RESEARCH LETTER – AMERICAN JOURNAL OF KIDNEY DISEASE
Chimeric antigen receptor T-cell (CAR-T) therapies use genetically engineered T cells to target tumor antigens. In response to antigen recognition, CAR-T cells rapidly expand in number and produce inflammatory cytokines leading to cytokine release syndrome (CRS). CRS is a systemic inflammatory response, on a spectrum with macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH), which can manifest with fever, tachycardia, fatigue, and multiorgan system dysfunction, including acute kidney injury (AKI). Two prior studies demonstrated an AKI incidence of approximately 19-30% after commercial CAR-T.1,2 The majority of patients (>80%) described in these series received axicabtagene ciloleucel (Yescarta), a CD19-targeting CAR-T that has a CD28 costimulatory domain and is characterized by rapid T-cell expansion and robust inflammatory cytokine secretion.1,2 However, use of tisagenlecleucel (Kymriah), a CAR-T that targets the same epitope of CD19 but has a different costimulatory domain (4-1BB), is increasing.3,4 Tisagenlecleucel is associated with a reduced inflammatory profile and lower rates of toxicity which may lead to lower rates of CRS.5,6,7 Due to these important differences, we hypothesized that AKI may be less common in patients receiving tisagenlecleucel.
We performed a retrospective review of adults ≥ 18 years of age with diffuse large B cell lymphoma (DLBCL) treated with tisagenlecleucel at Massachusetts General Hospital between January 2019-April 2020. The primary aim was to describe the incidence and clinical features of AKI following treatment with tisagenlecleucel. Baseline demographics, laboratory data, and clinical outcomes were obtained from electronic health records. AKI was defined as a ≥1.5-fold rise in creatinine from the pre-CAR-T baseline (Day 0). CRS grading were determined by the patient’s primary oncology team.8 We also collected baseline, peak, and nadir values for electrolytes, including sodium, potassium, and phosphate. The study was approved by the IRB at Partners Healthcare and the need for informed consent was waived.
Overall, 37 patients received tisagenlecleucel; mean age was 60 (SD 18), 65% were male, and 86% were white. CRS occurred in 20 patients (54%): eleven patients had grade 1 CRS, four had grade 2 CRS, and only one had high-grade CRS (grade 5) (Table 1). Sixteen patients (42%) received immunosuppressive therapy to treat CRS, including dexamethasone (35%), tocilizumab (22%), and anakinra (22%). Electrolyte abnormalities including hyponatremia, hypokalemia, and hypophosphatemia were common and occurred in the first week after tisagenlecleucel (Table 1).
Table 1. Baseline characteristics and Clinical outcomes among patients receiving tisagenlecleucel.
Baseline characteristics and medication use defined at the time of receiving tisagenlecleucel.
| Outcome | Count (%) |
|---|---|
| Baseline Characteristics | |
| Mean Age (SD) | 60 (18) |
| Gender (male) | 24 (65) |
| Race (white) | 32 (86) |
| Comorbidities | |
| Diabetes | 6 (16) |
| Hypertension | 9 (24) |
| Congestive Heart Failure | 0 (0) |
| Cirrhosis | 0 (0) |
| Cytokine release syndrome (CRS) | 20 (51) |
| Grade 1 | 15 (41) |
| Grade 2 | 4 (11) |
| Grage 3 or 4 | 0 (0) |
| Grade 5 | 1 (3) |
| Baseline Medication Use, n (%) | |
| Acyclovir | 19 (51) |
| ACE/ARB | 5 (14) |
| Bactrim | 14 (38) |
| Proton Pump Inhibitor | 16 (43) |
| H2 blocker | 9 (22) |
| Statin | 9 (24) |
| Allopurinol | 9 (24) |
| Diuretic | 3 (8) |
| NSAIDs | 2 (5) |
| Use of immunosuppression to treat CRS or | |
| neurotoxicity* | 16 (43%) |
| Dexamethasone | 13 (35) |
| Tocilizumab | 8 (22) |
| Anakinra | 8 (22) |
| Acute kidney injury** | 2 (5) |
| Electrolyte disorders | |
| Hyponatremia < 130mEq/L | 7 (19) |
| Hypokalemia < 3.0 | 5 (14) |
| Hypophosphatemia < 2.0mg/dL | 26 (70) |
| 30-day Mortality | 5 (14) |
A total of 16 patients required immunosuppression, most received both dexamethasone and either anakinra or tocilizumab.
Of the two patients with AKI, both progressed to stage 3 AKI but neither required dialysis prior to death.
