Acute Kidney Injury After the CAR-T Therapy Tisagenlecleucel

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapies use genetically engineered T cells to target tumor antigens. After 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/hemophagocytic lymphohistiocytosis (MAS/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 about 19%-30% after commercial CAR-T.1Gupta S. Seethapathy H. Strohbehn I.A. et al.Acute kidney injury and electrolyte abnormalities after chimeric antigen receptor T-cell (CAR-T) therapy for diffuse large B-Cell lymphoma.Am J Kidney Dis. 2020; 76: 63-71Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,2Gutgarts V. Jain T. Zheng J. et al.Acute kidney injury after CAR-T cell therapy: low incidence and rapid recovery.Biol Blood Marrow Transplant. 2020; 26: 1071-1076Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Most of these patients (>80%) 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.1Gupta S. Seethapathy H. Strohbehn I.A. et al.Acute kidney injury and electrolyte abnormalities after chimeric antigen receptor T-cell (CAR-T) therapy for diffuse large B-Cell lymphoma.Am J Kidney Dis. 2020; 76: 63-71Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,2Gutgarts V. Jain T. Zheng J. et al.Acute kidney injury after CAR-T cell therapy: low incidence and rapid recovery.Biol Blood Marrow Transplant. 2020; 26: 1071-1076Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar 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.3Pasquini M.C. Locke F.L. Herrera A.F. et al.Post-marketing use outcomes of an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, axicabtagene ciloleucel (Axi-Cel), for the treatment of large B cell lymphoma (LBCL) in the United States (US).Blood. 2019; 134: 764Crossref Google Scholar,4Jaglowski S. Hu Z.-H. Zhang Y. et al.Tisagenlecleucel chimeric antigen receptor (CAR) T-cell therapy for adults with diffuse large B-cell lymphoma (DLBCL): real world experience from the Center for International Blood & Marrow Transplant Research (CIBMTR) Cellular Therapy (CT) Registry.Blood. 2019; 134: 766Crossref Google Scholar Tisagenlecleucel is associated with a reduced inflammatory profile and lower rates of toxicity, which may lead to lower rates of CRS.4Jaglowski S. Hu Z.-H. Zhang Y. et al.Tisagenlecleucel chimeric antigen receptor (CAR) T-cell therapy for adults with diffuse large B-cell lymphoma (DLBCL): real world experience from the Center for International Blood & Marrow Transplant Research (CIBMTR) Cellular Therapy (CT) Registry.Blood. 2019; 134: 766Crossref Google Scholar, 5Ying Z. He T. Wang X. et al.Parallel comparison of 4-1BB or CD28 co-stimulated CD19-targeted CAR-T cells for B cell non-Hodgkin’s lymphoma.Mol Ther Oncolytics. 2019; 15: 60-68Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 6Kawalekar O.U. O’Connor R.S. Fraietta J.A. et al.Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells.Immunity. 2016; 44: 380-390Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar 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 or older with diffuse large B-cell lymphoma (DLBCL) treated with tisagenlecleucel at Massachusetts General Hospital from January 2019 to April 2020. The primary aim was to describe the incidence and clinical features of AKI following tisagenlecleucel treatment. Baseline demographics, laboratory data, and clinical outcomes were obtained from electronic health records. AKI was defined as a ≥1.5-fold increase in creatinine level from the pre–CAR-T baseline (day 0). CRS was graded by the patient’s primary oncology team.7Lee D.W. Santomasso B.D. Locke F.L. et al.ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells.Biol Blood Marrow Transplant. 2019; 25: 625-638Abstract Full Text Full Text PDF PubMed Scopus (880) Google Scholar We also collected baseline, peak, and nadir values for electrolytes. The study was approved by the Partners Healthcare Institutional Review Board; the need for informed consent was waived. Overall, 37 patients received tisagenlecleucel; mean age was 60 years, 65% were men, and 86% were White. CRS occurred in 20 patients (54%): 11 patients had grade 1; 4, grade 2; and only 1, high-grade CRS (grade 5; Table 1). Sixteen patients (42%) received immunosuppressive (IS) 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 treatment (Table 1).Table 1Baseline Characteristics and Clinical Outcomes Among Patients Receiving TisagenlecleucelValueBaseline characteristics Mean age ± SD, y60 ± 18 Male sex24 (65%) White race32 (86%)Comorbid conditions Diabetes6 (16%) Hypertension9 (24%) Congestive heart failure0 (0%) Cirrhosis0 (0%)CRS20 (51%) Grade 115 (41%) Grade 24 (11%) Grade 3 or 40 (0%) Grade 51 (3%)Baseline medication use Acyclovir19 (51%) ACEi/ARB5 (14%) Bactrim14 (38%) Proton pump inhibitor16 (43%) H2 blocker9 (22%) Statin9 (24%) Allopurinol9 (24%) Diuretic3 (8%) Nonsteroidal anti-inflammatory drugs2 (5%)Use of IS to treat CRS or neurotoxicityaNeither required dialysis.16 (43%) Dexamethasone13 (35%) Tocilizumab8 (22%) Anakinra8 (22%)AKIaNeither required dialysis.2 (5%)Electrolyte disorders Hyponatremia: sodium < 130 mEq/L7 (19%) Hypokalemia: potassium < 3.0 mmol/L5 (14%) Hypophosphatemia: phosphate < 2.0 mg/dL26 (70%)30-d mortality5 (14%)Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SD, standard deviation.a Neither required dialysis. Open table in a new tab Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SD, standard deviation. Overall, 5 patients (14%) died within 30 days, all attributable to disease progression and/or infectious complications (Table 1). AKI occurred in only 2 patients (5%), stage 3 for both. The first was an 80-year-old man who had grade 2 CRS and neurotoxicity and aspirated the day after the