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Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma

Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma Background: There 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 presentation: We 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. Conclusions: This 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. Keywords: Nivolumab, Ipilimumab, Dual checkpoint inhibitor therapy, Insulin-dependent diabetes mellitus and diabetic ketoacidosis Background programmed cell death-1 (PD-1) receptors, which Utilization of immunotherapy in the treatment of negatively regulate immune responses by binding to hematologic and oncologic disorders has grown their ligands programmed cell death ligands 1 and 2 exponentially over the last decade, with the number of (PD-L1 and PD-L2). Cancer cells evade the host im- diseases being treated continuing to grow. Given their mune system by expressing these ligands. Similarly wide use, many of the common adverse effects have cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) already been recognized and incorporated into the ad- is expressed by activated T cells, which acts as an immune verse events management guidelines. However, there are checkpoint and downregulates immune responses some rare immune mediated effects that remain under- against cancer cells. Immunotherapy, specifically, check- recognized and therefore pose a diagnostic challenge to point inhibitor regimens such as nivolumab (anti-PD-1 clinicians. T cells, B cells and macrophages express monoclonal antibody) and ipilimumab (anti-CTLA-4 monoclonal antibody) target these receptors, thereby allowing the host immune system to mount a response * Correspondence: shiva.mukkamalla@chartercare.org; against cancer cells. shiva.mukkamalla@gmail.com 1 Anti-PD-1 and anti-CTLA-4 agents have been linked to Division of Hematology and Oncology, Roger Williams Medical Center, Providence, RI 02908, USA several autoimmune related side effects arising from T- Boston University School of Medicine, Boston, MA, USA cell activation. The incidence of autoimmune hypophysitis © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Changizzadeh et al. Journal for ImmunoTherapy of Cancer (2017) 5:97 Page 2 of 4 induced by anti-CTLA-4 monoclonal antibodies has Table 1 Complete Metabolic Panel on presentation varied from 0 to 17% of treated melanoma patients. [1] Sodium 127 mmol/L Nivolumab, an anti- PD-1 monoclonal antibody, is known Potassium 5.7 mmol/L to cause immune mediated side effects including pneu- Chloride 88 mmol/L monitis, colitis, hepatitis, nephritis, and hypothyroidism. Bicarbonate 14 mmol/L Apart from these, there also exists the likelihood of BUN 27 mg/dL developing immune mediated new onset type 1 diabetes Creatinine 1.5 mg/dL mellitus, which has been described in mice models as well as in humans. [2] This entity remains under recognized Glucose 728 mg/dL and currently is not part of the National Comprehensive Calcium 10.8 mg/dL Cancer Network’s (NCCN) and American Society of Total Bilirubin 0.5 mg/dL Clinical Oncology’s (ASCO) guidelines on management of Alkaline Phosphatase 128 U/L immunotherapy related side effects. Only few cases of im- AST 13 U/L munotherapy related fulminant diabetes mellitus have ALT 27 U/L been reported so far. [3–5] We present a case of a patient treated with combin- Total Protein 8.9 g/dL ation checkpoint inhibitor therapy (ipilimumab and Albumin 4.5 g/dL nivolumab) for metastatic melanoma, who presented Anion Gap 25 with diabetic ketoacidosis (DKA) arising from new onset diabetes mellitus, initially thought to be auto- immune related. But, the autoimmune biomarkers returned negative pointing towards type 2 diabetes drip along with IV fluids as per DKA protocol. His blood mellitus related DKA. glucose levels subsequently improved. Hemoglobin A1c (HbA1c) level from admission was 6.5%, indicating a ra- Case presentation ther new onset diabetes mellitus. Stool studies returned A 42-year-old man with no other significant medical negative for infectious etiologies and he was started on history was diagnosed with metastatic melanoma that anti-motility agents (Imodium and Lomotil), which failed was BRAF V617F mutated, with