Abstract
Background:
Chimeric antigen receptors redirect T-cells (CAR-T) to target cancer cells. There are limited data characterizing cardiac toxicity and cardiovascular events (CV) events among adults treated with CAR-T.
Objectives:
The purpose of this study was to evaluate the possible cardiac toxicities of CAR-T.
Methods:
The registry included 137 patients who received CAR-T. Covariates included the occurrence and grade of cytokine release syndrome (CRS) and the administration of tocilizumab for CRS. Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction or an increase in serum troponin. Cardiovascular events were a composite of arrhythmias, decompensated heart failure, and CV death.
Results:
The median age was 62 years (interquartile range [IQR]: 54 to 70 years), 67% were male, 88% had lymphoma, and 8% had myeloma. Approximately 50% were treated with commercial CAR-T (Yescarta or Kymriah), and the remainder received noncommercial products. CRS, occurring a median of 5 days (IQR: 2 to 7 days) after CAR-T, occurred in 59%, and 39% were grade $2. Tocilizumab was administered to 56 patients (41%) with CRS, at a median of 27 h (IQR: 16 to 48 h) after onset. An elevated troponin occurred in 29 of 53 tested patients (54%), and a decreased left ventricular ejection fraction in 8 of 29 (28%); each occurred only in patients with grade $2 CRS. There were 17 CV events (12%, 6 CV deaths, 6 decompensated heart failure, and 5 arrhythmias; median time to event of 21 days), all occurred with grade $2 CRS (31% patients with grade $2 CRS), and 95% of events occurred after an elevated troponin. The duration between CRS onset and tocilizumab administration was associated with CV events, where the risk increased 1.7-fold with each 12-h delay to tocilizumab.
Conclusions:
Among adults, cardiac injury and CV events are common post–CAR-T. There was a graded relationship among CRS, elevated troponin, and CV events, and a shorter time from CRS onset to tocilizumab was associated with a lower rate of CV events.
Keywords: Chimeric antigen receptor T-cells, Troponin, Cardiovascular events, Cytokine release syndrome, Tocilizumab
Condensed abstract:
Chimeric antigen receptor T-cells (CAR-T) have demonstrated significant promise in treating patients with several relapsed or refractory hematologic malignancies. There are limited data characterizing cardiac injury or CV events following CAR-T among adults. In 137 adult patients treated with CAR-T, cardiac injury (troponin elevation), cardiac dysfunction, and CV events were common (12%). An elevated troponin post-CAR-T among patients with grade ≥ CRS was associated with an increased risk for subsequent CV events and a shorter time from the start of CRS to the administration of tocilizumab was associated with a reduction in CV events.
Introduction:
Leveraging the immune system to target cancer cells is an exciting new paradigm in the treatment of cancer (1). Chimeric antigen receptor T cells (CAR-T) are a novel immunotherapy in which T-cells are genetically engineered to attack cancer cells (1). CARs are artificial proteins consisting of both antigen recognition and T-cell signaling domains. T-cells from patients are genetically altered to express the CAR allowing them to attack cancer cells which express the target antigen (1,2). This therapy is a novel and efficacious treatment modality for patients with relapsed or refractory hematologic malignancies including leukemia and lymphoma without other treatment options (1,3). Two CAR-T therapies were recently approved: one used for children with acute lymphoblastic leukemia as well as for adults with lymphoma (3,4) and another for adults with lymphoma (1). The use of CAR-T for other solid (5) and hematologic tumors is under active investigation (6). There are limited data characterizing the cardiovascular (CV) toxicities of CAR-T among adults, mostly consisting of brief case reports or safety reporting in clinical trials (1). For example, in a pivotal clinical trial of 101 patients with refractory large B-cell lymphoma being treated with CAR-T, a cardiac arrest was reported in 1 subject and, in case reports, a decrease in cardiac function and arrhythmias have also been described in relation to the development of cytokine release syndrome (CRS) after CAR-T (7,8). A more descriptive analysis beyond case reports is important for several reasons. First, other types of immunotherapy are known to cause cardiac toxicity; specifically, immune checkpoint inhibitors, which block the immunosuppressive actions of several surface molecules on T cells, are associated with an increased risk for highly morbid and even fatal cardiac effects (9-12). Second, one of the most common CAR-T specific toxicities is CRS (13), which is a clinical syndrome characterized by isolated fevers, hypotension, hypoxia, and end-organ dysfunction (14), all of which which require adequate cardiac reserve. Finally, many adult patients treated with CAR-T have pre-existing CV disease and/or prior exposure to cardiotoxic agents such as anthracyclines or radiation and as such may be at elevated risk for CV events after CAR-T (15). As the number of indications and new CAR-T therapies are expected to increase, an improved understanding of potential CV toxicities is of great clinical relevance (7). Therefore, we created a registry to describe the cardiac effects associated with CAR-T and to determine if there are diagnostic and treatment variables associated with those outcomes.
