Published online Nov 24, 2023. doi: 10.5306/wjco.v14.i11.535
Peer-review started: July 13, 2023
First decision: September 26, 2023
Revised: October 13, 2023
Accepted: October 30, 2023
Article in press: October 30, 2023
Published online: November 24, 2023
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Immunotherapy, specifically the use of checkpoint inhibitors such as pembrolizumab, has become an important tool in personalized cancer therapy. These inhibitors target proteins on T-cells that regulate the immune response against tumor cells. Pembrolizumab, which targets the programmed cell death 1 receptor on T-cells, has been approved for the treatment of metastatic melanoma and non-small cell lung cancer. However, it can also lead to immune-related side effects, including pneumonitis, colitis, thyroid abnormalities, and rare cases of type 1 diabetes.
The case presented involves an adult patient in 30s with breast cancer who developed hyperglycemia after receiving pembrolizumab treatment. The patient was diagnosed with diabetic ketoacidosis and further investigations were performed to evaluate for new-onset type 1 diabetes. The patient had a history of hypothyroidism and a family history of breast cancer. Treatment for diabetic ketoacidosis was initiated, and the patient was discharged for close follow-up with an endocrinologist.
This literature review highlights the occurrence of diabetic ketoacidosis and new-onset type 1 diabetes in patients receiving pembrolizumab treatment for different types of cancer. Overall, the article emphasizes the therapeutic benefits of immunotherapy in cancer treatment, particularly pembrolizumab, while also highlighting the potential side effect of immune-related diabetes that can occur in a small percentage of patients. Here we present a case where pembrolizumab lead to development of diabetes after a few cycles highlighting one of the rare yet a serious toxicity of the drug.
Core Tip: Our review highlights an important and rare adverse effect of Pembrolizumab. We have also reviewed the number of cycles patients were treated with Keytruda before the onset of diabetes. Clinicians should be watchful for the signs and symptoms. Early discontinuation of immunotherapy is needed to prevent significant morbidity and mortality.
- Citation: Bhanderi H, Khalid F, Bodla ZH, Muhammad T, Du D, Meghal T. Autoimmune diabetes from pembrolizumab: A case report and review of literature. World J Clin Oncol 2023; 14(11): 535-543
- URL: https://www.wjgnet.com/2218-4333/full/v14/i11/535.htm
- DOI: https://dx.doi.org/10.5306/wjco.v14.i11.535
Immunotherapy has become an essential tool in the treatment of cancers and represents therapeutic advancement in the individualized cancer therapy[1]. The role of immunotherapy is based on the ability to recognize abnormal tissue and enhance body’s immune system against tumor cells. Immune system has both stimulators and inhibitors for the immune response generation in order to maintain balance and avoid auto-immune response to self antigens by means of positive selection of T cells. But sometimes this positive selection leads to lack of required immune response against tumor cells, which leads to tumor growth[2]. There are multiple check-points in cell production have been identified like T cell immunoglobulin and mucin-domain containing-3, T cell immunoglobulin and ITIM domain, lymphocyte activation gene-3, indoleamine 2, 3-dioxygenase 1, and V-domain immunoglobulin suppressor of T cell activation, but to date only United States Food and Drug Administration (FDA) approved check-point inhibitors are those which targets cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death protein-ligand 1 (PD-L1)[3]. The mechanism behind is the inhibition of check point inhibitors namely CTLA-4, PD-1, or PD-L1 which results in the increased anti-tumor immune response. These check point inhibitors are expressed on T-cells and their activation leads to the decreased T-cell proliferation from inhibition of T-cell receptor mediated signaling, reduced cytokines secretion limiting inflammatory response and autoimmunity[4]. The immune check point inhibitors are the monoclonal antibodies directed against the above mentioned ligands which results in the immune activation against the tumor cells[5]. Pembrolizumab is a monoclonal antibody designed against check point inhibitor PD-1 receptor on surface of T-cells resulting in the proliferation of T-cells and enhanced intrinsic immune mediated anticancer activity[6]. PD-1 receptor is a cell surface protein expressed on activated T cells which on binding with the ligands PD-L1 and PD-L2 leads to the inhibition of kinase signaling pathways causing suppression of T-cell[7]. Pembrolizumab was originally approved by FDA for metastatic melanoma in 2014 and for non-small cell lung cancer in 2014[1]. Since then it has been widely used in the treatment of different cancers especially those with resistance to first line therapies. Excessive immune activation has been a frequent and serious side effect of the immune therapies. Most common adverse effects reported from the clinical trials are pneumonitis, colitis, thyroid abnormalities, liver and kidney issues[8]. Type 1 diabetes was only reported in 0.1% of the patients in the clinical trials making this rare but significant side effect of the treatment[1]. Here we present a case of a young female who presented with hyperglycemia after getting treatment with the pembrolizumab for the breast cancer.
