Safety of checkpoint inhibitors for cancer treatment: strategies for patient monitoring and management of immune-mediated adverse events

Abstract Background Treatment with immune checkpoint inhibitors has revolutionized cancer treatment over the past several years. Despite their clinical benefits, a wide range of immune-mediated toxicities can be observed including hematological toxicities. Although, the majority can easily be managed, immune-mediated adverse events rarely can be severe and difficult to approach. Herein, we are reporting a case of very severe aplastic anemia secondary to ipilimumab (I) and nivolumab (N) treatment that failed various treatment including intensive immune suppressive therapy. Case presentation We described a case of a 45-year old white male, heavy smoker presented to the clinic complaining of left flank pain. He was found to have a metastatic renal cell carcinoma for which he was treated with dual immunotherapy and later complicated by severe immune related adverse events. The patient later died after failing intensive immune suppressive therapy. Conclusion Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with variant malignancies. Yet, lethal adverse events can occur in rare cases. It is our duty, as physicians, to remain alert and cautious.

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Aplastic Anemia Secondary to Dual Cancer Immunotherapies A Physician Nightmare: Case Report and Literature Review

10.21203/rs.3.rs-299607/v1 ◽

2021 ◽

Author(s):

Romy G. Younan ◽

Roy A. Raad ◽

Bassem Y. Sawan ◽

Rabih Said

Keyword(s):

Adverse Events ◽

Cancer Treatment ◽

Aplastic Anemia ◽

Checkpoint Inhibitors ◽

White Male ◽

Heavy Smoker ◽

Immune Mediated ◽

Wide Range ◽

Clinical Benefits ◽

Cancer Immunotherapies

Abstract BackgroundTreatment with immune checkpoint inhibitors has revolutionized cancer treatment over the past several years. Despite their clinical benefits, a wide range of immune-mediated toxicities can be observed including hematological toxicities. Although, the majority can easily be managed, immune-mediated adverse events rarely can be severe and difficult to approach. Herein, we are reporting a case of very severe aplastic anemia secondary to ipilimumab (I) and nivolumab (N) treatment that failed various treatment including intensive immune suppressive therapy.Case presentationWe described a case of a 45-year old white male, heavy smoker presented to the clinic complaining of left flank pain. He was found to have a metastatic renal cell carcinoma for which he was treated with dual immunotherapy and later complicated by severe immune related adverse events. The patient later died after failing intensive immune suppressive therapy.ConclusionImmunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with variant malignancies. Yet, lethal adverse events can occur in rare cases. It is our duty, as physicians, to remain alert and cautious.

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Comparative risk of serious and fatal treatment-related adverse events caused by 19 immune checkpoint inhibitors used in cancer treatment: a network meta-analysis

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920940927 ◽

2020 ◽

Vol 12 ◽

pp. 175883592094092 ◽

Cited By ~ 1

Author(s):

Tingting Liu ◽

Bo Jin ◽

Jun Chen ◽

Hui Wang ◽

Shuiyu Lin ◽

...

Keyword(s):

Adverse Events ◽

Cancer Treatment ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Combinatorial Therapy ◽