Methods:
The study cohort was derived from all patients receiving CAR-T at Massachusetts General Hospital, Boston, Massachusetts and the patients at Moffitt Cancer Center Tampa, Florida who were receiving CAR-T between January 1, 2016, and November 10, 2018. This was a retrospective cohort study, and was approved by the institutional review board of each organization. The requirement for written informed consent was waived due to the study design. All patients were followed up until a fixed calendar date (i.e., January 31, 2019). The clinical events were extracted from the detailed chart review. The patients who died during the follow up, the last follow up date was the date of death. Out of the 137 patients who received CAR-T, four patients lost follow up. For those four patients, the last date of the patient seen at the index hospitalization was considered as the date of last follow up.
Covariates:
Data on the covariates were extracted retrospectively from the electronic medical records. including age, sex, race, body mass index (BMI). Pre-existing CV disease and risk factors including hypertension, dyslipidemia, diabetes mellitus, tobacco use, coronary artery disease (CAD), stroke, cardiomyopathy, heart failure (HF), and atrial fibrillation or flutter were recorded. Cancer-specific covariates included the type of malignancy, previous cancer treatments and type of CAR-T administered, as well as the development of CRS and use of tocilizumab post- CAR-T infusion. The CRS grading system (grades 1-4) utilized at both institutions was the standardized Lee scale and is described in Supplemental Table 1 (16). If available, both troponin and C-reactive protein (CRP) values were provided from baseline, pre-CAR-T, and post-CAR-T. Additionally, echocardiographic variables were recorded where available. Cardiac testing was performed at the discretion of the treating team and was not pre-specified.
Definitions and Outcomes:
An elevated troponin after CAR-T was defined as a troponin T of >0.03 ng/ml or high sensitivity (HS) troponin of >14 ng/L. These assays and range of normal limits were same in both participating institutions. A reduction in LVEF was defined as a decrease of at least 10 percentage points to a value below 50% (17). The clinical outcome of interest, CV events, were defined as a composite of decompensated HF (Supplemental table 2) (18), clinically-significant arrhythmias (19,20) (Supplemental table 2) , and CV death. CV death was defined as death due to HF, cardiogenic shock (21), cardiac arrest (20), or an arrhythmia (22). All outcomes were adjudicated and confirmed by review of the EHR by the study team blinded to other variables. The onset of CRS was defined as standard as the first apperance of a fever after CAR-T therapy. The time to tocilizumab administration was defined as the time from the onset of CRS to the adminstration of tocilizumab.
Statistical analysis:
Continuous variables were presented as mean and SD or median (Interquartile range, IQR), as appropriate, based on normality, and categorical variables were presented as percentages. Continuous data were compared with the use of unpaired Student t tests or Wilcoxon rank-sum tests, as appropriate. Categorical data were compared using the chi-square or the Fisher exact test. Univariate analyses were performed to determine the association between the time of CRS symptoms and tocilizumab administration with CV events. Statistical significance was defined using a two-tailed p-value ≤0.05. Statistical analyses were performed using SPSS software version 24 (IBM Corp., Armonk, New York).
Results:
Baseline Patient Characteristics:
Baseline demographics and clinical characteristics are summarized in Table 1 for the 137 patients who received CAR-T therapy. The median (IQR) age was 62 (54,70) years and the majority were male (68%). Hypertension was present in 39%, diabetes in 10%, dyslipidemia in 18%, pre-existing atrial fibrillation or flutter in 13%, CAD in 7%, and prior cardiomyopathy or clinical HF in 3.6%. The most common indication for CAR-T was relapsed diffuse large B-cell lymphoma (61%) followed by transformed follicular lymphoma (27%) and myltiple myeloma (8%). Approximately 50% were treated with commercial CAR-T (axicabtagene ciloleucel [Yescarta], Kite Pharmaceuticals; or tisagenlecleucel [Kymriah], Novartis Pharmaceuticals), while the remainder received non-commercial (investigational) cellular therapy products (Table 1). Prior to the CAR-T treatment, 79% were treated with an anthracycline, 57% were treated with cyclophosphamide, 53% were treated with vincristine, 58% were treated with carboplatin, 40% were treated with gemcitabine, 23% were treated with lenalidomide, 28% received mediastinal radiation, and 28% received autologous stem cell transplantation. Within the limitations of the sample size, there was no association between pre-CAR-T therapies and troponin elevation or CRS grading. (Table 1 & 2). Of the entire cohort, 129 (94%) had a pre-CAR-T echocardiogram. The left ventricular ejection fraction (LVEF) on the pre-CAR-T echocardiogram was 62±7% and the LV internal dimension-diastole (LVIDD) was of 46±6 mm. Among the entire cohort, 71 (41%) patients had a pre-CAR-T troponin assay and all had a normal troponin at baseline. All had a baseline CRP prior to conditioning chemotherapy and the median value was 4.7 mg/L (IQR: 2.0, 9.7).
