Login Register Cart 0
Generic placeholder image

Reviews on Recent Clinical Trials

Editor-in-Chief

ISSN (Print): 1574-8871
ISSN (Online): 1876-1038

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Management of Immunotherapy Adverse Events in Oncological Patients: Anti-CTLA-4, Anti-PD-1/PD-L1

Author(s): Mattia Brigida, Alessia Perricelli, Fausto Sposato, Maria Giovanna Spadafora, Angelo Pomillo and Milito Sisto*

Volume 15, Issue 4, 2020

Page: [339 - 346] Pages: 8

DOI: 10.2174/1574887115666200622161418

Price: $65

Abstract

Background: The widespread use of immunotherapy drugs in the oncological field has led to the spread of new toxicities compared to the more common chemotherapy treatments. This is because immunotherapy with anti-CTLA-4 (Cytotoxic T Lymphocytes-Associated Antigen 4), anti- PD-1 and anti-PD-L1 monoclonal antibodies has become the standard-of-care in a growing number of indications. Any organ or tissue can be involved, but more commonly, side effects are reported regarding skin, colon, endocrine glands, liver, lung and kidney. Other less frequent, but more serious, adverse events are neurological and myocarditis.

Methods: We performed an electronic search on PUBMED of the literature concerning immunotherapy- related toxicities and their management in oncological patients from 2007 to 2020, with particular attention to the most recent publications.

Aim: To summarize the different types of immunotherapy-related toxicities, together with their incidence and diagnosis, and to simplify their management, especially in the emergency setting.

Conclusion: Usually, for grade I toxicities, it is not recommended to stop immunotherapy; for most of grade II toxicities, immunotherapy should be postponed to when toxicity will have regressed to grade I, considering the possibility of corticosteroid treatment for most toxicities. The majority of grade III and IV require administration of high-dose corticosteroid intravenous therapy and suspension of immunotherapy.

Mortality related to immune checkpoint inhibitors’ toxicity, occurring at a rate of 0.3-1.3%, is well below fatality rates due to other oncologic interventions and should not discourage the promising results so far reached by immunotherapy.

Keywords: Immunotherapy, toxicity, adverse, events, management, oncology, emergency.