Nausea, Vomiting and Hyperglycemia at outpatient chemotherapy infusion center.
The patient presented to the emergency department for the evaluation of hyperglycemia, which was found at the infusion center during 4th cycle. The patient complained of nausea, vomiting which was non-bilious and non-bloody associated with dizziness. The patient denied any fever, shortness of breath, chest pain, abdominal pain or loss of consciousness, recent weight loss, travel history, constipation or diarrhea.
Hypothyroidism and triple negative left invasive mammary breast carcinoma with Ki 67%-90% diagnosed an year ago which was at anatomical stage 2A/Clinical prognostic stage 2B status post chemotherapy with carboplatin and Paclitaxel along with 3 cycles of Pembrolizumab.
The patient social history was significant for 2-3 cigarettes a day before getting diagnosed with breast cancer and occasional alcohol consumption and marijuana consumption. The family history was significant for breast cancer in mother and sister.
Physical examination was unremarkable.
The initial blood work up revealed Hemoglobin level of 12.8 g/dL, white cell count of 4.7 K/CMM, Hematocrits of 37.2% and platelet count of 332 K/CMM. Complete metabolic panel was significant for sodium level of 133 mEq/L, Bicarbonate level of < 10 mEq/L with anion gap of > 19 mEq/L, blood glucose level of 343 mg/dL. Liver and Kidney functions were benign. Beta hydroxy butyrate level was found to be elevated > 46.8 mg/dL. Urinalysis was positive for glucose and ketones. Amylase and lipase level were within normal limits. Arterial blood gas analysis showed pH of 7.13 with pCO2 of 23 mmHg, pO2 of 65 mmHg, and bicarbonate level of 8 mmol/L. HbA1c level was found to be 6.8. During hospitalization, work up for the new onset type 1 diabetes mellitus (T1DM) was done. IA-2 antibody, Insulin antibody, glutamic acid decarboxylase antibody was negative. C-peptide level was found to be low at 0.24. Cortisol and Thyroid stimulating hormone level was within normal limits. So, involvements of other endocrine abnormalities were ruled out.
No imaging studies were done.
Endocrinologist was consulted because of labile glucose level and to optimize insulin regimen on discharge.
Diabetic ketoacidosis.
Intensive care unit was consulted and the patient was managed as per protocol for diabetic ketoacidosis.
Patient was discharged for the close follow up with endocrinologist. Pembrolizumab was stopped and the chemotherapy was continued.
Our literature review mentions the prior studies highlighting the effects of pembrolizumab leading to autoimmune diabetes. The mean number of cycles was 4 and the mean number of weeks leading to presentation after the start of treatment was 15.4. The mean HbA1c of the patients was 7.97. Below mentioned are the baseline characteristics of the patients along with the disease presentation (Tables 1 and 2)[9-56].
Ref. | No. of patients | Age/Sex | Type of cancer | Time from first administration (wk) | No. of cycle |
de Filette et al[9], 2019 | 61/M | NSCLC | 8 | 2 | |
de Filette et al[9], 2019 | 91 | 65 | Melanoma/NSCLC | 4.5 | |
Clotman et al[10], 2018 | 73/F | Melanoma | 8 | 2 | |
Clotman et al[10], 2018 | 14 | 63 | 6 | 3 | |
Farina et al[11], 2019 | 10 | 62 | Melanoma/Lung cancer | 5 | |
Kyriacou et al[12], 2020 | 68/F | Lung cancer | 7 | 2 | |
Banatwalla et al[13], 2021 | 83/F | Melanoma | 23 | 7 | |
Hernandez et al[14], 2021 | 67/M | SCC tongue | 3 | 1 | |
Bansal et al[15], 2022 | 85/F | Lung adeno | 9 | 3 | |
Kedzior et al[16], 2021 | 51/F | Lung adeno | 8 | 2 | |
Cunha et al[17], 2022 | 59/F | Lung adeno | 3 | 1 | |
Kähler et al[18], 2020 | 5 | 74-85, 3F and 2M | Melanoma | 4 | |
Tohi et al[19], 2019 | 75/M | Urothelial CA | 10 | 3 | |
Edahiro et al[20], 2019 | 61/F | Lung adeno | 25 | 8 | |
Magis et al[21], 2018 | 41/F | Melanoma | 57 | 19 | |
Samoa et al[22], 2020 | 12/M | Hodgkin's lymphoma | 15 | 5 | |
Li et al[23], 2018 | 67/M | NSCLC | 10 | 3 | |
Boyle et al[24], 2019 | 56/M | Melanoma | 22 months | ||
