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. 2023 Oct 1;9(10):1390-1400.
doi: 10.1001/jamaoncol.2023.2934.

Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19

Shuchi Gulati  1   2 , Chih-Yuan Hsu  3 , Surbhi Shah  4 , Pankil K Shah  5 , Rebecca Zon  6 , Susan Alsamarai  7 , Joy Awosika  2 , Ziad El-Bakouny  8 , Babar Bashir  9 , Alicia Beeghly  10 , Stephanie Berg  11 , Daniel de-la-Rosa-Martinez  12 , Deborah B Doroshow  13 , Pamela C Egan  14 , Joshua Fein  7 , Daniel B Flora  15 , Christopher R Friese  16 , Ariel Fromowitz  17 , Elizabeth A Griffiths  18 , Clara Hwang  19 , Chinmay Jani  20 , Monika Joshi  21 , Hina Khan  14 , Elizabeth J Klein  14 , Natalie Knox Heater  11 , Vadim S Koshkin  22 , Daniel H Kwon  22 , Chris Labaki  8 , Tahir Latif  2 , Rana R McKay  23 , Gayathri Nagaraj  24 , Elizabeth S Nakasone  25 , Taylor Nonato  23 , Hyma V Polimera  21 , Matthew Puc  26 , Pedram Razavi  23 , Erika Ruiz-Garcia  12 , Renee Maria Saliby  8 , Aditi Shastri  17 , Sunny R K Singh  27 , Vicky Tagalakis  28 , Diana Vilar-Compte  12 , Lisa B Weissmann  20 , Cy R Wilkins  29   30 , Trisha M Wise-Draper  2 , Michael T Wotman  13 , James J Yoon  16 , Sanjay Mishra  31 , Petros Grivas  25 , Yu Shyr  3 , Jeremy L Warner  10   31 , Jean M Connors  32 , Dimpy P Shah  5 , Rachel P Rosovsky  33 ; COVID-19 and Cancer Consortium
Collaborators, Affiliations

Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19

Shuchi Gulati et al. JAMA Oncol. .

Abstract

Importance: Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.

Objective: To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.

Design, setting, and participants: This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.

Exposure: Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.

Main outcomes and measures: Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.

Results: Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).

