SAT-LB112 An Unusual Case of Ipilimumab/Nivolumab Induced Fulminant Diabetic Ketoacidosis (DKA) in a Non Diabetic Patient - a Case Report
Authors: Abdelmasih Randa , Abdelmaseih Ramy , Patel Jay , Monsour Elio Paul , Abusaada Khalid 
Published: May 2020

Abstract
INTRODUCTION
Immune Checkpoint Inhibitors (ICIs) have become a revolutionary milestone in the immune-oncology field and have shown a significant improvement in survival rates and outcomes of advanced malignancies. ICIs including: Ipilimumab (1) - monoclonal antibody that inhibits Cytotoxic T Lymphocyte associated Antigen 4 (CTLA4) - Nivolumab (2) - monoclonal antibody that blocks Programmed Cell Death Ligand 1 (PDL1) - and others turn off the tumor mediated immune system inhibition and boost the immune response against tumor cells resulting in decreased tumor growth. However, targeted immunotherapy has a wide spectrum of immune related side effects (3) that can affect various body organs ranging from mild skin rash to a critical immunotherapy induced pneumonitis and severe colitis. We present a case report of Ipilimumab/Nivolumab induced fulminant DKA in a non-diabetic patient.
CASE PRESENTATION
We present a case of a 71 year old male with a history of hypertension, hyperlipidemia, hemorrhagic stroke and stage 4 renal cancer with metastasis to the lungs who presented to the Emergency Department with altered mental status for 1 day and respiratory depression. He was accompanied by his wife who provided most of the history and denied any head trauma, seizure, uncontrolled hypertension, recent infections, arrhythmias, endocrine diseases or alcohol/drug use. Initial blood glucose was 1052, pH 7.11, bicarbonate 6, potassium 6.7, CO2 20.1, anion gap of 29 and WBCs 19.3 without any source of infections. Diabetic ketoacidosis (DKA) protocol was started and patient was intubated for worsening respiratory depression. Patient’s wife denied any personal or family history of diabetes mellitus and stated that his Hemoglobin A1c (HbA1c) has always been below 6% during his follow ups. Upon further questioning about any new medications, she stated that 15 years ago he had renal cell carcinoma treated with left radical nephrectomy and was recently discovered to have pulmonary nodules that were biopsy positive for renal cell carcinoma, to which he recently started Ipilimumab and Nivolumab immunotherapy about 2 month and last received doses was 3 days prior to presentation. She also reported one-month history of lethargy, polyuria and polydipsia. HbA1c was found to be 8.0% and lipase enzyme &gt; 4000 u/L without any pancreatic changes or inflammation on Computed Tomography (CT) scan of the abdomen. Insulin autoantibodies, islet cells antibodies and serum C-peptide were undetectable. During the admission DKA and respiratory depression resolved but the patient continued to have hyperglycemia with blood glucose level of 300-400 and was treated with correctional insulin scale. Patient was discharged on long acting and regular insulin after appropriate education.
DISCUSSION
Ipilimumab and Nivolumab; the novel revolutionary targeted immunotherapy have been approved by the United States Food and Drug Administration in 2011 (4) and 2014 (5) respectively. They enhance the immune response against tumor cells through blocking the immune checkpoints CTLA4 and PDL1 which are activated by the tumor cells as an inhibitory mechanism to interrupt the T lymphocyte - tumor cell destruction pathway (6-7).
Ipilimumab and Nivolumab are used in combination for inoperable or metastatic melanoma (8-9), advanced renal cell carcinoma (10), metastatic squamous non-small cell lung cancer (11) and currently in trials for recurrent small cell lung cancer treatment (12-13). They are also used for primary or metastatic urothelial carcinoma and prostate cancer (14).
As ICIs enhance T lymphocytes immunity by disrupting the inhibitory signaling, they also decrease immune tolerance and, thereby; cause autoimmune toxicities. Yet, ICIs are usually not stopped since their beneficial outcomes seem to outweigh the adverse events. Immunotherapy related adverse events (irAEs) includes: systemic symptoms of fatigue, weakness, muscle and joint pain, dermatological: rash and itchy skin - reported in 10% of patients in trials for melanoma and lung cancer (15) - pneumonitis (16) (4%), gastrointestinal: decreased appetite, abdominal pain, nausea and vomiting, colitis (17) (10%), hepatic toxicity (18) (1-17%), and endocrinopathies: hypothyroidism and hyperthyroidism (19) (8.5% and 3.7% respectively). Severe neurologic disorders including acute demyelination polyneuropathy, ascending motor paralysis and myasthenia gravis have been reported (20). Although there are no guidelines for managing irEAs, most of them are managed with high-dose corticosteroids.
Several cases of autoimmune diabetes mellitus have been reported (2% of cases) as endocrinologic irEAs, most of them were genetically susceptible to type 1 diabetes mellitus. Less than 1% of cases had diabetes mellitus of rapid onset and complete insulin insufficiency leading to fulminant DKA (19). However, the clinical course of their insulin secretion disruption was not well studied.
