Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies

Abstract

BackgroundChimeric antigen receptor (CAR) T-cell-associated cytokine release syndrome (CRS) may present with tachycardia, hemodynamic instability and reduced cardiac function. Pediatric CAR studies examining cardiac toxicity are limited.MethodsWe report on cardiac toxicity observed in children and young adults with hematologic malignancies enrolled in a CD19-28ζ CAR T-cell phase I trial (NCT01593696). All patients had a formal baseline echocardiogram. Real-time studies included echocardiograms on intensive care unit (ICU) transfer, and serial troponin and pro-B-type natriuretic peptide (pro-BNP) in the select patients.ResultsFrom July 2012 to March 2016, 52 patients, with a median age of 13.4 years (range 4.2–30.3) were treated. CRS developed in 37/52 (71%), which was grade 3–4 CRS in nine patients (17%). The median prior anthracycline exposure was 205 mg/m2 (range 70–620 mg/m2) in doxorubicin equivalents. The median baseline left ventricle ejection fraction (LVEF) and baseline LV global longitudinal strain (GLS) were 60% (range 50%–70%) and 16.8% (range 14.1%–23.5%, n=37) respectively. The majority, 78% (29/37), of patients had a reduced GLS <19% at baseline, and 6% (3/52) of patients had baseline LVEF <53%. ICU transfers occurred in 21 patients, with nine requiring vasoactive hemodynamic support and three necessitating >1 vasopressor. Six (12%) patients developed cardiac dysfunction (defined by >10% absolute decrease in LVEF or new-onset grade 2 or higher LV dysfunction, per CTCAE v4), among whom 4 had grade 3–4 CRS. Troponin elevations were seen in 4 of 13 patients, all of whom had low LVEF. Pro-BNP was elevated from baseline in 6/7 patients at the onset of CRS, with higher levels correlating with more severe CRS. Cardiac dysfunction fully resolved in all but two patients by day 28 post-CAR.ConclusionCardiac toxicity related to CD19-28ζ CAR T-cell-associated CRS was generally reversible by day 28 postinfusion. Implementation of more frequent monitoring with formal echocardiograms incorporating systemic analysis of changes in GLS, and cardiac biomarkers (troponin and proBNP) may help to earlier identify those patients at highest risk of severe cardiac systolic dysfunction, facilitating earlier interventions for CRS to potentially mitigate acute cardiac toxicity.

Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management

“…In the ELIANA trial, 29% of patients developed hypotension, and 17% were grade 3–4 ( Table 1 and Table 4 ) [ 8 ]. Other studies of pediatric and young adult patients have found that 18–38% of patients will develop grade 3–4 hypotension ( Table 5 ) [ 8 , 24 , 25 , 26 , 27 ], with 13–27% of these patients requiring vasopressor support [ 24 , 25 , 28 , 29 ], and up to one-third of patients requiring admission to the intensive care unit (ICU) [ 25 ]. In a retrospective study by Fitzgerald et al, 13 patients that developed cardiovascular toxicity developed fluid-refractory shock that necessitated the use of alpha agonists.…”

“…Patients with cardiac dysfunction in this study were more likely to have earlier CRS, more severe CRS, receive tocilizumab, and have a lower baseline global longitudinal strain (GLS). In this patient cohort, of the 37 patients that developed CRS, 9 (24%) developed hypotension requiring vasopressors, with 3 of these patients requiring two or more vasopressor agents [ 28 ].…”

“…In children, cardiotoxic complications associated with CAR-T appear to largely be self-limited, with most patients recovering cardiac function back to pre-treatment baseline, including patients that had cardiac arrest [ 28 , 29 ]. In the study by Shalabi et al, all 6 individuals with heart failure had recovery by 3 months, and in the retrospective study by Burstein, 6 of the 7 with impaired systolic function had recovery by 6 months of follow up.…”

“…In the study by Shalabi et al, all 6 individuals with heart failure had recovery by 3 months, and in the retrospective study by Burstein, 6 of the 7 with impaired systolic function had recovery by 6 months of follow up. None of the cardiac events contributed to mortality [ 28 , 29 ].…”

“…Knowledge or risk factors directly contributing to cardiotoxicity are largely limited to retrospective studies. In pediatric and young adult patients, the risk of developing hypotension requiring inotropic support appears to be associated with a pre-treatment blast percentage >25% on bone marrow biopsy, lower baseline ejection fraction or GLS, or pre-existing diastolic dysfunction [ 28 , 29 ]. Studies have not found previous anthracycline-based chemotherapy, radiation exposure, or history of stem cell transplantation to be associated with the risk of developing clinically significant hypotension or cardiac dysfunction [ 16 , 29 ] ( Table 7 ).…”