Myasthenia Gravis Associated With Programmed Death-1 (PD-1) Receptor Inhibitor Pembrolizumab: A 40-day Case Report

Purpose: This case report describes myasthenia gravis-like symptoms after treatment with a programmed cell death 1 inhibitor, pembrolizumab, the treatment modalities utilized, and associated patient outcomes. Summary: A 76-year old male treated with pembrolizumab for palliative therapy for metastatic melanoma presented with increasing weakness, neck pain, diplopia in the left eye, abducens palsy, periorbital edema, and decreased appetite. The patient was diagnosed with acetylcholine receptor antibody (AChR) negative myasthenia gravis. The patient was started on prednisone 1 mg/kg/day, followed by pyridostigmine 60 mg by mouth 3 times a day, and IVIg for 5 days. Due to minor improvements in myasthenia gravis symptoms, 5 cycles of plasmapheresis were ordered. The patient was successfully treated for aspiration pneumonia after cardiopulmonary arrest. On day 28, the patient was diagnosed with ventilator associated pneumonia and received appropriate therapy. Due to ICU agitation and delirium, VAP, and long duration of treatment, the patient requested withdrawal of care and passed. Conclusion: Programmed cell death inhibitors, such as pembrolizumab, can provide great benefit to patients but can also be associated with rare but serious adverse events. With new reports of MG after use, providers should continually weigh the benefits versus harm in using these products and monitor patients closely for such adverse events.

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Faculty Opinions recommendation of Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726090914.793518613 ◽

2016 ◽

Author(s):

Mariya Miteva

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Adverse Events ◽

Metastatic Melanoma ◽

Single Institution

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Side effects of immune-checkpoint inhibitors: Can multiple side effects be seen in a patient?

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211038136 ◽

2021 ◽

pp. 107815522110381

Author(s):

Esra Özyurt ◽

Serhat Özçelik ◽

Heves Sürmeli ◽

Mehmet Çelik ◽

Murat Ayhan ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Side Effects ◽

Programmed Cell Death ◽

Adverse Events ◽

Checkpoint Inhibitors ◽

Host Cells ◽

Immunoglobulin G4 ◽

Programmed Cell Death 1 ◽

Recurrent Renal Cell Carcinoma

Introduction Nivolumab is a human immunoglobulin G4 monoclonal antibody that inhibits programmed cell death-1 activity by binding to the programmed cell death-1 receptors. Cancer cells express increased number of programmed cell death-1 ligands and this allows them to escape the cytotoxic effects of the T cells. Therefore, the negative programmed cell death-1 receptor signal regulates T-cell proliferation and activation is disrupted. However, this change in the activity of the T cells can cause them to lose their ability to recognize host cells. The immune response enabled by these agents has led to side effects, commonly known as “immune-related adverse events.” Case report We report a case of a 66-year-old male patient who was treated with nivolumab for recurrent renal cell carcinoma presented with hepatitis and adrenalitis. Three weeks after starting nivolumab, the patient had abdominal pain and weakness, and then aspartate and alanine transaminase levels were found to be elevated. Management and outcome Hepatitis was predicted to be due to nivolumab, because other causes were excluded. He started using oral methylprednisolone and then, hepatitis improved. However, while receiving methylprednisolone treatment, fludrocortisone was started with the pre-diagnosis of adrenalitis due to the persistence of fatigue, weakness, and hyponatremia and hyperkalemia. With both treatments, the patient's symptoms and sodium and potassium level returned to normal. Discussion This case emphasizes the need for patient's education and awareness of immune-related adverse events, and the importance of understanding the management of life-threatening complications of the checkpoint inhibitors, because these side effects require prompt recognition and treatment.