To our knowledge, the case that we are presenting here is one of a few cases described in literature of fulminant diabetes/DKA caused by immunotherapy. In fulminant diabetes, patients present with severely elevated blood glucose or DKA; however, their HbA1c is unexpectedly low (7-8%) due to the abrupt onset of presentation. C-peptide and Islet cell autoantibodies levels are low or even undetectable which suggest that pancreatic B-cells are totally destroyed via a process that is not completely understood and not similar to the one causing classic autoimmune type 1 diabetes mellitus. In fulminant diabetes/DKA pancreatic islet cells are attacked by autoreactive T lymphocytes. Thiswas initially thought to be a cell-mediated phenomenon; however, some reported cases had 1 or more islet cell autoantibodies which suggests the implication of a humoral immune response component as well. Diagnosis of such an endocrinopathy should be proper and prompt due to the increased risk of death within the first 24 hours.
CONCLUSION
Identification of rare but serious irAEs like DKA, is very important. This requires a multi-dimensional approach involving effective education about the symptoms of DKA and hyperglycemia in patients receiving immunotherapy along with close monitoring of these patients. More research is needed in this area to clarify the frequency of this entity and its mechanism.
DISCLAIMER
This research was supported (in whole or in part) by HCA Healthcare and/or HCA Healthcare affiliated entity. The views expressed in this publication represent those of author(s) and do not necessarily the official views if HCA Healthcare or any of its affiliated entities.
REFRENCES
1-Tarhini A., Lo E., Minor D.R. Releasing the brake on the immune system: Ipilimumab in melanoma and other tumors. Cancer Biother. Radiopharm. 2010;25:601-613. doi: 10.1089/cbr.2010.0865.
2-Guo L, Zhang H, Chen B. Nivolumab as programmed death-1 (PD-1) inhibitor for targeted immunotherapy in tumor. J Cancer. 2017;8(3):410-416. doi: 10.7150/jca.17144.
3-Kadono T. Immune-related adverse events by immune checkpoint inhibitors. Nihon Rinsho Meneki Gakkai Kaishi. (2017) 40:83-9. 10.2177/jsci.40.83
4-Lacroix, Marc (2014). Targeted Therapies in Cancer. Hauppauge, NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7.
5-“Nivolumab Monograph for Professionals”. Drugs.com. Retrieved 14 November 2019.
6-Rotte, A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res 38, 255 (2019) doi:10.1186/s13046-019-1259-z
7-Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. (2018) 8:86. 10.3389/fonc.2018.00086
8-Johnson DB, Peng C, Sosman JA (March 2015). “Nivolumab in melanoma: latest evidence and clinical potential”. Therapeutic Advances in Medical Oncology. 7 (2): 97-106
9-Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (December 2017). “De-novo and acquired resistance to immune checkpoint targeting”. The Lancet Oncology. 18 (12): e731-e741.
10-Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab vs. sunitinib in first-line treatment for advanced renal cell carcinoma: Extended followup of efficacy and safety results from a randomized, controlled, phase 3 trial. Lancet Oncol. 2019 Aug 16;
11-Sundar R, Cho BC, Brahmer JR, Soo RA (March 2015). “Nivolumab in NSCLC: latest evidence and clinical potential”. Therapeutic Advances in Medical Oncology. 7 (2): 85-96
12-S.J. Antonia, J.A. Lopez-Martin, J. Bendell, P.A. Ott, M. Taylor, J.P. Eder, et al.Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial, Lancet Oncol., 17 (2016), pp. 883-895
13-Clinical trial number NCT00527735 at ClinicalTrials.gov Phase II Study for Previously Untreated Subjects With Non Small Cell Lung Cancer (NSCLC) or Small Cell Lung Cancer (SCLC)
14-“Impact of gemcitabine + cisplatin + ipilimumab on circulating immune cells in patients (pts) with metastatic urothelial cancer (mUC). - 2015 ASCO Annual Meeting - Abstracts - Meeting Library”
15-Nivolumab Label. Last updated November 2015.
16-Tay, Rebecca Y. et al., Checkpoint Inhibitor Pneumonitis — Real-World Incidence and Risk, Journal of Thoracic Oncology, Volume 13, Issue 12, 1812 - 1814
17-Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, Mattar MC. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J Clin Cases. 2019;7(4):405-418. doi: 10.12998/wjcc.v7.i4.405.
18-Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373: 23-34.
19-de Filette J, Andreescu CE, Cools F, Bravenboer B, Velkeniers B (March 2019). “A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors”. Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme. 51(3): 145-156. doi:10.1055/a-0843-3366. PMID 30861560
20-“Two Cases of Myasthenia Gravis Seen With Ipilimumab”. 2014-04-29.
21-Godwin, J.L., Jaggi, S., Sirisena, I. et al. Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. j. immunotherapy cancer 5, 40 (2017) doi:10.1186/s40425-017-0245-2
22-Gaudy C., Clévy C., Monestier S., et al. Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care. 2015;38(11):e182-e183. doi: 10.2337/dc15-1331.