IMPACT OF COVID-19 ON CANCER PATIENTS RECEIVING IMMUNE CHECKPOINT INHIBITORS

Abstract

Background There are conflicting data regarding the vulnerability of cancer patients receiving immune checkpoint inhibitors (ICIs) to COVID-19 infection.^1–3 In addition, immune-related adverse events (irAEs) driven in part by cytokine dysregulation could parallel the cytokine storm implicated in COVID-19. We sought to evaluate the impact of COVID-19 infection on irAEs and mortality in cancer patients receiving ICIs. Methods We performed a retrospective matched cohort study of 25 patients receiving ICIs within one year of a confirmed COVID-19 diagnosis between March 20, 2020 and June 3, 2020 at the Dana-Farber Cancer Institute/Mass General Brigham network. Cases were matched 1:1 with controls without ICI use based on age, sex, and use of non-ICI anti-cancer therapy within 6 months prior to COVID-19 diagnosis. The primary outcome was death due to COVID-19, and potential covariates (patient comorbidities, concomitant medications, ICI therapy, other anti-cancer therapy) were explored using multivariable logistic regression models. Results We reviewed the records of 611 patients with prior ICI use who were evaluated at our institutions. The final study population included 25 patients who tested positive for COVID-19. The median age was 72 years (range 45–83) and 11 patients (44%) were female (table 1). Seven of 25 (28%) patients on ICIs died from COVID-19 compared to 9 of 25 (36%) controls (figure 1). In multivariable analysis, determinants of mortality included age (OR 1.14, 95% CI 1.03–1.27) and chronic obstructive pulmonary disease (OR 12.26, 95% CI 1.76–85.14), while concomitant statin use was protective against mortality (OR 0.08, 95% CI 0.01–0.63). After adjusting for age, sex, and anti-cancer therapy, ICI use was not associated with increased risk for COVID-19 death (OR 0.36, 95% CI 0.07–1.87, figure 2). Two patients experienced persistent irAEs (hypophysitis) and one patient had new onset irAE (hypothyroidism) during their COVID-19 course. Patients with ICI use presented with significantly higher platelet (p = 0.017) and D-dimer (p = 0.037) levels compared to controls (figure 3A). Elevated troponin levels (p = 0.01) were associated with COVID-19 death in patients using ICI but not in controls (figure 3B). Demographic, clinical and treatment characteristics of cancer patients treated with or without immune checkpoint inhibitors (ICI) before testing positive for COVID-19This study included 25 cancer patients with prior ICI use (case) and 25 cancer patients without prior ICI use (controls).a For cases, thoracic cancers include 5 squamous cell, 4 adenocarcinoma, and 1 non-small-cell lung cancer, not otherwise specified (NOS). For controls, 1 case of small cell lung cancerb For cases, skin cancers include 3 melanoma and 2 non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma)c For cases, gastrointestinal cancers include 1 esophageal, 1 liver, 1 colon, and 1 gastric cancer. For controls, 1 liver, 4 colon, 1 gastric, and 1 pancreatic cancer.d For cases, hematologic cancers include 1 acute myeloid leukemia (AML). For controls, 1 breast, 1 AML, 1 chronic myeloid leukemia (CML), 1 acute lymphoblastic leukemia (ALL) 1 myelofibrosis, 3 B-cell lymphoma, 1 T-cell lymphoma, 1 multiple myeloma.e For cases, other cancer types include 4 oropharyngeal, 1 breast. For controls, 2 prostate, 1 ovarian, 1 thyroid, 1 bladder, 1 renal, and 1 brain cancer.f Including coronary artery disease (CAD), congestive heart failure (CHF), arrhythmia, atrial fibrillation, and cardiac disease not otherwise specified (NOS)ICI = Immune checkpoint inhibitor, COPD = Chronic obstructive pulmonary disease, BMI = Body mass index COVID-19 outcomes among 25 cases and 25 controlsFlow graphic demonstrating the hospitalization status, highest level of care, and final COVID-19 outcomes among the two patient cohorts (25 patients with prior ICI use and 25 controls). Complications are defined as patients who continue to require supplemental oxygen after discharge Predictors of COVID-19 mortality in multivariable analysisOdds ratios for the impact of baseline patient characteristics on COVID-19 mortality, including age, sex, use of non-ICI anti-cancer therapy (chemo/targeted) in the past 6 months, ICI therapy in the past year, active statin use, and COPD. Odds ratios were calculated by multivariable logistic regression. Error bars represent 95% confidence intervals (CI). The x-axis is on a log10 scale. The odds ratio for age is per increasing year. (*) p-value < 0.05 Significant lab values in cancer patients with COVID-19(A) Comparison of D-dimer levels between patients taking ICI in last year and non-ICI controls. Patients with ICI use had elevated presenting D-dimer level (median 1850 vs. 1123 ng/mL) compared to non-ICI patients. (B) Comparison of troponin levels between survivors and COVID-19 deaths within ICI and non-ICI case control cohorts. Elevated presenting, peak, and nadir troponin levels were related to COVID-19 mortality in ICI patients (p = 0.04, 0.01, 0.03) but not in non-ICI patients. Laboratory results were taken at date closest to presentation for COVID-19 (presenting), as well as peak and nadir values throughout COVID-19 course or within 21 days of presentation. Dots represent individual patient values, the solid black line represents median, and thin black lines represent 25% and 75% percentiles. The vertical dotted line separates the two cohorts (ICI vs. non-ICI). Gray lines indicate normal reference ranges for each laboratory test. Violins show range and kernel density estimate distributions of each group. The Wilcoxon rank-sum test was used to calculate p-values. (*) p < 0.05, (**) p < 0.01, (***) p < 0.001). Conclusions In our study, ICI use was not associated with increased risk of COVID-19 related death. We observed low rates of new or persistent irAEs within our small sample. The potential protective effect of statin therapy and predictive role of laboratory biomarkers warrants further investigation. Our findings are promising for the continuation of immunotherapy in cancer patients with COVID-19. Acknowledgements K.T. and A.N.B. contributed equally. N.R.L. and O.E.R. contributed equally.The authors would like to acknowledge the DFCI Oncology Data Retrieval System (OncDRS) for the aggregation, management, and delivery of the clinical and operational research data used in this project. The content is solely the responsibility of the authors. Ethics Approval This project was approved by the Partners Healthcare Institutional Review Board (#2020P000851). References Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer. Nature Medicine 2020. In press. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1 blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov 2020. In press. Lee LYW, Cazier JB, Starkey T, Turnbull CD, Kerr R, Middleton G. COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study. Lancet 2020;395(10241):1919–1926.