Boyle et al[24], 2019 | 74/F | Merkel cell cancer | 23 | 7 | |
Sankar et al[25], 2021 | 85/F | Bladder CA | 9 months | ||
Hakami et al[26], 2019 | 52/M | Melanoma | 21 | 7 | |
Chaudry et al[27], 2020 | 75/M | NSCLC | 12 | 4 | |
Kotwal et al[28], 2019 | 11 | 61 | 4 | ||
Zand et al[29], 2022 | 81/F | Melanoma | 26 | 8 | |
Maamari et al[30], 2019 | 47/F | Cardiac angiosarcoma | 6 | 1 | |
Alrifai et al[31], 2019 | 69/M | NSCLC | 15 | 4 | |
Hong et al[32], 2020 | 76/M | Lung | 11 | 3 | |
Hong et al[32], 2020 | 78/F | Melanoma | 4 | 1 | |
Hong et al[32], 2020 | 65/F | Biliary CA | 21 | 7 | |
Skorpen et al[33], 2019 | 60s/M | Lung adeno | 8 | 2 | |
Martin-Liberal et al[34], 2015 | 54/F | Melanoma | 9 | 3 | |
Gaudy et al[35], 2015 | 44/F | Melanoma | 8 | 2 | |
Aleksova et al[36], 2016 | 61/M | Melanoma | 6 | 1 | |
M A et al[37], 2016 | 55/M | Melanoma | 27 | 9 | |
Hansen et al[38], 2016 | 58/M | Melanoma | 17 | ||
Alhusseini et al[39], 2017 | 65/M | Lung adenocarcinoma | 3 | 1 | |
F A et al[40], 2017 | 48/F | Melanoma | 2 | 1 | |
Tay et al[41], 2017 | 74/F | Melanoma | 3 | 1 | |
Chae et al[42], 2017 | 76/M | Lung adenocarcinoma | 1 | 1 | |
Smith-Cohn et al[43], 2017 | 61/F | Cholangiocarcinoma | 18 | 6 | |
C M et al[44], 2017 | 58/M | Melanoma | 4 | ||
Abayev et al[45], 2018 | 71/M | Melanoma | 26 | ||
Ioana et al[46], 2018 | 52/M | Melanoma | 13 | ||
Kalkan et al[47], 2018 | 73/F | NSCLC | 9 | 3 | |
Reslan et al[48], 2018 | 79/M | Melanoma | 24 | 5 | |
Fernandez et al[49], 2019 | 15/M | Soft tissue sarcoma | 2 | 1 | |
Sfeir et al[50], 2019 | 90/M | Melanoma | |||
Talib et al[51], 2019 | 67/F | Esophageal squamous cell CA | 8 | 2 | |
Gunjur et al[52], 2019 | 77/F | Melanoma | 3 Days | 1 | |
Singh et al[53], 2019 | 70/M | Melanoma | 10 | 3 | |
Akopyan et al[54], 2020 | 66/F | Urothelial CA | 6 months | ||
Zagouras et al[55], 2020 | 52/M | Lung adenocarcinoma | 9 | 3 | |
Kethireddy et al[56], 2021 | 85/M | 9 | 3 |
Ref. | Presentation | HbA1C | C-peptide | Auto Ab | Outcome |
de Filette et al[9] | DKA | 0.02 nmol/L | GADA | Not known | |
de Filette et al[9] | 71% DKA | 7.6 | Low in 84% | 51% GADA 18% IA213% ICA26% Anti-Insulin | Not known |
Clotman et al[10] | DKA | 7.1 | Low | GADA, ICA | Stayed on insulin |
Clotman et al[10] | 70% DKA | 7.5 | Low in 93% | 56% GADA | |
Farina et al[11] | 69% DKA | 7.76 | 0.1 | 50% GADA+ | 97% remained on Insulin therapy |
Kyriacou et al[12] | DKA | 7 | Low | GADA+ | Stayed on insulin |
Banatwalla et al[13] | DKA | 8.2 | 0.09 | All neg | Stayed on insulin |
Hernandez et al[14] | DKA | 6.9 | Stayed on insulin | ||
Bansal et al[15] | HHS | 8.3 | Normal | GADA + | Stayed on insulin |
Kedzior et al[16] | DKA | 8.3 | Undetected | GADA+ | |
Cunha et al[17] | DKA | 5.6 | Undetected | GADA+ | Stayed on insulin |
Kähler et al[18] | DKA | 9.7, 6.5, 7.5, No data for other 2 | Low in 1 | GADA+ in 2 | |
Tohi et al[19] | DKA | 6.7 | Undetected | GADA negative | Stayed on insulin |
Edahiro et al[20] | DKA | 8.4 | Low | GADA negative | Stayed on insuline |
Magis et al[21] | DKA | 6.8 | < 0.003 | GADA negative,IA-2 Positive | Stayed on insulin |
Samoa et al[22] | DKA | 8.9, Intial was 6.0 | Low | GADA negative,IA-2 PositiveIA Positive | Stayed on insulin |
Li et al[23] | DKA | 8 | Low | All ab negative | Stayed on insuline |
Boyle et al[24] | DKA | 7.4 | Low | All ab negative | Stayed on insulin |
Boyle et al[24] | DKA | Low | All ab negative | ||
Sankar et al[25] | DKA | 6.8 | All ab negative | Stayed on insulin | |
Hakami et al[26] | DKA | 8.3 | < 0.001 | All ab negative | Stayed on insulin |
Chaudry et al[27] | DKA | GADA + | Stayed on insulin | ||
Kotwal et al[28] | 8 DKA,1 HHS,1 Ketosis,1 Hyperglycemia | 9.7 | 5/6 Low | 4/7 GADA+, 1/7 IAA+, 1/7 IA2A+ | Stayed on insulin |
Zand et al[29] | DKA | 8.9 | All ab negative | Stayed on insulin | |
Maamari et al[30] | DKA | 6.4 | Low | GADA+ | Stayed on insulin |
Alrifai et al[31] | DKA | 9.2 | Low | GADA+ | Stayed on insulin |
Hong et al[32] | DKA | 10.4 | Low | All ab negative | Stayed on insulin |
