Official Title
Allogeneic Stem Cell Transplantation for Children and Adolescents With Acute Lymphoblastic Leukaemia
Phase
Phase 2/Phase 3Lead Sponsor
St. Anna KinderkrebsforschungStudy Type
InterventionalStatus
RecruitingIndication/Condition
Acute Lymphoblastic LeukaemiaIntervention/Treatment
busulfan fludarabine thiotepa etoposide treosulfan ...Study Participants
1000The 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.
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 center level based on the assessment of each individual patient.
60 mg/kg BW,1 day
2 x 2Gy/day , 3 days (total 12Gy)
2x5 mg/kg BW, 1 day
14g/m² BS, 3 days
30 mg/m² BS, 5 days
iV, dosage according therapeutic drug monitoring, 4 days
MD: ATG Thymo: 2,5mg/kg BW/d 3 days.
50mg/kg BW/d 2 days with Mesna
MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days
Fludarabine/Thiotepa/Treosulfan is for conditioning before HSCT from MSD or MD. ATG Thymo or Grafalon is used for patients who receive stem cells from unrelated donors. Fludarabine/Thiotepa/Treosulfan with either ATG Thymo or Grafalon is also used for HSCT from MMD with in vitro T-Cell Depletion (TCD) or with CD34+ selection. Fludarabine/Thiotepa/Treosulfan with Post Tx-Cyclophosphamide is used for MMD-graft without in vitro TCD.
TBI (Total Body Irradiation) / VP16 is used for conditioning for HSCT with MSD or MD graft with patients who are older than 48 months at the time of conditioning. TBI/VP16 is also used with Post TX-Cyclophosphamide for MMD-graft without in vitro T-Cell Depletion. TBI/VP16 with either ATG Thymo or Grafalon is used for MMD-HSCT with in vitro T-Cell Depletion or with CD34+ selection.
Fludarabine/Thiotepa/iV Busulfan is used for conditioning before HSCT from MSD or MD. Fludarabine/Thiotepa/iBu with either ATG Thymo or Grafalon is also used for HSCT from MMD-HSCT with T-Cell Depletion (TCD) or haplo with CD34+ selection. Fludarabine/Thiotepa/iV Busulfan with Post Tx-Cyclophosphamide is used for MMD-graft without in vitro TCD.
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
