Outcomes of CD19-Targeted Chimeric Antigen Receptor T Cell Therapy for Patients with Reduced Renal Function Including Dialysis

Abstract

Patients with renal impairment (RI) are typically excluded from trials evaluating chimeric antigen receptor (CAR) T cell therapies. We evaluated the outcomes of patients with RI receiving standard of care (SOC) CAR T cell therapy for relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this retrospective, single-center cohort study of patients with R/R DLBCL treated with SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after 2 or more prior lines of therapy, renal and survival outcomes were compared based on RI and fludarabine dose reduction (DR) status. RI was defined by an estimated glomerular filtration rate <60 mL/min/1.73 m² as determined by the Modification of Diet in Renal Disease equation using day -5 creatinine (Cr) values. Acute kidney injury (AKI) was identified and graded using standard Kidney Disease: Improving Global Outcomes criteria. Renal recovery was considered to occur if Cr was within .2 mg/mL of baseline by day +30. Fludarabine was considered DR if given at <90% of the recommended Food and Drug Administration label dose. Among 166 patients treated with CAR T cell therapy were 17 patients (10.2%) with baseline RI and 149 (89.8%) without RI. After CAR T cell infusion, the incidence of any grade AKI was not significantly different between patients with baseline RI and those without RI (42% versus 21%; P = .08). Similarly, severe grade 2/3 AKI was seen in 1 of 17 patients (5.8%) with baseline RI and in 11 of 149 patients (7.3%) without RI (P = 1). Decreased renal perfusion (28 of 39; 72%) was the most common cause of AKI, with cytokine release syndrome (CRS) contributing to 17 of 39 AKIs (44%). Progression-free survival (PFS) and overall survival (OS) did not differ between patients with RI and those without RI or between those who received standard-dose fludarabine and those who received reduced-dose fludarabine. In contrast, patients with AKI had worse clinical outcomes than those without AKI (multivariable PFS: hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2 to 3.7; OS: HR, 3.9; 95% CI, 2.1 to 7.4). Notably, peak inflammatory cytokine levels were higher in patients who experienced AKI. Finally, we describe 2 patients with end-stage renal disease (ESRD) on dialysis who received lymphodepletion and CAR T cell therapy. Baseline renal function did not affect renal or efficacy outcomes after CAR T cell therapy in DLBCL. On the other hand, patients with AKI went on to experience worse clinical outcomes. AKI was commonly related to CRS and high peak inflammatory cytokine levels. CAR T cell therapy is feasible in patients with ESRD and requires careful planning of lymphodepletion.

Keywords: Acute kidney injury; Chimeric antigen receptor T cell; Chronic kidney disease; Dialysis; Fludarabine.

Figure 1.. Clinical outcomes in patients with renal impairment or fludarabine dose reduction.

A. Progression-free survival (PFS) stratified by renal impairment (RI) at time of initiating lymphodepletion. B. Overall survival (OS) stratified by RI at time of initiating lymphodepletion. C. PFS stratified by fludarabine dose reduction (DR). D. OS stratified by fludarabine DR.

Figure 2.. Clinical outcomes in patients experiencing AKI.

A. Progression-free survival (PFS) stratified by presence or lack thereof an acute kidney injury (AKI). B. Overall survival (OS) stratified by presence or lack thereof an AKI. C. PFS stratified by severity (Grade = G) of AKI. D. OS stratified by severity of AKI.

Figure 3.. Peak cytokine levels after CAR T cell therapy are higher in patients who developed AKI.

Peak cytokine levels (y-axis) stratified by presence or lack of AKI (x-axis) between days −5 and +30 during CAR T-cell therapy. Underlined and asterisked p-values denote statistical significance (p<0.05 by T-test).