Acute kidney injury after chimeric antigen receptor T-cell therapy is associated with inferior survival in patients with relapsed/refractory large B-cell lymphoma.

INTRODUCTION

Chimeric antigen receptor T‐cell (CAR‐T) therapy revolutionized the treatment of relapsed/refractory large B‐cell lymphomas (LBCL) 1 , 2 , 3 , 4 , 5 and was approved in this setting. 6 It has unique toxicities, including cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity (ICANS). 7 Acute kidney injury (AKI), an abrupt decrease in renal function causing dysregulation of extracellular volume, electrolytes and nitrogenous waste products, is an increasingly recognized toxicity associated with CAR‐T. 8 , 9

Mechanisms of AKI in CAR‐T include cytokine‐driven vasodilation, 10 capillary leak, 11 decreased cardiac output 12 and inflammatory cell infiltration of the kidney and vasculature, 12 among others. A meta‐analysis of 22 CAR‐T‐treated patient cohorts revealed a significant association between AKI and severe CRS. 13 AKI during CAR‐T has been associated with increased short‐term mortality of 21%–40%, 14 , 15 although mechanisms for this association remain unclear. Additionally, risk factors predictive of AKI during CAR‐T therapy are unclear. Previous studies suggested prior haematopoietic stem cell transplant and higher lactate dehydrogenase (LDH) level prior to CAR‐T may be predictive, but they were limited by small sample size ( n = 46 14 and n = 78 15 ) precluding robust statistical analysis. Another study showed grade 3+ CRS and intensive care unit (ICU) admission during CAR‐T were associated with AKI 16 ; however, these factors are not available prior to CAR‐T administration, limiting their utility in risk assessment. More recently, low serum albumin has been associated with risk of AKI in patients undergoing CAR‐T. 17 Herein, we sought to evaluate the incidence of AKI, pre‐CAR‐T risk factors associated with AKI during therapy, as well as prognostic relevance of AKI in patients with relapsed/refractory LBCL.

MATERIALS AND METHODS

Study design

This is a single‐centre, retrospective study of patients with relapsed/refractory LBCL treated with commercial CD19‐directed CAR‐T products between 1 January 2018 and 30 September 2022. This study was approved by the institutional review board, included a waiver of informed consent given its retrospective nature and was conducted in compliance with the Declaration of Helsinki. To be eligible for analysis, adult patients (≥18 years old) must have received commercial CD19‐directed CAR‐T products for relapsed/refractory LBCL. Patients who received CAR‐T products on clinical trial were excluded.

Data collection

Baseline demographic and disease characteristics and CAR‐T administration details were obtained from the medical record. We assessed peak creatinine and the need for haemodialysis within 30 days of CAR‐T infusion and assessed renal recovery in patients experiencing AKI. For patients with AKI, daily physician progress notes were reviewed to assess for suspected causes of AKI. Medications considered potentially nephrotoxic to which the patient was exposed between CAR‐T infusion and the onset of AKI were recorded, which included non‐steroidal anti‐inflammatory drugs, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, iodinated contrast media, intravenous vancomycin, intravenous acyclovir, aminoglycoside antibiotics, amphotericin B and foscarnet. Incidence and severity of CRS and ICANS were recorded. For patients with AKI after CAR‐T and subsequent progressive disease, the treating oncologist's notes were manually reviewed to ascertain whether the presence of post‐CAR‐T AKI impacted subsequent salvage therapy selection.

Study outcomes and definitions

The primary outcome was incidence of AKI. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria 18 as an increase in serum creatinine by ≥0.3 mg/dL in 48 h or to ≥1.5 times baseline within the prior 7 days. Urine volume <0.5 mL/kg/h for 6 h was not utilized as a criterion due to high frequency of incomplete charting of urine output during routine clinical care. Secondary outcomes included determination of risk factors associated with development of AKI, progression‐free survival (PFS) and overall survival (OS) between those with and without AKI. PFS was defined from date of CAR‐T infusion to date of progression or death, censoring those alive and without progression at last follow‐up. OS was defined from date of CAR‐T infusion to death, censoring those alive at last follow‐up.

Definitions of AKI stages, CKD and renal recovery are available in Appendix S1 . 18 , 19 CRS and ICANS were graded according to American Society for Transplantation and Cellular Therapy criteria. 20 Response to CAR‐T was assessed using Lugano criteria. 21 Full dose lymphodepletion (LD‐chemo) was defined as cyclophosphamide 500 mg/m 2 and fludarabine 30 mg/m 2 for 3 days for axicabtagene ciloleucel (axi‐cel), cyclophosphamide 250 mg/m 2 and fludarabine 25 mg/m 2 for 3 days for tisagenlecleucel (tisa‐cel) and cyclophosphamide 300 mg/m 2 and fludarabine 30 mg/m 2 for 3 days for lisocabtagene maraleucel (liso‐cel), in accordance with respective Food and Drug Administration prescribing information. All doses less than full dose were considered reduced‐dose LD‐chemo.