Grade 5 ◽

Comparative Risk ◽

Grade 3

Background: This network meta-analysis assessed the comparative risk of grade 3–5 and grade 5 treatment-related adverse events (TRAEs) for immune checkpoint inhibitors (ICIs), either alone or in combination with other modalities, for cancer treatment. Methods: PubMed, Embase, Cochrane Library, Web of Science, and recent predominant oncology congresses were searched for relevant phase II and phase III randomized controlled trials (RCTs). As outcomes, grade 3–5, and grade 5 TRAE outcomes were reported as odds ratios and 95% confidence intervals. Results: In 67 RCTs involving 36,422 patients and 19 ICIs, the incidence of grade 3–5 and grade 5 TRAEs was 17.9% and 0.8% with ICI monotherapy and 46.3% and 1.4%, respectively, with combinatorial therapy. Pneumonitis was the most common cause of grade 5 TRAEs following either monotherapy (16.3%) or combinatorial therapy (11.4%). Regarding grade 3–5 TRAEs, atezolizumab + chemotherapy (CT) and antiangiogenic therapy (AT) (atezolizumab + CAT), pembrolizumab + CT, ipilimumab + CT, and atezolizumab + CT were more toxic than any ICI monotherapy, pembrolizumab or nivolumab + radiotherapy (RT), and ICIs dual therapy (durvalumab + tremelimumab and nivolumab + ipilimumab). Tremelimumab, ipilimumab, durvalumab, and pembrolizumab were, however, associated with higher grade 5 TRAEs than combinatorial treatments. Atezolizumab + CAT was the most toxic and nivolumab + RT was the least toxic of combinatorial treatments; among monotherapies, tremelimumab and avelumab were the most and least toxic, respectively. The toxicity ranking changed with type of grade 3–5 TRAEs. Conclusions: Compared with combinatorial therapy, ICI monotherapy caused lower grade 3–5 TRAEs, but some monotherapies resulted in a higher incidence of fatal TRAEs. Atezolizumab + CAT and nivolumab + RT were the most and least toxic of combinatorial treatments, respectively, and tremelimumab and avelumab were the most and least toxic of the monotherapies, respectively.

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A case report of psoriasis flare following immunotherapy: Report of an important entity and literature review

SAGE Open Medical Case Reports ◽

10.1177/2050313x19897707 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X1989770 ◽

Cited By ~ 2

Author(s):

Anastasia Politi ◽

Dimas Angelos ◽

Davide Mauri ◽

George Zarkavelis ◽

George Pentheroudakis

Keyword(s):

Adverse Events ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Skin Lesions ◽

Inflammatory Disorder ◽

Immune Mediated ◽

Programmed Death ◽

History Of ◽

Programmed Death 1 ◽

Cessation Of Treatment

Immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed death-1, are a type of cancer immunotherapy approved for late-stage malignancy treatment. However, such therapies often induce immune-related adverse events. During anti-programmed death-1 blockade therapy, the most commonly reported adverse effects are skin toxicities, such as psoriasis—a chronic immune-mediated inflammatory disorder affecting the skin. We present the clinical characteristics of flared psoriasis in one patient under anti-programmed death-1 therapy who was diagnosed with T2N2M0/IIIB squamous lung carcinoma with a history of psoriasis for the past 5 years, exacerbated after the first cycle of nivolumab. After the third cycle, the extensive skin plaques necessitated treatment cessation. Following the discontinuation of anti-programmed death-1 treatment, skin lesions were treated locally. Possibly, anti-programmed death-1 immunotherapy can trigger immune-mediated diseases, such as psoriasis. Physicians should be alert to immune-related adverse events. Continuation or permanent cessation of treatment depends on the severity and reversibility of immune-related adverse events.

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Immuno-related endocrinopathy in patients treated with immune checkpoint inhibitors

Medical Council ◽

10.21518/2079-701x-2020-9-16-24 ◽

2020 ◽

pp. 16-24

Author(s):

D. I. Yudin ◽

K. K. Laktionov ◽

K. A. Sarantseva ◽

O. I. Borisova ◽

V. V. Breder ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Clinical Practice ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Serious Adverse Events ◽

Immune Mediated ◽

Discontinuation Of Treatment ◽

The Russian Federation

Recently immune checkpoint inhibitors amazingly changed the landscape of cancer therapy worldwide. The number of immune checkpoint molecules in clinical practice is constantly increasing. There are some monoclonal antibodies recently registered in the Russian Federation: anti-PD1 antibodies (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab), anti-CTLA-4 (ipilimumab). Immune-mediated endocrinopathies are some of the most common complications of immunotherapy. According to the results of clinical studies, the incidence of serious endocrine immuno-mediated adverse events with anti-PD1 monoclonal antibodies is low (3.5–8%). The use of anti-CTLA4 antibodies, combined regimens, and the use of immunotherapy after chemoradiotherapy significantly increase the incidence of serious adverse events to 30%. In clinical practice of N.N. Blokhin Cancer Research Center among 245 non-small cell lung cancer and hepatocellular carcinoma patients treated with immunotherapy, 22 (8,9%) developed an immune-mediated endocrinopathy. Most patients developed adverse events of 1–2 degrees, in two patients – 3 degrees, requiring discontinuation of treatment. The aim of this article was to provide useful information and recommendations regarding the management of common immuno-related endocrine adverse events (including hypothyroidism, hyperthyroidism, pituitary, adrenal insufficiency) for clinical oncologists.

