Case Report

Fulminant New Onset Autoimmune Diabetes Mellitus with Ipilimumab/Nivolumab Followed by Interferon/Atezolizumab/Bevacizumab Combined Therapies

Jelena Maletkovic
Department of Endocrinology, UCLA School of Medicine, 200 Medical Plaza Los Angeles, California-90095, USA
*Corresponding author:

Jelena Maletkovic, Department of Endocrinology, UCLA School of Medicine, 200 Medical Plaza Los Angeles, California- 90095, USA, Tel: (818) 271-2471, Email:

Management of immune related adverse events associated with immune checkpoint inhibitors therapy is a dynamic field in medicine that has been growing parallel with growing success and use of these medications [1,2]. Immune check points refer to pathways of the immune system that allow self-tolerance and modulate immune responses either by stimulating or inhibiting immune system [3]. Targeting immune check points such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has resulted in impressive improvement in treatment of multiple cancers by blocking immune-inhibitory signals and enabling patients to produce an effective antitumor response [4]. Immune checkpoint inhibitor therapies have important clinical benefits in different types of cancer including metastatic melanoma, renal carcinoma, non-small lung cancer, head and neck cancer, urothelial carcinoma and Hodgkin’s lymphoma [5,6]. Although some patients responds to single-agent blockade, combinations of checkpoint inhibitors further improve response rates [7,8]. New side effects that are acceptable, although not benign have emerged together with the use of these therapies [9-11]. It is reasonable to expect more side effects when combined therapies are used [12,13]. Endocrine autoimmune conditions of ipilimumab are recognized side effects of this medication [14]. Most common conditions were hypothyroidism (6%), hypophysitis (11%) and autoimmune adrenal insufficiency (0.3-1.5%) [6] Type 1 diabetes mellitus has rarely been found to occur with nivolumab and pembrolizumab [15]. It has been reported to appear 1 week to 12 months after starting a treatment with novolumab and up to 4 years with pembrolizumab [15,16]. In one report autoimmune diabetes mellitus was developed with combination therapy that included ipilimumab and nivolumab [17]. Same combination was also once reported to cause transformation for existing type 2 diabetes mellitus autoimmune diabetes that presented with diabetic ketoacidosis [18]. Therapeutic role of cortsicosteroids on the evolution of T1DM induced by immunotherapy has not been established [19]. Atezolizumab was approved by the FDA last year in treatment of urothelial cancer [20]. It is also known to induce several endocrinopathies, most commonly hypophysitis and thyroid dysfunction [21]. One case of atezolizumab-induced autoimmune diabetes after 5 cycles of therapy was recently published [22]. Here is a case where treatment with combination therapy ipilimumab/nivolumab followed by interferon/atezolizumab/bevacizumab induced fulminant autoimmune diabetes mellitus in a patient who presented with diabetic ketoacidosis and new-onset autoimmune hypothyroidism.