Statistical considerations

Baseline clinical and disease characteristics were summarized using descriptive statistics. The Poisson regression model with robust variance option was used to evaluate risk factors for the development of AKI. This analytic approach provides an unbiased estimate of the relative risk when the outcome is common (greater than 10%). 22 Univariable analysis was performed to assess associations between baseline clinical characteristics and development of AKI. Stepwise regression technique was used to build the multivariable analysis model including factors from the univariable analysis with p < 0.10 and clinically relevant factors such as low albumin. Each factor with p ‐value < 0.1 in the univariable analysis was added back to the multivariable analysis model, one at a time, to check whether any of these factors were significant in the multivariable analysis model. As AKI was evaluated within the first 30 days of CAR‐T, landmark (from day 30 after CAR‐T) analysis was used to evaluate the associations between development of AKI and survival outcomes such as PFS and OS. Cox proportional hazard regression models were used to estimate the associations between individual patient characteristics and survival outcome, and each risk factor was also checked for potential confounding between AKI and survival. Confounding effect was defined as a greater than 10% relative change in the association between AKI and survival outcome with or without the covariate of interest in the model. Confounders were included in the final multivariable model. Survival curves were generated after multivariable models for PFS and OS together with adjusted hazard ratios (aHRs). Statistical analysis was performed using Stata 18 (College Station, TX).

RESULTS

Baseline characteristics

A total of 155 patients were included in the study with a median follow‐up of 3.3 years (range: 1.23–5.88 years). Median age was 63 years (range: 23–85 years) and 91 (59%) were male. Eighty‐seven (56%) patients had primary refractory disease. Median lines of prior therapy were 2 (range: 1–7) and 86 (55%) patients received bridging therapy. Eighty‐eight (57%) patients received tisa‐cel while 65 (42%) received axi‐cel and 2 (1%) received liso‐cel. Twenty‐two (14%) patients received dose‐reduced LD‐chemo. In total, 28 (18%) patients developed AKI. Median time to peak serum creatinine was 9.5 days (range: 3–30 days) from CAR‐T infusion. Baseline characteristics stratified by AKI are shown in Table 1 . Notably, given the impact of baseline renal function on LD‐chemo dosing, we assessed receipt of reduced‐dose LD‐chemo by the presence of baseline CKD and found that patients with a history of CKD were more likely to receive reduced‐dose LD‐chemo than those without CKD (45% vs. 10%, p < 0.0001).

AKI—Aetiology and course

Aetiologies (non‐mutually exclusive) for AKI included volume depletion ( n = 20, 71%), CRS ( n = 5, 18%), nephrotoxin exposure ( n = 5, 18%), tumour lysis syndrome ( n = 1, 4%), with six cases (21%) being multifactorial. Table S1 lists causes of AKI identified in each patient. Among patients with AKI, 21 (75%) patients had stage 1, while 1 (4%) and 6 (21%) patients had stage 2 and 3 AKI respectively.

Most patients with AKI experienced renal recovery (25 of 28, 89%). The median time to recovery was 14 days (range: 5–85 days). Of the three patients who did not experience renal recovery, two required long‐term haemodialysis and one experienced rapid progressive disease and died 34 days after CAR‐T infusion. Four (3%) patients required renal replacement therapy during their index hospitalization for CAR‐T. Two of these four required long‐term haemodialysis while the other two experienced full renal recovery. Patients with AKI experienced a longer index hospitalization for CAR‐T compared to those without AKI (median: 16 days vs. 9 days, p = 0.0007).

Risk factors associated with AKI

In the univariable analysis, factors significantly associated with the development of AKI in the 30 days following CAR‐T infusion included receipt of axi‐cel (compared to tisa‐cel, RR 2.09, 95% CI: 1.05–4.17, p = 0.0358), history of CKD (RR 3.54, 95% CI: 1.90–6.61, p = 0.0001), elevated pre‐lymphodepletion ferritin level (RR 3.06, 95% CI: 1.12–8.38, p = 0.0297), and serum creatinine (RR 2.89, 95% CI: 1.35–6.19, p = 0.0063) (Table 2 ). On multivariable analysis, history of CKD (aRR 3.48, 95% CI: 1.91–6.35, p < 0.0001) and receipt of axi‐cel (aRR 2.08, 95% CI: 1.08–4.03, p = 0.0288) retained statistical significance (Table 2 ).