metastasis to liver, lung to provide any relief from diarrhea. Computerized and adrenal glands. He had a past history of early stage tomography of abdomen and pelvis showed pan-colitis melanoma that was initially diagnosed eight years ago, and he was started on prednisone 1 mg/kg daily for pre- for which he underwent wide local excision with a nega- sumed immune mediated colitis. Despite steroids he tive sentinel lymph node biopsy. He did not receive any continued to have diarrhea, which were intermittently adjuvant chemo or immunotherapy. Subsequently, he bloody. He was then started on octreotide (50 mcg sub- started noticing multiple cutaneous lesions that were cutaneous injection TID, which was later increased to positive for melanoma, which led to a complete staging 100 mcg TID), with which his diarrhea was controlled. work up that revealed metastatic disease. Patient had an We had planned to start him on infliximab (a tumor excellent performance status with no known history of necrosis factor inhibitor) if he failed the octreotide trial. endocrinopathies, including diabetes mellitus. He had Subsequently, he was discharged home on an normal fasting glucose levels, which was checked by his insulin regimen for presumed new onset insulin primary care physician. He was started on first line dependentdiabetesmellitus(IDDM)and prednisone systemic immunotherapy with the combination of ipili- taper for colitis. Initially he had trouble controlling mumab and nivolumab. He completed three out of the blood glucose levels while on prednisone taper. But, four planned cycles of combined regimen, that was ad- once he was off prednisone, his IDDM was better ministered at ipilimumab 3 mg/kg IV and nivolumab controlled. One month later into follow up repeat 1 mg/kg IV every three weeks, prior to emergency room hemoglobin A1c was 7.9%, but his glucose levels were presentation. Chief complaints at this presentation much better controlled. Since no testing for auto- included intractable nausea, vomiting and diarrhea. He immune diabetes was done during his initial presenta- reported to having more than 8 loose bowel movements tion, anti-GAD65 antibody, ZnT8 antibody, and IA-2 a day, some of which were associated with blood streak- antibody testing was done during his subsequent ing. In the ER his serum glucose was elevated to clinic follow up. Anti- GAD65 antibody was <5 IU/ 728 mg/dL (Table 1) and he was in DKA with significant ml, ZnT8 antibody was <10 U/Ml, and IA-2 antibody anion gap metabolic acidosis, for which he was admitted was <0.8 U/ml, all being within normal limits. to intensive care unit for further management. He was Though DKA is more common with autoimmune or given intravenous insulin as bolus and started on insulin type 1 diabetes mellitus, it can be seen with type 2 Changizzadeh et al. Journal for ImmunoTherapy of Cancer (2017) 5:97 Page 3 of 4 diabetes mellitus. Since, patient had no evidence of initiation of immunotherapy may have exacerbated diabetes or pre-diabetes prior to immunotherapy, we underlying autoimmune diabetes, leading to DKA. Our think treatment with combined checkpoint blockade patient had no prior diagnosis or testing performed for is what led to DKA. diabetes and his autoimmune biomarkers were within normal limits. However, at presentation with DKA his Discussion and conclusions HbA1c was 6.5%. He had no prior abnormal fasting or IDDM associated with immunotherapy has been re- postprandial glucose levels, nor did he have a baseline ported with non-checkpoint inhibitor agents like high HbA1c for comparison. This patient was a fit, non-obese dose interleukin-2 (IL-2) and interferon-alpha (IFN-α). male with no other comorbidities or significant family [6, 7] New onset IDDM associated with the use of newer history of diabetes mellitus. Prior to beginning his im- immunotherapy agents such as nivolumab and pembro- munotherapy his thyroid-stimulating hormone, cortisol lizumab (checkpoint inhibitors) has been documented in and adrenocorticotrophic hormone levels were all within case reports. [4] Ipilimumab was shown to be associated normal limits. with the onset of other endocrinopathies like thyroiditis, Checkpoint inhibitor immunotherapy has proven its hypophysitis and adrenal