Characterizing Cardiovascular Outcomes Associated with … · 2020. 7. 22. · 1)Leukapheresis: T cells are extracted from the patient’s blood. 2)Cells are transduced to express
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Characterizing Cardiovascular Outcomes Associated with Chimeric Antigen Receptor T Cell Therapy Background Results & Discussion Research Question: Among cancer patients treated with CAR-T cell therapy, what adverse cardiovascular outcomes occur, and are what are the identifiable risk factors exist? Michael Rothberg, Patrick Holman MD, Daria Gaut MD, Joshua Sasine MD PhD, Tomas Neilan MD MPH, Syed Saad Mahmood MD, Eric Yang MD References Conclusions • We included 60 patients receiving standard of care CAR T at UCLA since 2017 Patients receiving CAR-T as part of a clinical trial were excluded from the study. • Patients were stratified into CV Event or Control (no cardiovascular event developed) groups. • “CV Event” (Major Adverse Cardiovascular Event or MACE) defined as 1) CV death from HF, cardiogenic shock, cardiac arrest or arrhythmia 2) New evidence of heart failure (HF) 3) Clinically significant de novo arrhythmias (e.g. SVT, Afib, excluding QTc prolongation) 4) Non-Fatal Acute Coronary Syndrome (with evidence of LVEF decrease >10% to final LVEF of <53%) • Retrospective analysis of possible risk factors for CV Events performed using chi-square tests of independence for categorical variables and t-tests of means for continuous variables. • We analyzed QTc intervals as a secondary outcome by collecting all 12-lead EKG measurements for each patient prior to and after CAR-T Methodology Limitations • CAR-T cell therapy is a breakthrough in the treatment of cancer. It redirects the immunological activity of T-cells to target malignant cells 1,2 . • Despite its efficacy CAR-T often spurs a massive immunological reaction, manifested clinically as Cytokine Release Syndrome (CRS). 4 CRS is mediated by a number of cytokines, including Interleukin 6 (IL-6). 5 Clinically, it can lead to fever, hypotension, hypoxia, and in severe cases, lead to multi- organ involvement. • 2 FDA approved CAR-T therapies exist, both targeting CD19 on B- Cells 3 : • axicabtagene ciloleucel (Yescarta®): relapsed/refractory DLBCL • tisagenlecleucel (Kymriah®): relapsed/refractory B-ALL (up to 25yo) and relapsed/refractory DLBCL • While CRS has become increasingly investigated , 7, 8 , the impact of CAR-T therapy on the cardiovascular system remains incompletely characterized. Studies at other sites have identified cardiotoxicity including new arrhythmias, cardiomyopathy, arterial vascular disease, venous thromboembolism, and pulmonary hypertension. 9 • In this study, we assess the range of cardiotoxicities in the cohort of UCLA CAR-T patients since FDA approval in 2017 through May of 2020. • This was a retrospective study performed using patient data that was incomplete and varied for multiple pertinent parameters. For instance, not all patients had baseline, intra-admission, and post-discharge echocardiography testing or 12- lead ECG’s. • CAR-T therapy is quite novel, so our cohort is not currently sufficient to draw clinically actionable conclusions about the CV complications of CAR- T. We are contributing our data to a national multi-site registry to study and improve the safety of this therapy. • Many patients in the UCLA cohort were pre- screened for cardiovascular health and may not reflect the general population. • Adverse cardiovascular events occurred in a subset of patients undergoing CAR-T at UCLA (23.3%), including arrhythmias, heart failure, and acute coronary syndrome. • Increased severity of CRS by ASTCT grading was associated with CV events. • While in other cohort studies, CV Events occurred only in Grade II or higher CRS, we observed an instance of a patient who developed CV events with only grade I CRS. • Pre-treatment CV evaluation and monitoring during and after admission are likely warranted given the inflammatory stress inherent to CAR-T therapy. 1) Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980 2) Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):439-448. doi:10.1056/NEJMoa1709866 3) Ying Z, Huang XF, Xiang X, et al. A safe and potent anti-CD19 CAR T cell therapy. Nat Med. 2019;25(6):947-953. doi:10.1038/s41591-019-0421-7 4) Neelapu SS. Managing the toxicities of CAR T-cell therapy. Hematol Oncol 2019;37:48-52 5) Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti- inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878-888. doi:10.1016/j.bbamcr.2011.01.034 6) Linette GP, Stadtmauer EA, Maus MV, et al. Cardiovascular toxicity and titin cross- reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122(6):863-871. doi:10.1182/blood-2013-03-490565 7) Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517–528. 8) Oved JH, Barrett DM, Teachey DT. Cellular therapy: Immune-related complications. Immunol Rev. 2019;290(1):114-126. doi:10.1111/imr.12768 9) Herrmann J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia [published online ahead of print, 2020 Mar 30]. Nat Rev Cardiol. 2020;10.1038/s41569-020-0348-1. doi:10.1038/s41569-020-0348-1 10) Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758 Figure 5: Examples of Newly Prolonged QTc Intervals Following CAR-T Infusion: 1) Leukapheresis: T cells are extracted from the patient’s blood. 2) Cells are transduced to express receptors recognizing cancer-specific antigens (CAR-T) and expanded. 3) The CAR-T cells are re-introduced into the patient’s body, where they can begin binding and killing cancer cells 3 1 2 3 Acknowledgments Thank you to Eric Yang and Patrick Holman for your guidance and teaching throughout the project, and especially for showing me the basics of echocardiography. Thank you to Josh Sasine and Daria Gaut for your help in guiding the research toward clinical relevance. And thank you to Tomas Neilan and Syed Saad Mahmood for providing the expertise and support to make this project possible. Potential Conflicts of Interest: Dr. Neilan has been a consultant to and received fees from Parexel Imaging, BMS, AbbVie, Intrinsic Imaging, H3-Biomedicine outside of the current work. Dr. Sasine will be part of a speaker program for Kite Pharma. Fig. 1: 60 patients underwent CAR-T therapy at UCLA with a median time to follow-up or death of 206 days. 14 patients (23.3%) developed adverse cardiovascular outcomes. Figure 4: Past Treatment Regimens for Each Patient ? ? ? ? ? ? Therapy associated* with: Arrhythmia Cardiomyopathy Arterial Vascular Disease Venous thromboembolism Pulmonary HTN Systemic HTN Pericardial Disease No CV event (n = 28) Patients in study receiving CAR-T therapy (n = 60) Developed no CRS or Grade I CRS (fever w/out hypoxia or hypotension) (n = 32) Developed Grade II or higher CRS (fever + hypotension or hypoxia) (n = 28) CV event (n = 3) No CV event (n = 18) CV event (n = 11) (90.6%) (9.4%) (39.3%) (60.7%) -Arrhythmias (n=10) -Heart failure (n=2) -Acute coronary syndrome (n=2) Figure 1: Overview of Outcomes Fig. 4: Each column represents a unique patient with each row representing a cancer therapy. Almost all the therapies have established cardiotoxicity profiles, some of which (e.g. anthracyclines) display a lifetime-dose dependent compounding in risk. 9 Doxorubicin Equivalent Dose / BSA (mg/m2) CV Case Control Figure 3: Lifetime Anthracycline Dose Among Cases and Controls Fig. 5: Larger cohorts are necessary to establish a causative or associative link between CAR-T cell treatment and QTc prolongation. Above are instances of 3 CAR-T patients developed a prolonged QTc. The red horizontal divider represents a QTc of 460ms. Table 1: Patient Characteristics and Outcomes Table 1: P-values were generated from Chi-square tests for independence and t-tests for differences of means. Patients on beta- blockers prior to CAR-T were significantly more likely to develop CV events than those who were not (p=0.039), although