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Immune-mediated adverse events in immune checkpoint inhibitors therapy: literature review

Modern Oncology ◽

10.26442/18151434.2021.2.200502 ◽

2021 ◽

Vol 23 (2) ◽

pp. 319-326

Author(s):

Marina A. Lyadova ◽

Vladimir K. Lyadov

Keyword(s):

Adverse Events ◽

Interstitial Nephritis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Acute Interstitial Nephritis ◽

Early Symptom ◽

Immune Mediated ◽

Cutaneous Rash ◽

Pancreatic Dysfunction

Immune-mediated adverse events (imAEs) are complications of therapy with immune checkpoint inhibitors, which arise as a result of autoimmune inflammation. The article summarizes systemic (fatigue, fever), cutaneous (rash, itching), gastrointestinal (diarrhea, colitis, hepatitis, pancreatic dysfunction), endocrinological (hypothyroidism, hypophysitis, adrenal insufficiency, diabetes mellitus), pulmonary (pneumonitis, pleuritis), rheumatological (arthralgia), neurological (headache, sensory and motor disorders), renal (acute interstitial nephritis, lupus-like nephritis, granulomatous nephritis, diffuse interstitial nephritis and minimal change disease), hematological (anemia, cytopenia), cardiovascular (myocarditis) and ocular (conjunctivitis, episcleritis, ceratitis, blepharitis and uveitis) imAE. Pathogenetic mechanisms and treatment approaches (in accordance with toxicity grade and clinical recommendations) are discussed. Early symptom recognition, patient education and timely intervention are crucial for imAE correction.

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The Application of Nanoparticle-Based Drug Delivery Systems in Checkpoint Blockade Cancer Immunotherapy

Journal of Immunology Research ◽

10.1155/2018/3673295 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 6

Author(s):

Huan Zhao ◽

Yuanqi Li ◽

Dan Wei ◽

Hongrong Luo

Keyword(s):

Cancer Treatment ◽

Small Molecule ◽

Photothermal Therapy ◽

Drug Delivery Systems ◽

Tumor Metastasis ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Checkpoint Blockade ◽

Human Beings ◽

Cancer Immunity

Tumor is the most serious threat to human beings. Although war against cancer has been launched over forty years, cancer treatment is still far away from being satisfactory. Immunotherapy, especially checkpoint blockade immunotherapy, is a rising star that shows a promising future. To fulfill the requirement of depleting primary tumor and inhibiting tumor metastasis and recurrence, many researchers combined checkpoint blockade immunotherapy with other treatment strategies to extend the treatment outcome. Photodynamic therapy could induce immunogenic cell death, and checkpoint blockade could further accelerate the immunity; therefore, combining these two strategies publishes many papers. Additionally, photothermal therapy and immunotherapy were also utilized for combining with checkpoint blockade, which were also reviewed in this paper. Furthermore, antibodies, siRNA, and small molecule inhibitors are developed to block the checkpoint; therefore, we categorized the papers into three sections, combination nanoparticles with checkpoint blockade antibody, combination nanoparticles with checkpoint blockade siRNA, and combination nanoparticles with small molecule checkpoint inhibitors, and related researches were summarized. In conclusion, the combination nanoparticle with checkpoint blockade cancer immunity is a promising direction that may fulfill the requirement of cancer treatment.

