Acute Kidney Injury Following Chimeric Antigen Receptor T-Cell Therapy Is Associated with Inferior Survival for Patients with Relapsed or Refractory Large B-Cell Lymphoma
Authors: Sharp John , Zhao Qiuhong , Voorhees Timothy , Bond David A. , Sawalha Yazeed , Reneau John C. , Sigmund Audrey M. , Hanel Walter , Sehgal Lalit , Alinari Lapo , Baiocchi Robert , Brammer Jonathan E. , Maddocks Kami J. , Christian Beth , Bezerra Evandro , Denlinger Nathan , Vasu Sumithira , de Lima Marcos , Prosek Jason , Epperla Narendranath 
Published: December 2024

Background: Chimeric antigen T-cell receptor therapy (CAR-T) has revolutionized treatment of relapsed/refractory (R/R) large B-cell lymphomas (LBCL). Acute kidney injury (AKI) is a notable toxicity of CAR-T that may be associated with inferior outcomes. The etiology of AKI during CAR-T is likely multi-factorial and may include cytokine release syndrome (CRS), intravascular volume depletion, tumor lysis syndrome (TLS), exposure to nephrotoxic agents, and others. A prior study examining AKI in LBCL patients (pts) treated with CAR-T was limited by sample size (n=46) limiting their ability to evaluate statistically significant risk factors. Hence, we sought to describe incidence of AKI among adults undergoing CD19-directed CAR-T for R/R LBCL, to identify biomarkers predictive of AKI, and to describe risk of progression and death as a function of AKI.

Methods: This is a single-center retrospective cohort study of adult pts undergoing CD19-directed commercial CAR-T for R/R LBCL from 2018 to 2022. We assessed for AKI, defined by rise in serum creatinine (Cr) of ≥0.3 mg/dL or to ≥1.5 times baseline within 30 days of CAR-T. Renal recovery was defined as no longer meeting AKI criteria. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate (eGFR)&lt;60mL/min/1.73m2 for ≥3 months. Baseline clinical and disease characteristics were summarized using descriptive statistics and compared between pts with and without AKI using Wilcoxon rank sum test, chi-square test or Fisher's exact test. Poisson regression with robust variance model was used to evaluate the risk factors for AKI. A multivariable analysis model (MVA) was built to evaluate risk factors for AKI using significant factors from univariable analysis models (UVA) and clinically relevant factors (baseline C-reactive protein level and nephrotoxin exposure). Progression-free survival (PFS) was calculated from CAR-T to progression or death, censoring those alive without progression at last assessment. Overall survival (OS) was calculated from CAR-T to death, censoring those alive at last contact. Kaplan-Meier method was used to estimate survival functions with log-rank test for inter-group comparisons. Cox proportional hazard regression models were used to estimate hazard ratios for PFS and OS.

Results: 155 pts were included in the study with a median follow up of 3.3 years (range: 1.2 - 5.9 years). Median age was 63 years (range: 23-85), 91 (59%) were male, and 154 (99.4%) had LBCL. One patient (0.6%) had primary mediastinal B-cell lymphoma. Twenty-eight (18%) pts developed AKI with median time to peak Cr from CAR-T of 9.5 days (range: 3-30). Causes identified for AKI included volume depletion (8, 29%), CRS (5, 18%), nephrotoxin exposure (5, 18%), TLS (1, 4%), and no cause identified (12, 43%). Some cases were considered multifactorial (n=6). On UVA, variables associated with AKI included history of CKD (RR 3.5 [95% CI: 1.9, 6.6] p&lt;0.01), receipt of axicabtagene ciloleucel (RR 2.1 [95% CI: 1.1, 4.2] p=0.04), and baseline elevated ferritin (RR 3.1 [95% CI: 1.1, 8.4] p=0.03). Only history of CKD was predictive of AKI on MVA (RR 2.7 [95% CI: 1.1, 7.0] p=0.04). Most pts with AKI had renal recovery (25 of 28) with median time to recovery of 14 days (range: 5-85). Of 3 pts without renal recovery, 2 required long-term HD and 1 experienced disease progression and died 34 days after CAR-T infusion. Four (2.6%) pts required renal replacement therapy during CAR-T with 2 of these requiring long-term HD. Median PFS was 2.4 months (95% CI: 1.1, 3.2) vs 6.8 months (95% CI: 4.0, 12.0) for pts with and without AKI, respectively (log rank p=0.015). Median OS was 8.4 months (95% CI: 2.2, 14.9) vs 30 months (95% CI: 18.2, not reached) for pts with and without AKI, respectively (log rank p=0.003). PFS and OS were significantly shorter for pts who had AKI compared to those who did not in UVA and MVA (PFS aHR 1.8 [95% CI: 1.1, 3.0] p=0.02; OS aHR 2.3 [95% CI: 1.3, 3.9] p=0.004).

Conclusion: AKI is common within 30 days of CAR-T therapy for R/R LBCL. History of CKD was associated with increased risk of AKI. Renal recovery is common, though these pts had shorter PFS and OS. Further research is needed to better understand the mechanisms of AKI during CAR-T and devise strategies to prevent this toxicity as it carries prognostic relevance.