New drugs, old problems: immune checkpoint inhibitors and cancer-associated thrombosis

Submitted: 15 January 2024
Accepted: 29 February 2024
Published: 16 May 2024
Abstract Views: 249
PDF: 132
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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.

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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 Research

How 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