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

St. Anna Kinderkrebsforschung

Status and phase: Enrolling; Phase 3; Phase 2

Conditions: Acute Lymphoblastic Leukaemia

Treatments: Drug: VP16; Drug: Thiotepa; Drug: Treosulfan; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Busulfan; Drug: Grafalon; Radiation: TBI; Drug: ATG Thymoglobulin

Study type: Interventional

Funder types: Other; NETWORK

Identifiers

NCT01949129

ALL SCTped FORUM 2012

Details and patient eligibility

About

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.

Full 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

Enrollment: 1,800 estimated patients

Sex: All

Ages: 1 month to 18 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,800 participants in 4 patient groups

Flu/Thio/Treo

Experimental group

Description:

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

Treatment:

Drug: ATG Thymoglobulin

Drug: Grafalon

Drug: Fludarabine

Drug: Treosulfan

Drug: Thiotepa

TBI/VP16

Active Comparator group

Description:

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).

Treatment:

Drug: ATG Thymoglobulin

Drug: Grafalon

Radiation: TBI

Drug: VP16

Flu/Thio/ivBu

Experimental group

Description:

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

Treatment:

Drug: ATG Thymoglobulin

Drug: Busulfan

Drug: Grafalon

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Thiotepa

Bu/VP16/Cy

Experimental group

Description:

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.

Treatment:

Drug: Busulfan

Drug: Cyclophosphamide

Drug: VP16