Hong et al[32] | DKA | 11.4 | Low | All ab negative | Stayed on insulin |
Hong et al[32] | DKA | 5.8 | Low | All ab negative | Stayed on insulin |
Skorpen et al[33] | DKA | 8.4 | Undetected | All ab negative | Stayed on insulin |
Martin-Liberal et al[34] | DKA | GADA+ | Stayed on insulin | ||
Gaudy et al[35] | DKA | 6.85 | Undetected | All ab negative | Stayed on insulin |
Aleksova et al[36] | DKA | Low | All ab negative | Stayed on insulin | |
M A et al[37] | DKA | 10.7 | All ab negative | Stayed on insulin | |
Hansen et al[38] | Simple T1DM | 7.1 | Low | GADA+ | Dced insulin |
Alhusseini et al[39] | DKA | 8.5 | Undectable | GADA+, ICA+ | Stayed on insulin |
F A et al[40] | DKA | 8 | Undectable | GADA+, IA+ | Stayed on insulin |
Tay et al[41] | DKA | 9.3 | Undectable | All ab Negative | Stayed on insulin |
Chae et al[42] | DKA | 5.8 | Low | GADA+, ICA+ | Stayed on insulin |
Smith-Cohn et al[43] | DKA | 8.7 | GADA+ | Stayed on insulin | |
C M et al[44] | DKA | 7.4 | Undetectable | All ab Negative | |
Abayev et al[45] | DKA | 11.8 | Normal | All ab Negative | Stayed on insulin |
Ioana et al[46] | DKA | 8.3 | Undetectable | All ab Negative | |
Kalkan et al[47] | DKA | Low | All ab Negative | ||
Reslan et al[48] | DKA | 7.5 | Stayed on insulin | ||
Fernandez et al[49] | DKA | 5.5 | Low | GADA+ | |
Sfeir et al[50] | DKA | 10.2 | Low | All ab negative | Stayed on insulin |
Talib et al[51] | DKA | 7.9 | Low | GADA+ | |
Gunjur et al[52] | DKA | 6.9 | Low | GADA+, ICA+ | Stayed on insulin |
Singh et al[53] | DKA | GADA+ | Stayed on insulin | ||
Akopyan et al[54] | DKA | All ab negative | Stayed on insulin | ||
Zagouras et al[55] | Hyperglycemia | 5.7 | Low | GADA+ | Stayed on insulin |
Kethireddy et al[56] | T1DM | 9 | GADA+ | Stayed on insulin |
This study presents a comprehensive literature review of similar cases that were reported on various databases. These patients were started on various chemotherapy regimens for different cancer, but after no or little improvement from those modalities, were eventually started on immunotherapy particularly pembrolizumab. These patients presented to the emergency department with various chief complaints including from asymptomatic hyperglycemia to diabetic ketoacidosis (DKA) and were eventually diagnosed with insulin dependent diabetes mellitus. The time of presentation for all these patients varied a lot in terms of range from after just one cycle to as long as 19 cycles with average beingcycles. This average number of cycles is skewed most probably, because the most number of patients developed this diabetic complication earlier rather than later in the course of starting immunotherapy. This observation is also supported by a relatively lower value of glycated hemoglobin value as compared to classic type 1 diabetic patients who develop diabetic ketoacidosis[57]. At the same time, a diagnosis of T1DM was established by presence of one or the other classic antibodies in most of the patients. Among patients who were tested for these antibodies, many of them were positive for anti-glutamic acid decarboxylase antibodiesand some of them were positive for others like islet cell antibodies or insulin antigen 2 antibodies. This conclusion is based on the data from the patients who were tested for these antibodies. To some extent this data suggest that presence of these antibodies is lower in these patients as compared to patients with classic T1DM, where a presence of at least one antibody in 97.8%[58]. On reviewing the literature it was found that incidence of newly diagnosed diabetic ketoacidosis is more in patients receiving pembrolizumab dose of 400 mg every 6 wk as compared to conventional 200 mg every 3 wk[18]. These patients are more prone to develop other endocrinopathies as well particularly thyroid related issues along with diabetes[59]. The pathophysiology of these immune checkpoint inhibitors induced diabetes mellitus is still not clear. Human leukocyte antigen is the key structure involved in the presentation of different peptides, one