« Previous Next »
Graphical Abstract

[1]
Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [published correction appears in Ann Oncol 2017; 28suppl_4 iv119-iv142. 2018 Oct 1;29(Suppl 4):iv264-iv266]
[2]
Ascierto PA, Simeone E, Sileni VC, et al. Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort. J Transl Med 2014; 12: 116.
[http://dx.doi.org/10.1186/1479-5876-12-116] [PMID: 24885479]
[3]
European Medicines Agency: EMEA/H/C/002213-PSUSA/00009200/201409-Ipilimumab Product information 19/06/2015 Yervoy. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002213/WC500109299.pdf
[4]
European Medicines Agency: EMEA/H/C/003985 - Nivolumab Product information 19/06/2015 Opdivo. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/003985/WC500189765.pdf
[5]
European Medicines Agency: EMEA/H/C/003820 - Pembrolizumab Product information 17/07/2015 Keytruda. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/003820/WC500190990.pdf
[6]
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372(26): 2521-32.
[http://dx.doi.org/10.1056/NEJMoa1503093] [PMID: 25891173]
[7]
Masuda K, Shoji H, Nagashima K, et al. Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab. BMC Cancer 2019; 19(1): 974.
[http://dx.doi.org/10.1186/s12885-019-6150-y] [PMID: 31638948]
[8]
Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: Systematic review and meta-analysis. BMC Med 2015; 13: 211.
[http://dx.doi.org/10.1186/s12916-015-0455-8] [PMID: 26337719]
[9]
Zhao B, Zhao H, Zhao J. Serious adverse events and fatal adverse events associated with nivolumab treatment in cancer patients: Nivolumab-related serious/fatal adverse events. J Immunother Cancer 2018; 6(1): 101. [published correction appears in J Immunother Cancer. 2019 Jan 11;7(1):9].
[http://dx.doi.org/10.1186/s40425-018-0421-z] [PMID: 30285872]
[10]
Linardou H, Gogas H. Toxicity management of immunotherapy for patients with metastatic melanoma. Ann Transl Med 2016; 4(14): 272.
[http://dx.doi.org/10.21037/atm.2016.07.10] [PMID: 27563659]
[11]
Baxi S, Yang A, Gennarelli RL, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ 2018; 360: k793.
[http://dx.doi.org/10.1136/bmj.k793] [PMID: 29540345]
[12]
Kartolo A, Sattar J, Sahai V, Baetz T, Lakoff JM. Predictors of immunotherapy-induced immune-related adverse events. Curr Oncol 2018; 25(5): e403-10.
[http://dx.doi.org/10.3747/co.25.4047] [PMID: 30464691]
[13]
Haratani K, Hayashi H, Chiba Y, et al. Association of immune-Related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol 2018; 4(3): 374-8.
[http://dx.doi.org/10.1001/jamaoncol.2017.2925] [PMID: 28975219]
[14]
Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 2016; 60: 190-209.
[http://dx.doi.org/10.1016/j.ejca.2016.02.025] [PMID: 27085692]
[15]
Horiguchi M, Uno H, Wei LJ. Patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab as a result of adverse events lived significantly longer than patients who continued treatment. J Clin Oncol 2018; 36(7): 720-1.
[http://dx.doi.org/10.1200/JCO.2017.76.0983] [PMID: 29337638]
[16]
Hryniewicki AT, Wang C, Shatsky RA, Coyne CJ. Management of immune checkpoint inhibitor toxicities: A review and clinical guideline for emergency physicians. J Emerg Med 2018; 55(4): 489-502.
[http://dx.doi.org/10.1016/j.jemermed.2018.07.005] [PMID: 30120013]
[17]
Marin-Acevedo JA, Chirila RM, Dronca RS. Immune checkpoint inhibitor toxicities. Mayo Clin Proc 2019; 94(7): 1321-9.
[http://dx.doi.org/10.1016/j.mayocp.2019.03.012] [PMID: 31272574]
[18]
Pollack MH, Betof A, Dearden H, et al. Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol 2018; 29(1): 250-5.
[http://dx.doi.org/10.1093/annonc/mdx642] [PMID: 29045547]
[19]
