Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma

Abstract

BackgroundThere has been a significant improvement in survival of advanced malignancies with the advent of checkpoint inhibitors. These newer treatment modalities come with a wide spectrum of unique side effects, termed immune related adverse events (irAE), ranging from mild skin rash to severe colitis. Included in that spectrum is the rare side effect of autoimmune diabetes mellitus. Despite a few case reports illustrating the incidence of autoimmune diabetes associated with immunotherapy, there has not been much mentioned about exacerbation or acceleration of hyperglycemia in non-autoimmune settings leading to de novo diagnosis of type 2 diabetes mellitus.Case presentationWe report the case of a 42 year old man with metastatic melanoma and no prior history of diabetes mellitus, who presented with diabetic ketoacidosis (DKA) after 3 cycles of combination checkpoint inhibitor therapy using nivolumab and ipilimumab. New onset diabetes mellitus was diagnosed on the basis of elevated hemoglobin A1c, in the absence of prior personal or family history. Autoimmune or type 1 diabetes mellitus was ruled out with normal levels of anti-glutamic acid decarboxylase 65 (GAD65) antibody, zinc transporter 8 (ZnT8) antibody, and islet antigen-2 (IA-2) antibody.ConclusionsThis case report highlights the importance of recognizing rare but serious adverse events related to immunotherapy and incorporation of appropriate tools for early identification and management in national cancer treatment guidelines.

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

“…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.…”

A Patient with Nivolumab-related Fulminant Type 1 Diabetes Mellitus whose Serum C-peptide Level Was Preserved at the Initial Detection of Hyperglycemia

“…Given the patient's CPR level of 5.92 ng/mL, his ability to secrete insulin appeared to be preserved at the time of his first visit, which might have caused us to overlook the onset of FT1DM. Table 3 summarizes previously published case reports on PD-1 inhibitor-related T1DM, including DKA and changes in the serum level of CPR (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Most previously reported patients had depleted insulin secretion or DKA at their initial visit; 2 patients reported by Matsumura et al and Saito et al had preserved CPR levels without DKA (20,21).…”

Combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab causing acute-onset type 1 diabetes mellitus following a single administration: two case reports

“…The most striking finding in our two cases is the remarkably short time to onset of autoimmune T1DM with severe DKA following a single infusion of a combination ICI therapy with anti-CTLA-4 and anti-PD-1. ICI-induced T1DM is specific to anti-PD-1/PD-L1 use [9–27] as PD-L1 is expressed in β-cells, and PD-1 receptor is expressed by T cells. The interaction PD-1/PD-L1 inhibits the activation of autoreactive T-cells, thereby protecting against autoimmune diabetes [28].…”

“…Injection of anti-PD-1 or anti-PD-L1 in NOD mice caused the development of diabetes with extensive destructive insulitis mediated by specific CD8 T cells [30]. In clinical settings, the occurrence of T1DM under ICI combination therapy has been rarely reported [9–11, 31]. It is characterised by an earlier onset compared to T1DM induced by single-agent anti-PD-1/PD-L1 therapy.…”