Outcomes for adult patients with Severe Aplastic Anemia (SAA) aged more than 40 years who are refractory or in relapse after first-line IST remain poor. Hematopoietic stem cell transplantation (HSCT) is the unic valid therapeutic option but results have always been disappointing in patients aged 40 years or older. The first cause of death after HSCT in those refractory/relapse SAA patients is still graft versus host disease (GvHD). Recently, new strategies to prevent GvHD, including T-cell replete grafts with administration of post-transplantation cyclophosphamide (PTCy), have revolutionized the field, notably in haplo-identical donor setting. Using marrow as source of stem cells and a PTCy strategy not only in haplo-identical donor setting but also in case of an available matched sibling or unrelated donor might prevent drastically GvHD and eventually be practice changing. Evaluating this new strategy is the main objectives of "APARR".
Aged from 40 to 60 years old
Suffering from acquired refractory severe idiopathic aplastic anemia after at least 6 months treatment with anti-thymocyte globulin, cyclosporine with Eltrombopag or in relapse
Allograft validated in the National Multidisciplinary expertise meetings of the French reference centre for aplastic anemia
With an available geno-identical donor or 10/10 matched donor or haploidentical donor
With morphologic evidence of clonal evolution (patients with isolated bone marrow cytogenetic abnormalities are also eligible excepted chromosome 7 abnormalities and complex karyotype).
With seropositivity for HIV or HTLV-1-2 or active hepatitis B or C and associated hepatic cytolysis
Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix)
Pregnant (βHCG positive) or breast-feeding
Single group
Allogeneic hematopoietic stem cell transplantation Stem cell source only Bone Marrow
Biological/Vaccine1. Conditioning regimen Thymoglobulin (0.5/mg/kg à D-9, 2 mg /kg at D-8 and 2.5 mg/kg à D-7), Fludarabine (30mg/m2/day i.v: day -6 to day -2), pre-transplant, Cyclophosphamide (14.5 mg/kg/day i.v: day -6 and day -5), and Total Body Irradiation (2 Gray on day -1). 2. Stem cell source Bone Marrow only. Target of 4 × 10\^8 nucleated cells/kg recipient body weight. Granulocyte colony stimulating factor is given subcutaneously starting on day +5 at 5 mg/ kg/day until the absolute neutrophil count is greater than 1.5 × 10\^9/L for 3 days. 3. GVHD prophylaxis Cyclophosphamide 50 mg/Kg/day at D+3 and D+4. Tacrolimus (0,2 à 0,3 mg/kg/day per os divided into 2 doses or 0.05 to 0.1 mg/kg/d IVSE) and mycophenolate (MMF) will begin from D+5. In absence of GvHD, MMF will be stopped between D35 and D45 and Tacrolimus at day 365. 4. Prevention of EBV reactivation Rituximab 150mg/m2 intravenously at Day+5 post HSCT (except patients and their donor with EBV serology and EBV PCR negative).
GRFS (Graft Versus Host Disease (GvHD) and Relapse/rejection-Free Survival)
GRFS is a composite right-censored endpoint, defined as the time from HSCT to the first of the following events: * primary graft failure, defined as the absence of engraftment from aplasia at day 60 after graft (D0) (i.e., persistence of neutrophils\< 500 AND platelets \< 20 Giga/L) * secondary graft failure, defined as the reoccurrence of aplasia after engraftment (defined as both occurrence of neutrophils\< 500 for 3 days and platelets \< 20 Giga/L for 7 consecutive days) * grade 3-4 acute GVHD, according to the MAGIC CONSORTIUM 2016 * severe chronic GVHD, according to the NIH classification * death, whatever the cause
Neutrophil engraftment
Neutrophils engraftment will be defined as first day of 3 consecutive days with neutrophils \>0.5 G/L. With donor chimerism\> 85% on the total blood.
Platelets engraftment
Platelets engraftment will be defined as first day of 7 consecutive days with platelets \>20 G/L. With donor chimerism\> 85% on the total blood.
Absolute number of neutrophils
Absolute number of neutrophils
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