Systematic Review of Risk factors and Incidence of Acute Kidney Injury Among Patients Treated with CAR-T Cell Therapies

Abstract

Immunotherapy has grown significantly in the management of hematological and solid organ tumors. In-depth knowledge of T-cell pathways has led to the development of adoptive cell transfer techniques and subsequent evolution of chimeric antigen receptor T-cell (CAR-T) therapies.1Gill S. Maus M.V. Porter D.L. Chimeric antigen receptor T cell therapy: 25 years in the making.Blood Rev. 2016; 30: 157-167Crossref PubMed Scopus (136) Google Scholar CAR-T cells are biologically engineered cells with a CAR receptor that recognizes a tumor antigen. T-cell receptors are equipped with extracellular domain and variable costimulatory domains yielding divergent T-cell response.2Rosenberg S.A. Restifo N.P. Adoptive cell transfer as personalized immunotherapy for human cancer.Science. 2015; 348: 62-68Crossref PubMed Scopus (1235) Google Scholar Along with their utility among refractory B cell lymphomas, adult diffuse large B-cell lymphoma (DLBCL), and pediatric acute lymphoblastic leukemia (ALL), CAR-T therapies are now being explored in the management of solid organ tumors and multiple myeloma.3Raje N. Berdeja J. Lin Y. et al.Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma.N Engl J Med. 2019; 380: 1726-1737Crossref PubMed Scopus (466) Google Scholar Cytokine release syndrome (CRS), macrophage activation syndrome (MAS)/ hemophagocytic lymphohistiocytosis (HLH), and immune effector cell−associated neurotoxicity syndrome (ICANS) are among the most alarming complications of CAR-T cells.S1 The incidence of acute kidney injury (AKI) reported in the literature among patients with CAR-T therapies varies from 5% to 33%.S1−S22 The mechanism of AKI in patients with CAR-T cell therapy is not completely understood. However, it is proposed that AKI could be secondary to inflammation associated with cytokine release, potentially leading to acute tubular injury.S19 Even though high-grade CRS is associated with AKI,S18 the correlation between severe AKI requiring renal replacement therapies (AKI-RRT) and high grades of CRS is not widely known. We conducted a current systematic review of literature and meta-analysis of articles reporting the incidence of AKI among patients receiving CAR-T therapies and the correlation between severity of CRS and AKI-RRT incidence. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)S23 statement in conducting systematic review. EMBASE, Cochrane, and Ovid MEDLINE databases were systematically searched from database inception through May 2020. Full details are provided in the Supplementary Material. A total of 481 potentially relevant articles were identified and screened. In all, 32 articles were assessed in detail, of which 22 cohort studies S1−S22 with 3376 patients (Table 1) were included in our systematic review (Figure 1).Table 1Main characteristics of studies included in this meta-analysis of AKI incidence and mortality among patients treated with CAR-T cell therapyStudyYearAgeIndications for CAR-T therapyTotal number of patients (n)AKI definitionAKI incidence/ severe AKICause of AKI/biopsyCRS gradingBaseline GFRCRS with AKI vs. CRS without AKIMortalitySauter et al.S2201461 yr (34−68 yr)DLBCLB-NHL6Not definedOverall AKI, 1/6 = 16.6%NANon-severe CRS, 1/2 =50%Severe (grade 4 CRS), 1/2 =50%NAOverall CRS, 2/6 = 33.3%No