Miranda Poma J, Ostios Garcia L, Villamayor Sanchez J, D’errico G. What do we know about cancer immunotherapy? Long-term survival and immune-related adverse events. Allergol Immunopathol (Madr) 2019; 47(3): 303-8.
[http://dx.doi.org/10.1016/j.aller.2018.04.005] [PMID: 29983240]
[20]
Quirk SK, Shure AK, Agrawal DK. Immune-mediated adverse events of anticytotoxic T lymphocyte-associated antigen 4 antibody therapy in metastatic melanoma. Transl Res 2015; 166(5): 412-24.
[http://dx.doi.org/10.1016/j.trsl.2015.06.005] [PMID: 26118951]
[21]
Toi Y, Sugawara S, Kawashima Y, et al. Association of immune-related adverse events with clinical benefit in patients with advanced non-small-cell lung cancer treated with nivolumab. Oncologist 2018; 23(11): 1358-65.
[http://dx.doi.org/10.1634/theoncologist.2017-0384] [PMID: 29934411]
[22]
Sato K, Akamatsu H, Murakami E, et al. Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. Lung Cancer 2018; 115: 71-4. [published correction appears in Lung Cancer. 2018 Dec;126:230-231].
[http://dx.doi.org/10.1016/j.lungcan.2017.11.019] [PMID: 29290265]
[23]
Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book 2015; 76-83.
[http://dx.doi.org/10.14694/EdBook_AM.2015.35.76] [PMID: 25993145]
[24]
Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist 2016; 21(10): 1230-40.
[http://dx.doi.org/10.1634/theoncologist.2016-0055] [PMID: 27401894]
[25]
Weber JS. Challenging cases: Management of immune-related toxicity. Am Soc Clin Oncol Educ Book 2018; 38: 179-83.
[http://dx.doi.org/10.1200/EDBK_209557] [PMID: 30231403]
[26]
Xu C, Chen YP, Du XJ, et al. Comparative safety of immune checkpoint inhibitors in cancer: Systematic review and network meta-analysis. BMJ 2018; 363: k4226.
[http://dx.doi.org/10.1136/bmj.k4226] [PMID: 30409774]
[27]
Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: Update on management of immune-related toxicities. Transl Lung Cancer Res 2015; 4(5): 560-75.
[http://dx.doi.org/10.3978/j.issn.2218- 6751.2015.06.06] [PMID: 26629425]
[28]
Zimmer L, Goldinger SM, Hofmann L, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer 2016; 60: 210-25.
[http://dx.doi.org/10.1016/j.ejca.2016.02.024] [PMID: 27084345]
[29]
Lacouture ME, Wolchok JD, Yosipovitch G, Kähler KC, Busam KJ, Hauschild A. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol 2014; 71(1): 161-9.
[http://dx.doi.org/10.1016/j.jaad.2014.02.035] [PMID: 24767731]
[30]
Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016; 60: 12-25.
[http://dx.doi.org/10.1016/j.ejca.2016.02.010] [PMID: 27043866]
[31]
Patel AB, Pacha O. Skin reactions to immune checkpoint inhibitors. Adv Exp Med Biol 2018; 995: 117-29.
[http://dx.doi.org/10.1007/978-3-030-02505-2_5] [PMID: 30539508]
[32]
Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016; 44: 51-60.
[http://dx.doi.org/10.1016/j.ctrv.2016.02.001] [PMID: 26874776]
[33]
Sznol M, Postow MA, Davies MJ, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev 2017; 58: 70-6.
[http://dx.doi.org/10.1016/j.ctrv.2017.06.002] [PMID: 28689073]
[34]
González-Rodríguez E, Rodríguez-Abreu D. Immune checkpoint inhibitors: Review and management of endocrine adverse Events. Oncologist 2016; 21(7): 804-16.
[http://dx.doi.org/10.1634/theoncologist.2015-0509] [PMID: 27306911]
[35]
Torino F, Corsello SM, Salvatori R. Endocrinological side-effects of immune checkpoint inhibitors. Curr Opin Oncol 2016; 28(4): 278-87.
[http://dx.doi.org/10.1097/CCO.0000000000000293] [PMID: 27136136]
[36]
Weber J, Gibney G, Yu B, et al. Survival, biomarker, and toxicity analysis of nivolumab (NIVO) in patients that progressed on ipilimumwab (IPI). American Society Clinical Oncology (ASCO), Chicago 2015 J Clin Oncol 2015; 33Suppl.; abstr 9055.
[37]