This report describes a 59 year old woman who presented to an outside center in 2014 with headaches and decreased vision in the right eye and was diagnosed with diffuse ciliochoroidal melanoma, 16 mm x 12 mm x 4.8 mm, staged as T3aN0M0. She underwent surgery with tantalum ring placement and had 4 daily fractions of 14Gy proton beam therapy, a total of 56Gy. In 2015 the patient was found to have recurrent tumor and had enucleation of the affected eye. Pathology report revealed choroidal melanoma, mixed type, basal diameter 27 mm, thickness 2 mm, no extrascleral extension, 2 mitotic figures per 40 HPF, no ciliary body involvement, macrophage infiltration present, extravascular matrix patterns present. HMB45+, MelanA+, T4aN0M0. The patient was referred to our hospital for further management. There was no evidence of metastatic disease on initial presentation with us. Six month follow-up CT scans revealed no evidence of metastatic disease. At that time there were faint ground glassmicronodules in left upper lobe that were too small to characterize. Next 3-month follow up revealed interval development of anjuxta diaphragmatic micronodule in right lower lobe (RLL) while previously noted ground glass micronodules in left upper lobe remained unchanged. RLL nodule progressed from 4x3 mm to 5x8 mm 4 months later. Right lower lobe wedge resection was performed. Surgical pathology confirmed right lower lobe metastatic melanoma of 1.1cm, with negative surgical margins for tumor. Following month postoperative CT scan of the lungs was done. It revealed interval development of innumerable pulmonary nodules, concerning for widespread pulmonary metastatic disease and pleural carcinomatosis. Also there were subtle sclerotic foci throughout the vertebral bodies and sternum, also concerning for osseous metastases. It also showed interval development of multiple hypovascular liver lesions scattered throughout the liver, most sub and pericentimeter. Prognosis was discussed with the patient. Combination treatment with ipilumumab and nivolumab was discussed. The following month Dose 1 of nivolumab 3 mg/kg and ipilimumab 1 mg/kg was given. At the same time thyroid function tests were done and showed normal TSH of 0.93mcIU/mL and Free T4 of 1.3ng/dL (reference range on this test 0.8-1.6ng/dL). Two weeks later patient complained of palpitations and was found to have suppressed TSH with <0.01mcIU/mL and Free T4 of 6.0ng/dL. Propranolol 20mg TID and methimazole 10mg TID were started. Dose 2 of nivolumab 3 mg/kg andipilimumab 1 mg/kg was given. At the visit for 3rd dose of nivolumab/ipilimumab the patient had elevated TSH with 8.0mcIU/mL and methimazole and propranolol were stopped. On the next blood test 2 weeks later the patient was even more profoundly hypothyroid and she was started on full replacement dose of levothyroxine. Thyroid peroxidase antibodies and thyroglobulin antibodies were positive with 71.5IU/mL (normal <20IU/mL) and 13.3IU/mL (normal<4IU/mL), respectively. Glucose results on fasting and non-fasting labs during treatment with ipilimumab/nivolumab ranged between 95mg/dL and 207mg/dL.

Time after starting ipilimumab/nivolumab therapy (months)



















Table 1. Glucose results on random labs after starting treatment with ipilimumab/nivolumab.

After 4 doses of therapy were given follow up CT chest/abdomen/pelvis showed progression of liver lesions. A new trial was started with interferon + atezolizumab + bevacizumab. After 15 days on this therapy random comprehensive panel showed glucose of 476mg/dL. Two days later she presented to primary care doctor after being informed about lab results and at this time the patient reported polydipsia/polyuria and fatigue. HbA1C was checked and was 7.2% and point of care glucose in the office was now 377mg/dL. Presuming immune therapy related new onset diabetes mellitus the patient was started on lantus 0.4U/kg, advised to start checking preprandial glucose at home and referred to endocrinology. On the same evening prior to starting any insulin the patient developed worsening clinical picture with abdominal pain, vomiting and was taken to an outside hospital where she was diagnosed with diabetic ketoacidosis (DKA). On admission plasma glucose was 686mg/dL. Her arterial blood gas analysis showed acidosis with pH of 7.06, pCO2 11.9mmHg, pO2 136mmHg, serum CO2 of 3mEq/L and anion gap of 34. She was also in acute renal failure with GFR of 38. The patient was treated in intensive care unit with intravenous insulin and intravenous fluids and promptly responded to treatment. After 24 hours gap was closed and she was stabilized. On the following day she was transferred from intensive care unit to medical floor for further care and soon after discharged to home. After the discharge from hospital the patient was seen with endocrinology and was found to have low C-peptide with <0.2 ng/mL (1.1-4.3 ng/mL) and low insulin levels with <1uU/mL (3-25 uU/mL ) while glucose at that time resulted 272mg/dL. She remains on basal/bolus regimen with moderately controlled glucose. Over the next 2 months the patient finished 4 cycles of interferon + atezolizumab + bevacizumab. Her post treatment CT scan shows further increase in the size of liver lesions, new lung nodules and possibly a new bone lesion.