AKI mortality definedNANo AKI mortality definedLee et al.S320145−27 yr (range)Refectory B-ALL, NHL21Not definedOverall AKI, 1/21 = 5%NACRS grade 1, 8/16 =50%CRS grade 2, 2/16 =12.5%CRS grade 3, 3/16 =18.75%CRS grade 4, 3/16 =18.75%NAOverall CRS, 16/21 = 76%,No AKI CRS definedNAKochenderfer et al.S4201549 yr (range 30−68 yr)DLBCL,CLL,B CELL lymphoma15Not definedOverall AKI, 1/15 = 7%NANANANAOverall, 30- day mortality, 1/15= 7%No AKI mortality definedAli et al.S5201650 yr (range not reported)MM12Not definedOverall AKI, 2/12 = 16.6%NACRS grade 3 and 4, 2/4 = 50%NAOverall CRS, 4/12 = 33.3%NAFitzgerald et al.S12017Median 11 yr (range 5−22 yr)B-ALL39KDIGOOverall AKI,18/39 = 46%Stage 1, 9/39 = 23%Stage 2, 6/39 = 15%Stage 3,3/39 = 8%None required RRTNACRS grade 1, 2/36 = 6%Grade 2,16/36 = 44.4%Grade 3,7/36 = 19.4%Grade 4,11/36 = 30.5%NAOverall CRS, 36/39 = 92%NALocke et al.S6201749 yr (range 29−68 yr)DLBCL7Needing RRTAKI needing RRT, 1/7 = 14%NACRS grade 1 and 2, 5/6 =83%CRS grade 3, 0CRS grade 4, 1/6 = 17%NAOverall CRS, 6/7 = 86%AKI with CRS, 1/6 = 16%9-mo Overall mortality, 4/7=57%No AKI mortality definedHay et al.S7201754 y (median 20−73 yr)ALLCLLNHL133Not definedOverall AKI, 3/133 = 2.25% (AKI reported in only grade 4 CRS patients)AKI needing RRT, 1/133 = 0.75%NACRS grade 1−3,83/93= 89.3%CRS grade4−5, 10/93= 10.7%.NAOverall CRS,93/133 = 70%AKI with CRS,3/93 = 3%NAMaude et al.S8201811 yr (3−23 yr)B- ALL75Needing RRTAKI needing RRT, 7/75 = 9%NACRS grade 1 and 2, 23/58 = 40%CRS grade 3, 16/58 = 28%CRS grade 4, 19/58 = 32%NAOverall CRS, 58/75= 77%AKI with CRS needing RRT, 7/58 = 12%Overall 12- mo mortality, 19/75 = 25%Rives et al.S92018Two groups:1) <18 yr)(median = 10 yr, range 3−17 yr)2) 18−25 yr (median 20 yr, range 18−25 y)B- ALL<18 yr, n = 8418−25yr, n = 20Needing RRTNeeding RRTNANANANACRS > grade 3, = 44%CRS >/ grade 3,45%NAOverall CRS, 66/84 = 79%AKI/RRT with CRS, 7/66 = 11%Overall CRS, 18/20 = 90%AKI/RRT with CRS, 4/18 = 22%Overall mortality>30 days,21/84 = 25%Overall mortality,>30 days8/20 = 40%Hartsell et al.S102019<25 yr (no range mentioned)ALLDLDCLAML40Not definedOverall AKI, 7/40 = 17.5%NANANANAOverall mortality in-hospital,=3/40 = 7.5%Hartsell et al.S112019>18 yr (no range mentioned)B Cell Lymphoma,MM,Follicular lymphoma, ALL735Not definedOverall AKI,110/735 = 15%NANANANAOverall-in hospital mortality,30/735 = 4%TalleurS122019<21 yr (no range mentioned)Refractory ALL5Grade 3 AKIGrade 3 AKI, 1/5 = 20%NAGrade 1 CRS, 1/1 = 100%.No mention of other gradesNAOverall CRS, 1/5 = 20%CRS with AKI, 1/1 = 100%NAMyers et al.S13201911 yr (range 1.4−29.1 yr)Refractory B ALL125KDIGOOverall AKI, = 26/125 (21.0%; 95% CI = 14.5−28.9),Severe AKI (KDIGO stage 2 and 3)15 patients (12%; 95% CI = 7.3− 19.1),3 patients (2.4%; 95%CI = 0.7−7.3) required RRT.Patients with CRS had a 4.9 times greater risk of developing AKI (95% CI = 2.4− 9.9; P < 0.001) and a 10.3 times greater risk of developing severe AKI (95% CI = 3.1− 4.3; P < 0.001)NANAOverall CRS, 100/125= 80%NAMetwally et al.S142019Adults (age not defined)DLBCLN = 58Rise in creatinine >0.3 above baselineOverall AKI, 19/58 = 33%NANANANAAKI mortality at 6 months,47% compared to 13% in non-AKIpatients (P = 0.008)Myers et al.S15201912 yr (range 1.4− 29.1 yr)ALLTotal N =213,ICU admission, n = 49Needing RRTAKI needing RRT among ICU-admitted patients, 4/213 = 1.9%NANANANAOverall 30-day mortality,2/213 = 1%Harris et al.S162020>18 