Reduced-Intensity Conditioning Is Successful in Matched Sibling Bone Marrow Transplantation As a Cure for Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is the most common genetic disease in this country, affecting 1 in every 72,000 individuals in the United States, with sickle cell trait found in 1 in 12 African-Americans. Without curative therapy, disease related mortality is as high as 14% in adolescents and young adults, with a decreased life expectancy compared to individuals without SCD. Hematopoietic stem cell transplantation (HSCT) is the only established cure, and matched sibling HCST have been performed for 30 years with great success. Unfortunately, only about 14% of SCD patients have a matched sibling. Most SCD HSCT protocols use myeloablative (MAB) conditioning in matched sibling transplants with average overall survival (OS) and disease-free survival (DFS) of 90% and 95% respectively, but with potential long-term complications including infertility following its use. Reduced Intensity Conditioning (RIC) has been used in young patients with malignancies with better tolerance and fewer complications. In an attempt to minimize risk and maximize cure, our study examined the use of a RIC regimen for both matched sibling and alternative donor HSCT in SCD patients ages 2-30.

Primary Objective: To determine DFS after matched sibling or unrelated transplant after a conditioning regimen consisting of Alemtuzumab, Fludarabine, and Melphalan.

Methods: The Institutional Review Board of Hackensack University Medical Center approved this study for human subjects. Strict stopping rules were established for graft rejection and death. Eligibility criteria included a diagnosis of SCD for patients receiving matched sibling donor HSCTs, but did not require any specific complications. For alternative donor HSCTs, eligibility criteria included specific complications associated with severe disease, and required a 9-10/10 unrelated donor or 5-6/6 UCB in the donor registry. All patients underwent partial exchange transfusions for a goal of HbS <45% at the start of conditioning. Conditioning initially consisted of Alemtuzumab beginning on d -22 followed by Fludarabine and Melphalan. However, Alemtuzumab was moved up to d -16 after 7 patients were enrolled to reduce graft vs host disease (GVHD). Due to increasing host chimerisms in 3 patients, the Alemtuzumab was moved back to d-22 after an additional 7 patients were enrolled. Post-HSCT, GVHD prophylaxis consisted of Tacrolimus (trough goal of 10-20) through d+100, mycophenolate mofetil through d+45, and steroids (for unrelated donors) through d+28. Patients were monitored closely for signs of infection with weekly PCRs for adenovirus, CMV and EBV. Donor chimerism by STR and HbS percentages by electropheresis were assessed at d+30, d+60, d+100, 1 year and 2 years post HSCT.

Results: A total of 20 patients (17 related, 3 unrelated) were enrolled, with age at transplant ranging from 2.25 to 25.4 years. 3 patients were initially consented to the related arm, but then were found to be ineligible due to organ dysfunction or compliance issues. OS and DFS in patients with related donors were 100% and 94%, with one patient suffering secondary graft rejection. The OS and DFS in patients with unrelated donors were 66% and 33%, with one patient dying from GVHD complications and a second patient suffering secondary graft rejection. The unrelated patient with graft failure did receive a second HSCT off study, but died due to GVHD complications. Mean neutrophil engraftment occurred at d+14 and d+11 and platelet engraftment occurred at d+40 and d+26 for related and unrelated donors, respectively. The incidence of acute GVHD stage II-IV was 35% (7/20 patients), occurring in 6/17 (35%) related and 1/3 (33%) unrelated BMT patients. Chronic GVHD was noted in 20% of patients (4/20), occurring in 3/17 (18%) related and 1/3 (33%) unrelated BMT patients. Chimerisms ranged from 20-100% with HbS% of 0-62%.

Conclusions : Our results show that a RIC regimen is well-tolerated with successful engraftment in patients undergoing matched sibling HSCT. However, the complications of GVHD & graft rejection in unrelated transplants greatly affected the DFS. The results are promising for continued use of this regimen for related HSCT even in SCD patients with minimal complications, but other alternatives need to be developed for unrelated HSCT.