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

Abstract

Background: Chimeric 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.

Methods: We 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.

Results: From 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.

Conclusion: Cardiac 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.

Keywords: chimeric antigen; cytokines; hematologic neoplasms; immunotherapy; pediatrics; receptors.

Conflict of interest statement

Competing interests: CM is a founder, holds equity in and is a consultant for Lyell Immunopharma which is developing CAR T-cell therapeutics, consults for Neoimmune Tech, Apricity and Nektar, holds equity in Apricity and Allogene and has received royalties from NIH for a CD22-CAR licensed to Juno. DWL consults for Juno Therapeutics/Celgene, Harpoon Therapeutics and Amgen and his institution receives clinical trial support from Kite Pharma.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

(A) Left ventricular EF (%) in all patients with CRS. Each line represents a patient’s EF during the course of CRS as determined by echocardiogram. Black lines indicate those patients with CRS who had preserved EF; without cardiac dysfunction. Red lines indicate those patients with CRS who had decreased EF and experienced cardiac dysfunction. (B) Cumulative anthracycline dose for all patients treated on CD19-28ζ CAR T-cell trial stratified by those who had decreased EF (min: 100 mg/m2, max: 570 mg/m2) and those that had preserved EF (min: 70 mg/m2, max: 620 mg/m2) as compared with their baseline echocardiograms. (C) Pre-CAR and Post-CAR T-cell therapy proBNP levels in seven patients. Two patients with the highest post-therapy pro-BNP levels (depicted by the *) had decreased EF and cardiac dysfunction. CAR, chimeric antigen receptor; CRS, cytokine release syndrome; pro-BNP, pro-B-type natriuretic peptide.

Figure 2

Cardiac screening and monitoring algorithm for pediatric and young adult patients undergoing CAR T-Cell Therapy. *Obtain cardiology consult in patients with a history of heart failure (preserved or reduced ejection fraction (EF), known cardiomyopathy, cardiac arrhythmias, prior chest/mediastinum radiotherapy, baseline BNP or troponin elevated above upper limit of normal. Consider cardiology consult in patients with asymptomatic LV dysfunction (LVEF 300 mg/m2; $Monitor for conduction abnormalities and QT prolongation; #High-risk patients include those that required cardiology consult prior to infusion; ∧Consider cardiac MR in patients with new or worsened LV dysfunction (LVEF <53% or drop in GLS >15% from baseline) that has persisted after CAR T-cell therapy. BNP, B-type natriuretic peptide; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; GLS, global longitudinal strain; TTE, transthoracic echocardiogram.