Title
HLA Haploidentical Bone Marrow Transplant in Patients With Severe Sickle Cell Disease
Bone Marrow Transplantation HLA Haploidentical After a Reduced Intensity Conditioning and Prevention of GvHD Based on Post-transplant Cyclophosphamide Administration in Patients With Severe Sickle Cell Disease
Phase
Phase 2Lead Sponsor
Centre Hospitalier Intercommunal CreteilStudy Type
InterventionalStatus
Active, not recruitingIndication/Condition
Sickle Cell DiseaseIntervention/Treatment
bone marrow transplantStudy Participants
18multicentric interventional biomedical research phase II, prospective, non-randomized evaluating a haploidentical marrow transplants after reduced-intensity conditioning and prevention of GvHD based on cyclophosphamide administration post transplantation in patients with severe sickle cell disease.
Sickle cell disease is a severe disease with frequent occurrence of painful crises and progressive installation of a multi organ injuries. Despite the progress in its management, particularly since the introduction of hydroxycarbamide, the median age of death in sickle cell patients was about 40 years in a recent US study. Severe forms resistant to hydroxyurea or cerebral vasculopathy require transfusion programs throughout susceptible to risks of iron overload and alloimmunization. The bone marrow transplantation cures almost 95% of children and adolescents transplant from an HLA-identical siblings. In patients without HLA-identical donor, interesting results have been reported in haploidentical transplants marrow without ex vivo T cell depletion taken after non myeloablative conditioning regimen and GvHD prevention with cyclophosphamide high dose injection after bone marrow transplant . This approach performed in 14 patients was effective to cure 50% of the patients and 50% have rejected the transplant . No death or severe GvHD were related to the procedure.
DREPHAPLO protocol aims to evaluate that approach in a population of sickle cell patients with severe complications of the disease, bringing direct benefit to patients with a cure of the disease in at least half of them.
haploidentical bone marrow transplant
All the included patient will receive an haploidentical bone marrow transplant with the following protocol concerning the conditioning and GvHD prevention Conditioning THYMOGLOBULINE : 0.5mg/kg at D-9 and 2 mg/kg at D-8 and D-7 THIOTEPA: 10mg/kg/j at D-7 CYCLOPHOSPHAMIDE (Endoxan®):14.5mg/kg/j at D-6 and D-5 FLUDARABINE (Fludara®): 30mg/m2 per Day from D-6 to D-2 TBI : 2GY : D -1 Graft : Injection at D0 of G-CSF-stimulated bone marrow transplant. Prophylaxis of GvHD CYCLOPHOSPHAMIDE (Endoxan®): 50mg/Kg per Day from D+3 to D+4 Sirolimus and MycophénolateMofétil (MMP) from D+5. In the absence of acute GvHD (aGvHD), stop of MMP to D35 and pursuit of sirolimus 1 year after the graft.
Inclusion criteria recipient: Age: 13 years-40 years Severe Sickle cell with at least one of the following criteria: Stenosing vasculopathy with abnormal MRA despite prolonged transfusion program PAH confirmed by right catheterization with mPAP> 25mmHg Systolic ejection fraction <55% and tricuspid regurgitation speed> 2.5m /s at distance from an acute episode No possibility of blood transfusion or very complicated blood transfusion Report albumin / creatinine> 30 mg / mmol, confirmed 3 times, away at distance from acute episode and persistent despite hydroxyurea or IEC GFR <80ml / min /1.73m2 (CKD-Epi without ethnic criterion) Previous history of acute liver sequestration with liver failure Acute chest syndrome or vaso-occlusive crises under hydroxyurea Complications of sickle cell transfusion imposing an exchange program with no possible withdrawal beyond a period of one year Not having geno-identical donor, but a haploidentical major donor (parent, sibling, adult child, or HbAA AS) Having red and understood the information letter and signed the informed consent Patients affiliated to a social security system (Social Security or Universal Medical Coverage) Exclusion Criteria recipient: Patient with a geno-identical donor Performans status: ECOG> 1 lung disease: FEV1 and FVC <50% predicted, score of PAH NYHA≥2 Liver disease with bilirubin> 50 .mu.mol / L heart failure defined by NYHA≥3 score ejection fraction <45% or shortening fraction <24% anti HLA alloimmunization against the donor or against red cell antigens of the donor Serology or HIV viral load positively Patients who for family, social or geographical reasons, do not wish to be regularly monitored in consultation severe uncontrolled infection at the time of inclusion or graft pregnant woman (positive beta HCG) or during lactation incapable adult patient, trust, guardianship, or safeguard justice Inclusion criteria donor Age> 18 years and <60 years Viral serologic economy allows the graft No contraindication for general anesthesia No contraindication the administration of G-CSF (the existence of sickle cell trait is not a contraindication) Lack antigens HLA recognized by the recipient antibody Hemoglobin S <50% When several donors are compatible: choose according to the ABO recipient: prefer ABO compatibility and major incompatibility and minor incompatibility, and finally major and minor incompatibility. Signature of informed consent Non-inclusion criteria donors: β HCG positive or known pregnancy