This is a case where use of ipilimumab/nivolumab followed by interferon/atezolizumab/bevacizumab therapy induced multiple autoimmune endocrinopathies. The development of autoimmune thyroiditis occurred after the first dose ipilimumab/nivolumab therapy however autoimmune diabetes mellitus presented only after completion of this treatment and possibly additionally triggered by use of combined therapy with interferon/atezolizumab/bevacizumab in a clinical trial. The patient had relatively low HbA1C with 7.2% when glucose of 476mg/dL was recorded and that is in concordance with our assumption that elevated glucose did not last longer than just a few days. Also previous glucose records indicate that there was no significant elevation in glucose for months during ipilimumab/nivolumab therapy. Our patient’s diabetes mellitus was abrupt in onset and fulminant given the timing between normal glucose results on labs to an admission with severe DKA that occurred within two weeks. This can be explained by completely undetectable C-peptide levels and absence of any insulin secretion in this patient. In terms of her metastatic choroidal melanoma treatment she poorly responded to ipilimumab/nivolumab therapy as well as the following interferon/atezolizumab/bevacizumab and remains with significant and progressive metastatic disease and dismal prognosis.

Over the past 3 years multiple anti-PD1 antibodies including ipilimumab (Yervoy, Bristol-Myers Squibb), nivolumab (Opdivo, Bristol-Myers Squibb) and anti-PD-L1 antibody atezolizumab (Tecentriq, Genentech) have been approved in treatment of different cancers. As these therapies use receptors for inhibitory signals to T-cells increasing T-cell activity for anti-tumor immune response it is not surprising that side effects are frequently autoimmune conditions. Many endocrinopathies were described since these therapies were introduced, mostly hypophysitis, thyroiditis and autoimmune adrenal insufficiency [23]. Type 1 diabetes mellitus has rarely been reported and this was primarily in case reports [24-26]. This side effect was never reported with ipilimumab alone but only when ipilimumab was combined with either nivolumab or petrolizumab therapy in isolated case reports [27,28].

It is not clear whether autoimmune diabetes mellitus in this patient was caused only by ipilimumab/nivolumab or the following treatment with interferon/atezolizumab/bevacizumab additionally or exclusively increased activity of autoreactive T cells causing destruction of pancreatic beta cells. The use of combination immunotherapy remains controversial, because of the toxic effects. Type 1 diabetes mellitus has never been reported in this combination where ipilimumab, nivolumab and atezolizumab were used in one patient.

Cancer immunotherapy has generated impressive results in multiple malignancies refractory to standard therapies and continues to expand in treatment of variety of malignancies. The development of these medications is a dynamic and current process and this report serves the purpose to add to existing knowledge in immune related endocrinopathies. Clinicians must maintain high index of suspicion for immune related endocrinolopathies including autoimmune diabetes mellitus especially when combined therapy is used.

