08-05-2025
Lymphoma and CAR T–Related Renal Injury: Assessing the Risks
In the treatment of non-Hodgkin lymphoma with CD19 chimeric antigen receptor (CAR) T-cell therapy, baseline kidney function did not appear to be associated with an increased risk of developing acute kidney injury (AKI) from the treatment. However, other key factors, including low albumin, showed a link.
'Our study is the largest to date examining renal toxicity in CD19 CAR T–treated lymphoma patients,' senior author Roni Shouval, MD, PhD, director of the Precision Cellular Therapy Laboratory at Memorial Sloan Kettering (MSK) Cancer Center, New York City, said in an interview.
While the findings show no link between baseline kidney function and the development of AKI, ultimately, 'hypoalbuminemia may be a better flag for AKI risk and a prompt for closer monitoring or proactive interventions such as fluid management and nephrotoxin avoidance,' Shouval said.
The study was published in March in Haematologica .
CAR T-cell therapy is known to provide durable disease remission in relapsed or refractory non-Hodgkin lymphoma, including in the disease subsets of large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL).
While the common treatment-related toxicities of cytokine release syndrome (CRS) and immune effector cell–associated neurologic syndrome (ICANS) are well documented, less has been reported regarding AKI treatment–related effects and outcomes.
The US Food and Drug Administration Adverse Event Reporting System (FAERS) AKI Reports
To investigate, Shouval, first author Alexander P. Boardman, MD, also of MSK, and colleagues first screened data from the FAERS database, identifying 5912 patients who had adverse events related to CD19 CAR T-cell therapy reported between January 2017 and September 2022.
The patients had a median age of 62 years, and the most common CAR T-cell therapies utilized were axi-cel (n = 3526 patients), followed by tisa-cel (n = 1780), liso-cel (n = 178), and brexu-cel (n = 428).
The main indications for CAR T-cell treatment were non-Hodgkin lymphoma (88%) and acute lymphoblastic leukemia (11%).
Overall, 211 (3.6%) patients developed AKI that was determined to have a primary etiology of CD19 CAR T-cell therapy, with no significant differences based on age, sex, event year, type of CD19 CAR T-cell therapy, or indication.
Of note, AKI was more common among patients treated with CD19 CAR T-cell therapy than among all other patients with cancer in the FAERS database (age- and sex-adjusted reporting odds ratio [ROR], 1.72).
AKI developed at a median of 2.5 days post-infusion, and patients with AKI were more likely to have had concurrent CRS than those with other CAR T-cell reports not involving AKI (64% vs 50%; P < .001).
The rates of life-threatening illness (22.75% vs 8.00%) and mortality (49% vs 23%; P < .001 for all) were higher among patients with AKI than among those with other CD19 CAR T-cell reports not involving AKI.
'In the FAERS dataset, we observed a disproportionately high reporting of AKI among CAR T recipients compared to other oncology patients, reinforcing that renal toxicity is a consistent safety signal on a population level,' Shouval said.
A Closer Look
In a subsequent single-center analysis, the authors identified 399 patients with relapsed or refractory non-Hodgkin lymphoma treated with CD19 CAR T-cell therapy at MSK Cancer Center between April 2016 and December 2023.
Of the patients, 84% had LBCL, 11% had MCL, and 5% had non-LBCL.
Their median age was 66 years, and the most common treatments included were axi-cel (46%), tisa-cel (20%), liso-cel (29%), and brexu-cel (5%).
Of note, patients' pre-lymphodepletion estimated glomerular filtration rate (eGFR) was not associated with overall or progression-free survival, CRS grade ≥ 2, ICANS grade ≥ 2, or neutropenia.
'Thus, baseline renal function was not significantly associated with efficacy or toxicity endpoints,' the authors reported.
AKI, Kidney Outcomes
From the time of CAR T-cell infusion to day 100, AKI of any grade was reported among 39 (10%) of the MSK patients, with only a small percentage (5%) having grade ≥ 2 AKI.
The majority of AKI cases (71.8%) were attributed to prerenal factors; 14 cases occurred concurrently with CRS.
For survival outcomes, those developing AKI within 100 days of treatment had significantly lower progression-free survival (hazard ratio [HR], 2.63; P < .001) and overall survival (HR, 3.36; P < .001) than those without AKI.
And among those with AKI grade ≥ 2, progression-free survival was significantly lower (HR, 3.14; P < .001), as was overall survival (HR, 4.18; P < .001).
Low Albumin, Inflammatory Markers Linked to Increased AKI Risk
Notably, after a multivariate adjustment, serum albumin level prior to lymphodepletion was a significant risk factor for AKI (HR, 0.15; P < .001).
In addition, higher levels of inflammatory markers, specifically serum interleukin 6 (HR, 1.74; P = .008) and tumor necrosis factor alpha (HR, 2.23; P < .001), on day 0, just prior to CAR T-cell infusion, were significantly associated with the risk for AKI
'Intriguingly, we are the first to determine that hypoalbuminemia is strongly associated with risk of AKI after CAR T-cell therapy,' the authors reported. 'Hypoalbuminemia emerged as an even more robust independent predictor of AKI than baseline eGFR,' Shouval added.
'In clinical terms, we believe hypoalbuminemia is surrogate for frailty and possibly systemic inflammation,' he said. 'Therefore, patients with low albumin should be recognized as high risk for renal complications.'
'Overall, we find that most AKI events after CAR T-cell infusion are of grade 1 and that most patients recover from these events within 3 months,' the authors wrote.
However, in looking at the eGFR and AKI outcomes together, Shouval concluded that 'these data position AKI as both a clinically meaningful and prognostically significant complication, deserving greater attention in the CAR T risk-benefit assessment.'
Findings Point to a 'Cytokine-Driven Phenomenon'
Commenting on the research, Michael D. Jain, MD, PhD, medical director of the Immune and Cellular Therapy Program at the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, noted that the findings underscore that CAR T-cell therapy 'is really a cytokine-driven phenomenon rather than related to comorbidities that cause baseline chronic kidney disease [CKD].'
He added that low albumin, often a marker of inflammation/cytokines, 'might contribute to AKI because it affects intravascular volume and thus blood flow to the kidney.'
Jain agreed that the risk for AKI and other complications from CAR T is 'related more to tumor burden and inflammation than to baseline renal dysfunction.'
'In our center, we have protocols to give CAR T cells to patients who are on dialysis and believe we can safely deliver their therapy,' he noted.
A Word of Caution Re CKD
In a smaller study of 155 patients treated with CAR T-cell therapy for relapsed/refractory LBCL, a history of CKD was, contrarily, found to indeed be associated with AKI on a multivariate analysis (RR, 2.7; P = .04).
However, while in Shouval's study, most patients who had low eGFR (< 60 mL/min/1.73 m2) received either liso-cel or tisa-cel, in this study, the majority of patients received axi-cel.
Based on that, 'I would offer caution [using CAR T-cell therapy] in those with CKD, especially in those receiving axi-cel,' senior author Narendranath Epperla, MD, of the James Cancer Hospital, The Ohio State University, Columbus, Ohio, said in an interview.
He added, however, that Shouval's research importantly 'highlights a clinically relevant yet understudied complication of CAR-T that would aid clinicians in decision-making and counseling peri-CAR T.'