Table 1:
Baseline characteristics, Overall and by Grade of CRS (Lee 2014 Criteria).
| Total Cohort (n=137) |
CRS ≥ Grade 2 (n=55) |
No CRS/CRS ≤ Grade 1 (n=82) |
p-value | |
|---|---|---|---|---|
| Sex (male) | 93 (68%) | 37 (67%) | 56 (68%) | 0.90 |
| Age | 61±11.0 | 64±8.9 | 59±11.6 | 0.008 |
| BMI (kg/m2) | 27.0±6.9 | 26.7±5.1 | 27.1±8.0 | 0.74 |
| Ethnicity | 0.35 | |||
| Non-Hispanic | 125 (91%) | 49 (89%) | 76 (95%) | |
| Hispanic | 4 (3%) | 1 (1.8%) | 3 (3.6%) | |
| Other | 8 (6%) | 5 (9.0%) | 3 (2.4%) | |
| Race | 0.91 | |||
| White | 126 (92%) | 50 (91%) | 76 (88%) | |
| Black | 4 (3%) | 2 (3.6%) | 2 (2.4%) | |
| Other | 7 (5%) | 3 (5.4%) | 4 (4.8) | |
| Diabetes | 14 (10%) | 7 (12.7%) | 7 (8.5%) | 0.57 |
| Hypertension | 53 (39%) | 26 (47%) | 27 (33%) | 0.13 |
| Hyperlipidemia | 24 (18%) | 11 (20%) | 13 (16%) | 0.37 |
| Smoking | 2 (1.5%) | 0 (0%) | 2 (2.4%) | 0.52 |
| CAD | 10 (7.3%) | 6 (11%) | 4 (4.8%) | 0.20 |
| Heart failure | 5 (3.6%) | 2 (3.6%) | 3 (3.6%) | 1.00 |
| Atrial fibrillation | 18 (13%) | 8 (14.5%) | 10 (12%) | 0.80 |
| CRPmax (mg/L) | 102 (51, 173) | 137 (98, 262) | 79 (41, 134) | <0.001 |
| Cancer type | 0.45 | |||
| Diffuse large B-cell Lymphoma | 83 (61%) | 36 (65%) | 47 (58%) | |
| Transformed Follicular Lymphoma | 36 (27%) | 14 (25%) | 22 (28%) | |
| Multiple Myeloma | 11 (8%) | 2 (3.6%) | 9 (11%) | |
| Other | 7 (4.5%) | 3 (5.4%) | 4 (4.8%) | |
| CAR-Administered | 0.07 | |||
| Yescarta | 68 (50%) | 38 (69%) | 30 (36.5%) | |
| Kymriah | 1 (0.7%) | 0 (0%) | 1 (1.2%) | |
| Investigational CAR-T | 66 (48%) | 17 (31%) | 49 (60%) | |
| Other cancer therapies before CAR-T | ||||
| Anthracycline | 108 (79%) | 45 (82%) | 63 (77%) | 0.48 |
| Cyclophosphamide | 78 (57%) | 29 (53%) | 49 (59%) | 0.41 |
| Vincristine | 73 (53%) | 31 (56%) | 42 (51%) | 0.55 |
| Carboplatin | 79 (58%) | 33 (60%) | 46 (56%) | 0.65 |
| Gemcitabine | 55 (40%) | 20 (36%) | 35 (42%) | 0.46 |
| Lenalidomide | 31(23%) | 12 (22%) | 19 (23%) | 0.85 |
| Mediastinal radiation | 39 (28%) | 17 (30%) | 22 (27%) | 0.60 |
| Stem cell transplant | 38 (28%) | 14 (25%) | 24 (29%) | 0.62 |
| Echo parameters | ||||
| Ejection fraction (%) | 62±7.0 | 62±8.4 | 63±5.9 | 0.41 |
| LVIDD (mm) | 46±5.7 | 47±5.7 | 46±5.7 | 0.32 |
| LVIDS (mm) | 31±5.0 | 32±5.2 | 31±4.8 | 0.25 |
| Intraventricular septum Thickness (mm) | 9.9±2.0 | 10.0±1.8 | 9.9±2.1 | 0.77 |
| RVSP (mmHg) | 30.5±7.5 | 30.2±8.8 | 31.0±6.4 | 0.44 |
CRP=C-reactive protein, CAR-T= Chimeric antigen receptor T-cells, LVIDD= left ventricular internal dimension-diastole, LVIDS= left ventricular internal dimension-systole, RVSP= right ventricular systolic pressure.