Overall, 5 patients (14%) died within 30 days. In all cases, death was attributable to disease progression and/or infectious complications (Table 1). AKI occurred in only 2 patients (5%); both had stage 3 AKI. The first was an 80-year-old gentleman who had grade 2 CRS and neurotoxicity and aspirated the day following tisagenlecleucel infusion; septic shock led to rapidly progressive non-oliguric AKI and death 4 days after tisagenlecleucel. The second was a 50-year-old gentleman with a new diagnosis of DLBCL. One week after tisagenlecleucel he developed severe CRS with clinical and laboratory findings of MAS/HLH-like syndrome in the setting of rhinocerebral mucormycosis requiring hemi-maxillectomy, with fever, splenomegaly, pancytopenia, coagulopathy, hyperferritinemia, and hypertriglyceridemia (Table 2). He developed non-oliguric AKI and had spot protein-to-creatinine ratio >5grams/gram creatinine measured twice on non-consecutive days. AKI progressed during administration of liposomal amphotericin B for invasive mucormycosis and acyclovir for herpes simplex prophylaxis, and the patient ultimately died on day +28.
Table 2. Baseline and lab values in the patient who developed MAS/HLH and nephrotic syndrome.
| Baseline | Diagnosis of MAS/HLH | |
|---|---|---|
| Kidney Function / Markers of Nephrotic Syndrome | ||
| Creatinine | 0.54 mg/dL | 1.36 mg/dL* |
| Blood Urea Nitrogen | 19 mg/dL | 44 mg/dL |
| Proteinuria | Negative on dipstick | 5.0g/g creatinine** |
| Hematuria | Negative on dipstick | 2+ on dipstick |
| Albumin | 2.5 g/dL | 2.4 g/dL |
| Triglycerides | 370 mg/dL | 629 mg/dL |
| Inflammatory Markers | ||
| Ferritin | 5,010 ug/L | 298,610 ug/L |
| CRP | 138.7 mg/L | 9.3 mg/L |
| LDH | 274 U/L | 17,642 U/L |
| IL-2 Receptor | ND | 11,763 pg/mL |
| Blood Counts | ||
| WBC | 0.12 K/uL | 2.30 K/uL |
| Hemoglobin | 8.0 g/dL | 5.5 g/dL |
| Platelets | 32 K/uL | 15 K/uL |
| Coagulation Markers | ||
| INR | 1.1 | 1.9 |
| PTT | 27 seconds | 48 seconds |
| D-dimer | ND | >10,000 ng/mL |
Creatinine continued to rise and was 1.82mg/dL at death on day +28 after tisagenlecleucel.
Proteinuria was repeated again 6 days later and was 6.0g/g creatinine. Abbreviations: ND= not done, CRP= C-Reactive Protein, LDH= Lactic Acid Dehydrogenase, IL= Interleukin-2, WBC= White Blood Count, INR= International Normalized Ratio, PTT= Partial Thromboplastin Time
We found lower rates of AKI (5%) in patients receiving tisagenlecleucel compared to prior series evaluating AKI after CAR-T. Two historical series, predominantly evaluating patients receiving axicabtagene ciloleucel, found higher rates of overall CRS (~83%), severe CRS (13%), and AKI (23%).1.2 In this series, we found lower rates of hyponatremia and hypokalemia after tisagenlecleucel, which may also be due to lower rates of CRS. However, severe hypophosphatemia < 2.0 mg/dL was extremely high in both this and a prior series, affecting ≥70% of patients.1 Hypophosphatemia likely results from the rapid T-cell expansion which occurs after infusion of either CAR-T product.
AKI after CAR-T is driven by cytokine-mediated vasodilation and capillary leak leading to third spacing, intravascular volume depletion, and reduced cardiac output, typically causing prerenal azotemia or acute tubular necrosis (ATN).9 In this series, however, we also identified the first case of new-onset proteinuria and AKI occurring in a patient with CAR-T-triggered MAS/HLH. MAS/HLH is a rare, life-threatening complication of CAR-T therapy that has been observed but not extensively reported.10 MAS/HLH is most commonly associated with acute tubular necrosis, yet associated collapsing glomerulopathy has been reported in other settings.10 Unfortunately, a kidney biopsy was not performed in this case due to the patient’s critical illness. Our study is limited by the relatively small cohort size from a single center, as well as the retrospective ascertainment of outcomes, which lead to uncertainty that AKI rates would be 5% in a larger sample. Furthermore, because of the small number of patients receiving axicabtagene ciloleucel at our center during the study period, we compare only to historical controls. However, this is the largest series describing the rates of AKI in patients receiving tisagenlecleucel.
This series highlights the importance of recognizing that each CAR-T product must be evaluated individually to define its unique toxicity profile; this is important for nephrologists to understand, given the intense interest in developing novel cellular-based therapies for multiple cancer-types.
Acknowledgments
Support
MES is supported by NIH K23 DK117014. MF is supported by NIH K12 CA087723. Funders did not have any role in study design, data collection, analysis, reporting, or the decision to submit for publication.
Footnotes
Financial Disclosure
MF receives research grant funding from Novartis and Kite, and has received consulting fees/honorarium from Novartis, Kite, Celgene/BMS, and Arcellx.
The remainder of the authors (MES, DEL, SG, ML, IAS, HSS, NR, KSC) have no relevant financial disclosures.
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