De Martin E, Michot JM, Papouin B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol 2018; 68(6): 1181-90.
[http://dx.doi.org/10.1016/j.jhep.2018.01.033] [PMID: 29427729]
[38]
Wang W, Lie P, Guo M, He J. Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis of published data. Int J Cancer 2017; 141(5): 1018-28.
[http://dx.doi.org/10.1002/ijc.30678] [PMID: 28263392]
[39]
Zen Y, Yeh MM. Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol 2019; 36(6): 434-40.
[http://dx.doi.org/10.1053/j.semdp.2019.07.009] [PMID: 31358424]
[40]
Bostwick AD, Salama AK, Hanks BA. Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis. J Immunother Cancer 2015; 3: 19.
[http://dx.doi.org/10.1186/s40425-015-0064-2] [PMID: 25992290]
[41]
Wang DY, Ye F, Zhao S, Johnson DB. Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: A systematic review and meta-analysis. OncoImmunology 2017; 6(10): e1344805.
[http://dx.doi.org/10.1080/2162402X.2017.1344805] [PMID: 29123955]
[42]
Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 2007; 30(8): 825-30.
[http://dx.doi.org/10.1097/CJI.0b013e318156e47e] [PMID: 18049334]
[43]
Chang C, Gershwin ME. Drugs and autoimmunity-a contemporary review and mechanistic approach. J Autoimmun 2010; 34(3): J266-75.
[http://dx.doi.org/10.1016/j.jaut.2009.11.012] [PMID: 20015613]
[44]
Franzen D, Schad K, Kowalski B, et al. Ipilimumab and early signs of pulmonary toxicity in patients with metastastic melanoma: a prospective observational study. Cancer Immunol Immunother 2018; 67(1): 127-34.
[http://dx.doi.org/10.1007/s00262-017-2071-2] [PMID: 28983773]
[45]
Spagnolo F, Picasso V, Lambertini M, Ottaviano V, Dozin B, Queirolo P. Survival of patients with metastatic melanoma and brain metastases in the era of MAP-kinase inhibitors and immunologic checkpoint blockade antibodies: A systematic review. Cancer Treat Rev 2016; 45: 38-45.
[http://dx.doi.org/10.1016/j.ctrv.2016.03.003] [PMID: 26975020]
[46]
Garcia CA, El-Ali A, Rath TJ, et al. Neurologic immune-related adverse events associated with adjuvant ipilimumab: Report of two cases. J Immunother Cancer 2018; 6(1): 83.
[http://dx.doi.org/10.1186/s40425-018-0393-z] [PMID: 30170622]
[47]
Johansen A, Christensen SJ, Scheie D, Højgaard JLS, Kondziella D. Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies: Systematic review. Neurology 2019; 92(14): 663-74.
[http://dx.doi.org/10.1212/WNL.0000000000007235] [PMID: 30850443]
[48]
Larkin J, Chmielowski B, Lao CD, et al. Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis. Oncologist 2017; 22(6): 709-18.
[http://dx.doi.org/10.1634/theoncologist.2016-0487] [PMID: 28495807]
[49]
Heinzerling L, Ott PA, Hodi FS, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer 2016; 4: 50.
[http://dx.doi.org/10.1186/s40425-016-0152-y] [PMID: 27532025]
[50]
Saade A, Mansuet-Lupo A, Arrondeau J, et al. Pericardial effusion under nivolumab: case-reports and review of the literature. J Immunother Cancer 2019; 7(1): 266. [published correction appears in J Immunother Cancer. 2019 Dec 2;7(1):335].
[http://dx.doi.org/10.1186/s40425-019-0760-4] [PMID: 31627742]
[51]
Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016; 375(18): 1749-55.
[http://dx.doi.org/10.1056/NEJMoa1609214] [PMID: 27806233]
[52]
Rahouma M, Karim NA, Baudo M, et al. Cardiotoxicity with immune system targeting drugs: A meta-analysis of anti-PD/PD-L1 immunotherapy randomized clinical trials. Immunotherapy 2019; 11(8): 725-35.
[http://dx.doi.org/10.2217/imt-2018-0118] [PMID: 31088241]
[53]
Cappelli LC, Gutierrez AK, Baer AN, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 2017; 76(1): 43-50.
[http://dx.doi.org/10.1136/annrheumdis-2016-209595] [PMID: 27307501]
[54]