The incidence of all grade CRS was numerically higher in those with versus without AKI but did not reach statistical significance (86% vs. 70%, p = 0.0919). However, the grade 3+ CRS was significantly higher in patients who developed AKI compared to those who did not (25% vs. 6%, p = 0.0024). The incidence of all grade (54% vs. 32%, p = 0.0338) and grade 3+ (36% vs. 16%, p = 0.0155) ICANS was significantly higher among patients who developed AKI. The timing of CRS, ICANS and AKI is summarized in Figure 1 .

Outcomes post‐CAR‐T based on the presence or absence of AKI

Response rates

Among all patients, the overall response rate was 53% with a complete response rate of 32%. Compared to patients without AKI, patients with AKI had a lower overall response rate to CAR‐T (36% vs. 57%, p = 0.0441) though complete response rates did not significantly differ (25% vs. 34%, p = 0.3641, Table 3 ).

Progression‐free survival

Median PFS was shorter among patients with AKI (2.4 months vs. 6.9 months, HR 1.76, 95% CI: 1.10–2.81, p = 0.0189). This finding remained significant on multivariable analysis with an aHR of 1.79 (95% CI: 1.08–2.97, p = 0.0243, Figure 2A ). Increasing stage of AKI was associated with increased risk of progression or death (aHR 2.53 [95% CI: 1.68–3.83], p < 0.0001). Other factors that were noted to be independently associated with significantly inferior PFS included receipt of tisa‐cel (compared to axi‐cel, aHR 1.53, 95% CI: 1.00–2.34, p = 0.0494) and presence of primary refractory disease (aHR 1.96, 95% CI: 1.31–2.93, p = 0.0010, Table S2 ).

Overall survival

Median OS was also shorter among patients who developed AKI (7.8 months vs. 29.7 months, HR 2.12, 95% CI: 1.28–3.52, p = 0.0035). This finding remained significant on multivariable analysis with an aHR of 2.21 (95% CI: 1.28–3.81, p = 0.0043, Figure 2B ). Increasing stage of AKI was associated with an increased risk of death (aHR 2.72 [95% CI: 1.81–4.10], p < 0.0001). Other factors that were independently associated with significantly inferior OS included receipt of tisa‐cel (compared to axi‐cel, aHR 2.45, 95% CI: 1.50–4.02 p = 0.0004), presence of primary refractory disease (aHR 2.09, 95% CI: 1.32–3.30 p = 0.0016) and pre‐LD elevation of C‐reactive protein (CRP) (aHR 2.05, 95% CI: 1.28–3.26, p = 0.0026, Table S3 ).

Landmark analysis

Because AKI was assessed within the first 30 days following CAR‐T, we performed a landmark analysis to evaluate the association between AKI within 30 days of CAR‐T and risk of subsequent relapse or death. Using this approach resulted in the exclusion of 14 PFS events (7 in the AKI group, 7 in the no AKI group) which occurred prior to 30 days after CAR‐T infusion. We found that patients with AKI did not have a subsequent statistically significantly inferior PFS compared to those without AKI in the univariable (HR 1.37, 95% CI: 0.79–2.38, p = 0.2646) or multivariable analysis (aHR 1.33, 95% CI: 0.73–2.42, p = 0.3508, Figure 3A ; Table S4 ). Increasing stage of AKI was associated with inferior PFS, with a hazard ratio of 2.16 (95% CI: 1.20–3.89, p = 0.0085) for each one‐unit increase in AKI stage. Three OS events were excluded from the evaluation when using the landmark analysis (all in the AKI group). We found that patients with AKI had significantly inferior OS compared to those without (aHR 1.82, 95% CI: 1.02–3.26, p = 0.0417, Figure 3B ; Table S5 ). Receipt of tisa‐cel (compared to axi‐cel) also demonstrated an independent association with inferior OS on multivariable analysis (aHR 2.32, 95% CI: 1.41–3.82, p = 0.0010). Increasing stage of AKI was associated with inferior OS, with a hazard ratio of 2.50 (95% CI: 1.58–3.96, p = 0.0001) for each one‐unit increase in AKI stage.

