Stable long term engraftment and amelioration of clinical phenotype following hematopoietic stem cell transplantation from a matched sibling donor for sickle cell disease using a reduced intensity conditioning regimen (2005)

Hematopoietic stem cell transplantation (HCT) from sibling donors has been demonstrated to cure hemoglobinopathies such as sickle cell disease (SCD) and Thalassemia. Concerns about high regimen related toxicity (RRT) have prevented the use of HCT in older patients, those with advanced organ damage or those without a HLA matched related donor. Also, potential for late sequelae such as chronic graft-versus-host disease (GVHD) and infertility have limited the acceptance of this treatment even by eligible patients. HCT following a reduced intensity conditioning (RIC) regimen has the potential for reducing toxicity and potentially making this curative therapy more acceptable and applicable to this group of patients. We initiated a pilot study to evaluate the safety and efficacy of HCT following a RIC regimen for patients with high risk hemoglobinopathies. We report stable long term engraftment with amelioration of clinical phenotype in the first three patients with SCD receiving HCT (unmodified bone marrow) from a matched sibling donor, on this study. The conditioning regimen consisted of Busulfan 2 mg/kg orally q 12 hr × 2 days (0.8 mg/kg IV q 6 hr × 2 days for patient #3), Fludarabine 35 mg/m2/dose IV daily × 5 days, antithymocyte globulin 30 mg/kg/dose IV daily × 5 days and total lymphoid irradiation administered as a single fraction of 500 cGy with shielding of the liver, lungs, heart, and gonads. Prophylaxis for GVHD consisted of cyclosporine A and Mycophenolate mofetil. Clinical characteristics of the patients and outcomes are summarized in Table 1. The preparative regimen was well tolerated with no serious infections or mucositis in any patient. Nadir of absolute neutrophil count was 140–200 × 109/L. Nadir of platelet count was 25–40 × 109/L. Transfusion requirements were modest (3 PRBC and 3–5 platelet transfusions). All patients are off immunosuppressive medications. Recovery of splenic function was observed except in patient #2 had who had prior splenectomy. No patient has had any recurrence of previous sickle cell related symptoms such as stroke, pain crisis, priapism or acute chest syndrome. End-organ changes are stable in all patients. Lineage-specific chimerism analysis (patient #3) suggest predominance of donor erythropoiesis. These findings indicate that HCT for sickle cell disease following a RIC regimen is well tolerated and can lead to stable long term engraftment with amelioration of clinical phenotype and stabilization of end- organ damage. Tabled 1Clinical Characteristics of Patients With Sickle Cell Disease Undergoing HCT From a Matched Sibling Donor Following a Reduced Intensity Conditioning RegimenPIN; Indication for HCT, Age (Years)Follow-up (Years)Organ ToxicityDuration of ANC <500 (Days)GVHD Acute/ChronicEngraft-ment % Donor (Bone Marrow) d + 30Engraft-ment % Donor (Bone Marrow) d + 100Engraft-ment % Donor (Bone Marrow) d + 3651. Stroke, allosensi-tization 8 yrs.4None7Nil891001002. Repeated ACS, 8 yrs.3None8Grade II Skin7581813. Repeated ACS, 6 yrs.1None9Nil758581 Open table in a new tab