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Immunotherapy-induced endocrinopathies: assessment, management and monitoring

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018819896182 ◽

2019 ◽

Vol 10 ◽

pp. 204201881989618 ◽

Cited By ~ 5

Author(s):

Edson Nogueira ◽

Tom Newsom-Davis ◽

Daniel L. Morganstein

Keyword(s):

Adverse Event ◽

Adverse Events ◽

Mechanism Of Action ◽

Checkpoint Inhibitors ◽

Hormone Deficiency ◽

High Dose ◽

Multiple Organs ◽

Immune Mediated

Immunotherapy with checkpoint inhibitors has transformed the treatment of cancer, but frequently results in immune-mediated adverse events affecting multiple organs, amongst which endocrine adverse events are frequent. The patterns of endocrine adverse events differ between inhibitors of the CTLA-4 and PD-1/PD-L1 pathways, but most frequently involve the thyroid and pituitary with insulin deficient diabetes also emerging as an important adverse event. These frequently result in long-lasting hormone deficiency requiring replacement. This review explores the mechanism of action of checkpoint inhibitors and details the expected endocrine adverse events and typical presentations. The effect of high-dose glucocorticoids therapy to treat nonendocrine adverse events is also discussed.

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Case Report: Lymphocytosis Associated With Fatal Hepatitis in a Thymoma Patient Treated With Anti-PD1: New Insight Into the Immune-Related Storm

Frontiers in Oncology ◽

10.3389/fonc.2020.583781 ◽

2020 ◽

Vol 10 ◽

Author(s):

Antonella Argentiero ◽

Antonio Giovanni Solimando ◽

Valentina Ungaro ◽

Mariarita Laforgia ◽

Sabino Strippoli ◽

...

Keyword(s):

Case Report ◽

Adverse Events ◽

Multidisciplinary Approach ◽

Tumor Response ◽

Checkpoint Inhibitors ◽

Therapeutic Option ◽

Immune Mediated ◽

Red Flag ◽

Immune Oncology ◽

Insight Into

Recent advances in tumor immunotherapy have made it possible to efficiently unleash immune effectors, reacting against neoplastic cells. Although these approaches primarily aim to eradicate malignancy, immune-related adverse events (irAEs) often influence patients’ prognosis, constituting a new spectrum of side effects. Taking into account the typical microenvironment and the intricate equilibrium between the anti-tumor response and the immune cells, the thymoma constitutes a unicum in the immune-oncology field. We report a fatal immune-mediated adverse events’ storm in a thymoma patient treated with Pembrolizumab, leading to hepatotoxicity accompanied by lymphocytosis, thrombocytopenia, and thyroid dysfunction, unveiling a novel potential pathophysiological effect of immunotherapy. The clinical proficiency of the immune checkpoint inhibitors in thymoma patients warrants timely prevention and management of off-target consequences in order to optimize this promising therapeutic option. This case report describes a unique consequence of irAEs, emerging as a red flag warranting a multidisciplinary approach.

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Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e21712 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e21712-e21712 ◽

Cited By ~ 1

Author(s):

Chipman Robert Geoffrey Stroud ◽

Cynthia R. Cherry ◽

Abdul Rafeh Naqash ◽

Nitika Sharma ◽

Sulochana Devi Cherukuri ◽

...

Keyword(s):

Adverse Events ◽

Clinical Improvement ◽

Median Time ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Therapeutic Option ◽

Immune Checkpoint Blockade ◽

Inpatient Setting ◽

Immune Mediated ◽

Steroid Refractory

e21712 Background: Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events (irAEs) is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid-refractory irAEs. Methods:The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4 mg/kg given IV over 1 hour. C-reactive protein was drawn at first nivolumab infusion and at q 2 weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital d/c within 7 days. Results:Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All pts were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, cytokine release syndrome/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). Median CRP at initial tocilizumab dose was 100.5 mg/L (2.0 -350.4). Clinical improvement was noted in 27/34 pts (79.4%). 52.9% of pts required a single dose, while 35.3% required two, 8.8% required three and 1 pt required 4 doses. Twenty seven doses were given in the inpatient setting (49.1%). Median time to discharge was 4 days (range 1-27). Seventy four percent of pts were discharged home. For the 55 doses of tocilizumab that were delivered there was a cost savings of $147,174.94 (WAC) during the 18 month period versus infliximab 5 mg/kg IV dose. Conclusions: Tocilizumab is a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.

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