Hematopoietic Stem Cell Transplantation for Sickle Cell Anemia with Busulfan-Based Reduced Intensity Conditioning: Cure and Fertility

Hematopoietic stem cell transplantation (HSCT) is increasingly being used in the management of patients with sickle cell disease (SCD). Although cure remains the fundamental goal, preservation of fertility in this young patient population is an important consideration. While it is known that standard busulfan-based myeloablative conditioning uniformly causes permanent gonadal dysfunction, complete graft rejection is a serious drawback in busulfan-free exclusively immunosuppressive-based preparative regimens with fludarabine and cyclophosphamide alone. Therefore if busulfan is to remain a central part of the conditioning, a significant dose reduction may be necessary to cure and yet preserve fertility. The subsequent successful outcome and preservation of fertility in two young adults transplanted in our center with busulfan-based targeted-dose reduced intensity conditioning (RIC) for paroxysmal nocturnal hemoglobinuria, prompted us to consider this regimen in SCD.  Between September 2008 and April 2012, 16 patients with SCD underwent HSCT in the Sultan Qaboos University Hospital, Oman. The conditioning regimen consisted of fludarabine 30mg/m2/day for 6 days, two days of targeted-dose intravenous busulfan (target C_ss 850ng/ml) and rabbit anti-thymocyte globulin (10mg/kg/day for 4 days beginning on day minus 4). The median age was 18 yrs (range 9-40 yrs) and transplant indications were recurrent vaso-occlusive crises, acute chest syndrome and cerebrovascular events. There were nine males and seven female patients. The stem cell source was peripheral blood in 14 (88%) and bone marrow in 2 patients (12%). Fourteen patients (88%) are considered cured with a median follow up of 24 months (6-49 mths). Nine (64%) of these patients have complete donor chimerism (DC) while five (36%) patients have stable mixed chimerism ranging from 67-90%. Two patients (12%) rejected their grafts with rapid loss of DC by 6 months and are alive with their original SCA manifestations. Acute graft versus host disease (Grade III) occurred in only one patient and resolved with therapy. Of the 6 post pubertal female patients, only one has resumed normal periods following the transplant. The five others (median age 24yrs, range 16-27yrs) developed amenorrhea post transplant with high FSH and LH levels and have been started on hormonal replacement therapy. No tests of gonadal function in the male patients are available. Busulfan-based RIC HSCT is curative and appears to be safe even in older patients with SCA but gonadal damage continues to remain a long term complication. There may be a window of opportunity to further reduce busulfan exposure in an attempt to preserve fertility. If such a strategy is used, novel measures to induce immune tolerance may also be required to minimize rejection.