https://doi.org/10.4081/btvb.2024.113
New drugs, old problems: immune checkpoint inhibitors and cancer-associated thrombosis
Submitted: 15 January 2024
Accepted: 29 February 2024
Published: 16 May 2024
Accepted: 29 February 2024
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
A frequent side effect of cancer treatment is venous thromboembolism (VTE), which is made more likely by systemic anticancer medication. Immune checkpoint inhibitors (ICIs) have emerged as a paradigm-shifting treatment for many cancers. Early trials investigating the efficacy of ICIs did not identify thrombosis as a significant adverse event of concern. An initial meta-analysis reported a 1.1% [95% confidence interval (CI) 0.5-2.1] risk of arterial thromboembolism (ATE) and a 2.7% (95% CI 1.8-4.0) rate of vein thrombosis. ICIs have, however, been linked to ATE and VTE in an increasing number of post-marketing investigations. The reported incidence rates of cumulative VTE range from 5-8% at 6 months to 10-12% at 12 months, while the rates of ATE vary from 1-2% at 6 months to 17 months. Furthermore, a number of studies show a correlation between reduced survival and ICI-related thromboembolism. In order to provide a compiled and thorough narrative on the mechanisms, incidence, risk factors, and survival related to ICI-associated VTE and ATE, this narrative review summarizes the literature.
Moik F, Chan W-SE, Wiedemann S, et al. Incidence, risk factors, and outcomes of venous and arterial thromboembolism in immune checkpoint inhibitor therapy. Blood 2021;137: 1669-78.
DOI: https://doi.org/10.1182/blood.2020007878
Noble S, Pasi J. Epidemiology and pathophysiology of cancer-associated thrombosis. Br J Canc 2010;102:S2-S9.
DOI: https://doi.org/10.1038/sj.bjc.6605599
Kessler CM. The link between cancer and venous thromboembolism: a review. Am J Clin Oncol 2009;32:S3-S7.
DOI: https://doi.org/10.1097/COC.0b013e3181b01b17
Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 2009;27: 4839.
DOI: https://doi.org/10.1200/JCO.2009.22.3271
Khorana AA, Dalal MR, Lin J, Connolly GC. Health care costs associated with venous thromboembolism in selected high-risk ambulatory patients with solid tumors undergoing chemotherapy in the United States. Clin Econ Outcomes Res 2013:101-8.
DOI: https://doi.org/10.2147/CEOR.S39964
Khorana AA, Francis CW, Culakova E, et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007;110:2339-46.
DOI: https://doi.org/10.1002/cncr.23062
Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005;293:715-22.
DOI: https://doi.org/10.1001/jama.293.6.715
Mulder FI, Horvàth-Puhó E, van Es N, et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood 2021;137:1959-69.
DOI: https://doi.org/10.1182/blood.2020007338
Wang T-F, Khorana AA, Carrier M. Thrombotic complications associated with immune checkpoint inhibitors. Cancers 2021;13:4606.
DOI: https://doi.org/10.3390/cancers13184606
Agency EM. Yervoy: Ipilimumab EMA website: EMA. Available from: https://www.ema.europa.eu/en/medicines/humanEPAR/yervoy25/07/2011 (updated 16/10/2023)
Institute CR. Immunomodulators: Checkpoint Inhibitors, Cytokines, Agonists, and Adjuvants Online: Cancer Research Institute;. Available from: https://www.cancerresearch.org/treatment-types/immunomodulators (cited 2023 10/25/2023)
Solinas C, Saba L, Sganzerla P, Petrelli F. Venous and arterial thromboembolic events with immune checkpoint inhibitors: a systematic review. Thromb Res 2020;196:444-53.
DOI: https://doi.org/10.1016/j.thromres.2020.09.038
Giustozzi M, Becattini C, Roila F, et al. Vascular events with immune checkpoint inhibitors in melanoma or non-small cell lung cancer: A systematic review and meta-analysis. Cancer Treat Rev 2021;100:102280.
DOI: https://doi.org/10.1016/j.ctrv.2021.102280
Marin-Acevedo JA, Kimbrough EO, Lou Y. Next generation of immune checkpoint inhibitors and beyond. J Hematol Oncol 2021;14:1-29.
