Risk of Impaired Ovarian Reserve in Women Exposed to Fludarabine-Based Conditioning Prior to Cell Therapies

Objectives Cell-based therapies, including chimeric antigen receptor T-cell, are emerging as promising treatments for refractory systemic autoimmune diseases such as systemic lupus erythematosus (SLE). These therapies require lymphodepletion, a conditioning regimen typically consisting of fludarabine and cyclophosphamide, to induce immunosuppression and enhance cell expansion. While cyclophosphamide’s gonadotoxicity has been described in other settings, the effects of fludarabine-based conditioning remain poorly characterized. This is particularly important for women with SLE, who are often of reproductive age and may have non-gonadotoxic alternatives. Therefore, we conducted a systematic review to synthesize available evidence regarding the effect of fludarabine-based conditioning on ovarian function in women receiving cell therapies.

Methods We systematically searched PubMed, Embase, and Web of Science from January 1997 to October 2025 for keywords related to fludarabine, fertility, ovarian reserve, and cell therapies [ie, hematopoietic stem cell transplantation (HSCT), mesenchymal stem/stromal cell, or adoptive cell therapy]. Data were extracted by 2 independent reviewers for relevant subgroups or individual patients, including reproductive biomarkers, menstrual status, and pregnancies at last follow-up. Risk of bias was assessed using the Newcastle-Ottawa Scale. The review was conducted in accordance with PRISMA guidelines.

Results Of 253 records, 9 met inclusion criteria, reporting reproductive outcomes in adult women treated with fludarabine ± cyclophosphamide ± total body irradiation (TBI) without other alkylating agents. Included studies comprised 4 case reports, 4 case series, and 1 cohort study. Collectively, 50 women were analyzed, 32 of whom were exposed to fludarabine and cyclophosphamide without TBI. Only 4 did not receive cyclophosphamide. One study described patients with autoimmune disease (n=5), all of whom had SLE. Cumulative doses of fludarabine and cyclophosphamide ranged from 75-200 mg/m2 and 50-160 mg/kg respectively. Many patients (43-100%) exhibited premature ovarian insufficiency at last follow-up (3-60 months), with AMH levels generally below 0.5 ng/mL (Table 1). Amenorrhea was common, occurring in 58%. However, longitudinal data from several reports suggested delayed recovery of ovarian function. Six pregnancies occurred overall, all after fludarabine + cyclophosphamide ± TBI, including 2 via assisted reproductive technologies.

Conclusion Available evidence suggests that exposure to fludarabine ± cyclophosphamide ± TBI is associated with reduced ovarian function, although partial or complete recovery may occur over time. However, the independent effect of fludarabine remains difficult to assess due to concurrent exposures in most regimens. Our findings underscore the need for comprehensive study of women with autoimmune diseases to better define gonadotoxicity related to fludarabine-based conditioning in cell therapy.