Preservation of Ovarian Function after Hematopoietic Cell Transplantation (HCT): More Possible Than We Thought?

Background: Gonadal failure is a major long term health and quality of life concern in survivors of HCT. While ovarian dysfunction is nearly universal following myeloablative (MA) conditioning, it is likely variable after reduced-intensity conditioning (RIC) HCT where there are substantial differences in intensity. GnRH agonists, such as leuprolide, have been shown to decrease the rate of ovarian failure in those receiving conventional chemotherapy, but little is known about leuprolide’s effectiveness in the HCT population. We sought to determine the impact of leuprolide on ovarian function in recipients of MA conditioning and evaluate the incidence of ovarian failure in women undergoing RIC HCT.

Methods: Post-menarchal females <50 years of age who were scheduled to undergo HCT were recruited for the study. Adequate ovarian function, as defined by a baseline FSH level less than 40 and normal menstrual cycles, was required. Those undergoing MA HCT were treated with leuprolide (long-acting 11.25mg IM once + short-acting 0.2mg daily for 14 days) prior to conditioning. MA regimens were variable. Those undergoing RIC HCT were observed with no intervention. RIC regimens generally included cyclophosphamide (50 mg/kg), fludarabine (150-200 mg/kg) and TBI (200-300 cGy).  FSH was measured at baseline, Day 100, 180, 1 year, and 2 years following transplant.

Results: A total of 19 women were included (9 in the intervention arm and 10 observation only). In the intervention arm (age 17 to 45 years), 6 of the 7 evaluable patients had malignancies and one had an inherited bone marrow failure syndrome (IBMFS). The observation arm (age 13 to 45 years) included 6 patients with aplastic anemia, 1 with a hemoglobinopathy, 1 with a metabolic disorder, 1 with an IBMFS, and a single patient with a malignancy. Two patients in the intervention arm were not evaluable (one died 34 days following HCT and the other was lost to follow-up). There were no adverse events related to leuprolide therapy. Five out of the 7 intervention patients were heavily pretreated with chemotherapy for their malignant conditions prior to HCT. The incidence of ovarian failure in women undergoing MA transplant who received leuprolide was 57% (4 out of 7 subjects) at day +180 compared to historically reported rates of ovarian failure of >90% after MA transplant. In RIC HCT, the ovarian failure rate was 20% (2 out of 10 subjects).

Conclusions: Leuprolide is not only safe, but it appears to have a substantial impact on ovarian function preservation after MA conditioning. These results were found despite the majority of these women having received significant gonadotoxic chemotherapy prior to being referred for HCT. In addition, early data demonstrate that RIC with cyclophosphamide, fludarabine and low-dose TBI is associated with a low risk of ovarian failure. Further studies are needed to confirm these exciting findings.