Impact of AKI on subsequent therapy post CAR ‐T relapse/progression

The charts of patients with AKI following CAR‐T therapy were reviewed to assess whether AKI post‐CAR‐T impacted subsequent treatment decisions. Of the 28 patients with AKI, 20 (71%) experienced disease progression while 8 (29%) did not. Of the 20 with disease progression, 11 (55%) received subsequent therapy, including anti‐PD(L)1 therapy in 4 (36%), polatuzumab + bendamustine + rituximab in 2 (18%), ibrutinib in 1 (9%), Obinutuzumab + lenalidomide in 1 (9%), tafasitamab + lenalidomide in 1 (9%), loncastuximab in 1 (9%) and radiation alone in 1 (9%). Of the 9 (45%) patients with progression without subsequent therapy, 4 (44%) had other conditions precluding further treatment (liver dysfunction in 1, bowel perforation in 1, myocardial infarction and cardiomyopathy in 1, infection in 1), 4 (44%) pursued hospice and 1 (11%) experienced rapid disease progression after CAR‐T and died. Post‐CAR‐T AKI was not factored into decision‐making for selection of subsequent therapies in our cohort.

DISCUSSION

In this retrospective study of patients with relapsed/refractory LBCL undergoing commercial CD19‐directed CAR‐T therapy, we found that AKI is not an uncommon complication, with 18% of patients affected in our series, although the majority of cases were stage I and resolved at a median of 14 days after onset. Baseline variables associated with risk of AKI in multivariable analysis included history of CKD and receipt of axi‐cel. Four (2.6%) patients required renal replacement therapy during their CAR‐T course, with two of these going on to require long‐term haemodialysis. The one other patient without renal recovery experienced rapid disease progression and died 34 days after CAR‐T infusion. Although most patients experienced renal recovery, AKI during CAR‐T treatment was associated with inferior long‐term survival outcomes.

The incidence of AKI noted in our study generally aligns with other series 13 , 14 , 15 , 17 , 23 , 24 , 25 (Table S6 ). Our study adds to the literature by analysing a large cohort of patients undergoing CAR‐T for LBCL and examining not only the incidence of but also the risk factors for and prognostic associations with AKI, including important factors not previously assessed, such as primary refractory disease. Prior studies have been smaller 14 , 15 , 24 , 26 or have consisted of heterogenous populations, 8 , 9 , 13 , 23 including patients with multiple myeloma and acute lymphoblastic leukaemia, where inherent risks and mechanisms of AKI may vary from LBCL, or they have identified variables associated with AKI that are not available prior to CAR‐T infusion, such as grade 3–4 CRS 15 , 23 and requirement of ICU level of care. 14 We identified a history of CKD and receipt of axi‐cel as independently associated with risk of AKI. Notably, we did not replicate prior findings of higher pre‐LD LDH level, 15 low pre‐LD serum albumin level 17 or prior haematopoietic stem cell transplant 14 being associated with AKI. Use of transplant in this population has decreased as CAR‐T is increasingly utilised in early relapse settings; thus, we had a relatively low proportion of patients with prior transplant (autologous n = 36 [23%], allogeneic n = 1 [1%]). Additionally, the association between prior transplant and AKI has not been consistently detected. 23

It has been previously demonstrated that cytokines associated with systemic inflammation may contribute to the development of AKI 17 and that these cytokines have also been associated with worse outcomes after CAR‐T therapy. 27 Whether these cytokines cause a direct nephrotoxic effect or simply represent a surrogate measure of higher disease burden is unclear. Furthermore, the lack of association of AKI with primary refractory disease or progressive disease at CAR‐T in our study indicates that the development of AKI post CAR‐T involves a complex interplay between several factors and that it is not merely a surrogate for disease aggressiveness/burden. This needs to be explored further in future studies.

We found a significant association between increasing stages of AKI and inferior PFS and OS. Our findings align with those of Wood et al., documenting inferior PFS among patients with AKI versus without (3.2 months vs. 19.6 months, p = 0.003) 25 and of Broadman et al., documenting a hazard ratio for PFS of 2.63 (95% CI: 1.79–3.87, p < 0.001). 17 In line with prior studies, elevated pre‐LD CRP level was associated with inferior outcomes; however, in contrast, we did not see a similar trend with elevated pre‐LD ferritin level in our study. 27

Given the association between higher intensity LD‐chemo and favourable long‐term outcomes, 28 we controlled for LD‐chemo dose in multivariable models. This is especially important as patients with CKD (which was independently associated with the risk of AKI post CAR‐T in our study) would be more likely to receive reduced‐dose LD‐chemo. We found that receipt of reduced‐dose LD‐chemo was not independently associated with inferior PFS or OS, which decreases the likelihood that suboptimal LD‐chemo doses led to inferior survival outcomes, as has been previously reported. 29 Additionally, baseline CKD was not independently associated with inferior long‐term outcomes, arguing against the interpretation that imbalances in this comorbidity across groups were driving observed differences in survival. Furthermore, we systematically reviewed the charts of all patients with post‐CAR‐T AKI and progressive disease and determined that the prior AKI had not impacted subsequent therapy selection in any case.