Table 2:
Baseline demographics & characteristics by post-CAR-T troponin elevation
| Troponin measured | Troponin not measured (n=84) |
p-value (+) vs. (−) |
||
|---|---|---|---|---|
| Troponin (+) (n=29) |
Troponin (−) (n=24) |
|||
| Sex (male) | 23 (79%) | 15 (63%) | 54 (64%) | 0.23 |
| Age | 64±8.7 | 58±9.5 | 61±11.4 | 0.02 |
| BMI (kg/m2) | 27.6±4.4 | 25.7±5.3 | 26.8±4.8 | 0.16 |
| Ethnicity | 0.97 | |||
| Non-Hispanic | 26 (90%) | 21 (88%) | 77 (92%) | |
| Hispanic | 1 (3.4%) | 1(4.2%) | 3 (3.6) | |
| Other | 2 (6.9%) | 2 (8.3%) | 4 (4.8%) | |
| Race | 0.89 | |||
| White | 26 (90%) | 21 (88%) | 77 (92%) | |
| Black | 0 (0%) | 1 (0%) | 3 (0%) | |
| Other | 3 (10.3%) | 2 (8.3) | 4 (4.8%) | |
| Diabetes | 7 (24%) | 3 (12.5%) | 3 (3.6%) | 0.32 |
| Hypertension | 15 (52%) | 9 (37.5%) | 28 (33.3%) | 0.41 |
| Hyperlipidemia | 9 (31%) | 4 (16.7%) | 12 (14.3%) | 0.34 |
| Smoking | 0 (0%) | 1 (4.2%) | 1 (1.2%) | 0.45 |
| CAD | 3 (10.3%) | 2 (8.3%) | 5 (6.0%) | 1.00 |
| Heart failure | 2 (6.9%) | 2 (8.3%) | 1 (1.2%) | 1.00 |
| Atrial fibrillation | 5 (17%) | 2 (8.3%) | 10 (11.9%) | 0.44 |
| CRPmax (mg/L) (IQR) | 127 (63, 265) | 116 (61, 157) | 87 (52, 146) | 0.37 |
| Cancer type | 0.94 | |||
| Diffuse large B-cell Lymphoma | 15 (51%) | 11 (55%) | 54 (64%) | |
| Transformed Follicular Lymphoma | 9 (31%) | 5 (25%) | 22 (26%) | |
| Multiple Myeloma | 4 (14%) | 2 (8.3%) | 5 (6.0%) | |
| Other | 1 (3.4%) | 1 (4.2%) | 3 (3.6%) | |
| CAR-Administered | 0.14 | |||
| Yescarta | 13 (45%) | 10 (42%) | 45 (54%) | |
| Kymriah | 0 (0%) | 0 (0%) | 1 (1.2%) | |
| Investigational CAR-T | 16 (55%) | 14 (70%) | 43 (51%) | |
| Other cancer therapies before CAR-T | ||||
| Anthracycline | 23 (79%) | 20 (83%) | 65 (78%) | 1.00 |
| Cyclophosphamide | 17 (59%) | 13 (54%) | 48 (57%) | 0.79 |
| Vincristine | 16 (55%) | 13 (54%) | 44 (52%) | 1.00 |
| Carboplatin | 18 (62%) | 14 (58%) | 47 (56%) | 1.00 |
| Gemcitabine | 7 (52%) | 11 (46%) | 37 (44%) | 0.15 |
| Lenalidomide | 6 (21%) | 5 (20%) | 20 (24%) | 1.00 |
| Mediastinal radiation | 9 (31%) | 7 (29%) | 23 (27%) | 1.00 |
| Stem cell transplant | 8 (28%) | 6 (25%) | 24 (29%) | 1.00 |
| Echo parameters | ||||
| Ejection fraction (%) | 62±7.6 | 63±9.5 | 63±6.0 | 0.67 |
| LVIDD (mm) | 48±6.4 | 46±4.7 | 45±5.6 | 0.21 |
| LVIDS (mm) | 33±5.8 | 31±4.8 | 30.4±4.4 | 0.18 |
| Intraventricular septum Thickness (mm) | 10.6±1.7 | 10.1±1.9 | 9.6±1.9 | 0.32 |
| RVSP | 31±6.8 | 30±12.2 | 30±7.0 | 0.71 |
| Grade ≥2 CRS | 24 (83%) | 8 (33%) | 24 (29%) | <0.001 |
These groups are divided based on post-CAR-T troponin measured or not measured.