yrDLBCL1570Not definedOverall AKI, 247/1570 = 15.7%NANANANAOverall mortality,30/1570 = 1.5% (in-hospital mortality)No AKI mortality reportedHiramatsu et al.S172020Range5−24 yrB-ALL6Needing RRTAKI needing RRT, 2/6 = 33%NACRS grade 3, 2/5 = 40%CRS grade 4, 3/5 =60%NAOverall CRS, 5/6 =83%AKI with CRS, 2/5 = 40%Overall 12-mo mortality, 2/6 = 33%No AKI mortality definedGutgarts et al.S18202063 yr (range 19−86 yr)DLBCL,NHL46KDIGOOverall AKI, 14/46 = 30% (95% CI = 16.9%−43.9%)Grade 1 AKI, 10/46 = 22% (95% CI = 9.7%− 33.8%)Grade 2, 2/46 = 4.5%Grade 3, 1/46 = 2.17%Grade 2/3 AKI,8% (95% CI = 4%− 17%) incidence of grade 2−3 AKINo patients needed RRTCRS, 11/14 = 79%CRS grade 1 and 2, 31/37= 84%CRS grade 3 and 4, 6/37= 16%Median GFR, 88 ml/min per 1.73 m2 (range, 36−160 ml/min per 1.73 m2)Overall CRS, 37/46 = 80% (95% CI = 66% to 90.5%)CRS with AKI, 10/14 = 79%30-day AKI mortality, 2/14 =14%Gupta et al.S19202060 yr(mean age 60 ± 13 yr)DLBCL78KDIGOOverall AKI, 15/78 = 19%Stage 1, 7/78 = 9%Stage 2, 2/78 = 3%Stage 3, 6/78 = 6%AKI requiring RRT, 3/78 = 4%Decreased kidney perfusion, 8 = 8/15 =53% (CRS = 7/8)ATN, 6 =6/15 = 40% (CRS = 6/6)Post- obstruction, 11/15 = 7%CRSGrade 0, 12/66 =18%.CRS grade 1,28/66 =42.4%CRS grade 2, 28/66= 42.4%CRS grade 3, 8/66 = 12%CRS grade 4, 2/66 =3%109+/17 ml/min per 1.73 m2Overall CRS, 66/78 = 85%CRS with AKI, 13/15 = 86%Overall 6-mo mortality, 11/78= 14%6-mo AKI mortality, 5/15=33%Qu et al.S20202048 yr (range 41−58 yr)DLBCL10 (C-CAR-T, n = 4)(R- CAR-T, n = 6)Not definedOverall AKI, 3/10 = 30 %NACRS grade 3−5 (C-CAR-T),4/10 =40%CRS grade 1−2 (R-CAR-T), 6/10 = 60%NAOverall CRS, 10/10 = 100%NAValadeS21202056 yr (median (27−65 yr)DLBCLALL41AKI needing RRTOverall AKI, 2/41 = 5%NANANAOverall CRS, 39/41 = 95%NALee et al. S222020Mean age 60 yr (SD 18 yr)DLBCL37AKI≥1.5-fold rise in sCr from baselineOverall AKI,2/37 = 5%Stage 3 AKI, 2/37 = 5%AKI requiring RRT, 0/37 = 0%NACRS grade 1, 15/20 = 75%.Grade 2, 4/20 = 20%Grade 3 and 4, 0Grade 5, 1/20 = 5%Baseline creatinine = 0.54 mg/dlOverall CRS, 20/37 = 54%Overall mortality,5/37 = 14%AKI mortality,=2/37 = 5%AKI, acute kidney injury; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; B-NHL, B-cell non-Hodgkin’s lymphoma; CLL, chronic lymphoblastic leukemia; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; GFR, glomerular filtration rate; ICU, intensive care unit; KDIGO, Kidney Disease: Improving Global Outcomes; NA, not available; NHL, non-Hodgkin's lymphoma; MM, multiple myeloma; RRT, renal replacement therapy; sCr, serum creatinine. Open table in a new tab AKI, acute kidney injury; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; B-NHL, B-cell non-Hodgkin’s lymphoma; CLL, chronic lymphoblastic leukemia; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; GFR, glomerular filtration rate; ICU, intensive care unit; KDIGO, Kidney Disease: Improving Global Outcomes; NA, not available; NHL, non-Hodgkin's lymphoma; MM, multiple myeloma; RRT, renal replacement therapy; sCr, serum creatinine. Overall, the pooled estimated incidence of AKI among patients treated with CAR-T therapies was 18.6% (95% CI = 14.3%−23.8%, I2 = 77%) (Figure 2), and the pooled estimated incidence of AKI-RRT was 4.4% (95% CI 2.1%−8.9%, I2 = 61%) (Supplementary Figure S1). Subgroup analysis among adults treated with CAR-T therapies resulted in the pooled estimated incidence of AKI at 17.0% (95% CI = 12.8%−22.2%, I2 = 73%) (Supplementary