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Management of Hematologic Adverse Events Associated With Immune Checkpoint Inhibitors

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2021.12.4.4 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC ◽

Carolyn Zawislak, MPAS, PA-C ◽

Victoria Wong, PA-C

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Adverse Events ◽

Immune Checkpoint ◽

Blood Cells ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

White Blood Cells ◽

Activated T Cells

Immune checkpoint inhibitors target suppressor receptors, including cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). The activated T cells are not antigen specific; therefore, the blockade of the immune checkpoint may result in the development of autoimmune adverse events. The most common immune-related adverse events (irAEs) are rash, colitis, and endocrinopathies. However, irAEs that affect the hematologic system are rare and can affect red blood cells (e.g., autoimmune hemolytic anemia), white blood cells, and platelets (e.g., immune thrombocytopenia). Usually one cell line is affected; however, in some cases, multiple cell lines can be affected. Other changes in the hematologic system can also be affected (e.g., cryoglobulinemia, cytokine release syndrome). Due to the rarity and lack of recognition of these AEs, the timing, spectrum of events, and clinical presentation are poorly understood. Management of hematologic irAEs usually involves the use of steroids; however, other agents (e.g., IVIG, cyclosporine, rituximab) or procedures (e.g., plasma exchange, transfusions) can also be used.

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Programmed cell death-1 and programmed cell death ligand-1 antibodies-induced dysthyroidism

Endocrine Connections ◽

10.1530/ec-18-0079 ◽

2018 ◽

Vol 7 (5) ◽

pp. R196-R211 ◽

Cited By ~ 4

Author(s):

Jaafar Jaafar ◽

Eugenio Fernandez ◽

Heba Alwan ◽

Jacques Philippe

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Programmed Cell Death ◽

Adverse Events ◽

English Language ◽

Case Series ◽

Immune Checkpoints ◽

Pubmed Database ◽

Programmed Cell Death 1 ◽

Time To Onset

Background Monoclonal antibodies blocking the programmed cell death-1 (PD-1) or its ligand (PD-L1) are a group of immune checkpoints inhibitors (ICIs) with proven antitumor efficacy. However, their use is complicated by immune-related adverse events (irAEs), including endocrine adverse events (eAEs). Purpose We review the incidence, time to onset and resolution rate of dysthyroidism induced by PD-1/PD-L1 Ab, and the clinical, biological and radiological findings. We aim to discuss the potential mechanisms of PD-1/PD-L1 Ab-induced dysthyroidism, and to propose a management algorithm. Methods We performed a literature search of available clinical trials regarding PD-1/PD-L1 Ab in the PubMed database. We selected all English language clinical trials that included at least 100 patients. We also present selected case series or reports, retrospective studies and reviews related to this issue. Findings In patients treated with PD-1 Ab, hypothyroidism occurred in 2–10.1% and hyperthyroidism occurred in 0.9–7.8%. When thyroiditis was reported separately, it occurred in 0.34–2.6%. Higher rates were reported when PD-1 Ab were associated with other ICI or chemotherapy. The median time to onset of hyperthyroidism and hypothyroidism after PD-1 Ab initiation was 23–45 days and 2–3.5 months, respectively. Regarding PD-L1 Ab, hypothyroidism occurred in 0–10% and hyperthyroidism in 0.5–2% of treated patients. The average time to onset of dysthyroidism after PD-L1 Ab was variable and ranged from 1 day after treatment initiation to 31 months. Conclusion Dysthyroidism occurs in up to 10% of patients treated with PD-1/PD-L1 Ab. Hypothyroidism and reversible destructive thyroiditis are the most frequent endocrine adverse events (eAE) in PD-1/PD-L1 treated patients. Immune and non-immune mechanisms are potentially involved, independently of the presence of thyroid antibodies.

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Programmed cell death 1 blockade-induced cutaneous sarcoid-like epithelioid granulomas in advanced melanoma: a case report

Journal of the European Academy of Dermatology and Venereology ◽

10.1111/jdv.14781 ◽

2018 ◽

Vol 32 (7) ◽

pp. e260-e261 ◽

Cited By ~ 9

Author(s):

T. Ogawa ◽

Y. Ishitsuka ◽

K. Iwamoto ◽

H. Koguchi-Yoshioka ◽

R. Tanaka ◽

...