tisagenlecleucel infusion; septic shock led to rapidly progressive nonoliguric AKI and death 4 days after tisagenlecleucel treatment. The second was a 50-year-old man with a new diagnosis of DLBCL. One week after tisagenlecleucel treatment, 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 nonoliguric AKI and had spot protein-creatinine ratios > 5 g/g measured twice on nonconsecutive days. AKI progressed during administration of liposomal amphotericin B for invasive mucormycosis and acyclovir for herpes simplex prophylaxis, and the patient died on day +28.Table 2Baseline and Laboratory Values in the Patient Who Developed MAS/HLH and Nephrotic SyndromeBaselineDiagnosis of MAS/HLHKidney function/markers of nephrotic syndromeaCreatinine level continued to increase and was 1.82mg/dL at death on day +28 after tisagenlecleucel treatment. Proteinuria test was repeated 6 days after diagnosis and was 6.0g/g. Creatinine, mg/dL0.541.36 Serum urea nitrogen, mg/dL1944 ProteinuriaNegative on dipstick5.0 g/g Dipstick hematuriaNegative2+ Albumin, g/dL2.52.4 Triglycerides, mg/dL370629Inflammatory markers Ferritin, μg/L5,010298,610 C-Reactive protein, mg/L138.79.3 Lactic acid dehydrogenase, U/L27417,642 Interleukin 2 receptor, pg/mLNot done11,763Blood cell counts White blood cell count, ×103/μL0.122.30 Hemoglobin, g/dL8.05.5 Platelets, ×103/μL3215Coagulation markers International normalized ratio1.11.9 Partial thromboplastin time, s2748 D-dimer, ng/mLNot done>10,000a Creatinine level continued to increase and was 1.82 mg/dL at death on day +28 after tisagenlecleucel treatment. Proteinuria test was repeated 6 days after diagnosis and was 6.0 g/g. Open table in a new tab We found lower rates of AKI (5%) in patients receiving tisagenlecleucel compared with 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%).1Gupta S. Seethapathy H. Strohbehn I.A. et al.Acute kidney injury and electrolyte abnormalities after chimeric antigen receptor T-cell (CAR-T) therapy for diffuse large B-Cell lymphoma.Am J Kidney Dis. 2020; 76: 63-71Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,2Gutgarts V. Jain T. Zheng J. et al.Acute kidney injury after CAR-T cell therapy: low incidence and rapid recovery.Biol Blood Marrow Transplant. 2020; 26: 1071-1076Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar In the current series, we found lower rates of hyponatremia and hypokalemia after tisagenlecleucel treatment, which may also be due to lower rates of CRS. However, severe hypophosphatemia (phosphate < 2.0 mg/dL) was extremely common in both this and a prior series, affecting ≥70% of patients.1Gupta S. Seethapathy H. Strohbehn I.A. et al.Acute kidney injury and electrolyte abnormalities after chimeric antigen receptor T-cell (CAR-T) therapy for diffuse large B-Cell lymphoma.Am J Kidney Dis. 2020; 76: 63-71Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Hypophosphatemia likely results from rapid T-cell expansion 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 decreased kidney perfusion or acute tubular necrosis (ATN).8Perazella M. Shirali A. Nephrotoxicity of cancer immunotherapies: past, present, and future.J Am Soc Nephrol. 2018; 29: 2039-2052Crossref PubMed Scopus (79) Google Scholar However, in this series, 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.9Thaunat O. Delahousse M. Fakhouri F. et al.Nephrotic syndrome associated with hemophagocytic syndrome.Kidney Int. 2006; 69: 1892-1898Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar MAS/HLH is most commonly associated with ATN, yet associated collapsing glomerulopathy has been reported in other settings.9Thaunat O. Delahousse M. Fakhouri F. et al.Nephrotic syndrome associated with hemophagocytic syndrome.Kidney Int. 2006; 69: 1892-1898Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Unfortunately, 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 led 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 with historical controls. However, this is the largest series describing the AKI rates in patients receiving tisagenlecleucel. This series highlights 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. Meghan D. Lee, BS, Ian A. Strohbehn, BA, Harish S. Seethapathy, MBBS, Nifasha Rusibamayila, MPH, Keagan S. Casey, BS, Shruti Gupta, MD, MPH, David E. Leaf, MD, MMSc, Matthew J. Frigault, MD, and Meghan E. Sise, MD, MS. Research idea and study design: MDL, HS, MES; data acquisition: MDL, IAS, NR, MES, KSC, MJF; data analysis/interpretation: MDL, IAS, HS, NR, MJF, SG, DEL, MES; statistical analysis: NR, MES; supervision or mentorship: MES; joint senior authors: MJF and MES (equal contribution to this work). Each author contributed important intellectual content during manuscript drafting or revision, accepts personal accountability for the author’s own contributions, and agrees to ensure that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved, including with documentation in the literature if appropriate. MES is supported by NIH K23 DK117014 ; MJF, by NIH K12 CA087723 . Funders did not have any role in study design; data collection, analysis, or reporting; or the decision to submit for publication. MJF receives research grant funding from Novartis and Kite and has received consulting fees/honoraria from Novartis, Kite, Celgene/BMS, and Arcellx. The remaining authors declare that they have no relevant financial interests. Received July 17, 2020. Evaluated by 3 external peer reviewers, with direct editorial input from a Statistics/Methods Editor and an Associate Editor, who served as Acting Editor-in-Chief. Accepted in revised form August 29, 2020. The involvement of an Acting Editor-in-Chief was to comply with AJKD’s procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.