Godwin et al. Journal for ImmunoTherapy of Cancer (2017) 5:40 DOI 10.1186/s40425-017-0245-2
CASE REPORT
Open Access
Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer James Luke Godwin1, Shuchie Jaggi2, Imali Sirisena2, Pankaj Sharda3, Ajay D. Rao2, Ranee Mehra4 and Colleen Veloski3*
Abstract Background: Advances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10–20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM. Case Presentation: A 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy. (Continued on next page)
* Correspondence: [email protected] 3 Department of Medicine, Section of Endocrinology, Fox Chase Cancer Center, Philadelphia, PA, USA Full list of author information is available at the end of the article © 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.
Godwin et al. Journal for ImmunoTherapy of Cancer (2017) 5:40
Page 2 of 7
(Continued from previous page)
Conclusion: New onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM after anti-PD-1 therapy occurred in patients with no detectable diabetes related autoantibodies. Further studies are needed to delineate genetic and immunologic biomarkers that may be useful in identifying patients at risk of developing ICI related autoimmune DM. Keywords: PD-1 inhibitor, Nivolumab, Non-small cell lung cancer (NSCLC), Immune related adverse events (irAE), Autoimmune diabetes, Diabetic ketoacidosis (DKA)
Background Immunotherapy represents one of the most exciting areas of therapeutic advances and research in oncology today. Immune checkpoint inhibitors (ICI) are drugs which disrupt inhibitory signaling to T cells, thus potentially activating and augmenting an anti-tumor response. One of the best known checkpoints is “Programmed Death 1” (PD-1), a cell surface protein found on activated T cells which, when bound to its ligands (PD-L1 and PD-L2), inhibits kinase signaling pathways that normally lead to T-cell activation. Within the past 3 years, four monoclonal antibodies targeting the PD-1-PD-L1 axis have been approved by the FDA for use: nivolumab (anti-PD1, approved in melanoma, NSCLC, renal cell carcinoma, Hodgkin lymphoma, head and neck squamous cell carcinoma (HNSCC), urothelial carcinoma), pembrolizumab (anti-PD-1, approved in melanoma, NSCLC, HNSCC, Hodgkin lymphoma,) atezolizumab (anti-PD-L1, approved in urothelial cell carcinoma and NSCLC) and avelumab (anti-PD-L1, approved in Merkel cell carcinoma). Many other agents targeting the PD-1/PD-L1 axis, as well as other immune checkpoints, are currently being studied in phase III trials and future approvals across the spectrum of tumor types are expected within the next few years. As this field continues to expand, clinicians will be charged with managing the immune related adverse events (irAE) associated with ICI. Although relatively few patients (10–20%) develop significant irAE associated with ICI monotherapy, these events (e.g. pneumonitis, colitis) can be serious and life-threatening. Combination ipilimumab/nivolumab therapy has the highest rate of significant irAE (nearly 40%) while the newer antiPD-1 antibodies such as nivolumab and pembrolizumab have fewer significant irAE ( 80 mg/ dL. She was admitted to the ICU for IV fluids, continuous insulin infusion and frequent lab monitoring. A hemoglobin A1c level on 1/12/16 was 7.1% (normal range 4.6–6.1%). C-peptide levels on 1/16/16 (while BG 377 mg/dL) and 1/18/16 (while BG 423 mg/dL), were < 0.1 ng/mL (normal range 0.8–3.85). Further evaluation to establish the diagnosis of autoimmune diabetes (Type 1), provided the following results: glutamic acid decarboxylase 65 (GAD-65) antibody > 30 U/ml (normal < 1.0); tyrosine phosphatase islet 2 antibody (IA-2) 6.1 U/ml (normal < 0.8); insulin autoantibody (IAA) 0.4 U/ml (normal < 0.4). HLA genotyping was homozygous for A30 and DR9. (Table 1) Other endocrine testing showed: normal hypothalamic-pituitary-adrenal function with morning ACTH 24 pg/mL (normal 6–50) and cortisol 10 ug/dL (normal 6.7–22.6); subclinical hyperthyroidism with slightly suppressed TSH 0.21 uIU/mL (normal 0.34–5.6), FT4 1.41 ng/dL (normal 0.58–1.64). Thyroid stimulating immunoglobulins and thyroid autoantibodies obtained after hospitalization were negative. Due to the rare development of autoimmune diabetes in this patient, we obtained consent to retrieve and test a small amount of serum previously collected prior to therapy with nivolumab and the onset of autoimmune diabetes. The frozen specimen was tested for diabetes related autoantibodies with the following results: GAD65 Ab > 250 IU/ml (normal < 5.0); IA- 2 Ab 6.2 U/ ml (normal < 0.8); IAA < 0.4 U/ml (normal < 0.4); zinc transporter isoform 8 (ZnT8) antibody 64 U/mL (normal 30)a, + IA-2 A30:01,30:02 (A30) (6.1), + IAA (0.4), - ZnT8 D09:CTZ,09:CTZ (DR9) (13)b
Ab titers after nivolumab
Diabetic autoantibodies to GAD65, IA-2, and Insulin Ab were performed at Quest Diagnostics, San Juan Capistrano. Normal GAD65 titers < 0.5 IU/mL, IA-2 Ab < 0.8 U/mL, IAA < 0.4U/mL, and ZnT8 Ab
CASE REPORT
Open Access
Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer James Luke Godwin1, Shuchie Jaggi2, Imali Sirisena2, Pankaj Sharda3, Ajay D. Rao2, Ranee Mehra4 and Colleen Veloski3*
Abstract Background: Advances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10–20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM. Case Presentation: A 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy. (Continued on next page)
* Correspondence: [email protected] 3 Department of Medicine, Section of Endocrinology, Fox Chase Cancer Center, Philadelphia, PA, USA Full list of author information is available at the end of the article © 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.
