Fertility and Sexual Development Outcomes in Pubertal and Post-Pubertal Children and Young Adults after Myeloablative Conditioning (MAC) and Familial Haploidentical T-Cell Depleted Allogeneic Stem Cell Transplantation
Authors: Mouehla Hanif , Siegel Maya , Schaefer Edo , Talano Julie-An , Shenoy Shalini , Moore Theodore B. , Milner Jordan , Duncan Christine , Panarella Anne , Harrison Lauren , Morris Erin , Cairo Mitchell S. 
Published: December 2024

Background: Sickle cell disease (SCD) leads to chronic end-organ damage and reduced life span. Advancements in transplantation protocols and graft manipulation have enabled the use of other allogeneic donor sources as a curative measure for high-risk patients. We previously reported the safety and efficacy of familial haploidentical transplants (FHI) in pediatric SCD population with 100% engraftment (Cairo et al, JAMA Peds, 2020). Traditional myeloablative conditioning (MAC) regimens are considered necessary to improve engraftment but may lead to severe long-term effects such as infertility and/or gonadal dysfunction including ovarian dysfunction in females, lower sperm count in males, and delayed sexual development (Dalle, C R Biol, 2013). In post-pubertal females, primary ovarian insufficiency is diagnosed with low estrogen (&lt;15 pg/mL) and high FSH concentrations (&gt;25 mIU/mL); Anti-Müllerian hormone (AMH) correlates with ovarian reserve. In post-pubertal males, high LH (&gt;8.6 mIU/mL) with elevated levels of FSH (&gt;12.4 mIU/mL), and low testosterone levels (&lt;250 ng/dL) may indicate primary (hypogonadotropic) hypogonadism and infertility. Walters et. al (BBMT, 2010) reported that 50-75% of SCD recipients of HLA-matched sibling related BMT had evidence of decreased ovarian or testicular function. Due to a lack of available research, studies of fertility and sexual development focused on SCD haploidentical recipients are critically needed.
Objective: To determine the effects of MAC followed by FHI T-Cell depleted (TCD) AlloSCT on the fertility and sexual development of pubertal or post-puberal patients with high-risk SCD.
Design/Methods: We reviewed the results of SCD recipients ages 12-29 who underwent FHI AlloSCT following MAC regimens (busulfan, cyclophosphamide, thiotepa) for SCD, from 2012 to 2022 (NCT01461837 and NCT02675959, under IND14359 and IND 127812). Patients with high-risk SCD (stroke, ≥2 acute chest syndrome in the past 2 years, ≥3 pain crises in the last 2 years, abnormal TCD study, ≥1 silent infarct lesion on MRI) were eligible for transplant. Between October 2012 and July 2022, 12 patients were available for analysis. Multiple hormone levels were collected and analyzed including LH, FSH, testosterone (males), estradiol, and AMH levels (females) from baseline to year 6 post FHI AlloSCT. Follow-up sexual history was also obtained.
Results: Twelve patients were eligible for this analysis, with a mean age of 16.4 years (SD±3.1). Male to female ratio was 1:1, with a mean time of 4.0 years post-transplant follow-up. Pre-transplant hormonal evaluation for female patients were as follows, normal FSH (mean: 3.7 mIU/mL, SD±1.2), estradiol (mean: 127.3 pg/mL, SD±66.0), and AMH (mean: 2.8 ng/mL, SD±2.1). 1-year post-transplant mean FSH levels were significantly abnormal (with evidence of ovarian dysfunction) 97.0 mIU/mL (SD±11.3) with an estradiol of &lt;11 pg/mL. In year 2 post-transplant females, mean FSH increased to 211.5 mIU/mL (SD±210.6), and a slight improvement in ovarian reserve was indicated by mean estradiol of 12 pg/mL (SD±1). However, from year 3 and beyond patients had low estradiol levels (&lt;10 pg/mL). FSH levels remained high post-transplant, although mean FSH levels in years 4 and 5 were unexpectedly low at 59.4 mIU/mL and 17.3 mIU/mL, respectively. Mean AMH was also low at 0.01 (SD±0.007) 1-year post-transplant. Males had a mean baseline LH of 8.3 mIU/mL (SD±3.2), FSH of 4.4 mIU/mL (SD±2.9), and testosterone of 355 ng/dL. 1-year post-transplant both mean LH and FSH levels significantly increased to 14.0 mIU/mL (SD±10.5) and 19.6 mIU/mL (SD±16.8), respectively, suggesting testicular dysfunction. In years 2 and 3, this trend persisted, indicating some degree of hypogonadism. Similarly to females, at year 4 post-transplant there was an improvement in both LH (mean: 7.4 mIU/mL, SD±2.7) and FSH (mean: 7.0 mIU/mL, SD±4.4), with similar values at year 6. Testosterone levels mostly stayed normal post-transplant.
Conclusions: Our results show that after MAC followed by FHI T-Cell depleted (TCD) AlloSCT for high-risk SCD patients, most females will demonstrate early signs of infertility. Yet, males seem to be protected to some degree. Potentially, 4 years post-transplant there is some hormonal recovery, which might serve as a sperm and ovary preservation window. More studies are needed to further investigate infertility risk in this population.