CAR-T-associated cardiac toxicity ‘limited and reversible’ in younger patients with ALL
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Cardiovascular toxicity associated with chimeric antigen receptor T-cell therapy is both limited and reversible among high-risk children and young adults with acute lymphoblastic leukemia, according to results of a phase 1 clinical trial.
The findings — published in Journal for ImmunoTherapy of Cancer — showed cardiac toxicity related to cytokine release syndrome (CRS) after therapy with CD19-28-zeta CAR T cells occurred in 16% of patients and generally was reversible by day 28 after infusion.
“Novel immunotherapy strategies using CAR T cells to target hematologic malignancies have revolutionized treatment of pediatric relapsed or refractory B-cell ALL; however, limited data exist on the subacute side-effect profile, especially cardiac toxicity,” Haneen Shalabi, DO, assistant research physician in the pediatric oncology branch of the NCI, told Healio.
Shalabi, one of the study’s authors, said theirs was the first pediatric study to evaluate cardiac toxicity resulting from CRS among children and young adults who received CAR T cells using the CD19-28-zeta construct developed by Lee and colleagues at the NCI.
“CRS — the main acute toxicity after CAR T-cell therapy — is associated with many cardiac manifestations,” she added. “Nevertheless, our data suggest that cardiovascular toxicity was limited and reversible.”
Shalabi and colleagues performed a retrospective analysis of 52 children and young adults (median age, 13 years; range, 4-30; 79% male) who underwent treatment with CD19-28-zeta CAR T cells during a phase 1 clinical trial conducted by the NCI between July 2012 and March 2016. Median previous anthracycline exposure was 205 mg/m2 (range, 70-620) in doxorubicin equivalents.
Cardiac dysfunction served as the study’s primary endpoint.
Researchers defined cardiac dysfunction as a greater than 10% absolute decrease in left ventricular ejection fraction (LVEF) compared with baseline values, or new-onset left ventricular (LV) systolic dysfunction of grade 2 or LVEF less than 50%. They defined severe cardiac dysfunction as new-onset LV systolic dysfunction of grade 3 or greater or LVEF less than 40% as outlined in the Common Terminology Criteria for Adverse Events version 4.0.
Secondary endpoints included troponin and pro-B-natriuretic peptide levels.
Median baseline LVEF was 60% (range, 50-70). Baseline LV global longitudinal strain (GLS) was 16.8% (range, 14.1-23.5).
Thirty-seven patients (71%) developed CRS after CAR T-cell infusion and were included in the cardiac toxicity analysis. Nine (17%) experienced grade 3 or grade 4 CRS.
Most patients (78%) who had CRS after infusion had a reduced GLS less than 19% at baseline, and 6% of all patients had baseline LVEF less than 53%.
Twenty-one patients required transfer to the ICU after treatment, with nine requiring vasoactive hemodynamic support and three needing more than one vasopressor.
Six patients developed cardiac dysfunction after infusion; four of them had either grade 3 or grade 4 CRS. All patients who developed cardiac dysfunction did so during the clinical course of CRS, according to the investigators.
Pro-B-natriuretic peptide levels were elevated from baseline in six of seven patients at CRS onset, with higher levels correlating with more severe CRS. Four of 13 patients had elevated troponin levels, and all four had low LVEF.
Cardiac dysfunction was fully resolved in all but two patients at 28 days after infusion. Both of those patients had LVEF return to baseline levels by 3 months after infusion.
The retrospective design of the study served as a limitation, and researchers lacked comprehensive cardiac monitoring data for the first 13 patients in the study.
Shalabi told Healio that her group’s results were in line with a previously published report by Burstein and colleagues, who observed new systolic cardiac dysfunction in a proportion of patients who underwent CAR T-cell therapy.
“However, persistence of such dysfunction was rare,” she added.
Whether the results can be applied to younger patients with other hematologic malignancies will require more data, Shalabi said.
The study underscored the need for a methodical approach to manage CRS-associated cardiotoxicity after the administration of CAR T cells, according to the researchers.
“Currently, there is no systematic guidance on how to monitor for post-CAR T-cell cardiac toxicity; however, we provide an algorithm to systematically and prospectively monitor pediatric patients receiving CAR T-cell therapy in the hope that broad implementation will facilitate cross-trial comparisons of cardiac toxicity,” Shalabi told Healio.
The investigators suggested both pre- and post-infusion testing and laboratory measurements to monitor for changes in cardiac function, with increased surveillance for those who develop grade 2 or greater CRS.
“Application of prospective and systematic echocardiograms with real-time GLS monitoring before and after infusion may provide valuable information and potentially earlier identification of cardiac strain that may impact a patient’s toxicity profile and allow for earlier treatment intervention,” Shalabi added.
References
- Burstein DS, et al. Biol Blood Marrow Transplant. 2018;doi:10.1016/j.bbmt.2018.05.014.
- Lee DW, et al. Lancet. 2014;doi: 10.1016/S0140-6736(14)61403-3.
- Shalabi H, et al. J Immunother Cancer. 2020;doi:10.1136/jitc-2020-001159.
For more information:
Haneen Shalabi, DO, can be reached at haneen.shalabi@nih.gov.
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