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

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. - TBI/VP16 remains the standard of care for patients > 4 years. - Patients aged 2-4 years may optionally receive the TBI/VP16 conditioning at the discretion of the treating physician to avoid acute and long-term side effects, which are more pronounced in this age group. - Patients <2 years of age do not receive TBI. - For patients who are not eligible for TBI, treating physicians may choose either Flu/Thio/ivBu or Flu/Thio/Treo as both chemo-conditioning regimens result in similar OS, EFS and NRM. - Patients aged 0-2 years may receive Bu/VP16/Cy at the discretion of the treating physician. 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: - TBI/VP16 remains the standard of care for patients > 4 years. - Patients <4 years of age do not receive TBI. - For patients aged <4 years and those ineligible for TBI, treating physicians may choose either Flu/Thio/ivBu or Flu/Thio/Treo as both chemo-conditioning regimens result in similar OS, EFS and NRM. 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.