CRP=C-reactive protein, CAR-T= Chimeric antigen receptor T-cells, LVIDD= left ventricular internal dimension-diastole, LVIDS= left ventricular internal dimension-systole, RVSP= right ventricular systolic pressure.
CRS, Troponin and EF post-CAR-T:
Cytokine release syndrome of any grade was common and noted in 81/137 (59%) and occurred a median of 5 days (2, 7) after CAR-T; a CRS ≥ grade 2 was noted in 54/137 (39%) and a CRS ≥ Grade 3 was noted in 6/137 (4%). A complete comparison of variables between those with and without grade 2 or higher CRS is shown in Table 1. Tocilizumab was administered to 56 (41%) patients at a median of 5 days (3, 8) after CAR-T and 27 hours (16, 48) after the onset of CRS. In our cohort, tocilizumab was only administered to patients with grade 2 or higher CRS when patients develop fluid unresponsive hypotension and /or end organ damage/toxicity requiring IV fluids/ vasopressors, hypoxia requiring oxygen supplementation or mechanical ventilation (Supplemental table 1). These patients were typically transferred to intensive care unit for management (43%). Since fever is mostly the first objective sign of CRS, we measured the resolution CRS using the resolution of fever as timing and found that the median time from the development of fever (CRS onset) until the resolution of fever was 3 days (IQR: 2-5) days. The median dose of tocilizumab given for CRS was 640 mg (based on 8mg/kg dosing) with 38% of the patients receiving >1 dose (Supplemental table 3). Among the cohort of 137 patients, 53 (38%) had pre- and post-CAR-T troponin measure; of which, 29/53 (54%) had an increase in troponin after CAR-T administration. The median time from CAR-T to troponin increase was (median (interquartile range) 16 days (6,31) days). Among the patients with abnormal conventional troponin (troponin T) assay the median and interquartile range was 0.1 ng/ml (0.07, 0.21) and among patients with post-CART elevated high sensitivity assay, the median and interquartile range was 63 ng/L (34, 110) ng/L. There was no significant change in eGFR among the patients with post-CAR-T troponin elevation (mean change in the eGFR among patients with an elevated troponin post-CAR-T was 1.5±1.2 mL/min/1.73m2). A complete comparison of variables between those with and without an elevated troponin post-CAR-T administration is shown in Table 2. When the group with a measured troponin post-CAR-T were separated according to whether there was an increase in troponin after CAR-T, those with elevated troponin were older (64±8.7 vs. 58±9.5 years, p=0.02), and with an increase in the presence of cardiac risk factors (diabetes; 24 vs. 12.5%, hypertension; 52 vs. 38%, hyperlipidemia; 31 vs. 17%, atrial fibrillation/flutter; 17% vs. 8.3% and CAD; 10.3 vs. 8.3%, however, these differences were not statistically significant (p>0.05 for all)). There was a graded relationship between elevation in troponin after CAR-T and CRS. Specifically, The incidence of grade 2 or higher CRS among patients with a post-CAR-T elevated troponin was 83%, as compared to an incidence of grade 2 of higher CRS in 33% who were troponin negative (p<0.001) (Table 2). In reverse, among those with CRS of grade 2 or higher, an elevated troponin was noted in 71% while an elevated troponin was noted in only 22% of those with lower grades of CRS (p<0.001) (Figure 1). We also stratified based on higher grades of CRS (≥ grade 3 vs. no CRS/ CRS≤grade 2) and noted that 50% of the patients with CRS ≥ grade 3 had elevated troponin vs. 20% among patients with No CRS/ CRS≤grade 2 (p=0.10). In our cohort, tocilizumab was only administered to patients with grade 2 or higher CRS. The median dose of tocilizumab given for CRS was 640mg with 38% of the patients receiving more that 1 dose. Tocilizumab was more commonly administered to those with a positive troponin after CAR-T (83 vs. 37%, p=0.001). The patient characteristics stratified by median time to tocilizumab administration are shown in Supplemental Table 4. Among the patients who received tocilizumab, we found that a longer duration from the development of CRS to the administration of tocilizumab was associated with an increased likelihood of having a positive troponin in both unadjusted (HR 1.33, CI (1.04, 1.52), p=0.003) and adjusted analysis (adjusted for presence of CV risk factors, HR 1.28, CI (1.08, 1.58), p=0.008). In total, 29 patients had echocardiographic data pre- and post-CAR-T; of these, 8 (28%) had a new reduction in LVEF. The reduction in EF post-CAR-T was only noted in patients with an increase in troponin and a higher-grade (grade 2 or higher CRS) post-CAR-T. Overall, a reduction in EF occurred in 8/29 (28%) of patients with a positive troponin and 8/55 (15%) of patients with grade 2 or higher CRS after CAR-T.
