Fertility and CAR T-cells: Current practice and future directions

Abstract

Chimeric antigen receptor (CAR) T-cells serve to overcome chemotherapeutic resistance and have been proven to be highly effective in B-cell hematologic malignancies. Although initial use has been in patients with multiply relapsed/refractory disease, as CAR T-cells are used earlier in the treatment paradigm, it will be important to explore implications of this novel therapy on cancer late-effects. We sought to assess the current framework for considerations of fertility surrounding CAR T-cell use and identify opportunities for education and future research. To assess current practice patterns regarding post-CAR T-cell fertility, peri-CAR T-cell fertility guidance, utilization of fertility preservation surrounding CAR T-cell administration and identify future areas of research, a cross-sectional survey assessing practice patterns regarding fertility counseling and outcomes surrounding CAR T-cell therapy was distributed electronically to approximately 300 Center for International Blood and Marrow Transplant Research medical centers treating patients with CAR T-cell therapy in the United States and internationally between October 12 and November 2, 2021. One medical provider was asked to complete the study survey on behalf of their institution. We received 96 survey responses, of which 66 centers utilized CAR T-cells and provided at least partial responses that were used for the primary analysis. Centers were varied in demographics, experience in administering CAR T-cells, and aspects of patients receiving CAR T-cells. Eighteen centers exclusively treated pediatric patients, and patients at these centers were more likely to be treated for B-cell acute lymphoblastic leukemia. Seven pregnancies and 5 live births after CAR T-cells were reported from 6 centers (1 pediatric-only). Most centers had no established guidelines in place regarding fertility preservation in the peri-CAR T-cell period or regarding recommendations for avoiding pregnancy/fathering a child after receiving CAR T-cells. Areas for future research were elicited from responding centers and categorized into 3 broad themes, including: standardized peri-CAR T-cell fertility guidelines; long-term fertility outcomes after CAR T-cell therapy; impact of CAR T-cells on a developing fetus; and determining the relevance of studying fertility in patients who receive CAR T-cells. We identified a high degree of variability in peri-CAR T-cell guidance on avoidance of pregnancy/fathering a child, as well as a wide-range of practices surrounding referral for fertility preservation, the latter of which may be likely due to the fact that patients receiving CAR T-cells in the present era are likely multiply relapsed/refractory. In summary, this is the first report of several live-births following CAR T-cells, which highlights the important need for further research in CAR T-cell therapy and fertility, with a host of novel research questions identified.

Keywords: CAR T-cells; Cellular therapy; Fertility preservation; Immunotherapy.

Figure 1.

Basic characteristics of responding centers. (A) U.S. States represented among survey respondents along with number of responses from the state. (B) Number of centers with first CAR T-cell infusion in a given year. (C) Approximate number of CAR T-cell infusions per center (averaged over prior 3 years). (D) Centers focusing on pediatric CAR T-cell infusions versus adults versus a mixture. A center was considered to be “pediatric” if the oldest age in the range of ages treated was 35 or lower. A center was considered to be “adult only” if the youngest age in the range of ages was over 18. Centers meeting neither criteria were considered to be “mixed.” (E) Number of centers with specific diseases comprising the majority of indications (at least 50%) for CAR T-cell infusion. “Multiple” denotes centers where no single disease constituted at least 50% of indications for CAR T-cell infusion. MM indicates multiple myeloma; NHL, non-Hodgkin lymphoma. (F) Centers by the percentage of infusions which were a commercial CAR T-cell product (as opposed to an investigational product administered on a clinical trial).

Figure 2.

Factors affecting fertility and family planning after CAR T-cell infusion. Centers where a majority (>50%) of (A) male and (B) female patients are either prepubertal or postpubertal. For unclear reasons, a minority of centers reported neither prepubertal nor postpubertal patients as being a majority population. (C) Cyclophosphamide-equivalent dose given for lymphodepletion (LD) by centers. (D) Guidelines to avoid fathering a child after CAR T-cell infusion. (E) Guidelines to avoid pregnancy after CAR T-cell infusion. (F) Frequency of discussing fertility preservation before CAR T-cell infusion. (G) Peri-CAR T-cell referral patterns for fertility counseling. (H) Proportion of centers with a fertility preservation program. (I) Proportion of centers where fertility preservation procedures are covered by insurance.

Figure 3.

Fertility preservation procedures available at CAR T-cell centers. Brief graphical description of 5 most common fertility preservation procedures and the frequency with which they are available at CAR T-cell centers.

Figure 4.

Proposed algorithm to consider fertility preservation discussions with patients receiving CAR T-cell therapy.