insufficiency, but not so much mettle in improving survival in various solid malignan- in terms of new onset diabetes mellitus, especially type cies and continues to expand its territory to include 2. [1] In metastatic melanoma use of combined check- hematologic malignancies. With the ever-increasing point inhibitor therapy (nivolumab in combination with utilization of immunotherapies in the current era of can- ipilimumab) has been shown to increase overall survival. cer treatments, recognition of rare but serious adverse Though there is not much information available on inci- events like type 1 or 2 diabetes mellitus which can mani- dence of IDDM with the use of CTLA-4 inhibitors in fest as DKA, carries great importance. This requires a humans, mouse model studies have shed some light on multidisciplinary approach starting with proper patient the mechanisms involved with induction of insulitis and education prior to treatment initiation, close monitoring its progression to diabetes. [8, 9] Non-obese diabetic of appropriate biomarkers or tests with a low level of mouse model studies have suggested CD28/B7/CTLA-4 suspicion along with incorporation of appropriate tools co-stimulatory pathway to be important for induction of for early diagnosis and proper management of these ad- insulitis, whereas PD-1/PD-L1 pathway is involved with verse events in the national cancer therapy guidelines. regulation of both induction of insulitis and progression Abbreviations into autoimmune diabetes. This could have explained anti-GAD65 antibody: Anti-glutamic acid decarboxylase 65 antibody; the physiologic basis for incidence of new onset of dia- ASCO: American Society of Clinical Oncology; CD28: Cluster of differentiation 28; CTLA-4: Cytotoxic T-lymphocyte-associated protein-4; DKA: Diabetic betes in our patient, a process that is regulated by auto ketoacidosis; IA-2 antibody: Islet antigen-2 antibody; IDDM: Insulin- reactive T-cells that target and destroy pancreatic beta dependent diabetes mellitus; NCCN: National Comprehensive Cancer cells. However, subsequent negative autoimmune work Network; PD-1: Programmed cell death-1; PD-L1: Programmed cell death- ligand 1; PD-L2: Programmed cell death-ligand 2; TID: Three times a day; up indicates this being a non-autoimmune phenomenon. ZnT8 antibody : Zinc transporter 8 antibody In our review of literature, we found some case reports that demonstrated incidence of DKA starting as early as Acknowledgments Not applicable. 1 week and ranging up to 5 months after beginning treatment with nivolumab and pembrolizumab. [3, 4] Funding Our index case also falls into this time period since the No funding to disclose. patient was diagnosed with DKA about 3 months after Availability of data and materials initiation of combination checkpoint inhibitor therapy, Data sharing is not applicable to this article as no datasets were generated which led to our initial assumption that it was indeed or analyzed during the current study. IDDM. Unfortunately human leukocyte antigen (HLA) Authors’ contributions typing, anti-GAD65, IA-2 and ZnT8 antibody testing PNC: Study conception and design, acquisition of data, literature review, was not obtained as part of the initial workup, which are drafting the manuscript. SKRM: Study conception and design, literature review, drafting the manuscript. VAA: Study conception and design, drafting useful in the diagnosis of IDDM, nor did he have any the manuscript, expert supervision. All authors read and approved the final prior testing done before initiation of immunotherapy. manuscript. There was a recently published case report of Ethics approval and consent to participate autoimmune diabetes being diagnosed in the setting of Case reports exempt and did not need ethics approval. nivolumab treatment for non-small cell lung cancer. However, in that case, testing was performed on pre- Consent for publication Written informed consent was obtained from the patient for publication of treatment frozen blood samples that showed elevated their individual details and accompanying images in this manuscript. The biomarkers despite of there being no other signs or consent form is included in the patients’ chart and is available for review by symptoms of diabetes mellitus. [10] It was inferred that the Editor-in-Chief. Changizzadeh et al. Journal for ImmunoTherapy of Cancer (2017) 5:97 Page 4 of 4 Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Received: 11 July 2017 Accepted: 13 November 2017 References 1. Araujo PB, Coelho MCA, Arruda M, Gadelha MR, Neto LV. Ipilimumab- induced hypophysitis: review of the literature. J Endocrinol Investig. 