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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

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).

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

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.

60 mg/kg BW,1 day in TBI/VP16 conditioning; 40 mg/kg BW in Bu/VP16/Cy conditioning

VP16

iV, dosage according therapeutic drug monitoring, 4 days

ATG Thymoglobulin

as part of conditioning 60 mg/kg BW 2 days or as GvHD Prophylaxis 50mg/kg BW/d 2 days with Mesna

MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days

Grafalon

Christina Peters, Prof. MD PhD

Tijana Frank, MD, MScEng

Raquel Staciuk, MD PhD

Alcira Fynn, MD PhD

Formisano Sandra, MD PhD

Sandra Formisano, MD PhD

Daniela Iglesias, MD PhD

Wolfgang Schwinger, MD PhD

Herwig Lackner, MD

Gabriele Kropshofer, MD PhD

Bernhard Meister, MD

Herbert Pichler, MD

herbert.pichler@stanna.at

Roswitha Lüftinger, MD

Elisabeth Salzer, MD

Nina Minakovskaya, MD

Alina Ferster, MD PhD

Benedicte Brichard, MD PhD

Viktoria Bourdon, MD, PhD

Marleen Renard, MD PhD

Marie Françoise Dresse, MD PhD

Henrique Bittencourt, MD PhD

Donna Wall, MD PhD

Kirk Schultz, MD PhD

Jeffery Davis, MD

Geoff Cuvelier, MD PhD

Julia Palma, MD PhD

Ernest Bilic, MD PhD

Toni Matic, MD PhD

Petr Sedlacek, MD PhD

Petr Riha, MD

Renata Formankova, MD

Petra Keslova, MD

Jan Stary, MD

Marianne Ifversen, MD PhD

Marianne Ifversen, MD PHD

Carsten Heilmann, MD

Kim Vettenranta, MD PhD

Evgenios Goussetis, MD

Dikaia Eleni Ioannidou, MD

Anna Paisiou, MD

Dikaia-Eleni Ionnidou, MD

George Vessalas, MD

Gergely Krivan, MD PhD

Krisztián Kallay, MD PhD

Roni Gefen, MD PhD

Jerry Stein, MD PhD

Ronit Elhasid, MD PhD

Fraia Melchionda, MD

Maura Faraci, MD

Adriana Balduzzi, MD PhD

Francesco Paolo Tambaro, MD

Manuela Tumino, MD

Mario Zecca, MD PhD

Gabriella Casazza, MD PhD

Franco Locatelli, MD PhD

Hany Ariffin, MD PhD

Alberto Olaya Vargas, MD PhD

Arjan Lankester, MD PhD

Marc Bierings, MD PhD

Jochen Büchner, MD PhD

Mariusz Wysocki, MD PhD

Jerzy R. Kowalczyk, MD

Jacek Wachowiak, MD PhD

Alicja Chybicka, MD PhD

Anca Colita, MD PhD

Cristian Jinca, MD PhD

Mohammed Essa, MD PhD

Peter Svec, MD PhD

Dominika Tanuskova, MD

Simona Avčin, MD

Isabel Badell, MD

Cristina Díaz de Heredia, MD

José Luis Fuster, MD

Antonia Isabel Pascual, MD

Antonia Pascual, MD

Pilar Palomo, MD

Peter Bader, Prof. MD PhD

Franco Locatelli, Prof. MD PhD

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 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

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

According to the modified Seattle Glucksberg criteria

Incidence, type and timepoint of occurence

Chronic GVHD is diagnosed using criteria created through the NIH consensus development project

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.

EFS after allogeneic HSCT. EFS calculated from date of recruitment to disease progression or relapse, secondary neoplasm and death from any cause.

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

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.

Cumulative Incidence of Treatment-related mortality (TRM) for Stratum 1 and 2.

Cumulative Incidence of Relapse for Stratum 1a, 1b and 2.

The primary endpoint is the OS calculated from the date of the recruitment . Death from any cause will be considered an event.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia	NCT01949129	Acute Lymphobla...	VP16 TBI Thiotepa Treosulfan Fludarabine Busulfan ATG Thymoglobul... Cyclophosphamid... Grafalon	1 Month - 18 Years	St. Anna Kinderkrebsforschung
Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia	NCT01949129	Acute Lymphobla...	VP16 TBI Thiotepa Treosulfan Fludarabine Busulfan ATG Thymoglobul... Cyclophosphamid... Grafalon	1 Month - 18 Years	St. Anna Kinderkrebsforschung

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