Acute Lower Limb Ischaemia and Diabetes in a Patient Treated with Anti-PD1 Monoclonal Antibody for Metastatic Melanoma

Thoreau, Benjamin; Gouaillier-Vulcain, Flora; Machet, L.; Mateus, Christine; Robert, Caroline; Ferreira-Maldent, Nicole; Maillot, F.

doi:10.2340/00015555-2504

Cited by 22 publications

(8 citation statements)

References 7 publications

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“…Supplementary Table 1 (see section on supplementary data given at the end of this article) provides an overview of our search terms. Additionally, the authors reviewed the reference lists of the included articles (4, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68) and identified five additional cases (69, 70, 71, 72). The following data were extracted from each manuscript: author, year of publication, age, gender and ethnicity of the patient, cancer type, checkpoint inhibitor therapy, number of cycles of therapy, prior immunotherapy, relevant past medical history (PMH), presence of diabetic ketoacidosis, glycemia, glycated hemoglobin, C-peptide, islet autoantibodies, lipase, other irAE and HLA genotype.…”

Section: Methodsmentioning

confidence: 99%

Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review

Filette

Pen

Decoster

et al. 2019

European Journal of Endocrinology

188

196

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Objective To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs). Design and methods We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy. Results Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population. Conclusion ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.

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Section: Methodsmentioning

confidence: 99%

Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review

Filette

Pen

Decoster

et al. 2019

European Journal of Endocrinology

188

196

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“…The patient was later found to have arterial thrombosis, which was removed with fogarty thrombectomy and was believed to be secondary to PD-1 inhibitor. However, the patient had diabetes mellitus with diabetic ketoacidosis, which also could induce endothelial inflammatory damage under oxidative stress leading to arterial thrombosis [12].…”

Section: Discussionmentioning

confidence: 99%

Acral vascular necrosis associated with immune-check point inhibitors: case report with literature review

Khaddour

Singh²,

Shayuk

2019

BMC Cancer

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Background Treatment of solid malignancies has been revolutionized with the introduction of immune checkpoint inhibitors (ICIs) and their use is being expanded in therapy of different cancers. However, immune related adverse events (IRAEs) can occur during treatment. These side effects occur due to stimulation of the innate and adaptive immune system and can lead to serious complications. Recently, acral ischemia has been reported in some cases during treatment with programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors. Here, we discuss a case in which acral necrosis developed after initiation of a PD-1 inhibitor. We offer a review of the existing literature on the pathophysiology, clinical course and treatment outcomes. Case presentation A 68-year-old female was diagnosed with stage IV non-small cell lung adenocarcinoma and was started on pembrolizumab. The patient developed sudden onset numbness and discoloration of fingertips bilaterally at week 25 after initiation of ICI treatment. Extensive workup to rule out hypercoagulable, autoimmune and vascular disease was unremarkable except for mild elevation of ANA and ESR. The symptoms quickly progressed into dry gangrene within four weeks and did not respond to medical or surgical treatment. Pembrolizumab was subsequently discontinued due to progression of metastatic disease. The patient refused further interventions and transitioned to hospice care where she expired after two months. Conclusion Acral ischemia can develop during treatment of malignancies. This complication, although uncommon, canresult in digital amputation. Physicians should be aware of the possible progression of acral vascular necrosis when Raynaud’s like symptoms develop. Larger studies are needed to confirm the role of ICIs in the pathogenesis of acral vascular necrosis.

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“…[26] After extensive diagnostic evaluation that ruled out other possible causes, they similarly postulated that combination therapy induced thrombus formation. [26] While an animal model has shown proinflammatory and proatherogenic effects of anti-PD-1 agents, [27] it is unlikely in either of the cases that this led to an atheromatous plaque that either embolized or ruptured given the imaging findings and time course of the clinical presentation.…”

Section: Discussionmentioning

confidence: 99%

Ipilimumab-nivolumab therapy causing STEMI in a melanoma patient: A case report

Alkhathlan

Tofovic

Sullivan³

et al. 2017

CRIM

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The combination of ipilimumab and nivolumab has shown great promise in improving survival in patients with advanced melanoma. However, these novel agents are not without side effects, with adverse events occurring in up to 55% of patients on combination therapy. We report a case of ST-elevation myocardial infarction (STEMI) with resultant new severe systolic heart failure and left ventricular thrombus in a middle-aged woman with metastatic melanoma on ipilimumab-nivolumab therapy suspicious for de novo intra-arterial thrombus formation. We hypothesize that this is likely due to an immune-related adverse event, a documented phenomenon in patients on this combination therapy. To the best of our knowledge, this is the first case in patients on ipilimumab-nivolumab therapy to develop STEMI due to intra-arterial thrombus formation.

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Acute Lower Limb Ischaemia and Diabetes in a Patient Treated with Anti-PD1 Monoclonal Antibody for Metastatic Melanoma

Cited by 22 publications

References 7 publications

Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review

Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review

Acral vascular necrosis associated with immune-check point inhibitors: case report with literature review

Ipilimumab-nivolumab therapy causing STEMI in a melanoma patient: A case report

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