2015;38: 1159–66. https://doi.org/10.1007/s40618-015-0301-z. 2. Mellati M, Eaton KD, Brooks-Worrell BM, Hagopian WA, Martins R, Palmer JP, et al. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care. 2015;38:e137–8. https://doi.org/10.2337/dc15-0889. 3. Hughes J, Vudattu N, Sznol M, Gettinger S, Kluger H, Lupsa B, et al. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care. 2015;38:e55–7. https://doi.org/10.2337/dc14-2349. 4. Araújo M, Ligeiro D, Costa L, Marques F, Trindade H, Correia JM, et al. A case of fulminant type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient. Immunotherapy. 2017;9:531–5. https://doi. org/10.2217/imt-2017-0020. 5. Okamoto M, Okamoto M, Gotoh K, Masaki T, Ozeki Y, Ando H, et al. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig. 2016;7:915–8. https://doi.org/10.1111/jdi.12531. 6. Fraenkel P, Gollob J. Induction of myasthenia gravis, myositis, and insulin- dependent diabetes mellitus by high-dose interleukin-2 in a patient with renal cell cancer. J Immunother. 2002;25:373–8. https://doi.org/10.1097/ 00002371-200207000-00009. 7. Sossau D, Kofler L, Eigentler T. Type 1 diabetes mellitus caused by treatment with low-dose interferon-α in a melanoma patient. Melanoma Res. 2017;27: 516–8. https://doi.org/10.1097/CMR.0000000000000381. 8. Ansari MJI, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, et al. The programmed Death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med. 2003;198:63–9. https://doi.org/ 10.1084/jem.20022125. 9. Weber JS, Dummer R, De Pril V, Lebbé C, Hodi FS. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119:1675–82. https://doi.org/10.1002/ cncr.27969. 10. Godwin JL, Jaggi S, Sirisena I, Sharda P, Rao AD, Mehra R, et al. Nivolumab- induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. J Immunother Cancer. 2017;5:40. https://doi.org/10.1186/s40425-017-0245-2. 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Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma

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Springer Journals
Copyright
Copyright © 2017 by The Author(s).
Subject
Medicine & Public Health; Oncology; Immunology
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2051-1426
DOI
10.1186/s40425-017-0303-9
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29254501
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Abstract

Background: There 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 presentation: We 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. Conclusions: This 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. Keywords: Nivolumab, Ipilimumab, Dual checkpoint inhibitor therapy, Insulin-dependent diabetes mellitus and diabetic ketoacidosis Background programmed cell death-1 (PD-1) receptors, which Utilization of immunotherapy in the treatment of negatively regulate immune responses by binding to hematologic and oncologic disorders has grown their ligands programmed cell death ligands 1 and 2 exponentially over the last decade, with the number of (PD-L1 and PD-L2). Cancer cells evade the host im- diseases being treated continuing to grow. Given their mune system by expressing these ligands. Similarly wide use, many of the common adverse effects have cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) already been recognized and incorporated into the ad- is expressed by activated T cells, which acts as an immune verse events management guidelines. However, there are checkpoint and downregulates immune responses some rare immune mediated effects that remain under- against cancer cells. Immunotherapy, specifically, check- recognized and therefore pose a diagnostic challenge to point inhibitor regimens such as nivolumab (anti-PD-1 clinicians. T cells, B cells and macrophages express monoclonal antibody) and ipilimumab (anti-CTLA-4 monoclonal antibody) target these receptors, thereby allowing the