Figure 1: Results.
Diagram showing the results of the study. CAR-T = Chimeric antigen receptor T-cells, CRS= cytokine release syndrome, LVEF= left ventricular ejection fraction, HF= heart failure.
Cardiovascular events:
There were total of 17 CV events (12%) with a median time to event of 21 days (IQR: 11, 38). The overall median follow-up period was 10 months (IQR: 5, 14). The events consisted of 6 CV deaths, 6 patients with decompensated HF and 5 with new-onset arrhythmias. Among all the CV events, 18% occurred among patients with multiple myeloma and 66% occurred among patients with DLBCL and 11% occurred among patients with TFL. Of the CV deaths n=6), 50% of CV deaths occurred among patients with DLBCL, 17% occurred among patients with TFL and 33% occurred among patients with multiple myeloma. Three of the CV deaths occurred in patients with new onset of HF or tachyarrythmias complicated by hypotension and shock, and 3 deaths occurred in patients with circulatory shock followed by cardiac arrest (Supplemental Table 5). All patients with a HF event noted shortness of breath, had hypoxia and had signs of volume overload. Additionally, all 6 patients had an NT proBNP level of >3,000 pg/ml and all required IV diuretics. Four of the HF events were a new onset of HF, 2 were acute decompensation of previously stable HF. The arrhythmias consistent of 2 patients with a new SVT and 3 with new-onset atrial fibrillation or flutter. All arrhythmias required an intervention which included the administration of amiodarone and/or IV metoprolol. There were 16 events among the group with a positive troponin after CAR-T in comparison to a single CV event among a patient with a negative troponin (CV event rate among patients with positive troponin vs. negative troponin post-CAR-T: 55 vs. 4%, p<0.001). This single event in a patient with a negative troponin was a patient with pre-existing HF who developed decompensated HF in the setting of administration of 3 liters of IV fluids and steroids. An elevated troponin after CAR-T was associated with an increased risk for a CV event.
All 17 patients with CV events had ≥ grade 2 CRS post-CAR-T and prior to the event (event rate among patients with high-grade CRS vs. no CRS: 31 vs. 0%, p<0.001) (Figure 1, Table 3). We also tested the association between events and CRS after stratifying by higher grades of CRS. Out of the 6 patients with CRS ≥ 3, 3 patients (50%) had a CV event, whereas, among the group of patients with no CRS or CRS ≤ grade 2 (n=131 patients), 14 patients (11%) had a CV event. (Supplemental Table 6). A CV event occurred in 16/29 (55%) of patients with an elevated troponin vs 1/24 (4.1%) of patients with no elevation of troponin post-CAR-T administration (p<0.001). In a univariate and multivariate analysis, after adjusting for presence of a CV risk factor, a longer duration between CRS onset and tocilizumab administration was associated with an increase in CV events (unadjusted OR 1.30, 95% CI 1.00-1.63, p=0. 015; adjusted OR 1.22, 95% CI 1.01-1.53, p=0.022).
Table 3:
Outcomes—CRS ≥ grade 2 vs. No CRS/CRS ≤ Grade 1
| CRS ≥ Grade 2 (n=55) |
Event rate/100 patient-years |
No CRS/CRS ≤ Grade 1 (n=82) |
p-value | |
|---|---|---|---|---|
| CV events | 17 (31%) | 15.8 | 0 (0%) | <0.001 |
| CV deaths | 6 (11%) | 5.6 | 0 (0%) | |
| New onset of HF | 6 (11%) | 5.6 | 0 (0%) | |
| HF decompensation | 2 (3.6%) | 1.9 | 0 (0%) | |
| New arrhythmias (SVT, atrial fibrillation/flutter with RVR) | 7 (12%) | 6.5 | 0 (0%) | |
| Drop in ejection fraction | 8 (14.5%) | 7.5 | 0 (%) | 0.005 |
HF= heart failure, SVT = supraventricular tachycardia, RVR= rapid ventricular rate, CRS=cytokine release syndrome.