Keyword(s):

Cell Death ◽

Case Report ◽

Programmed Cell Death ◽

Advanced Melanoma ◽

Programmed Cell Death 1

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Programmed cell death ligand 1 expression is upregulated in the skeletal muscle of patients with myasthenia gravis

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2018.09.012 ◽

2018 ◽

Vol 325 ◽

pp. 74-78 ◽

Cited By ~ 3

Author(s):

Kazuo Iwasa ◽

Hiroaki Yoshikawa ◽

Yutaka Furukawa ◽

Masahito Yamada

Keyword(s):

Skeletal Muscle ◽

Cell Death ◽

Programmed Cell Death ◽

Myasthenia Gravis

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Simultaneous development of Graves’ disease and type 1 diabetes during anti‐programmed cell death‐1 therapy: A case report

Journal of Diabetes Investigation ◽

10.1111/jdi.13212 ◽

2020 ◽

Vol 11 (4) ◽

pp. 1006-1009 ◽

Cited By ~ 5

Author(s):

Susumu Kurihara ◽

Yoichi Oikawa ◽

Ritsuko Nakajima ◽

Atsushi Satomura ◽

Ryuhei Tanaka ◽

...

Keyword(s):

Cell Death ◽

Type 1 Diabetes ◽

Case Report ◽

Programmed Cell Death ◽

Graves Disease ◽

Simultaneous Development ◽

Programmed Cell Death 1

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Resumption of anti‐programmed cell death 1 monotherapy for severe immune‐related adverse events experienced patient with renal cell carcinoma

IJU Case Reports ◽

10.1002/iju5.12173 ◽

2020 ◽

Vol 3 (5) ◽

pp. 176-179 ◽

Cited By ~ 1

Author(s):

Yoko Maegawa ◽

Taigo Kato ◽

Shinichiro Fukuhara ◽

Hiroshi Kiuchi ◽

Ryoichi Imamura ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Death ◽

Programmed Cell Death ◽

Adverse Events ◽

Cell Carcinoma ◽

Renal Cell ◽

Experienced Patient ◽

Programmed Cell Death 1

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Fatal adverse events associated with programmed cell death protein 1 or programmed cell death-ligand 1 monotherapy in cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919895753 ◽

2020 ◽

Vol 12 ◽

pp. 175883591989575

Author(s):

Bin Zhao ◽

Hong Zhao ◽

Jiaxin Zhao

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Adverse Events ◽

Solid Tumors ◽

Sequential Analysis ◽

Trial Sequential Analysis ◽

Tumor Type ◽

Organ Systems ◽

Fatal Adverse Events ◽

Cell Death Protein

Background: The introduction of antibodies targeting programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) into clinical practice has had a revolutionary effect on cancer treatment. However, the incidence and risk of fatal adverse events (FAEs) following PD-1/PD-L1 inhibitor administration are controversial. Methods: We performed a systematic search for randomized controlled trials (RCTs) of PD-1/PD-L1 inhibitors (atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab) in Embase, PubMed, the Cochrane database, and abstracts presented at American Society of Clinical Oncology and European Society of Medical Oncology from inception to July 2018. FAEs were extracted from each study and pooled to calculate overall incidence and odds ratios (ORs). Results: In total, 20 RCTs involving 12,398 patients with solid tumors were included in this study. The overall incidence of FAEs with PD-1/PD-L1 inhibitors was 0.43% [95% confidence interval (CI), 0.25–0.66%]. However, the incidences of FAEs varied significantly by tumor type and median follow-up time. Compared with conventional agents, the application of PD-1/PD-L1 inhibitors significantly reduced the risk of FAEs (OR, 0.56; 95% CI, 0.35–0.89; p = 0.015). Moreover, trial sequential analysis confirmed that our results were solid and reliable; further studies were unlikely to alter this conclusion. FAEs occurred dispersed in major organ systems, with the most common mortalities appearing in the respiratory system (46.2%). Conclusions: Compared with conventional treatment, PD-1/PD-L1 blockade monotherapy is associated with a significantly reduced risk of mortality in patients with solid tumors.

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