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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Acute Lymphoblastic Leukaemia

Intervention / Treatment
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* Drug: VP16
* Radiation: TBI
* Drug: Thiotepa
* Drug: Treosulfan
* Drug: Fludarabine
* Drug: Busulfan
* Drug: ATG Thymoglobulin
* Drug: Cyclophosphamide
* Drug: Grafalon


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Flu/Thio/Treo<br>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. | Drug: Thiotepa<br>* 2x5 mg/kg BW, 1 day<br>* Other names: Thio;Drug: Treosulfan<br>* 14g/m² BS, 3 days<br>* Other names: Treo;Drug: Fludarabine<br>* 30 mg/m² BS, 5 days<br>* Other names: Flu;Drug: ATG Thymoglobulin<br>* MD: ATG Thymo: 2,5mg/kg BW/d 3 days.<br>* Other names: ATG Thymo;Drug: Grafalon<br>* MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days<br>* Other names: Anti-human T-lymphocyte immunoglobulin;|
| Active Comparator: TBI/VP16<br>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. | Drug: VP16<br>* 60 mg/kg BW,1 day<br>* Other names: Etoposide;Radiation: TBI<br>* 2 x 2Gy/day , 3 days (total 12Gy)<br>Drug: ATG Thymoglobulin<br>* MD: ATG Thymo: 2,5mg/kg BW/d 3 days.<br>* Other names: ATG Thymo;Drug: Grafalon<br>* MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days<br>* Other names: Anti-human T-lymphocyte immunoglobulin;|
| Experimental: Flu/Thio/ivBu<br>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. | Drug: Thiotepa<br>* 2x5 mg/kg BW, 1 day<br>* Other names: Thio;Drug: Fludarabine<br>* 30 mg/m² BS, 5 days<br>* Other names: Flu;Drug: Busulfan<br>* iV, dosage according therapeutic drug monitoring, 4 days<br>* Other names: Bu;Drug: ATG Thymoglobulin<br>* MD: ATG Thymo: 2,5mg/kg BW/d 3 days.<br>* Other names: ATG Thymo;Drug: Cyclophosphamide<br>* 50mg/kg BW/d 2 days with Mesna<br>* Other names: Cy;Drug: Grafalon<br>* MD: 15mg/kg BW/d 3 days MMD: 10mg/kg BW/d 3 days<br>* Other names: Anti-human T-lymphocyte immunoglobulin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Stratum 1a (randomisation TBI+ chemo-conditioning vs. chemo-conditioning only) | 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. | first: 18 months after inclusion of first patient, afterwards annually up to 10 years | 
| Event free survival (EFS) Stratum 2 (mismatched donor transplantation) | EFS after allogeneic HSCT. EFS calculated from date of recruitment to disease progression or relapse, secondary neoplasm and death from any cause. | first: 18 months after inclusion of first patient, afterwards annually up to 10 years | 
| Overall Survival (OS), Stratum 1b: MSD/MD without randomisation | 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 | first: 18 months after inclusion of first patient, afterwards annually up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFS (Stratum 1a and 1b) | 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. | first: 18 months after inclusion of first patient, afterwards annually up to 10 years | 
| TRM | Cumulative Incidence of Treatment-related mortality (TRM) for Stratum 1 and 2. | first: 18 months after inclusion of first patient, afterwards annually up to 10 years | 
| Relapse/progression | Cumulative Incidence of Relapse for Stratum 1a, 1b and 2. | first: 18 months after inclusion of first patient, afterwards annually up to 10 years | 
| Acute and late toxicity for Stratum 1a, 1b and 2 | according a preselection out of CTC3 | first: 18 months after inclusion of first patient, afterwards annually up to 10 years | 
| OS (Stratum 2) | The primary endpoint is the OS calculated from the date of the recruitment . Death from any cause will be considered an event. | first: 18 months after inclusion of first patient, afterwards annually up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stem cell transplantation, children and adolescents, high risk acute lymphoblastic leukaemia