this finding is limited by the low sample size and may be indicative of higher baseline cardiovascular risk. The degree of cytokine release syndrome was also significantly associated with CV events (p=0.0143, two-sided Fisher’s exact test), with a higher peak CRP trending toward but not reaching significant association with CV events. Figure 2: C-Reactive Protein After CAR-T by CV Cases Peak CRP (mg/dL) Case Control Fig. 2: Although clinical grade of CRS was significantly associated with the development of CV events, there was no significant difference in peak CRP between cases and controls. Fig. 3: While anthracyclines are known to cause cardiotoxicity, there was no significant difference between the distribution of doxorubicin equivalent lifetime dosage among CV cases versus controls. Demographics Total Cohort (n = 60) CV Event (n = 14) No CV Event (n = 46) p-value Age at time of admission (mean, SD) 54.94 (18.88) 58.09 (19.85) 53.98 (18.69) 0.48 Sex (%Male) 36 (60.0) 10 (71.4) 26 (56.5) 0.49 Race 0.06 Asian 8 (13.3) 4 (28.6) 4 (8.7) - Black 1 (1.7) 0 (0.0) 1 (2.2) - White 45 (75.0) 7 (50.0) 38 (82.6) - Unknown 6 (10.0) 3 (21.4) 3 (6.5) - Ethnicity 0.38 Hispanic/Latino 21 (35.0) 3 (21.4) 18 (39.1) - Non-Hispanic/Latino 38 (63.3) 11 (78.6) 27 (58.7) - Unknown 1 (1.7) 0 (0.0) 1 (2.2) - BMI in kg/m2 (mean, SD) 26.41 (6.20) 28.91 (7.39) 25.65 (5.66) 0.084 Diastolic BP mmHg (mean, SD) 72.82 (11.93) 76.93 (11.02) 71.57 (12.03) 0.14 Systolic BP mmHg (mean, SD) 121.10 (15.26) 124.79 (14.00) 119.98 (15.59) 0.31 Cardiovascular Risk Factors Hypertension 23 (38.3) 7 (50.0) 16 (34.8) 0.48 Coronary Artery Disease 4 (6.7) 2 (14.3) 2 (4.3) 0.49 Stroke or TIA 3 (5.0) 1 (7.1) 2 (4.3) 1 Atrial Fibrillation 4 (6.7) 2 (14.3) 2 (4.3) 0.49 Heart Failure 1 (1.7) 1 (7.1) 0 (0.0) 0.53 Comb. CV Risk (HTN+Stroke+CAD+AF+HF) 25 (41.7) 8 (57.1) 17 (37.0) 0.3 COPD 1 (1.7) 0 (0.0) 1 (2.2) 1 Diabetes Mellitus 13 (21.7) 3 (21.4) 10 (21.7) 1 Smoking History 17 (28.3) 4 (28.6) 13 (28.3) 1 Hyperlipidemia 15 (25.0) 4 (28.6) 11 (23.9) 1 Baseline LVEF (%) 61.58 (4.18) 61.69 (5.26) 61.54 (3.84) 0.91 Outpatient Medications Aspirin 7 (11.7) 2 (14.3) 5 (10.9) 1 Beta-blockers 12 (20.0) 6 (42.9) 6 (13.0) ACEi or ARB 8 (13.3) 3 (21.4) 5 (10.9) 0.57 Calcium channel blocker 16 (26.7) 4 (28.6) 12 (26.1) 1 Loop diuretic 3 (5.0) 1 (7.1) 2 (4.3) 1 Thiazide diuretic 1 (1.7) 1 (7.1) 0 (0.0) 0.53 Novel oral anticoagulants (NOAC) 10 (16.7) 3 (21.4) 7 (15.2) 0.89 Cytokine Release Syndrome No CRS 17 (28.3) 1 (7.14) 16 (34.8) - CRS Grade I 15 (25) 2 (14.3) 13 (28.3) - CRS Grade II 21 (35.0) 10 (71.4) 11 (23.9) - CRS Grade III 7 (11.7) 1 (7.14) 6 (13.0) - CRS Grade IV or higher - - - - Any Adverse Cardiovascular Event New Arrhythmias 12 (20.0) - - - Heart Failure 2 (3.33) - - - Acute Coronary Syndrome 2 (3.33) - - - Cardiac Death 0 (0.00) - - - Other CRP, Post-CAR Peak (mg/dL) 5.57 (5.00) 7.78 (5.79) 4.98 (4.67) 0.086
Characterizing Cardiovascular Outcomes Associated withChimeric
Antigen Receptor T Cell Therapy
Background
Results & DiscussionResearch Question:Among cancer patients
treated with CAR-T cell therapy, what adverse cardiovascular
outcomes occur, and are what are the identifiable risk factors
exist?
Michael Rothberg, Patrick Holman MD, Daria Gaut MD, Joshua
Sasine MD PhD,Tomas Neilan MD MPH, Syed Saad Mahmood MD, Eric Yang
MD
References
Conclusions
• We included 60 patients receiving standard of care CAR T at
UCLAsince 2017 Patients receiving CAR-T as part of a clinical trial
wereexcluded from the study.
• Patients were stratified into CV Event or Control (no
cardiovascularevent developed) groups.
• “CV Event” (Major Adverse Cardiovascular Event or MACE)defined
as
1) CV death from HF, cardiogenic shock, cardiac arrest
orarrhythmia
2) New evidence of heart failure (HF)3) Clinically significant
de novo arrhythmias (e.g. SVT, Afib,
excluding QTc prolongation)
4) Non-Fatal Acute Coronary Syndrome (with evidence ofLVEF
decrease >10% to final LVEF of