Discussion
Beyond case reports and isolated events in clinical trials, we present the first data on the cardiac toxicities and CV events after administration of CAR-T among adult patients. Cardiac injury (elevation in troponin, occurring in 21% of the entire cohort and 55% of the patients in whom the troponin assay was measured both pre- and post-CAR-T), cardiac dysfunction and CV events were common (12%) (Central Illustration). There was a close relationship between the development of CRS, cardiac injury, and the occurrence of a CV event. Specifically, troponin elevation was more common with higher-grade CRS, all CV events occurred in patients with CRS, and 94% of CV events occurred in patients with an elevated troponin and grade 2 or higher CRS. Interestingly, despite severe CRS typically being defined as ≥ grade 3, we found increased rates of cardiac events in ≥ grade 2 CRS suggesting that the threshold for intervention with CRS could be decreased to lower grades of CRS. Additionally, an elevated troponin after CAR-T was associated with an increased risk for a CV event suggesting a role for testing whether serial measurement of troponin may be of use for identifying high-risk patients after CAR-T and identifying those patients who should get earlier treatment with tocilizumab. These CV events after CAR-T, with the use of improved risk stratiftication, may be preventable, as the time from onset of CRS to administration of tocilizumab was associated with CV event risk such that the risk increased 1.7-fold with each 12-hour period from onset of CRS.
Central Illustration: Relationship between elevated troponin, CRS and tocilizumab with cardiovascular events.
Relationship of elevated troponin, CRS (Lee 2014 Criteria) and tocilizumab administration with cardiovascular events.
There are evolving data on the CV toxicities related to non-CAR-T cancer immunotherapies (23). Immune checkpoint inhibitors have a significantly different mechanism of action than CAR-T (24). These drugs activate the immune response to cancer cells by inhibiting immunsuppressive signals and are approved for a wide variety of solid tumors (25). Myocarditis is an uncommon but potentially fatal CV toxicity related to the administration of checkpoint inhibitors (9). CAR-T also works by harnessing the immune system but via a very different, and more targeted, mechanism and the use of CAR-T will likely expand (5,26). Complications secondary to CAR-T are principally related to the development of CRS and neurotoxicity (7), with no robust data characterizing the occurrence of cardiac toxicity or CV events among adults after CAR-T. In a single center, phase 1 clinical trial involving 21 children and young adults with ALL or non-Hodgkin lymphoma relapsed or refractory to standard cancer therapy who received a CD19 specific CD28zeta CAR, Lee et al, noted CRS of any grade occurred among 16 out of 21 patients. 8 patients had grade 1 CRS, 2 patients had grade 2, 3 patients had grade 3 CRS and 3 patients had grade 4 CRS. One patient had a cardiac arrest 4 days after CRS associated with a significant drop in LVEF (65% to 25%). One patient developed QTc prolongation, 4 patients developed hypotension, and 1 developed pulmonary edema. All these events occurred among patients with higher grade CRS (8). In the pivotal Zuma-1 multicenter phase 2 trial involving 111 patients with lymphoma who were treated with CAR-T (Axicabtagene ciloleucel), Neelapu et al, noted any grade CRS occurred in 93% of the patients, with 80% grade 1 or 2 CRS and 13% grade 3 or higher CRS, 39% developed tachycardia and 59% developed hypotension out of which 17% required vasopressors. There were no other cardiac events noted (1). Similarly, in the pivotal JULIET study of 93 patients that led to the FDA approval of tisagenlecleucel, no significant cardiac events were noted despite a 58% rate of CRS, 22% of which were considered ≥ grade 3 (per Penn criteria) (27). In this first report of 137 adult patients, we noted that between 21 and 59% had cardiac injury, 12% had a CV event, and 4% had a cardiac-related death. This higher rate of cardiac toxicity and worse cardiac outcomes likely relate, in part, to how these were defined, but also to the higher CV risk profile of adult patients receiving CAR-T. Our population had a median age of 62 years, had multiple pre-existing CV risk factors, and had been heavily pre-treated with cancer therapies (e.g. anthracycline chemotherapy and radiation) which themselves are associated with elevated CV risks.
This is the first study to demonstrate an association between elevated troponin values and the development of CV events in the setting of CAR-T therapy. The association between an elevated troponin and CV events has been established in broad groups of patients (9,28,29) and among patients receiving other therapies for cancer (10,30). The administration of CAR-T, via the development of CRS, may be associated with tachycardia and hypotension (7) and this, as opposed to myocarditis, is the probable mechanism for the increase in troponin observed in this cohort as all cases of an elevated troponin occurred with CRS. However, our patients did not undergo cardiac MRIs or endomyocardial biopsies so the exact mechanism is yet to be determined. In this study, troponin appeared to strongly related to the occurrence of a CV event after CAR-T in adults, where 16 of the 17 CV events occurred in patients with a positive troponin. These data suggest that measurement of troponin may be of additional value among adult patients being treated with CAR-T, especially among patients with CRS and support the testing of this hypothesis in a prospective study.
