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

Official Title

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

Summary:

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.

Trial Description

Primary Outcome:

• Overall Survival (OS) Stratum 1a (randomisation TBI+ chemo-conditioning vs. chemo-conditioning only)
• Event free survival (EFS) Stratum 2 (mismatched donor transplantation)
• Overall Survival (OS), Stratum 1b: MSD/MD without randomisation

Secondary Outcome:

• EFS (Stratum 1a and 1b)
• TRM
• Relapse/progression
• Acute and late toxicity for Stratum 1a, 1b and 2
• OS (Stratum 2)

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. This study aimed to explore the efficacy and efficiency of two different chemo-conditioning regimens (Flu/Thio with Treo or ivBu) in comparison to the standard conditioning regimen (TBI/VP16). All patients with an indication for HSCT, age > 4 years and a matched donor (MD) or matched sibling donor (MSD) underwent a randomisation between these two conditioning regimens. The decision if the irradiation free conditioning is Flu/Thio/Treo or Flu/Thio/ivBu was stratified by country. Patients with age < 4 years received the irradiation free conditioning. Patients with a mismatched donor were stratified according to the donor's stem cell source (cordblood, haploidentical tx or bone marrow/peripheral blood stem cells). After an interim analysis of the randomized FORUM-trial in December 2018, which showed superior OS for TBI/Etoposide with equal outcomes for Bu or Treo-containing regimen, the randomization was suspended. The reason was less relapse incidence whereas 1-year TRM was comparable in all 3 arms. The randomization was closed in March 2019 based on the results of additional analyses confirming the superiority of TBI/VP16 over chemo-conditioning. Consequently, the TBI conditioning has remained a standard for the patients older than 4 years with a MSD/MD. Use of a conditioning other than TBI/VP16 in this age group is made at the centre level based on the assessment of each individual patient.

View this trial on ClinicalTrials.gov