Acute kidney injury following treatment with CD19-specific CAR T-cell therapy in children, adolescent and young adult patients with B-cell acute lymphoblastic leukemia

Abstract

CD19-specific chimeric antigen receptor (CAR) T-cell therapy has shown promising disease responses in patients with high-risk B-cell malignancies. Treatment with CD19-CAR T-cell therapy is also associated with the risk of morbidity and mortality, primarily related to immune-mediated complications (cytokine release syndrome [CRS] and neurotoxicity [NTX]), infections, and end-organ dysfunction. Despite these well-described systemic toxicities, the incidence of post-CAR T-cell therapy acute kidney injury (AKI) in the children, adolescent and young adult (CAYA) patient population is largely unreported. The objectives of this study were to determine the incidence of AKI in CAYA patients with high-risk B-cell malignancies treated with CD19-CAR T-cell therapy, evaluate potential risk factors for developing AKI, and determine patterns of kidney function recovery. In this retrospective analysis of 34 CAYA patients treated with CD19-CAR T-cell at a single institution, we found a cumulative incidence of any grade AKI by day 30 post-infusion of 20% (n=7), with 4 cases being severe AKI (Stage 2-3) and one patient requiring kidney replacement therapy. All episodes of AKI developed within the first 14 days after receiving CAR T-cell therapy and 50% of patients with AKI recovered kidney function to baseline within 30 days post-infusion. No evaluated pre-treatment risk factors were associated with the development of subsequent AKI; there was an association between AKI and CRS and NTX. We conclude that the risk of developing AKI following CD19-CAR T-cell therapy is highest early post-infusion, with most cases of AKI being severe. Although most patients with AKI in our cohort had recovery of kidney function, frequent monitoring to facilitate early recognition and subsequent management of kidney complications after CD19-CAR T-cell therapy may reduce the severity of AKI in the CAYA patient population.

Keywords: CAR T-cell therapy; CD19-CAR; acute kidney injury; pediatric.

Figure 1. Renal function in CAYA patients after treatment with CD19-CAR T-cell Therapy.

(A)Glomerular filtration rate (GFR) of patients at 3 times points, determined by serum creatinine and, in a subset of patients with available data, cystatin C. GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration U25 equation. Time points shown include: Day 0, Day 14 and Day 30. In most patients with paired GFR data by creatinine and cystatin C, GFR by creatinine was higher than by cystatin C. (B)The cumulative incidence (CI) of acute kidney injury (AKI) post CD19-CAR T-cell therapy, within 30 days post infusion. AKI was defined as 1.5-fold or greater increase in serum creatinine level from baseline. All patients developed AKI within 14 days after CAR T-cell infusion, with a 20% CI (95% CI [dotted lines]: 8.7 – 34.7). (C) Summary of daily maximum creatinine within 30 days of CAR T-cell infusion by AKI group (blue, AKI; black, no AKI). Lines represent the average across patients within a group and shading corresponds to the range (min-max) within a group. For the first 3 days after infusion, all patients have available creatinine. For later days, the number of patients with available measurements on a given day ranged with later days typically having fewer available measurements (AKI group, range: 3–7; no AKI group, range: 3–27 values).

Figure 2. Association between development of AKI and post CD19-CAR T-cell immune mediated side effects.

Incidence of CAYA patients experiencing acute kidney injury (AKI) after CD19-CAR T-cell therapy in relation to presence of immune mediated side effects (cytokine release syndrome, CRS; and neurotoxicity, NTX). AKI severity was graded using KDIGO (Kidney Disease: Improving Global Outcome) criteria. Patients with AKI are presented in the colored bars, by max AKI grade; patients without AKI are accounted for in the gray bar. (A) Distribution of patient by highest grade CRS. All patients with AKI also had CRS, with AKI being more prevalent in patients with higher-grade CRS. (B) Distribution of patient by highest grade NTX. All patients with higher grade AKI also had NTX. (C) Swimmers plot depicting the course of AKI for each patient, with each lane representing a single patient. AKI onset is shown by the start of a colored bar; after onset, the max AKI grade is shown in week (7-day) intervals. Onset of immune-mediated side effects are denoted using symbols (circle, CRS; triangle, NTX).