Ovarian Function Following Reduced Intensity Conditioning (RIC) Allogeneic Hematopoietic Cell Transplantation (HCT): How Fertile is the Future?

BackgroundThe potential for ovarian recovery following RIC HCT in patients who do not have pre-existing ovarian failure is poorly understood. Previous investigations show that HCT confers high risk of premature ovarian insufficiency (POI) even in RIC. Cyclophosphamide equivalent dose (CED) calculations are increasingly used to standardize gonadotoxic chemotherapy exposure and counsel patients regarding future POI risk.MethodsFemales with immune deficiency or dysregulation enrolled on either of two protocols at our center (NCT02579967, NCT03663933) were included if they were either prepubertal or postpubertal and premenopausal pre-HCT, with minimum 1 year follow up. Patients received RIC with pentostatin, low dose cyclophosphamide (total 24-40mg/kg over 8 days), and 2 days of pharmacokinetically-dosed busulfan, along with high dose post-transplantation cyclophosphamide (total 100mg/kg). Endocrine evaluations and, for adults, gynecological evaluations, were performed pre-HCT and yearly post-HCT.ResultsOf 16 patients, 5 were prepubertal (age range 7-11 years), 5 were adolescents (age range 15-19 years), and 6 were 30 years or older (range 30-49), Figure 1. Two patients had received prior chemotherapy for lymphoma treatment (P6, P12). Four patients underwent successful oocyte harvest prior to HCT, while one had undergone unsuccessful in vitro fertilization (IVF) years prior (P14). Median CED associated with HCT was 6.6g/m2 (range 4.9-7.4), Figure 2. With median follow up 4 years (range 1.5-7.2), none of the patients received further gonadotoxic therapies and there was no chronic graft-versus-host disease. One spontaneous conception with live birth occurred 4 years post-HCT despite laboratory evidence of POI at 1 year (P7), while P11 underwent 3 failed IVF attempts 4 years post-HCT. There were no other conception attempts. Three of 5 girls who were prepubertal at HCT had spontaneous menarche, while the other 2 began hormone replacement proactively at age 13 years in the setting of low bone mineral density. Importantly, in this group, anti-Mullerian hormone (AMH) was undetectable in 1, extremely low in 3, and reduced to the diminished ovarian reserve range in P3, who received a lower CED than the others. Of 5 patients who underwent HCT in adolescence, the hypothalamic-pituitary-ovarian axis recovered in P6 and P7 at 3 years, and P8 at 6 years, but not P9 or P10 as of 5 and 3 years post-HCT respectively, Figure 3. All 6 older adults have POI or acute menopause post-HCT.ConclusionsPOI is common but not universally permanent following RIC HCT. Because baseline AMH was not checked routinely prior to HCT, it is unknown whether lifelong pre-HCT illness contributed to reduced ovarian reserve even pre-HCT. Our results suggest that pre-HCT fertility preservation should be offered regardless of regimen intensity, but also that there is potential for recovery in some patients years after HCT.