We found an independent association between receipt of tisa‐cel and inferior PFS and OS. This finding aligns with previously reported results. 30 , 31 Differences in costimulatory domains, expansion kinetics and cellular persistence have all been hypothesized to contribute to the observed differences between these CAR‐T products, 32 though the exact explanation for these findings remains unclear. In our cohort, the receipt of tisa‐cel was not associated with a risk of AKI, although both AKI and receipt of tisa‐cel were independently associated with inferior long‐term outcomes on multivariable analysis. This suggests that these two factors may contribute to decrements in PFS and OS through distinct mechanisms and further research is needed to fully elucidate this.

To address immortal time bias, we performed a 30‐day landmark analysis. Fourteen PFS events (7 in each group) occurred prior to the 30‐day landmark. While the finding that PFS among the cohort eligible for 30‐day landmark analysis was not significantly worse in those with AKI compared to those without, it is possible that this is largely due to exclusion of a high number of early PFS events in the AKI group (7 events among 28 patients). However, a detrimental effect of AKI on OS was still observed in the 30‐day landmark analysis.

Our study has limitations inherent to the retrospective design that warrant acknowledgement including variations in management of AKI and other toxicities by different providers and non‐uniform post‐discharge follow‐up data that may have the potential to influence findings. Furthermore, specialized biomarkers potentially predictive of AKI that are not routinely ascertained in clinical practice, such as metabolic tumour volume and cytokine panel testing, were not collected so could not be analysed. The relatively small number of patients who developed AKI could have limited our ability to detect statistically significant associations with baseline variables. As the focus of this study was to learn the association of pre‐CAR‐T variables with the risk of AKI post CAR‐T, we did not systematically assess for co‐occurrence of AKI with post‐CAR‐T toxicities other than CRS and ICANS, which could have had an impact on long‐term outcomes, such as persistent cytopenias or infections. Lastly, we could not assess the impact of liso‐cel on risk of AKI and survival outcomes due to the small number of patients who received this product in our cohort.

In conclusion, in our study examining the risk of AKI and its association with post CAR‐T outcomes in patients with relapsed or refractory LBCL, we found that history of CKD and receipt of axi‐cel were independently associated with the risk of AKI on multivariable analysis. The inferior survival outcomes following CAR‐T among those who developed AKI compared to those who did not underscore the need for further research to understand the complex interaction between renal impairment, CAR‐T expansion, effector cell function and persistence to hopefully improve post‐CAR‐T outcomes.

AUTHOR CONTRIBUTIONS

Conception and design: NE. Collection and assembly of data: All authors. Data analysis: JS, QZ and NE. Interpretation: All authors. Manuscript writing: First draft prepared by JS. All authors provided critical and insightful comments. Final approval of manuscript: All authors.

FUNDING INFORMATION

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number T32CA247815 (to JS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

CONFLICT OF INTEREST STATEMENT

NE: Research funding: Beigene, Lilly and Incyte; Speakers Bureau for Beigene and Genentech, Ad boards for ADC Therapeutics, Lilly and Ipsen; Honorarium from Novartis. TJV: Advisory Board: Genmab/AbbVie, ADC Therapeutics. Consultancy: Novartis, Recordati, Genmab. Research Funding: Kite, Viracta, Incyte/Morphosys, Genmab/AbbVie, Recordati. DAB: Advisory Board: Novartis, Nurix Therapeutics, ADC Therapeutics. Research Funding: Novartis, Kite/Gilead, Accutar, Nurix Therapeutics, Incyte, GenMab, BeiGene. Astra Zeneca. BC: Advisory Board: Ipsen, AstraZeneca; Research support: Genentech, Acerta, Millenium, Kite, Bristol Myers Squibb. SV: Consulting for Omeros Inc., Alexion Inc. Research funding from Sanofi Inc. KM: Consulting: AbbVie, ADC Therapeutics, AstraZeneca/Acerta, Beigene, BMS, Caribou, Genentech, Genmab, Gilead/KITE, Incyte, Janssen, Lilly, Morphosys, Pharmacyclics.

ETHICS STATEMENT

This study was approved by the institutional review board, included a waiver of informed consent given its retrospective nature and was conducted in compliance with the Declaration of Helsinki.

Supporting information

Appendix S1.

ACKNOWLEDGEMENTS

None.

DATA AVAILABILITY STATEMENT

Data available upon request to corresponding author as permitted by the IRB.

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