Title : Allogeneic hematopoietic stem cell transplantation in patients with low or intermediate-1 risk myelodysplastic syndrome: A prospective multicenter phase II study based on donor availability on behalf of the GFM & SFGM-TC

Short title : MDS-ALLO-RISK

Promotor : Groupe Francophone des Myélodysplasies (GFM)

Coordinators :  Marie Robin, PhD, Marie Sébert, PhD

Investigators Centers from the French MDS Group (see list of centers) and centers from the European community

Primary objective : Comparison of survival in patients with or without a matched donor (8/8 at molecular level unrelated donor or matched sibling) at 3 years

Secondary objective : To assess the prognostic factors, and quality of life

Study design : Comparative non-randomized phase II clinical trial

Inclusion criteria :
• Signed inform consent
• Classical IPSS intermediate 1 or low myelodysplastic syndrome associated with at least one poor prognosis feature:
       1) Intermediate or higher risk revised IPSS
       2) RBC transfusion dependent anemia and failure to 2 or more lines or therapy (including EPO,
       Lenalidomide or demethylating agent…) with the exception of pure RARS with isolated SF3B1 mutation
       3) thrombocytopenia < 20 G/L requiring transfusion
       4) neutropenia < 0.5 G/L associated with severe infection (defined as requiring hospitalization)
       5) 5q- and lenalidomid failure especially but not only with TP53 mutated
• Patient aged ≥ 18 and < 70 years
For young patients, 18-45 years, Fanconi disease and dyskeratosis should be ruled out
• For whom a transplantation from a matched donor, (8/8 unrelated donor or matched sibling), is considered irrespective of donor availability
• Performance status lower than 3 (ECOG 0, 1, or 2) at time of screening
• Negative pregnancy test and adequate contraception (including male wishing to father) if relevant
• Wash-out of at least 30 days since a previous treatment with Vidaza®, Lenalidomide, EPO or any other treatment inducing cytopenias

Exclusion criteria ;
• Classical IPSS int-2 or high
• ARSI with SF3B1 mutation
• Transformation into acute myeloid leukemia
• Severe active infection or any other uncontrolled severe condition
• Symptomatic cardiac failure
• Renal clearance < 60 ml/min
• Symptomatic respiratory chronic failure
• Aspartate transaminase (AST) or Alanine transaminase (ALT) > 3 x ULN or total bilirubin > 2 x ULN (except moderate unconjugated hyperbilirubinemia due to intramedullary hemolysis or Gilbert syndrome)
• Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, or other tumors if not active during the last 3 years)
• MDS with the following causal germline disease : Fanconi anemia, GATA2 related syndromes and telomere disorders.

Number of patients : 105 (62 in group A, 43 in group B)

Statistical analysis and calculation of number of patients :
The objective of this study is to demonstrate an improvement of the overall survival in patients with a donor that is reaching 70% at 36 months compared to 40% in those without a donor. To test this hypothesis (HR=0.39) based on a two-sided log-rank test, 50 events are required, and 105 patients are needed with a 80% power and type I error rate at 5%, with a probability to identify a donor at 70%

Study duration :
Patient recruitment: 36 months
Minimal Patient follow-up: 24 months and until the end of the trial scheduled 60 months after first inclusion (approximately June 2021)
Total duration of the study: 60 months

Number of centers : 20-25

Administration and authorities : CNIL, ANSM, CPP, Clinicaltrials.gov

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