Figure S2), and the incidence of AKI-RRT was 2.9% (95% CI = 0.9%−9.4%, I2 = 41%) (Supplementary Figure S3). Upon analyzing the results using Kidney Disease: Improving Global Outcomes (KDIGO) criteria, we report that the pooled estimated AKI incidence among adults was 24.1% (95% CI = 14.9%−36.5%, I2 = 49%) (Supplementary Figure S4). The incidence of AKI among adults on CAR-T therapies was slightly higher by KDIGO criteria as compared to overall AKI incidence. Among pediatric and young adult patients, the pooled estimated incidence of AKI was 22.5% (95% CI = 11.1%−40.1%, I2 = 79%) (Supplementary Figure S5) and AKI-RRT was 6.0% (95% CI = 2.2%−15.5%, I2 = 72%) (Supplementary Figure S6). We noticed higher rates of AKI and AKI-RRT among pediatric and young adults than reported among adults. In addition, higher rates of AKI were noted among pediatric and young adults even when analyzed using KDIGO criteria, with an estimated incidence of 31.7% (95% CI = 12.7%−59.6%, I2 = 89%) (Supplementary Figure S7). Among patients on CAR-T therapies, the estimated CRS incidence in all included studies was 75.4% (95% CI = 66.6%−82.4%, I2 = 71%) (Supplementary Figure S8). Upon analyzing the relationship between CRS severity and incidence of AKI-RRT, we found a strong correlation between them (slope = +0.0413, P = 0.01) (Supplementary Figure S9). Funnel plots (Supplementary Figures S10−S13) and Egger regression asymmetry tests were performed to evaluate for publication bias. We found no significant publication bias in the meta-analysis evaluating AKI incidence (P ≥ 0.05 for all analysis). In the current era, the utility of CAR-T therapies has extended widely among patients with various cancers. In our study, the pooled incidence of any AKI among all patients with CAR-T therapies was 19%, and the incidence of AKI-RRT was 4%. Upon analyzing studies that defined AKI by KDIGO criteria, the pooled incidence of AKI among adults was slightly higher at 24%. This observation could be secondary to using a definition with a higher sensitivity in identifying patients with AKI. Interestingly, most patients experienced only mild AKI, with a rise in serum creatinine ≥0.3 mg/dl to1.5 times baseline creatinine, and a smaller proportion of patients reached AKI stage 3 or AKI-RRT. Our findings are in concordance with the results of the largest published studies on AKI incidence among patients with CAR-T therapies.4Thongprayoon C. Hansrivijit P. Kovvuru K. et al.Diagnostics, risk factors, treatment and outcomes of acute kidney injury in a new paradigm.J Clin Med. 2020; 9: 1104Crossref Scopus (12) Google Scholar,S14, S18, S19 We found that the pooled incidence of CRS among patients with CAR-T therapies was 75%, which is in agreement with major published studies.S1,S3,S6−S9,S13,S17−S20 Our analysis reports a strong correlation between AKI-RRT incidence and severe CRS. In addition, our study indicated a higher incidence of AKI and AKI-RRT in the pediatric population than in older adults (22.5% vs. 17% and 6% vs. 2.9%, respectively). The current observation could be secondary to increased CRS incidence among the pediatric population as reported by Lee et al. and Maulde et al.S3,S8 The underlying mechanisms for a higher incidence of CRS among the pediatric population are unclear. However, it is hypothesized to be related to a higher dose, excessive tumor burden, and association of ALL with higher blast count leading to increased CRS risk,5Davila M.L. Riviere I. Wang X. et al.Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia.Sci Transl Med. 2014; 6: 224ra225Crossref Scopus (1510) Google Scholar and, finally, immaturity of the immune system among pediatric patients and young adults. Our study has several strengths. It is the first systematic review looking at the pooled incidence of AKI among adults and pediatric subgroups receiving CAR-T therapies and reporting a correlation between incidence of AKI- RRT and severe CRS. However, our systematic review also has a few limitations. We included a few retrospective cohort studies with smaller sample sizes that reported associations rather than a causal relationship between AKI incidence and CAR-T cell therapies. There is modest heterogeneity among various studies in defining AKI. In addition, we do not have data on baseline kidney function except for a few studiesS18,S19 that included patients with median and mean baseline GFR >60 ml/min per m2 respectively. In conclusion, we report that AKI incidence among patients with CAR-T therapies varies among pediatric and adult cohorts. We additionally report a strong correlation between the severity of CRS and AKI-RRT. As AKI-RRT is associated with higher mortality and morbidity, it would be helpful to undertake additional preventive strategies along with the addition of tocilizumab in patients at high risk for severe CRS to mitigate the risk of AKI. Future research on identifying models or biomarkers that could help to predict AKI among patients on CAR-T therapies and the impact of preventive measures on the incidence of AKI, AKI-RRT, and severe CRS is warranted. All the authors declared no competing interests. SMH is supported by K08 DK118120 from the National Institute of Diabetes and Digestive and Kidney Diseases and by a Mary Kathryn and Michael B. Panitch Career Development Award. SK, TP, and SM performed an independent literature search using search terms. WC, CT, and KK collected the data. SK, SH, and KK interpreted the data. SK, WC, CT, TP, YL, KK, SM, KK, and SH prepared the manuscript and approved the current version of the manuscript. Download .pdf (.42 MB) Help with pdf files Supplementary File (PDF) Supplementary Methods Figure S1. Incidence of severe AKI or AKI-RRT among patients on CAR-T therapies. Figure S2. Incidence of overall AKI among adults on CAR-T therapies. Figure S3. Incidence of AKI- RRT among adults on CAR-T therapies. Figure S4. Incidence of overall AKI (only KDIGO definition) among adults on CAR-T therapies. Figure S5. Incidence of overall AKI among pediatric patients and young adults on CAR-T therapies. Figure S6. Incidence of severe AKI- RRT among pediatric patients and young adults. Figure S7. Incidence of overall AKI (only KDIGO definition) among pediatric patients and young adults. Figure S8. Overall incidence of CRS among patients on CAR-T therapies. Figure S9. Relation between CRS severity of incidence of AKI-RRT among patients on CAR-T therapies. Figure S10. Funnel plot of adults with AKI on CAR-T therapy. Figure S11. Funnel plot of adults with severe AKI-RRT therapy. Figure S12. Funnel plot of pediatric patients and young adults with AKI on CAR-T therapy. Figure S13. Funnel plot of pediatric and young adult patients with severe AKI-RRT on CAR-T therapy. Supplementary References

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