Comparison of Allogeneic Matched Related Haematopoietic Stem Cell Transplantation After a Reduced Intensity Conditioning Regimen With Standard of Care in Adolescents and Adults With Severe Sickle Cell Disease

A Prospective Multicenter Trial Comparing Allogeneic Matched Related Haematopoietic Stem Cell Transplantation After a Reduced Intensity Conditioning Regimen, With Standard of Care in Adolescents and Adults With Severe Sickle Cell Disease

Although the survival of children with sickle cell disease (SCD) has dramatically improved over the last decades in the US and Europe, mortality remains high in adults. Moreover, many children and most adults develop a chronic debilitating condition due to organ damage. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the unique curative approach; it allows the cure of more than 95% of children transplanted from a matched related donor (MRD) after a myeloablative conditioning regimen.To date, few studies have addressed the role of HSCT in SCD adults, due to the risk of graft versus host disease (GVHD) and to the toxicity expected in older patients with a higher risk of organ damage. The development of safe, non-myeloablative conditioning regimens that allow stable mixed chimerism and avoid GVHD appears as an attractive option for HSCT to cure adults with severe SCD. The investigators design a prospective multicenter trial targeting patients over 15 years with severe SCD, and compare non-myeloablative transplant (when a matched related donor (MRD) is identified) versus no HSCT (for patients lacking MRD). The main objective is to assess the benefit of HSCT on the 2-year event free survival compared to standard care. The primary endpoint is the 2-year event free survival.

Inclusion criteria

• SCD patients (SS/Sβ0)
• Aged :15 to 45 years
• With at least one non-SCD sibling > 18 years from the same parental couple
• Who presented at least one of the following criteria:
• 3 VOC requiring hospitalization over one year within the past 2 years and at least a past history of an ACS
• At least 1 ACS within the past 2 years requiring transfusions
• History of ischemic stroke or cerebral/cervical arterial stenosis > 50%
• Pulmonary hypertension defined by mean pulmonary artery pressure ≥ 25 mmHg at rest, determined by right heart catherization
• Requiring treatment with Hydroxyurea or chronic transfusion, or already treated by Hydroxyurea or transfusion program (TP) at inclusion.
• Patients already receiving chronic transfusions for VOC or ACS not responding to hydroxyurea, will be eligible, provided at least 3 VOC requiring hospitalization/year within the 2 years before initiation of chronic transfusions, and at least past history of an ACS.
• Contraception during all the study period by sirolimus for women of child bearing potential
• Signed informed consent
• Amenable to HLA typing, HSCT if an HLA-identical sibling is available.
• Patients affiliated to the French health care insurance

Exclusion Criteria

• Performance status: ECOG scale>1
• Pulmonary function: FEV1 et CVF < 50% of the theorical value
• Post capillary and severe pre-capillary pulmonary hypertension with measured mean pulmonary artery pressure at rest >35 mmHg
• Cardiac ejection fraction < 45%
• Estimated glomerular fraction rate (GFR) <50ml/mn /1.73m2
• Conjugate bilirubin >50 µmole/L, cirrhosis, ALT>4N
• Uncontrolled infection
• Known hypersensitivity of alemtuzumab
• Known hypersensitivity to murine proteins and to the following excepients: disodium edetate, polysorbate 80, potassium chloride, potassium phosphate monobasic, sodium chloride, dibasic sodium phosphate, water for injections
• Positivity for HIV
• Pregnancy or breast-feeding women
• Alloimmunization or Delayed Hemolytic Transfusion Reaction precluding red cell transfusions