Matched Sibling Donor Hematopoietic Cell Transplantation for Sickle Cell Disease Using a Reduced Intensity Conditioning Regimen Can Lead To Stable Long Term Engraftment.

Abstract

Hematopoietic Cell Transplantation (HCT) from sibling donors has been demonstrated to cure sickle cell disease. Concerns about high regimen related toxicity particularly in older patients and in those with advanced organ damage and the potential for late sequelae such as chronic graft-versus-host disease (GVHD) and infertility have limited the applicability of HCT. HCT following a reduced intensity conditioning (RIC) regimen has the potential for reducing toxicity and making this curative therapy more acceptable and applicable to this group of patients. We report preliminary results on the first five patients enrolled on a pilot study to evaluate the safety and efficacy of HCT following a RIC regimen for patients with high risk sickle cell disease. All patients received bone marrow from a matched sibling donor. The conditioning regimen consisted of Busulfan 2 mg/kg orally q12 hr x 2 days (0.8mg/kg IV q 6 hr x 2 days for patient#3, 4, 5), Fludarabine 35 mg/m2/dose IV daily x 5 days, anti-thymocyte globulin 30 mg/kg/dose IV daily x 5 days and total lymphoid irradiation 500 cGy with shielding of the liver, lungs, heart, and gonads. GVHD prophylaxis consisted of cyclosporine A and Mycophenolate mofetil. Clinical characteristics, outcomes and donor chimerism in peripheral blood genomic DNA and of subjects are summarized in the Table.1 The preparative regimen was well tolerated with no serious infections or mucositis in any patient. No patient has had recurrence of previous sickle cell related symptoms. Lineage-specific chimerism analysis (patients # 3, 4, 5), reveal predominance of donor erythropoiesis (Table 2). These findings indicate that HCT for sickle cell disease following a RIC regimen is well tolerated and can lead to stable long term engraftment.Clinical Characteristics of patients with sickle cell disease undergoing HCT from a matched sibling donor following a reduced intensity conditioning regimenPIN. Age, IndicationFollow-up (days)Regimen Related ToxicityANC<500(days)GVHD Acute or Chronic% Engraftment Day 100% Engraftment Day180% Engraftment Day 3651. 8 yrs. Stroke, allosensitization2100None7None891001002. 8 yrs. Repeated ACS1800None8Grad II Skin7581813. 6yrs. Repeated ACS750None9None7585814. 8 years Repeated ACS295None14None7971-5.18 yrs. Stroke, allosensitization288Mild13None100100-Lineage Specific ChimerismPIN, GenotypeDonor Genotype% donor erythroid day 100% donor erythroid day 180% Donor Lymphoid day 100% Donor Lymphoid day 180% Hemoglobin S Day 100% Hemoglobin S Day 1803. Hb SSSickle trait100100303530344. HbS/β Thalassemiaβ Thalassemia trait100813358435. HbSSSickle trait1001001001003234