Optimizing fludarabine: The impact of fludarabine renal dose adjustment during lymphodepletion prior to CAR-T cell immunotherapy in multiple myeloma patients

Abstract Background: Fludarabine and cyclophosphamide is a standard-of-care lymphodepletion regimen for chimeric antigen receptor (CAR) T-cell therapy, including ciltacabtagene autoleucel and idecabtagene vicleucel for relapsed or refractory multiple myeloma (RRMM). Clinical trial protocols for CAR T-cell therapy have incorporated renal dose adjustments for fludarabine according to the recommendations outlined in its package insert. However, institutional practices differ from these recommendations, such as at Dana-Farber Cancer Institute (DFCI) and Brigham and Women's Hospital (BWH) where patients with CrCl 50 to 69 mL/min continue to receive full-dose fludarabine, while those with CrCl 30 to 49 mL/min receive a 40% dose reduction. This study aimed to compare the safety and efficacy of varying fludarabine renal dosing practices in multiple myeloma (MM) patients undergoing lymphodepletion prior to CAR T-cell therapy. Methods: This study was a single-site, retrospective medical record review that included adult patients with RRMM who received fludarabine and cyclophosphamide for lymphodepletion prior to CAR T-cell therapy with ciltacabtagene autoleucel and idecabtagene vicleucel at DFCI and BWH. Patients were required to have documented follow-up of at least 30 days following the CAR T-cell infusion. Data collected on patients who received CAR T-cell therapy from August 2021 to June 2024 were compared among three patient cohorts based on renal function: CrCl ≥70 mL/min, CrCl 50 to 69 mL/min, and CrCl 30 to 49 mL/min. The primary outcome was the rate of adverse events within 30 days following CAR T-cell infusion, and secondary outcomes evaluated efficacy. Continuous measures were summarized as median and inner quartile range (IQR), and categorical variables were summarized as proportions. Response outcomes and other categorical variables were tested for association with continuous and other categorical variables using Wilcoxon rank-sum (or Kruskal-Wallis for three or more groups) or Fisher's exact tests, respectively. Responses were reported as proportions with 95% exact binomial confidence intervals. Results: Of the 101 patients included in the study, CRS occurred in 82% of patients in the CrCl ≥70 mL/min group (grade 1 or 2, 99%; grade 3, 1%), 100% of patients in the CrCl 50 to 69 mL/min group (all grade 1 or 2), and 82% of patients in the CrCl 30 to 49 mL/min group (all grade 1 or 2; p = 0.15). ICANS occurred in 10% of patients in the CrCl ≥70 mL/min group (grade 1 or 2, 71%; grade 3, 29%), 12% of patients in the CrCl 50 to 69 mL/min group (all grade 3 or 4), and 0% of patients in the CrCl 30 to 49 mL/min group (p = 0.62). The rates of infection were 14% in the CrCl ≥70 mL/min group, 12% in the CrCl 50 to 69 mL/min group, and 18% in the CrCl 30 to 49 mL/min group, respectively (p = 0.90). Patients in the CrCl ≥70 mL/min, CrCl 50 to 69 mL/min, and CrCl 30 to 49 mL/min groups had comparable rates of new onset or worsened anemia (74% vs. 76% vs. 73%; p >0.99), thrombocytopenia (84% vs. 71% vs. 91%; p = 0.40), and neutropenia (52% vs. 59% vs. 64%; p = 0.73), respectively. The median percent decrease in ALC was 94.7% in the CrCl ≥70 mL/min group, 97.7% in the CrCl 50 to 69 mL/min group, and 96.5% in the CrCl 30 to 49 mL/min group (p = 0.45). The ORR was 88% in the CrCl ≥70 mL/min group, 94% in the CrCl 50 to 69 mL/min group, and 91% in the CrCl 30 to 49 mL/min group (p = 0.87). In all three groups, the majority of patients had a complete response (CR; 34% vs. 47% vs. 36%), followed by a stringent complete response (sCR; 22% vs. 24% vs. 36%). The median PFS was 12 months (95% CI, 10 to 20), 19 months [95% CI, 19 to not reached (NR)], and NR (95% CI, 17 to NR; p = 0.13), and the median OS was NR (95% CI, 26 to NR), NR (95% CI, NR to NR), and 27 months (95% CI, 27 to NR; p = 0.33) in the CrCl ≥70 mL/min, CrCl 50 to 69 mL/min, and CrCl 30 to 49 mL/min groups, respectively. Conclusion: This study validated the practice at DFCI and BWH in maintaining full-dose fludarabine for patients with CrCl 50 to 69 mL/min, as it showed no significant increase in risk of adverse events. Patients with CrCl 30 to 49 mL/min receiving dose-reduced fludarabine also maintained efficacy outcomes.