Female Reproductive Health Outcomes after Hematopoietic Cell Transplantation for Sickle Cell Disease: Is Reduced Intensity Better Than Myeloablative Conditioning?

Abstract

Curative therapy for sickle cell disease (SCD) through hematopoietic cell transplantation (HCT) is associated with a high level of risk for treatment-related gonadal dysfunction and future infertility. Both the myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens used for SCD HCT are considered to carry a high risk for ovarian damage. Cyclophosphamide equivalent doses (CEDs) are thought to correlate with the degree of gonadal damage in pediatric oncology patients. We aimed to evaluate ovarian outcomes previously reported from our center, characterize the conditioning regimens as MAC or RIC, and calculate the CED for each regimen. The ovarian outcomes diminished ovarian reserve (DOR), as determined by an anti-Müllerian hormone (AMH) below the normal limits for age and assay or <5%, and premature ovarian insufficiency (POI), defined as a follicle-stimulating hormone (FSH) level >40 mIU/ML, are presented by conditioning regimen from 3 clinical studies from our center (2 published and 1 presented as an abstract in 2022). The studies were not mutually exclusive of patients. CEDs were calculated for each regimen. The CED ranged from 3388 to 9705 mg/m² for MAC regimens and from 5600 to 18,750 mg/m² for RIC regimens. DOR was observed in all regimens; however, in one study 2 patients had normal AMH levels after a fludarabine/melphalan regimen, and 1 patient had a normal AMH level after a fludarabine/melphalan/thiotepa regimen. Rates of POI were more variable and ranged from 40% to 100% after MAC regimens and from 0 to 100% after RIC regimens. Female patients with SCD who undergo HCT have very high rates of DOR after both MAC HCT and RIC HCT. Two of the 3 RIC regimens evaluated had higher CEDs than were seen in any of the MAC regimens evaluated. Rates of POI were more variable but may increase with time from transplantation. All SCD patients need to be counseled about the risk of infertility and provided information about fertility preservation.

Keywords: Diminished ovarian reserve; Female reproductive health outcomes; Hematopoietic stem cell transplantation; Infertility; Myeloablative; Premature ovarian insufficiency; Reduced intensity; Sickle cell disease.