing MD HSCT will also receive ATG Thymo- or Grafalon.
Drug: VP16 · Drug: Busulfan · Drug: Cyclophosphamide
60 mg/kg BW,1 day in TBI/VP16 conditioning; 40 mg/kg BW in Bu/VP16/Cy conditioning
Also known as: Etoposide
2 x 2Gy/day , 3 days (total 12Gy)
2x5 mg/kg BW, 1 day
Also known as: Thio
14g/m² BS, 3 days
Also known as: Treo
30 mg/m² BS, 5 days
Also known as: Flu
iV, dosage according therapeutic drug monitoring, 4 days
Also known as: Bu
MD: ATG Thymo: 2,5mg/kg BW/d 3 days.
Also known as: ATG Thymo
as part of conditioning 60 mg/kg BW 2 days or as GvHD Prophylaxis 50mg/kg BW/d 2 days with Mesna
Also known as: Cy
MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days
Also known as: Anti-human T-lymphocyte immunoglobulin
Overall Survival (OS) Stratum 1a (randomisation TBI+ chemo-conditioning vs. chemo-conditioning only)
Stratum 1 - randomisation related question was closed in December 2018; patients are in active follow-up: To show that a non total body irradiation (TBI) containing conditioning (Flu/Thio/ivBu or Flu/Thio/Treo) results in a non-inferior survival as compared to conditioning with TBI/Etoposide in children older than 4 years after HSCT from a Human leucocyte antigen (HLA) identical sibling donor (MSD) or a HLA matched donor (MD). The primary endpoint is the OS calculated from the date of the randomisation. Death from any cause will be considered an event.
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)
EFS after allogeneic HSCT. EFS calculated from date of recruitment to disease progression or relapse, secondary neoplasm and death from any cause.
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
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
Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
EFS (Stratum 1a and 1b)
EFS calculated from date of randomization (1a) or recruitment (1b) to disease progression or relapse, secondary neoplasm and death from any cause. Patients lost to follow-up without event will be censored at the date of their last follow-up evaluation.
Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
TRM
Cumulative Incidence of Treatment-related mortality (TRM) for Stratum 1 and 2.
Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Relapse/progression
Cumulative Incidence of Relapse for Stratum 1a, 1b and 2.
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
according a preselection out of CTC3
Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
OS (Stratum 2)
The primary endpoint is the OS calculated from the date of the recruitment . Death from any cause will be considered an event.
Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Acute Graft versus Host Disease (aGVHD)
According to the modified Seattle Glucksberg criteria
Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Secondary malignancies
Incidence, type and timepoint of occurence
Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
Chronic Graft-versus-host disease (cGvHD)
Chronic GVHD is diagnosed using criteria created through the NIH consensus development project
Time frame: first: 18 months after inclusion of first patient, afterwards annually up to 10 years
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