Shah M, Tayar JH, Abdel-Wahab N, Suarez-Almazor ME. Myositis as an adverse event of immune checkpoint blockade for cancer therapy. Semin Arthritis Rheum 2019; 48(4): 736-40.
[http://dx.doi.org/10.1016/j.semarthrit.2018.05.006] [PMID: 29909921]
[55]
Wanchoo R, Karam S, Uppal NN, et al. Adverse renal effects of immune checkpoint inhibitors: A narrative review. Am J Nephrol 2017; 45(2): 160-9.
[http://dx.doi.org/10.1159/000455014] [PMID: 28076863]
[56]
Belliere J, Meyer N, Mazieres J, et al. Acute interstitial nephritis related to immune checkpoint inhibitors. Br J Cancer 2016; 115(12): 1457-61.
[http://dx.doi.org/10.1038/bjc.2016.358] [PMID: 27832664]
[57]
Lemoine M, Dilly B, Curie A, et al. Ipilimumab-induced renal granulomatous arteritis: A case report. BMC Nephrol 2019; 20(1): 366.
[http://dx.doi.org/10.1186/s12882-019-1552-2] [PMID: 31604452]
[58]
Cortazar FB, Marrone KA, Troxell ML, et al. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int 2016; 90(3): 638-47.
[http://dx.doi.org/10.1016/j.kint.2016.04.008] [PMID: 27282937]
[59]
Abdel-Rahman O, Oweira H, Petrausch U, et al. Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: A systematic review. Expert Rev Anticancer Ther 2017; 17(4): 387-94.
[http://dx.doi.org/10.1080/14737140.2017.1296765] [PMID: 28277102]
[60]
Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. Checkpoint inhibitor immune therapy: Systemic indications and ophthalmic side effects. Retina 2018; 38(6): 1063-78.
[http://dx.doi.org/10.1097/IAE.0000000000002181] [PMID: 29689030]
[61]
Fang T, Maberley DA, Etminan M. Ocular adverse events with immune checkpoint inhibitors. J Curr Ophthalmol 2019; 31(3): 319-22.
[http://dx.doi.org/10.1016/j.joco.2019.05.002] [PMID: 31528768]
[62]
Horvat TZ, Adel NG, Dang T-O, et al. Immune-Related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 2015; 33(28): 3193-8.
[http://dx.doi.org/10.1200/JCO.2015.60.8448] [PMID: 26282644]
[63]
Youssef A, Kasso N, Torloni AS, et al. Thrombotic Thrombocytopenic Purpura due to Checkpoint Inhibitors. Case Rep Hematol 2018; 20182464619
[http://dx.doi.org/10.1155/2018/2464619] [PMID: 30671268]
[64]
Leitinger M, Varosanec MV, Pikija S, et al. Fatal necrotizing encephalopathy after treatment with nivolumab for squamous non-small cell lung cancer: Case report and review of the literature. Front Immunol 2018; 9: 108.
[http://dx.doi.org/10.3389/fimmu.2018.00108] [PMID: 29441072]
[65]
Appelbaum J, Wells D, Hiatt JB, et al. Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: A case report. J Immunother Cancer 2018; 6(1): 82.
[http://dx.doi.org/10.1186/s40425-018-0396-9] [PMID: 30170630]
[66]
de Almeida DVP, Gomes JR, Haddad FJ, Buzaid AC. Immune-mediated pericarditis With pericardial tamponade during nivolumab therapy. J Immunother 2018; 41(7): 329-31.
[http://dx.doi.org/10.1097/CJI.0000000000000217] [PMID: 29461982]
[67]
Saibil SD, Bonilla L, Majeed H, et al. Fatal myocarditis and rhabdomyositis in a patient with stage IV melanoma treated with combined ipilimumab and nivolumab. Curr Oncol 2019; 26(3): e418-21.
[http://dx.doi.org/10.3747/co.26.4381] [PMID: 31285688]
[68]
Luecke E, Ganzert C, Vielhaber S, et al. Immune Checkpoint Inhibitor-induced Fatal Myositis in a Patient With Squamous Cell Carcinoma and a History of Thymoma [published online ahead of print, 2020 Jan 28]. Clin Lung Cancer S1525-7304(20)30008-5.2020;
[69]
Wang DY, Salem JE, Cohen JV, et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol 2018; 4(12): 1721-8. [published correction appears in JAMA Oncol. 2018 Dec 1;4(12):1792].
[http://dx.doi.org/10.1001/jamaoncol.2018.3923] [PMID: 30242316]

Rights & Permissions Print Cite
Article Metrics
27
© 2024 Bentham Science Publishers | Privacy Policy