Godwin et al. Journal for ImmunoTherapy of Cancer (2017) 5:40
Page 2 of 7
(Continued from previous page)
Conclusion: New onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM after anti-PD-1 therapy occurred in patients with no detectable diabetes related autoantibodies. Further studies are needed to delineate genetic and immunologic biomarkers that may be useful in identifying patients at risk of developing ICI related autoimmune DM. Keywords: PD-1 inhibitor, Nivolumab, Non-small cell lung cancer (NSCLC), Immune related adverse events (irAE), Autoimmune diabetes, Diabetic ketoacidosis (DKA)
Background Immunotherapy represents one of the most exciting areas of therapeutic advances and research in oncology today. Immune checkpoint inhibitors (ICI) are drugs which disrupt inhibitory signaling to T cells, thus potentially activating and augmenting an anti-tumor response. One of the best known checkpoints is “Programmed Death 1” (PD-1), a cell surface protein found on activated T cells which, when bound to its ligands (PD-L1 and PD-L2), inhibits kinase signaling pathways that normally lead to T-cell activation. Within the past 3 years, four monoclonal antibodies targeting the PD-1-PD-L1 axis have been approved by the FDA for use: nivolumab (anti-PD1, approved in melanoma, NSCLC, renal cell carcinoma, Hodgkin lymphoma, head and neck squamous cell carcinoma (HNSCC), urothelial carcinoma), pembrolizumab (anti-PD-1, approved in melanoma, NSCLC, HNSCC, Hodgkin lymphoma,) atezolizumab (anti-PD-L1, approved in urothelial cell carcinoma and NSCLC) and avelumab (anti-PD-L1, approved in Merkel cell carcinoma). Many other agents targeting the PD-1/PD-L1 axis, as well as other immune checkpoints, are currently being studied in phase III trials and future approvals across the spectrum of tumor types are expected within the next few years. As this field continues to expand, clinicians will be charged with managing the immune related adverse events (irAE) associated with ICI. Although relatively few patients (10–20%) develop significant irAE associated with ICI monotherapy, these events (e.g. pneumonitis, colitis) can be serious and life-threatening. Combination ipilimumab/nivolumab therapy has the highest rate of significant irAE (nearly 40%) while the newer antiPD-1 antibodies such as nivolumab and pembrolizumab have fewer significant irAE ( 80 mg/ dL. She was admitted to the ICU for IV fluids, continuous insulin infusion and frequent lab monitoring. A hemoglobin A1c level on 1/12/16 was 7.1% (normal range 4.6–6.1%). C-peptide levels on 1/16/16 (while BG 377 mg/dL) and 1/18/16 (while BG 423 mg/dL), were < 0.1 ng/mL (normal range 0.8–3.85). Further evaluation to establish the diagnosis of autoimmune diabetes (Type 1), provided the following results: glutamic acid decarboxylase 65 (GAD-65) antibody > 30 U/ml (normal < 1.0); tyrosine phosphatase islet 2 antibody (IA-2) 6.1 U/ml (normal < 0.8); insulin autoantibody (IAA) 0.4 U/ml (normal < 0.4). HLA genotyping was homozygous for A30 and DR9. (Table 1) Other endocrine testing showed: normal hypothalamic-pituitary-adrenal function with morning ACTH 24 pg/mL (normal 6–50) and cortisol 10 ug/dL (normal 6.7–22.6); subclinical hyperthyroidism with slightly suppressed TSH 0.21 uIU/mL (normal 0.34–5.6), FT4 1.41 ng/dL (normal 0.58–1.64). Thyroid stimulating immunoglobulins and thyroid autoantibodies obtained after hospitalization were negative. Due to the rare development of autoimmune diabetes in this patient, we obtained consent to retrieve and test a small amount of serum previously collected prior to therapy with nivolumab and the onset of autoimmune diabetes. The frozen specimen was tested for diabetes related autoantibodies with the following results: GAD65 Ab > 250 IU/ml (normal < 5.0); IA- 2 Ab 6.2 U/ ml (normal < 0.8); IAA < 0.4 U/ml (normal < 0.4); zinc transporter isoform 8 (ZnT8) antibody 64 U/mL (normal 30)a, + IA-2 A30:01,30:02 (A30) (6.1), + IAA (0.4), - ZnT8 D09:CTZ,09:CTZ (DR9) (13)b
Ab titers after nivolumab
Diabetic autoantibodies to GAD65, IA-2, and Insulin Ab were performed at Quest Diagnostics, San Juan Capistrano. Normal GAD65 titers < 0.5 IU/mL, IA-2 Ab < 0.8 U/mL, IAA < 0.4U/mL, and ZnT8 Ab