DOI: https://doi.org/10.1186/s13045-021-01056-8
Yoo MJ, Long B, Brady WJ, et al. Immune checkpoint inhibitors: An emergency medicine focused review. Am J Emerg Med 2021;50:335-44.
DOI: https://doi.org/10.1016/j.ajem.2021.08.038
Ma Z, Sun X, Zhang Y, et al. Risk of thromboembolic events in cancer patients treated with immune checkpoint inhibitors: a meta-analysis of randomized controlled trials. Thromb Haemost 2022;122:1757-66.
DOI: https://doi.org/10.1055/s-0042-1749185
Wang T-F, Carrier M. Immune Checkpoint Inhibitors-Associated Thrombosis: Incidence, Risk Factors and Management. Curr Oncol 2023;30:3032-46.
DOI: https://doi.org/10.3390/curroncol30030230
Gong J, Drobni ZD, Alvi RM, et al. Immune checkpoint inhibitors for cancer and venous thromboembolic events. Eur J Cancer. 2021;158:99-110.
DOI: https://doi.org/10.1016/j.ejca.2021.09.010
Moik F, Ay C, Horváth-Puhó E, et al. Risk of Venous and Arterial Thromboembolic Events in Patients Receiving Targeted Anti-Cancer Therapy—A Nationwide Cohort Study. Proceedings on Int Soc Thromb Haemost Congress, Philadelphia, PA, USA; 2021.
Overvad TF, Skjøth F, Piazza G, et al. The Khorana score and venous and arterial thrombosis in patients with cancer treated with immune checkpoint inhibitors: A Danish cohort study. J Thromb Haemost 2022;20:2921-9.
DOI: https://doi.org/10.1111/jth.15883
Khorana AA, Palaia J, Rosenblatt L, et al. Venous thromboembolism incidence and risk factors associated with immune checkpoint inhibitors among patients with advanced non-small cell lung cancer. J Immunother Cancer 2023;11.
DOI: https://doi.org/10.1136/jitc-2022-006072
Ay C, Dunkler D, Marosi C, et al. Prediction of venous thromboembolism in cancer patients. Blood 2010;116:5377-82.
DOI: https://doi.org/10.1182/blood-2010-02-270116
Sheng IY, Gupta S, Reddy CA, et al. Thromboembolism in patients with metastatic urothelial cancer treated with immune checkpoint inhibitors. Target Oncol 2022;17:563-9.
DOI: https://doi.org/10.1007/s11523-022-00905-x
Sheng IY, Gupta S, Reddy CA, et al. Thromboembolism in patients with metastatic renal cell carcinoma treated with immunotherapy. Target Oncol 2021;16:813-21.
DOI: https://doi.org/10.1007/s11523-021-00852-z
Roopkumar J, Swaidani S, Kim AS, et al. Increased incidence of venous thromboembolism with cancer immunotherapy. Med 2021;2:423-34.e3.
DOI: https://doi.org/10.1016/j.medj.2021.02.002
Hill H, Robinson M, Lu L, et al. Venous thromboembolism incidence and risk factors in non-small cell lung cancer patients receiving first-line systemic therapy. Thromb Res 2021;208:71-8.
DOI: https://doi.org/10.1016/j.thromres.2021.10.014
Sanfilippo KM, Luo S, Lyman GH, et al. Identification of Risk Factors for and Development of a Predictive Model for Immunotherapy-Associated Venous Thromboembolism (VTE) in Patients with Non-Small Cell Lung Cancer. Blood 2022;140:2803-4.
DOI: https://doi.org/10.1182/blood-2022-165748
Bar J, Markel G, Gottfried T, et al. Acute vascular events as a possibly related adverse event of immunotherapy: a single-institute retrospective study. Eur J Cancer 2019;120:122-31.
DOI: https://doi.org/10.1016/j.ejca.2019.06.021
Drobni ZD, Alvi RM, Taron J, et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 2020;142:2299-311.
DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.049981
Cochain C, Chaudhari SM, Koch M, et al. Programmed cell death-1 deficiency exacerbates T cell activation and atherogenesis despite expansion of regulatory T cells in atherosclerosis-prone mice. PloS one 2014;9:e93280.
DOI: https://doi.org/10.1371/journal.pone.0093280
Bu D-x, Tarrio M, Maganto-Garcia E, et al. Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler Thromb Vasc Biol 2011;31:1100-7.
DOI: https://doi.org/10.1161/ATVBAHA.111.224709
Del Prete G, De Carli M, Lammel RM, et al. Th1 and Th2 T-helper cells exert opposite regulatory effects on procoagulant activity and tissue factor production by human monocytes. Blood 1995;86:250-7.
DOI: https://doi.org/10.1182/blood.V86.1.250.bloodjournal861250
Horio Y, Takamatsu K, Tamanoi D, et al. Trousseau’s syndrome triggered by an immune checkpoint blockade in a non-small cell lung cancer patient. Eur J Immunol 2018;48: 1764-7.
DOI: https://doi.org/10.1002/eji.201847645
Moik F, Riedl J, Barth D, et al. Early dynamics of C-reactive protein predict risk of venous thromboembolism in patients with cancer treated with immune checkpoint inhibitors. Blood 2022;140:1250-1.
DOI: https://doi.org/10.1182/blood-2022-160087
Barth DA, Moik F, Steinlechner S, et al. Early kinetics of C reactive protein for cancer-agnostic prediction of therapy response and mortality in patients treated with immune checkpoint inhibitors: a multicenter cohort study. J Immunother Cancer 2023;11.
DOI: https://doi.org/10.1136/jitc-2023-007765
Petricciuolo S, Delle Donne MG, Aimo A, et al. Pre-treatment high-sensitivity troponin T for the short-term prediction of cardiac outcomes in patients on immune checkpoint inhibitors. Eur J Clin Investig 2021;51:e13400.
DOI: https://doi.org/10.1111/eci.13400
Waissengein B, Abu Ata B, Merimsky O, et al. The predictive value of high sensitivity troponin measurements in patients treated with immune checkpoint inhibitors. Clin Res Cardiol 2023;112:409-18.
DOI: https://doi.org/10.1007/s00392-022-02118-8
Lyon A, López-Fernández T, Couch L, et al. ESC Scientific Document Group. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J 2022;43: 4229-361.
DOI: https://doi.org/10.1093/eurheartj/ehac244
Hegde AM, Stroud CRG, Cherry CR, et al. Incidence and impact of thromboembolic events in lung cancer patients treated with nivolumab. Am Soc Clin Oncol 2017:35.
DOI: https://doi.org/10.1200/JCO.2017.35.15_suppl.e20624
Gutierrez-Sainz L, Martinez-Marin V, Viñal D, et al. Incidence of venous thromboembolic events in cancer patients receiving immunotherapy: a single-institution experience. Clin Translat Oncol 2021;23:1245-52.
DOI: https://doi.org/10.1007/s12094-020-02515-3
Ando Y, Hayashi T, Sugimoto R, et al. Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors. Investig New Drugs 2020;38:1200-6.
DOI: https://doi.org/10.1007/s10637-019-00881-6
Bjørnhart B, Kristiansen C, Asmussen J, et al. Clinical impact of venous thromboembolism in non-small cell lung cancer patients receiving immunotherapy. Thromb Res 2023;221:164-72.
DOI: https://doi.org/10.1016/j.thromres.2022.10.020
Cánovas MS, Garay DF, Moran LO, P et al. Immune checkpoint inhibitors-associated thrombosis in patients with lung cancer and melanoma: a study of the Spanish society of medical oncology (SEOM) thrombosis and cancer group. Clin Translat Oncol2022;24:2010-20.
DOI: https://doi.org/10.1007/s12094-022-02860-5
Endo S, Honda T, Kawahara T, et al. Profile of metastatic lung cancer patients susceptible to development of thromboembolism during immunotherapy. Cancer Treat Res Commun 2022;31:100547.
DOI: https://doi.org/10.1016/j.ctarc.2022.100547
Sussman TA, Li H, Hobbs B, et al. Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival. J Immunother Cancer 2021;9.