host immune system to mount a response * Correspondence: shiva.mukkamalla@chartercare.org; against cancer cells. shiva.mukkamalla@gmail.com 1 Anti-PD-1 and anti-CTLA-4 agents have been linked to Division of Hematology and Oncology, Roger Williams Medical Center, Providence, RI 02908, USA several autoimmune related side effects arising from T- Boston University School of Medicine, Boston, MA, USA cell activation. The incidence of autoimmune hypophysitis © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Changizzadeh et al. Journal for ImmunoTherapy of Cancer (2017) 5:97 Page 2 of 4 induced by anti-CTLA-4 monoclonal antibodies has Table 1 Complete Metabolic Panel on presentation varied from 0 to 17% of treated melanoma patients. [1] Sodium 127 mmol/L Nivolumab, an anti- PD-1 monoclonal antibody, is known Potassium 5.7 mmol/L to cause immune mediated side effects including pneu- Chloride 88 mmol/L monitis, colitis, hepatitis, nephritis, and hypothyroidism. Bicarbonate 14 mmol/L Apart from these, there also exists the likelihood of BUN 27 mg/dL developing immune mediated new onset type 1 diabetes Creatinine 1.5 mg/dL mellitus, which has been described in mice models as well as in humans. [2] This entity remains under recognized Glucose 728 mg/dL and currently is not part of the National Comprehensive Calcium 10.8 mg/dL Cancer Network’s (NCCN) and American Society of Total Bilirubin 0.5 mg/dL Clinical Oncology’s (ASCO) guidelines on management of Alkaline Phosphatase 128 U/L immunotherapy related side effects. Only few cases of im- AST 13 U/L munotherapy related fulminant diabetes mellitus have ALT 27 U/L been reported so far. [3–5] We present a case of a patient treated with combin- Total Protein 8.9 g/dL ation checkpoint inhibitor therapy (ipilimumab and Albumin 4.5 g/dL nivolumab) for metastatic melanoma, who presented Anion Gap 25 with diabetic ketoacidosis (DKA) arising from new onset diabetes mellitus, initially thought to be auto- immune related. But, the autoimmune biomarkers returned negative pointing towards type 2 diabetes drip along with IV fluids as per DKA protocol. His blood mellitus related DKA. glucose levels subsequently improved. Hemoglobin A1c (HbA1c) level from admission was 6.5%, indicating a ra- Case presentation ther new onset diabetes mellitus. Stool studies returned A 42-year-old man with no other significant medical negative for infectious etiologies and he was started on history was diagnosed with metastatic melanoma that anti-motility agents (Imodium and Lomotil), which failed was BRAF V617F mutated, with metastasis to liver, lung to provide any relief from diarrhea. Computerized and adrenal glands. He had a past history of early stage tomography of abdomen and pelvis showed pan-colitis melanoma that was initially diagnosed eight years ago, and he was started on prednisone 1 mg/kg daily for pre- for which he underwent wide local excision with a nega- sumed immune mediated colitis. Despite steroids he tive sentinel lymph node biopsy. He did not receive any continued to have diarrhea, which were intermittently adjuvant chemo or immunotherapy. Subsequently, he bloody. He was then started on octreotide (50 mcg sub- started noticing multiple cutaneous lesions that were cutaneous injection TID, which was later increased to positive for melanoma, which led to a complete staging 100 mcg TID), with which his diarrhea was controlled. work up that revealed metastatic disease. Patient had an We had planned to start him on infliximab (a tumor excellent performance status with no known history of necrosis factor inhibitor) if he failed the octreotide trial. endocrinopathies, including diabetes mellitus. He had Subsequently, he was discharged home on an normal fasting glucose levels, which was checked by his insulin regimen for presumed new onset insulin primary care physician. He was started on first line dependentdiabetesmellitus(IDDM)and prednisone systemic immunotherapy with the combination of ipili- taper for colitis. Initially he had trouble controlling mumab and nivolumab. He completed three out of the blood glucose levels while on prednisone taper. But, four planned cycles of combined regimen, that was ad- once he was off prednisone, his IDDM was better ministered at ipilimumab 