Conclusions and relevance: In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19-related thromboembolism in patients with cancer.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gulati reported a grant to institution from North American Thrombosis Forum for the conduct of this study; and research funding from AstraZeneca; advisory board fees from EMD Serono and AVEO; honoraria from Mashup Media, MJH LifeSciences, Medical Educators Consortium, and ASCO, outside of the submitted work. Dr Zon reported personal fees from Amagma Therapeutics outside the submitted work. Dr El-Bakouny reported personal fees from UpToDate, nonfinancial support from Bristol Myers Squibb, and grants from Genentech/imCORE outside the submitted work. Dr Bashir reported research support to institution from Boehringer Ingelheim, Bicycle Therapeutics, Gritstone Bio, KAHR Medical, Lyell Immunopharma, Merck, Pionyr Immunotherapeutics, RasCal Therapeutics, Syros Pharmaceuticals, and Tarveda Therapeutics and personal fees (advisory board) from Merck/Eisai outside the submitted work. Dr Berg reported serving on speakers bureaus for Eisai, Bristol Myers Squibb, and Exelixis outside the submitted work. Dr Doroshow reported personal fees from MJH Life Sciences, AstraZeneca, and Mirati outside the submitted work. Dr Egan reported other (serving as site PI for trial of pacritinib in the treatment of severe COVID-19) from CTI Biopharma during the conduct of the study. Dr Friese reported grants from Merck Foundation and NCCN Foundation/Pfizer outside the submitted work; and serving on the Patient-Centered Outcomes Research Institute Board of Governors and the National Cancer Institute National Cancer Advisory Board. Dr Griffiths reported grants from Genentech Inc to Roswell Park; personal fees from Apellis Pharmaceuticals, Novartis Pharmaceuticals, Taiho Oncology, AbbVie, Takeda Oncology, CTI Biopharma; consulting, unpaid, for Picnic Health and Artis Ventures; personal fees (CME honoraria) from AAMDSIF, Physicians Educational Resource, and ASH; personal fees (CME program development) from MediCom Worldwide; personal fees and free drug for clinical trial from Bristol Myers Squibb; other (PI on clinical trial) from Blueprint Medicines and Astex Pharmaceuticals; other (free drug for clinical trial) from Celldex Therapeutics; other (PI on study) from AstraZeneca Rare Disease/Alexion Pharmaceuticals; and other (free drug to the laboratory) from Imago Biosciences outside the submitted work; and serving on the scientific advisory council for the Dresner Foundation. Dr Hwang reported grants from Merck, Bayer, and AstraZeneca; personal fees from EMD Serono, Genentech, and TEMPUS; and stock holdings from Johnson & Johnson outside the submitted work. Dr Joshi reported grants to institution from AstraZeneca, Pfizer, and Bristol Myers Squibb and personal fees from Seagen (advisory board) outside the submitted work. Dr Labaki reported grants from imCORE/Genentech outside the submitted work. Dr McKay reported consulting/advisory role for Aveo, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Caris, Dendreon, Exelixis, Johnson & Johnson, Lilly, Myovant, Merck, Novartis, Pfizer, Sanofi, Sorrento Therapeutics, Telix, and Tempus; and research from AstraZeneca, Bayer, and Tempus outside the submitted work. Dr Shastri reported research funding and advisory committee fees from Kymera Therapeutics; consultancy fees from Janssen Therapeutics and Rigel Pharmaceuticals; and honorarium from NACE outside the submitted work. Dr Wise-Draper reported grants from Merck, Bristol Myers Squibb, Tesaro/GlaxoSmithKline, AstraZeneca, and Janssen and personal fees from Caris Life Sciences outside the submitted work. Dr Mishra reported grants from National Institutes of Health (NIH) through institution (P30 CA068485) and grants from International Association for the Study of Lung Cancer through institution during the conduct of the study; and personal fees from National Geographic for writing articles outside the submitted work. Dr Grivas reported grants from Bavarian Nordic, Clovis Oncology, Debiopharm Group, and GlaxoSmithKline; personal fees and grants from Bristol Myers Squibb, G1 Therapeutics, Gilead Sciences, Merck Sharp & Dohme, Mirati Therapeutics, EMD Serono, Pfizer, and QED Therapeutics; and personal fees from 4D Pharma PLC, Aadi Bioscience, Astellas Pharma, AstraZeneca, Boston Gene, CG Oncology, Dyania Health, Exelixis, Fresenius Kabi, Genentech/Roche, Guardant Health, Infinity Pharmaceuticals, Janssen, Lucence Health, PureTech, Regeneron Pharmaceuticals, Seattle Genetics, Silverback Therapeutics, and UroGen outside the submitted work. Dr Shyr reported grants from NIH/National Cancer Institute during the conduct of the study. Dr Warner reported grants from NIH during the conduct of the study; and personal fees from Westat, Roche, Melax Tech, and Flatiron Health and other from HemOnc.org (ownership) outside the submitted work. Dr Connors reported serving on scientific advisory boards and consulting for Abbott, Anthos, Bristol Myers Squibb, Pfizer, Roche, Sanofi, Werfen; and receiving research funding to the institution from CSL Behring outside the submitted work. Dr D. Shah reported grants from the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and grants from NIH (P30CA054174) during the conduct of the study. Dr Rosovsky reported grants to institution from Bristol Myers Squibb and Janssen and consulting fees from Abbott, Bristol Myers Squibb, Dova, Inari, Janssen, and Penumbra outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. UpSet Plot of Treatment Exposures of Interest
The largest subgroup (n = 3119) did not have any of the treatment exposures of interest within 3 months prior to COVID-19 diagnosis; the next 4 largest subgroups each consist of patients exposed to 1 of the exposure groups. Dual exposures, eg, cytotoxic chemotherapy plus ICI within 3 months, comprise the remainder of the common subgroups. No patient was simultaneously exposed to 4 or more of the 5 exposure groups. Across all patients, cytotoxic chemotherapy (n = 1002) was the most common exposure. ICIs indicates immune checkpoint inhibitors; IMiDs, immunomodulators; TKIs, tyrosine kinase inhibitors; VEGFis, vascular endothelial growth factor inhibitors.
Figure 2.
Figure 2.. Forest Plots for Venous Thromboembolism (VTE) and Arterial Thromboembolism (ATE)
Forest plots for the estimates of log risk ratios with the 95% CIs for exposure to the treatments of interest (TOI) within 3 months vs those not receiving systemic therapies in these 3 months. AAPI indicates Asian American and Pacific Islander; CAD, coronary artery disease; CVA, cerebrovascular accident; ECOG, Eastern Cooperative Oncology Group; ICIs, immune checkpoint inhibitors; IMiDs, immunomodulators; NED, no evidence of disease; PAD, peripheral arterial disease; TKIs, tyrosine kinase inhibitors; VEGFis, vascular endothelial growth factor inhibitors.
See this image and copyright information in PMC

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