Cardiac Injury and Cardiovascular Events Are Common After CAR T Therapy

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Chimeric antigen receptor T-cell therapy (CAR T) is now approved for the treatment of children with acute lymphoblastic leukemia and adults with lymphoma. This novel type of immunotherapy, in which T-cells are genetically engineered to attack cancer cells, is under active investigation and is expected to expand to other solid and hematologic malignancies.

Besides case reports and isolated events in clinical trials, few data are available about the cardiovascular (CV) toxicity of CAR T. This is a serious knowledge gap because many adults treated with CAR T have CV disease and/or prior exposure to cardiotoxic agents such as anthracyclines or radiation. In addition, cytokine release syndrome (CRS), common with CAR T, is characterized by fever, hypotension, hypoxia and end-organ dysfunction, all of which require adequate cardiac reserve.

Raza M. Alvi, MD, Cardiac MR PET CT Program research fellow at Massachusetts General Hospital, Matthew J. Frigault, MD, Administrative Director of the Cellular Therapy Service at the Mass General Cancer Center, Tomas G. Neilan, MD, MPH, director of the Cardio-Oncology Program at the Corrigan Minehan Heart Center and Mass General Cancer Center, and colleagues created a registry to describe the cardiac effects associated with CAR T. In the Journal of the American College of Cardiology, they report that cardiac injury and CV events are common after CAR T therapy, and they suggest management strategies that might reduce the risk.

Study Methods

The researchers retrospectively studied 137 patients, median age 62, who received CAR T therapy at Mass General or Moffitt Cancer Center in Tampa, Florida between January 1, 2016, and November 10, 2018. Most patients were treated for relapsed diffuse large B-cell lymphoma (61%) while 27% had transformed follicular lymphoma and 8% had multiple myeloma.

The end of follow-up was January 31, 2019; the median follow-up period was 10 months.

Incidence of CRS

CRS of any grade developed in 59% of patients at a median of five days after CAR T. On the Lee scale, the syndrome was grade ≥2 in 39% of patients and grade ≥3 in 4%. Tocilizumab was required by 41% of all patients.

Troponin Measurements

Of 53 patients who had troponin measured both before and after CAR T, 29 (54%) had elevated troponin after therapy (defined as new troponin T >0.03 ng/mL or high-sensitivity troponin >14 ng/L). The median time from CAR T to troponin increase was 16 days.

There was a graded relationship between CRS and elevated troponin after CAR T:

• The incidence of grade ≥2 CRS was 83% among patients with elevated troponin vs. 33% among those who were troponin-negative (P < .001)
• Conversely, elevated troponin was present in 71% of patients with grade ≥2 CRS vs. 22% with lower grades of CRS (P < .001)
• The need for tocilizumab treatment of CRS was significantly more common in patients with elevated troponin after CAR T than in those with normal troponin (83% vs. 37%; P = .001).

Echocardiography Results

Twenty-nine patients underwent echocardiography both before and after CAR T. Eight (28%) showed reduced left ventricular ejection fraction after therapy (defined as a decline of ≥10 percentage points to a value below 50%). The reduction was observed only in patients with elevated troponin and grade ≥2 CRS.

CV Events

The clinical outcome of interest was the composite of decompensated heart failure, clinically significant arrhythmia and CV-related death. 17 patients (12%) had CV events at a median of 21 days after CAR T:

• Six died of CV-related causes
• Six had decompensated heart failure (new-onset in four patients)
• Five had new-onset arrhythmias

Factors Associated with CV Events

• All 17 patients with CV events had grade ≥2 CRS (event rate with grade ≥2 CRS vs. no CRS: 31% vs. 0%; P < .001)
• 16 of the 17 patients with CV events had elevated troponin after CAR T (event rate with elevated vs. nonelevated troponin: 55% vs. 4%; P < .001)
• In multivariate analysis, longer duration between CRS onset and tocilizumab administration was associated with 22% increased risk of CV events (OR, 1.22; 95% CI, 1.01–1.53; P = .02). The risk increased 1.7-fold with each 12-hour period from onset of CRS to administration of tocilizumab

Takeaway Messages

Severe CRS is typically defined as grade ≥3, but in this study, the rate of CV events was increased with grade ≥2. It may be worthwhile to decrease the threshold for intervention in CRS.

Serial troponin measurement may be useful after CAR T to identify patients at high risk of CV events and those who should get earlier tocilizumab treatment for CRS. Improved risk stratification might make it possible to prevent CV events after CAR T, especially in patients with CRS.

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