Sickle Cell Disease
Conditions
Keywords
sickle cell disease, haploidentical, graft, marrow
Brief summary
multicentric 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.
Detailed description
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.
Interventions
BIOLOGICALbone marrow transplant
haploidentical bone marrow transplant
Sponsors
Keocyt
Association Clinique Thérapeutique Infantile du val de Marne
Centre Hospitalier Intercommunal Creteil
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
Haploidentical Marrow Transplants
Eligibility
Sex/Gender
ALL
Age
13 Years to 40 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival rate | 2 years | Survival without sickle cell survival rate (electrophoresis of hemoglobin similar to that from the donor, that is to say a percentage of HbS not exceeding 10% of that of distance donor transfusions and that of a stable manner and without GvHDc other than mild |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| haematologic reconstitution | 2 years | defined as a neutrophil count\> 500 / mm3 and platelets\> 20000 / mm3, for three consecutive days. |
| Chimerism | at month 1 | Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers |
| hemoglobin electrophoresis | at 1 month | — |
| occurence of graft versus host disease | at month 24 | evaluated monthly from M1 to M6, and M9, M12, M24 |
| grade of graft versus host disease | at month 24 | Incidence and grade of GvHD, toxic deaths and infectious complications and secondary cancer |
| occurrence of toxic deaths | at month 24 | — |
| Survival rate | 1 year | Survival without sickle cell survival rate (electrophoresis of hemoglobin similar to that from the donor, that is to say a percentage of HbS not exceeding 10% of that of distance donor transfusions and that of a stable manner and without GvHDc other than mild |
| occurrence of secondary cancer | at month 24 | — |
| Lymphocyte immunophenotyping | 2 years | Lymphocyte immunophenotyping T, B and NK + The Extended Phenotype including activation markers, assessment of naive people and memories, T reg populations etc) and plasma protein electrophoresis: 1 month, 3 months, 6 months, 12 months and 24 months post-transplantation. |
| ECOG score value | 2 years | Index Trading ECOG complete physical examination with determination of weight |
| Assessment of sickle cell disease complications | at 1 year | Microalbuminuria, creatinuria; echocardiography for measurement of systolic ventricular ejection fraction (February), PAH research and measurement IT Vmax; respiratory function tests with measurement of DLCO; MRI brain with ARM and Cervical Pre-transplant anomalies; Radio of the pelvis |
| ferritin dosage | at month 3 | Evaluation of iron overload by ferritin |
| MRI iron overload | at 12 months | hepatic and cardiac MRI to assess the iron overload |
| occurrence of infectious complications | at month 24 | — |
Countries
France
Outcome results
None listed