1. Lomax AJ, McNeil C (2017) Acute management of autoimmune toxicity in cancer patients on immunotherapy: Common toxicities and the approach for the emergency physician. Emerg Med Australas 29:245-251.
2. Bourke JM, O’Sullivan M, Khattak MA (2016) Management of adverse events related to new cancer immunotherapy (immune checkpoint inhibitors). Med J Aust 205:418-424.
3. Mahoney KM, Rennert PD, Freeman GJ (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14:561-584.
4. Mahoney KM, Freeman GJ, McDermott DF (2015) The Next Immune-Checkpoint Inhibitors: PD-1/PD- L1 Blockade in Melanoma. Clin Ther 37:764-782.
5. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252-264.
6. Ott PA, Hodi FS, Robert (2013) CTLA-4 and PD-1/PD- L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. C Clin Cancer Res 19:5300-5309.
7. Camacho LH (2015) CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Cancer Med 4:661-672.
8. La-Beck NM, Jean GW, Huynh C, Alzghari SK, Lowe DB (2015) Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy. Pharmacotherapy 35:963-976.
9. Chow LQ (2013) Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-small cell lung cancer. Am Soc Clin Oncol Educ Book.
10. Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, et al. (2017) Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev 58:70-76.
11. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M (2017) Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol 13:195-207.
12. Wu Y, Shi H, Jiang M, Qiu M, Jia K, et al. (2017) The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta-analysis of efficacy and safety. Int J Cancer.
13. Hao C, Tian J, Liu H, Li F, Niu H, et al. (2017) Efficacy and safety of anti-PD- 1 and anti-PD- 1 combined with anti-CTLA- 4 immunotherapy to advanced melanoma: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 96:e7325.
14. Joshi MN, Whitelaw BC, Palomar MT, Wu Y, Carroll PV (2016) Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review. Clin Endocrinol (Oxf) 85:331-339.
15. Chae YK, Chiec L, Mohindra N, Gentzler R, Patel J, et al. (2017) A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Cancer Immunol Immunother 66:25-32.
16. Hansen E, Sahasrabudhe D, Sievert L (2016) A case report of insulin-dependent diabetes as immune- related toxicity of pembrolizumab: presentation, management and outcome. Cancer Immunol Immunother 65:765-767.
17. Lowe JR, Perry DJ, Salama AK, Mathews CE, Moss LG, et al. (2016) Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy. J Immunother Cancer 4:89.
18. Alzenaidi AA, Dendy J, Rejjal L (2017) Autoimmune Diabetes Presented with Diabetic Ketoacidosis Induced by Immunotherapy in an Adult with Melanoma. J La State Med Soc 169: 49.
19. Aleksova J, Lau PK, Soldatos G, McArthur G (2016) Glucocorticoids did not reverse type 1 diabetes mellitus secondary to pembrolizumab in a patient with metastatic melanoma. BMJ Case Rep pii: bcr2016217454.
20. Ning YM, Suzman D, Maher VE, Zhang L, Tang S, et al. (2017) FDA Approval Summary: Atezolizumab for the Treatment of Patients with Progressive Advanced Urothelial Carcinoma after Platinum-Containing Chemotherapy. Oncologist 22:743-749.
21. Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, et al. (2017) Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev 58:70-76.
22. Hickmott L, De La Peña H, Turner H, Ahmed F, Protheroe A, et al. (2017) Anti-PD- L1 atezolizumab- Induced Autoimmune Diabetes: a Case Report and Review of the Literature. Target Oncol 12:235-241.
23. Yamauchi I, Sakane Y, Fukuda Y, Fujii T, Taura D, et al. (2017) Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study. Thyroid 27:894-901.
24. Miyoshi Y, Ogawa O, Oyama Y (2016) Nivolumab, an Anti-Programmed Cell Death-1 Antibody, Induces FulminantType1 Diabetes. Tohoku J Exp Med 239:155-158.
25. Godwin JL, Jaggi S, Sirisena I, Sharda P, Rao AD, et al. (2017) Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. J Immunother Cancer 5:40.
26. Gauci ML, Laly P, Vidal-Trecan T, Baroudjian B, Gottlieb J, et al. (2017) Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. Cancer Immunol Immunother.
27. Lowe JR, Perry DJ, Salama AK, Mathews CE, Moss LG, et al. (2016) Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy. J Immunother Cancer 4:89.
28. Humayun MA, Poole R (2016) A case of multiple immune toxicities from Ipilimumab and pembrolizumab treatment. Hormones (Athens) 15:303-306.

Citation: Maletkovic J (2017) Fulminant New Onset Autoimmune Diabetes Mellitus with Ipilimumab/Nivolumab followed by Interferon/Atezolizumab/Bevacizumab Combined Therapies. J Diabetes Care Endocrinol 1:002.

Published: 15 November 2017

Reviewed By : Dr. Baliram Annie,


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