3 mg/kg IV and nivolumab controlled. One month later into follow up repeat 1 mg/kg IV every three weeks, prior to emergency room hemoglobin A1c was 7.9%, but his glucose levels were presentation. Chief complaints at this presentation much better controlled. Since no testing for auto- included intractable nausea, vomiting and diarrhea. He immune diabetes was done during his initial presenta- reported to having more than 8 loose bowel movements tion, anti-GAD65 antibody, ZnT8 antibody, and IA-2 a day, some of which were associated with blood streak- antibody testing was done during his subsequent ing. In the ER his serum glucose was elevated to clinic follow up. Anti- GAD65 antibody was <5 IU/ 728 mg/dL (Table 1) and he was in DKA with significant ml, ZnT8 antibody was <10 U/Ml, and IA-2 antibody anion gap metabolic acidosis, for which he was admitted was <0.8 U/ml, all being within normal limits. to intensive care unit for further management. He was Though DKA is more common with autoimmune or given intravenous insulin as bolus and started on insulin type 1 diabetes mellitus, it can be seen with type 2 Changizzadeh et al. Journal for ImmunoTherapy of Cancer (2017) 5:97 Page 3 of 4 diabetes mellitus. Since, patient had no evidence of initiation of immunotherapy may have exacerbated diabetes or pre-diabetes prior to immunotherapy, we underlying autoimmune diabetes, leading to DKA. Our think treatment with combined checkpoint blockade patient had no prior diagnosis or testing performed for is what led to DKA. diabetes and his autoimmune biomarkers were within normal limits. However, at presentation with DKA his Discussion and conclusions HbA1c was 6.5%. He had no prior abnormal fasting or IDDM associated with immunotherapy has been re- postprandial glucose levels, nor did he have a baseline ported with non-checkpoint inhibitor agents like high HbA1c for comparison. This patient was a fit, non-obese dose interleukin-2 (IL-2) and interferon-alpha (IFN-α). male with no other comorbidities or significant family [6, 7] New onset IDDM associated with the use of newer history of diabetes mellitus. Prior to beginning his im- immunotherapy agents such as nivolumab and pembro- munotherapy his thyroid-stimulating hormone, cortisol lizumab (checkpoint inhibitors) has been documented in and adrenocorticotrophic hormone levels were all within case reports. [4] Ipilimumab was shown to be associated normal limits. with the onset of other endocrinopathies like thyroiditis, Checkpoint inhibitor immunotherapy has proven its hypophysitis and adrenal insufficiency, but not so much mettle in improving survival in various solid malignan- in terms of new onset diabetes mellitus, especially type cies and continues to expand its territory to include 2. [1] In metastatic melanoma use of combined check- hematologic malignancies. With the ever-increasing point inhibitor therapy (nivolumab in combination with utilization of immunotherapies in the current era of can- ipilimumab) has been shown to increase overall survival. cer treatments, recognition of rare but serious adverse Though there is not much information available on inci- events like type 1 or 2 diabetes mellitus which can mani- dence of IDDM with the use of CTLA-4 inhibitors in fest as DKA, carries great importance. This requires a humans, mouse model studies have shed some light on multidisciplinary approach starting with proper patient the mechanisms involved with induction of insulitis and education prior to treatment initiation, close monitoring its progression to diabetes. [8, 9] Non-obese diabetic of appropriate biomarkers or tests with a low level of mouse model studies have suggested CD28/B7/CTLA-4 suspicion along with incorporation of appropriate tools co-stimulatory pathway to be important for induction of for early diagnosis and proper management of these ad- insulitis, whereas PD-1/PD-L1 pathway is involved with verse events in the national cancer therapy guidelines. regulation of both induction of insulitis and progression Abbreviations into autoimmune diabetes. This could have explained anti-GAD65 antibody: Anti-glutamic acid decarboxylase 65 antibody; the physiologic basis for incidence of new onset of dia- ASCO: American Society of Clinical