DOI: https://doi.org/10.1136/jitc-2020-001719
Deschênes-Simard X, Richard C, Galland L, et al. Venous thrombotic events in patients treated with immune checkpoint inhibitors for non-small cell lung cancer: a retrospective multicentric cohort study. Thromb Res 2021;205:29-39.
DOI: https://doi.org/10.1016/j.thromres.2021.06.018
Nichetti F, Ligorio F, Zattarin E, et al. Is there an interplay between immune checkpoint inhibitors, thromboprophylactic treatments and thromboembolic events? Mechanisms and impact in non-small cell lung cancer patients. Cancers 2019;12:67.
DOI: https://doi.org/10.3390/cancers12010067
Guven DC, Aksun MS, Sahin TK, et al. Poorer baseline performance status is associated with increased thromboembolism risk in metastatic cancer patients treated with immunotherapy. Support Care Cancer 2021;29:5417-23.
DOI: https://doi.org/10.1007/s00520-021-06139-3
Alma S, Eloi D, Léa V, et al. Incidence of venous thromboembolism and discriminating capacity of Khorana score in lung cancer patients treated with immune checkpoint inhibitors. J Thromb Thrombolysis 2022;54:287-94.
DOI: https://doi.org/10.1007/s11239-022-02649-x
Kewan T, Ko T, Flores M, et al. Prognostic impact and risk factors of cancer-associated thrombosis events in stage-IV cancer patients treated with immune checkpoint inhibitors. Eur J Haematol 2021;106:682-8.
DOI: https://doi.org/10.1111/ejh.13598
Icht O, Darzi N, Shimony S, et al. Venous thromboembolism incidence and risk assessment in lung cancer patients treated with immune checkpoint inhibitors. J Thromb Haemost 2021;19:1250-8.
DOI: https://doi.org/10.1111/jth.15272
Sussman TA, Roopkumar J, Li H, et al. Venous thromboembolism (VTE) in melanoma patients (pts) on immunotherapy (IO). Am Soc Clin Oncol 2020:38.
DOI: https://doi.org/10.1200/JCO.2020.38.5_suppl.94
Twomey JD, Zhang B. Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics. AAPS J 2021;23:1-11.
DOI: https://doi.org/10.1208/s12248-021-00574-0
GSK. Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrentendometrial cancer. GSK 2023. Available from: https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/
Ibrahimi S, Machiorlatti M, Vesely SK, et al. Incidence of vascular thromboembolic events in patients receiving immunotherapy: a single institution experience. Blood 2017; 130:4864.
Hsu JC, Lin J-Y, Hsu M-Y, Lin P-C. Effectiveness and safety of immune checkpoint inhibitors: A retrospective study in Taiwan. PLoS One 2018;13:e0202725.
DOI: https://doi.org/10.1371/journal.pone.0202725
Haist M, Stege H, Pemler S, et al. Anticoagulation with factor Xa inhibitors is associated with improved overall response and progression-free survival in patients with metastatic malignant melanoma receiving immune checkpoint inhibitors—a retrospective, real-world cohort study. Cancers 2021; 13:5103.
DOI: https://doi.org/10.3390/cancers13205103
Madison CJ, Melson RA, Conlin MJ, et al. Thromboembolic risk in patients with lung cancer receiving systemic therapy. Br J Haematol 2021;194:179-90.
DOI: https://doi.org/10.1111/bjh.17476
May SB, La J, Milner E, et al. Venous Thromboembolism Risk in Cancer Patients Receiving First-Line Immune Checkpoint Inhibitor Vs. Chemotherapy. Blood 2022;140:7968-70.
DOI: https://doi.org/10.1182/blood-2022-162658
Supporting Agencies
National Heart, Lung and Blood Institute, Sondra and Stephen Hardis Chair in Oncology ResearchHow to Cite
Patel, M. H., & Khorana, A. A. (2024). New drugs, old problems: immune checkpoint inhibitors and cancer-associated thrombosis. Bleeding, Thrombosis and Vascular Biology, 3(s1). https://doi.org/10.4081/btvb.2024.113
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