Our findings also have therapeutic implications. In this study, there was an association between the time to administration of tocilizumab in the setting of CRS and adverse CV events. Treatment with CAR-T is associated with a marked increase in IL-6 (14,31) and the administration of tocilizumab for patients after CAR-T with high-grade CRS is recommended (32,33). The use of tocilizumab has not precluded prolonged and durable responses following CAR-T (32). In our study tocilizumab was administered at grade 2 or higher CRS, and current guidelines are promoting earlier utilization in patients with prolonged CRS or significant comorbidities. In this study, the earlier administration of tocilizumab was associated with a reduction in CV events. These findings support prospective trials to routinely measure troponin, and potentially perform echocardiography, to see confirm if these measure may identify high-risk groups who may benefit from earlier tocilizumab. This study, if supportive, would then be followed by testing whether immediate administration of tocilizumab to patients with CRS and a positive troponin is associated with a reduction in CV events. In brief, it is important to differentiate the management of cardiac toxicities in the setting of CAR-T to that of checkpoint inhibitors. In the latter, administration of high-dose steroids is recommended (12); however, in contrast, although steroid use in patients with refractory CRS does not appear to negatively impact CAR-T efficacy, it is unclear if earlier use of high dose steroids for lower grade CRS in the context of cardiovascular disease is warranted (12,34).
Study limitations
This study needs to be interpreted within the context of the study design. The study was performed in two large academic centers, where study populations may differ; however, results were similar when each center’s population were examined in isolation. This was not a prospective protocol driven study; therefore, cardiac testing and evaluation as well as treatment decisions were not standardized and varied based on the discretion of each treating team. For example, measurement of the troponin assay or assessment of LV function by echocardiogram and the serum troponin assay was performed at the discretion of the medical team. This lack of standardized testing algorithms may have led to an underestimation of the numbers of patients with both an elevation in troponin and a reduction in cardiac function. In reverse, the number of patients with an elevated troponin may be overestimated since it was only checked in 38% of these patients. Specifically, because troponin testing in our study was prompted only by sufficient clinical suspicion for cardiac injury (and not by pre-specified study protocols), the rate of positive troponins among all CAR-T recipients is likely less than our estimate. There was a high CV event rate (12%) over a relatively short median follow-up period. However, this number of events precludes a thorough examination of the association of baseline factors (such as cardiac disease or cardiac function) and CV events after CAR-T and will be the focus of a planned expanded registry. Additionally, without a cardiac biopsy or cardiac MRI, the exact mechanism of cardiac injury cannot be determined. An addition of a cardiac MRI to the standard work-up and in cases of concerning hemodynamics, a biopsy, would help address this knowledge gap. Finally, though we report an increased risk of cardiac toxicity and CV events with longer duration to tocilizumab infusion, we cannot determine if tocilizumab itself can reduce the likelihood of these events from occurring but this will also be the focus of future work.
Conclusions
An elevation in troponin post-CAR-T is commonly seen in patients with CRS and is associated with an increased risk for subsequent CV events among patients treated with CAR-T. A shorter time from recognition of CRS to the administration of tocilizumab was associated with a reduction in CV events. These data support further investigation of the clinical utility of measuring troponin values among all adult patients pre- and post-CAR-T, consideration of interventions earlier in less severe grades of CRS, and testing the possible benefits of tocilizumab administration based on changes in troponin values.
Supplementary Material
CLINICAL PERSPECTIVES.
Competency in Patient Care: Troponin elevation is common in adults receiving cancer chemotherapy with chimeric antigen receptor T-cells (CAR-T) and is associated with adverse cardiovascular events. A shorter interval between the administration of tocilizumab and development of cytokine release syndrome is associated with a lower incidence of cardiac toxicity.
Translational Outlook: Whether measurement of serum troponin levels and routine echocardiography before and after CAR-T therapy can be used to guide tocilizumab administration has not been established.
Acknowledgments
Funding: This work was supported by National Institutes of Health/National Heart, Lung, Blood Institute [T32HL076136 to R.A.], [R01HL137562-, R01HL130539, and K24HL113128-06 to T.N.]. Dr. T. Neilan was also supported, in part, through a kind gift from A. Curtis Greer and Pamela Kohlberg. Dr. Banerji and Dr. Alvi were supported by NIH/NHLBI 5T32HL076136.
Abbreviations
- CAR-T
Chimeric antigen receptor T-cells
- HF
Heart failure
- CV
Cardiovascular
- CRS
Cytokine release syndrome
- CRP
C-reactive protein
Footnotes
Disclosures: TGN reports acting as a consultant for Parexel, Bristol Myers-Squibb, Aprea Therapeutics and Intrinsic Imaging, unrelated to the current research. F.L.L. reports acting as a scientific advisor for Kite/Gilead and Novartis and a consultant to Cellular BioMedicine Group Inc. M.J.F reports acting as a scientific advisor for Arcellx and Xenetic Bio and consulting activities with Novartis, and Celgene. The remaining authors have nothing to disclose.
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