of which might be containing “diabetogenic peptide” in genetically susceptible individuals[60]. Recognition of this complex by T cell receptor stimulates cytotoxic T-cells that lead to destruction of B-cells in pancreas. Alternatively, these auto-antigenic peptides gets presented to the regulatory T cells, stimulation of which leads to secretion of different kind of cytokines like Interleukin 1, Interleukin 2, Interferon gamma, Tumor necrosis factor alpha and beta. These cytokines in turn stimulate cytotoxic T cells and eventual destruction of B cells ensues. To avoid this phenomenon, interaction between PD-1 and its PD-L1 is really important to maintain self tolerance against pancreatic islets[9]. Different Immune checkpoint inhibitors affect different pathways. Pembrolizumab in particular inhibits the PD-1/PD-L1 pathway, which leads to destruction of pancreatic islet cells and development of T1DM.
The predisposing factors in an individual for development of immune checkpoint inhibitors induced diabetes is not well defined as opposed to individuals with classic T1DM. Individuals with certain genotypes like DR3-DQ2 and DR4-DQ8 have shown to have higher risk of developing classic T1DM as compared to the general population[61]. In our study, we have not included genotypes of patients as there was not much data available regarding that in most cases, but studies particularly focusing on these aspects have shown that individuals with high risk genotypes have developed diabetes more while being on immune checkpoint inhibitors as compared individuals with other genotypes[9]. So, these individuals were at a high risk, but rapid onset of diabetes with presentation of ketoacidosis and relatively a low glycated hemoglobin value as compared to classic T1DM makes it different. In our study, some of the patients also had history of autoimmune disease, which makes them more susceptible to develop other autoimmune disease. Patients with already diagnosed and well controlled type 2 diabetes are also shown to be at high risk of worsening diabetes and presenting with diabetic ketoacidosis along with blood work showing presence of autoantibodies.
Although this is one of the rare side effects of the immunotherapies but with development of new immunotherapy agents, these cases should be kept in mind particularly while giving therapies to patients with high risk factors. Initial check for glycated haemoglobin before starting therapy for both diagnosed and undiagnosed diabetic patients can be useful for the risk stratification. A regular and timely checkup for glucose along with education for signs and symptoms of hyperglycemia should be introduced in patients receiving these agents. This could lead to detection of early development or worsening diabetes. Another significant finding in most of the patients was continuation of immunotherapy after initial management of diabetic ketoacidosis was possible with introduction of as needed long and short acting insulin regimen. This is not the best option, but stopping immunotherapy in advanced malignancies, where very few treatment options are available is not desirable. The prognosis particularly because of the development of these endocrinopathies did not seem to change in most of the patients.
In the end, there is a need for a lot of research in this particular aspect regarding recognition of high risk individuals for developing these rare side effects, which might eventually help patients to avoid these side effects. Identifying different biomarkers apart from classic autoantibodies can also help in early detection of diabetes. More studies are needed to find out exact pathophysiology behind this side effect which is also the need of the hour.
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country/Territory of origin: United States
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P-Reviewer: Wu QN, China; Zhang H, China S-Editor: Liu JH L-Editor: A P-Editor: Chen YX
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