Oncology; CD28: Cluster of differentiation 28; CTLA-4: Cytotoxic T-lymphocyte-associated protein-4; DKA: Diabetic betes in our patient, a process that is regulated by auto ketoacidosis; IA-2 antibody: Islet antigen-2 antibody; IDDM: Insulin- reactive T-cells that target and destroy pancreatic beta dependent diabetes mellitus; NCCN: National Comprehensive Cancer cells. However, subsequent negative autoimmune work Network; PD-1: Programmed cell death-1; PD-L1: Programmed cell death- ligand 1; PD-L2: Programmed cell death-ligand 2; TID: Three times a day; up indicates this being a non-autoimmune phenomenon. ZnT8 antibody : Zinc transporter 8 antibody In our review of literature, we found some case reports that demonstrated incidence of DKA starting as early as Acknowledgments Not applicable. 1 week and ranging up to 5 months after beginning treatment with nivolumab and pembrolizumab. [3, 4] Funding Our index case also falls into this time period since the No funding to disclose. patient was diagnosed with DKA about 3 months after Availability of data and materials initiation of combination checkpoint inhibitor therapy, Data sharing is not applicable to this article as no datasets were generated which led to our initial assumption that it was indeed or analyzed during the current study. IDDM. Unfortunately human leukocyte antigen (HLA) Authors’ contributions typing, anti-GAD65, IA-2 and ZnT8 antibody testing PNC: Study conception and design, acquisition of data, literature review, was not obtained as part of the initial workup, which are drafting the manuscript. SKRM: Study conception and design, literature review, drafting the manuscript. VAA: Study conception and design, drafting useful in the diagnosis of IDDM, nor did he have any the manuscript, expert supervision. All authors read and approved the final prior testing done before initiation of immunotherapy. manuscript. There was a recently published case report of Ethics approval and consent to participate autoimmune diabetes being diagnosed in the setting of Case reports exempt and did not need ethics approval. nivolumab treatment for non-small cell lung cancer. However, in that case, testing was performed on pre- Consent for publication Written informed consent was obtained from the patient for publication of treatment frozen blood samples that showed elevated their individual details and accompanying images in this manuscript. The biomarkers despite of there being no other signs or consent form is included in the patients’ chart and is available for review by symptoms of diabetes mellitus. [10] It was inferred that the Editor-in-Chief. Changizzadeh et al. Journal for ImmunoTherapy of Cancer (2017) 5:97 Page 4 of 4 Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Received: 11 July 2017 Accepted: 13 November 2017 References 1. Araujo PB, Coelho MCA, Arruda M, Gadelha MR, Neto LV. Ipilimumab- induced hypophysitis: review of the literature. J Endocrinol Investig. 2015;38: 1159–66. https://doi.org/10.1007/s40618-015-0301-z. 2. Mellati M, Eaton KD, Brooks-Worrell BM, Hagopian WA, Martins R, Palmer JP, et al. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care. 2015;38:e137–8. https://doi.org/10.2337/dc15-0889. 3. Hughes J, Vudattu N, Sznol M, Gettinger S, Kluger H, Lupsa B, et al. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care. 2015;38:e55–7. https://doi.org/10.2337/dc14-2349. 4. Araújo M, Ligeiro D, Costa L, Marques F, Trindade H, Correia JM, et al. A case of fulminant type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient. Immunotherapy. 2017;9:531–5. https://doi. org/10.2217/imt-2017-0020. 5. Okamoto M, Okamoto M, Gotoh K, Masaki T, Ozeki Y, Ando H, et al. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig. 2016;7:915–8. https://doi.org/10.1111/jdi.12531. 6. Fraenkel P, Gollob J. Induction of myasthenia gravis, myositis, and insulin- dependent diabetes mellitus by high-dose interleukin-2 in a patient with renal cell cancer. J Immunother. 2002;25:373–8. https://doi.org/10.1097/ 00002371-200207000-00009. 7. Sossau D, Kofler L, Eigentler T. 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Journal for ImmunoTherapy of Cancer – Springer Journals

Published: Dec 19, 2017

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