The fertility outcome in a cohort of SCD patients undergoing haploidentical allogeneic stem cell transplant using NMA regimen. Free

Abstract title: The fertility outcome in a cohort of SCD patients undergoing haploidentical allogeneic stem cell transplant using NMA regimen.

Introduction: Fertility preservation is an important consideration for individuals with sickle cell disease (SCD) who may face reproductive challenges. While SCD itself does not directly affect fertility, certain complications and its treatment such as hematopoietic cell transplantation (HCT) can impact the reproductive health in SCD patients. HCT is a potential curative therapy for SCD, however, one of the negative outcomes is the premature gonadal failure and infertility specially with more intensive chemotherapy regimen. Previously we have reported the reproductive outcome of adult SCD patients who underwent MRD NMA allogeneic HCT with 80% of female and 50% of male patients retain fertility potential. In this study, we report the fertility outcome of SCD patients undergoing haploidentical HCT using NMA conditioning.

Methods: After IRB approval, we retrospectively collected the data for all SCD patients who underwent haploidentical allogeneic HCT in our center. These patients were treated under study protocol as part of Vanderbilt international consortium of haploidentical transplant for sickle cell disease patients. Inclusion: All adult and adolescent SCD patients aged 14 or more who underwent non-myeloablative haploidentical allogeneic HCT with minimum 1 year follow up post-transplant. Patients with graft failure or those who died or lost to follow up post-transplant were excluded.

Transplant regimen: all patients received hydroxyurea 30 mg/kg and hypertransfusion every 3 weeks for 2 months pre transplant. The conditioning regimen consisted of Thiotepa 10mg/kg, ATG 4.5 mg /kg, Fludarabine 30 mg/m²x5 days, and TBI 200cGy. GVHD prophylaxis with post-transplant cyclophosphamide 50mg/kg x 2 days, sirolimus for 1 year and MMF for 30 days. Pre transplant fertility preservation were provided to all patients. Male patients underwent sperm cryopreservation after holding hydroxyurea for 3 months and female patients referred to specialized oncology fertility clinic for either oocyte cryopreservation or treatment with GnRH agonists pre transplant.

Primary objective of the study is to assess post-transplant infertility (defined by either inability to conceive for married patients, or development of azospermia for male patient or secondary amenorrhea for female patients). Secondary objectives is to compare the fertility outcome using NMA regimen Campath / TBI 3Gy for MRD transplant to haploidentical NMA presented in this study.

Results: a total of 22 patients underwent the haploidentical HCT from July 2019 till May 2024, 13 male patients and 7 female patients, age range between 14-36 years with median age of 20.4 years. Genotype was SS in 20 patients and SB⁰ in 2 patients. The indications of transplant included stroke in 9 patients, recurrent ACS in 6 patients, and recurrent VOCs in 7 patients. Median follow up is 2 years (1 - 5) and all patients have stopped their immunosuppressive medications except one.

For male patients 7 out of 13 (54%) did the semen analysis 1 year post transplant all of them had azospermia. For female patients 2 out of 7 (28.5%) patients regain the menstrual cycles spontaneously one at 5 years and the other one at 6 months post-transplant. 5 patients (71%) had secondary amenorrhea, 3 out of them regain menstruation with hormonal therapy replacement. None of the married patients (2) were able to conceive post-transplant.

For the hormonal profile post-transplant: for male patients testosterone was normal in 20 patients, low in one patient and not done in one patient. For female patients; all had Follicle-stimulating hormone and luteinizing hormone at postmenopausal level and Anti-Mullerin hormone was done in 2 patients and it was found to be low with associated amenorrhea

In conclusion: in this small cohort of SCD patients the infertility rate is very high reaching 100% for male patients and 77.5% for female patients. Although this regimen is NMA but there are different factors could explain this high rate including post-transplant cyclophosphamide, pre transplant disease related complications (VOCs, iron overload) or treatment related (hydroxyurea). All adult patients should be counseled for fertility preservation methods before undergoing curative allogeneic HCT regardless of what conditioning regimen be used.