Transient left ventricular dysfunction following chimeric antigen receptor T‐cell‐mediated encephalopathy: A form of stress cardiomyopathy

Abstract Chimeric antigen receptor (CAR) T‐cell therapy represents a new strategy in treating lymphoid malignancies, such as relapsed‐refractory diffuse large B‐cell lymphoma (DLBCL). Several toxicities including cytokine release syndrome (CRS), neurotoxicity, and cardiovascular toxicity have been linked to CAR T‐cell therapy. Transient impairment in left ventricular systolic function is described after CAR‐T, however, the mechanism remains poorly understood. This paper reports the clinical presentation and outcome of two patients with relapsed‐refractory DLBCL who experienced encephalopathy and CRS following CAR T‐cell therapy and developed transient left ventricular dysfunction consistent with stress cardiomyopathy.


INTRODUCTION
Chimeric antigen receptor T (CAR-T) cells have emerged as a promising therapy for patients with refractory adult hematologic malignancies. Cardiovascular (CV) toxicity, such as transient left ventricular (LV) systolic dysfunction has been observed following CAR-T cell therapy, however the mechanism remains poorly understood [1,2]. This paper presents two adult patients with diffuse large B-cell lymphoma (DLBCL) who experienced encephalopathy and CRS following CAR-T and developed stress cardiomyopathy.

CASE 1
A 76-year-old female presented with DLBCL, refractory to two prior therapies. CV history was significant for hypertension, hyperlipidemia,

CASE 2
A 61-year-old female presented with DLBCL, refractory to two prior therapies. There was no previous CV history, and LVEF 1 month pre-CAR-T was 55%. Following Flu/Cy immunoablation, axicabtagene ciloleucel was administered at 2.0 × 10 6 CAR-T cells/kg.  Day +40 echocardiogram demonstrated resolution of systolic dysfunction, LVEF of 55%, confirming stress cardiomyopathy.

DISCUSSION
CAR-T associated CV toxicity is a serious therapy-related complication, the understanding of which is hampered by a paucity of data from clinical trials [5]. The true incidence is unknown, however studies in adult patients have reported an incidence of 12%-21% [6,7]. Similar to our cases, the median onset duration of CV toxicity following CAR-T infusion is 12.5 days (range 2-24 days) [8]. A wide spectrum of clinical manifestations exists, including dysrhythmias and LV systolic dysfunction [2]. LV systolic dysfunction has been observed in patients with elevated troponin and those with grade 2 CRS or greater [6].
While most cases of CAR-T associated CV toxicity occur secondary to high-grade CRS [3,9], it can also happen in patients who are not in shock and in some may be associated with encephalopathy. Interestingly, neurotoxicity has been shown to be closely linked with CV toxicity and CRS [10]. The pathophysiology for this form may be similar to stress cardiomyopathy [11]. Stress cardiomyopathy is defined as acute and transient LV systolic dysfunction mediated by a neuro-cardiogenic mechanism and classically precipitated by an emotionally or physically stressful event. Both of our patients' cardiotoxicity were preceded by physical stressors ICANS and CRS, resulting in cardiomyopathy. The presence of reversible LV regional wall motion abnormalities extending beyond a single epicardial coronary artery distribution is consistent with this diagnosis [4]. During the acute phase of stress cardiomy-F I G U R E 2 Cardiac MRI native T1 and T2 maps with color scale (obtained on a Siemens Vida 3-Tesla MRI scanner) of patient 2 is shown above. Native T2 values (A) were increased throughout the myocardium with several values greater than 50 ms (upper limit normal 38 ± 3.5 ms). Native T1 values (B) were also diffusely increased with several values greater than 1550 ms (upper limit normal 1227 ms). The increased T1 and T2 values were most prominent in the segments with regional wall motion abnormalities (basal and mid segments of the septum and anterior walls), and no delayed enhancement was appreciated following IV contrast. These findings were most consistent with the diagnosis of stress cardiomyopathy opathy, T 2 weighted CMR may show myocardial edema as high signal intensity in the acute phase. Lack of delayed gadolinium enhancement on CMR is also suggestive of this diagnosis, as seen with our second patient [4].
Management of CAR-T associated CV toxicity includes supportive measures and the use of tocilizumab, an IL-6 receptor antagonist [9].
Further studies are needed to define the role of corticosteroids for the treatment of CV events [12]. The prognosis of these patients is not well understood [2]. Cardiomyopathy is reversible in some, as demon-strated in a recent study, in which LVEF recovered in 75% of patients with supportive care [8,11]. However, CAR-T cells can persist more than 10 years posttreatment, and therefore potential long-term CV effects remain unclear [11].
In conclusion, this paper supports the potential neuro-cardiogenic mechanism of CAR-T associated CV toxicity as both of our patients developed stress cardiomyopathy with encephalopathy and CRS as the likely triggers. However, given the small sample size of our case series, further studies are needed to confirm these findings.