Survey on fertility management and outcomes after cellular therapies, on behalf of the EBMT cellular therapy and immunobiology working party

Abstract

Abstract Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in the treatment of B-cell and plasma cell hematologic malignancies. Initially reserved for patients with refractory disease, it is now being introduced earlier in the treatment course. Moreover, promising evidence is emerging for its application in autoimmune disorders. As CAR T-cell therapy becomes more widely used, it is essential to understand its long-term effects, particularly regarding survivorship and late complications such as the impact on fertility. Importantly, both prior lines of therapy and the lymphodepleting regimens often include alkylating agents, known to impair ovarian reserve and spermatogenesis. Despite the expanding clinical use, data on its impact on fertility remain limited, and no formal guidelines currently address fertility preservation in this setting. To fill this gap, we conducted a cross-sectional survey on behalf of the Cellular Therapy and Immunobiology Working Party (CTIWP) of the EBMT to assess current practices related to fertility counselling and preservation in patients undergoing CAR T-cell therapy. Survey was launched to 341 centers from January until April 2025 and 63 centers (19%) provided data and were included in the primary analysis. Responding centers varied widely in geographic distribution across Europe, CAR T cell experience and patient demographics. Lymphoid malignancies were the most common indications for CAR T cell therapy. Most centers initiated CAR T-cell programs in 2019, treating a median of 56 patients per center. Although fertility counselling is commonly provided prior to treatment, 11 centers (17%) reported not to routinely inform patients of the potential impact of CAR T-cell therapy on fertility. The majority of centers offered fertility preservation procedures, in particular 49 centers (78%) for female patients and 50 (79%) for male patients. Surprisingly, 41% of the reporting centers do not routinely provide psychological support during CAR T-cell therapy. The primary factors prompting fertility preservation referrals included patients' desire to conceive (43%) and young age (39%). In contrast, the most common reasons for not referring patients were the urgency of treatment in aggressive disease (38%) and a history of extensive prior chemotherapy (more than three lines) (36%). Among male patients, natural semen collection and cryopreservation was the most commonly used method (63%). For female patients, oocyte cryopreservation (43%) and ovarian tissue cryopreservation (40%) were the most frequent strategies. Five centers reported a total of seven pregnancies, which resulted in four live births. Two of these live births occurred in female patients who had previously undergone oocyte cryopreservation, and two additional pregnancies were ongoing at the time of the survey; one miscarriage was reported in a female patient. Endocrinologic follow-up after CAR T-cell treatment was highly variable. Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) were the most frequently monitored markers in women (90% and 92%, respectively), whereas only 36% routinely assessed Anti-Müllerian Hormone (AMH). In men, testosterone was the most commonly monitored marker (93%). Most female patient did not receive ovarian functional rest treatment as majority of centers (62%) reported that they never recommend these strategies. Our findings highlight substantial heterogeneity in fertility-related practices surrounding CAR T-cell therapy. This variability likely reflects both the historical focus of CAR T-cell therapy on heavily pretreated patients with physiologically limited fertility potential. However, as CAR T-cell therapy moves earlier in the treatment algorithm and is increasingly administered to younger patients, fertility preservation must become a routine part of care. Importantly, this study includes some of the first documented cases of live births following CAR T-cell therapy, emphasizing the need for more comprehensive research into its long-term reproductive effects. Establishing formal guidelines with standardized fertility counselling and preservation protocols will be essential to ensure equitable, informed, and proactive fertility care for patients undergoing this transformative treatment.