CAR T-Cell Therapy Outcomes Are Not Impacted by Baseline Renal Function, Study Finds

Baseline renal function did not impact clinical outcomes for patients treated with chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), according to a recent analysis. Patients with acute kidney injuries (AKIs), however, experienced worse clinical outcomes.

The findings were published in an article in press in the journal Transplantation and Cellular Therapy.

The approvals of 3 CD19-targeted CAR T-cell therapies (axicabtageneciloleucel [axi-cel], tisagenlecleucel [tisa-cel], and lisocabtagenemaraleucel [liso-cel]) have expanded the treatment landscape for R/R DLBCL following disease progression on chemoimmunotherapy. But clinical trials of CAR T-cell therapy generally exclude patients with renal impairment (RI), despite chronic kidney disease often appearing during pretreatment evaluations in real-world settings. 

Kidney dysfunction contributes to overall poor health and can impact lymphodepletion, which is typically used ahead of CAR T-cell therapy treatment. It is recommended that patients with a creatinine clearance of less than 60 mL/minute receive reduced doses of fludarabine, a key component of lymphodepletion, but there are concerns about a potential impact on CAR T-cell treatment efficacy.

The retrospective, single-center study assessed outcomes in 166 patients treated with CAR T-cell therapy, 17 of whom (10.2%) had baseline RI and 149 (89.8%) who did not have RI. A total of 22 patients (13%) received tisa-cel, and 144 (87%) received axi-cel. The mean patient age was 65 years, 81% of patients had advanced DLBCL, and 58% had high-intermediate or high International Prognostic Index scores.

Median progression-free survival (PFS) time was 8.9 months in patients with RI and 9.9 months in those without baseline RI at a median follow-up of 13 months. Overall survival (OS) for patients with RI was a median of 10.4 months, and median OS was not reached in patients without baseline RI. There were no significant differences between outcomes in patients given a reduced dose of fludarabine and those who received full doses, potentially because decreased excretion resulted in similar exposure in reduced-dose patients as in those receiving full doses. More research on optimal fludarabine dosing is also needed, as the recommended standard dose differs between CAR T-cell therapies.

AKIs occurred in 39 (23%) of patients in the study between days –5 and 30: 5 occurring between days –5 and 0, and 34 (87%) occurring after infusion with CAR T cells. Most AKIs (69%) were grade 1, 13% were grade 2, and 18% were grade 3. The most common AKI was decreased renal perfusion, and cytokine release syndrome (CRS) contributed to 44% of AKIs overall. Patients with baseline RI were not significantly more or less likely to develop any grade of AKI than patients without baseline RI.

Those who experienced AKI after CAR T-cell infusion had worse clinical outcomes compared with patients who did not experience any AKI. This included higher peak inflammatory cytokine levels and more intensive care unit admissions. Mean PFS in patients who experienced AKI of any grade was 3.2 months, vs 19.6 months in patients with no AKI. Median OS was 9.8 months in patients with AKI and was not reached in patients without AKI. Those with severe AKI had the worst outcomes, with a median PFS of 0.8 months in those with grade 2 or 3 AKI vs 6 months in patients with grade 1 AKI. Patients with grade 2 or 3 AKI had a median OS of 0.9 months, while those with grade 1 AKI had a median OS of 14.6 months.

“The association that we observed between AKI and shorter PFS and OS likely relates to AKI being a markerfor patients who have high levels of inflammation, poor tolerance of fluid shifts, multiorgan illness, and lymphoma at higher risk of relapse after CAR T cell therapy,” the authors wrote.

The authors also highlighted 2 patients with end-stage renal disease (ESRD) who were dialysis-dependent before CAR T-cell treatment: 1 DLBCL patient from the cohort, and 1 who was not part of the cohort but had mantle-cell lymphoma treated with brexucabtagene autoleucel. One had a complete response to therapy and remained in remission until 271 days post infusion, and the other partially responded to CAR T-cell therapy but experienced disease progression by day 90 after infusion.

The findings show that both renal outcomes and CAR T-cell therapy efficacy were unaffected by baseline RI status in this cohort, although AKI during treatment was associated with worse clinical outcomes. CAR T-cell therapy was also possible for patients with ESRD with careful preinfusion lymphodepletion.

“CD19-directed CAR T-cell therapy is feasible in patients with RI including dialysis dependent cases with careful planning of lymphodepletion,” the authors concluded.“However, optimal lymphodepletion strategies still need to be determined regardless of renal function.”

Reference

Wood AC, Perez A, Arciola B, et al. Outcomes of CD19 targeted CAR T-cell therapy for patients with reduced renal function including dialysis. Transplant Cell Ther. Published online September 26, 2022. doi:10.1016/j.jtct.2022.09.009