Immune checkpoint inhibitor (ICI) therapies are now first-line therapy for many advanced malignancies in adults, with emerging use in children. With increasing ICI use, prompt recognition and optimal management of ICI-associated immune-related adverse events (IRAEs) are critical. Nearly 60% of ICI-treated adults develop IRAEs, which commonly manifest as autoimmune skin, gastrointestinal, and endocrine disease and can be life-threatening. The incidence, presentation, and disease course of spontaneous autoimmune diseases differ between adults and children, but the pattern of pediatric IRAEs is currently unclear. We report a case of a pediatric patient presenting with new onset autoimmune diabetes mellitus and diabetic ketoacidosis during ICI treatment of fibrolamellar hepatocellular carcinoma (FLC). Distinct from spontaneous type 1 diabetes mellitus (T1DM), this patient progressed rapidly and was negative for known β cell autoantibodies. Additionally, the patient was positive for 21-hydroxylase autoantibodies, suggesting development of concomitant adrenal autoimmunity. Current guidelines for the management of IRAEs in adults may not be appropriate for the management of pediatric patients, who may have different autoimmune risks in a developmental context.

Immune checkpoint inhibitors (ICIs) have shown great promise in the treatment of advanced cancers by stimulating the body’s own immune system to attack cancer cells. Specifically, ICIs block the regulatory protein programmed cell death protein-1 (PD-1), or its ligand, or cytotoxic T lymphocyte associated-4 (CTLA-4) to increase T-cell activation.1  Since their initial US Food and Drug Administration (FDA) approval for metastatic melanoma in 2011, ICIs have shown durable responses in multiple adult cancers, including nonsmall cell lung cancer, Hodgkin lymphoma, kidney and bladder cancer, and head and neck cancer.2  Currently, 19 cancers are FDA-approved for treatment with ICIs,3  and >40% of adult patients with cancer are now eligible for ICI therapy.4 

While there has been limited efficacy and safety data in pediatric patients, there is ongoing interest in expanding the use of ICIs in this population.1,2,57  Based on adult data, anti-PD1 was recently approved by the FDA for the treatment of classic Hodgkin lymphomas in children.2,8  Currently, trials are either underway or planned for B-cell acute lymphoblastic leukemia, ependymoma, Ewing sarcoma, and other treatment-resistant cancers (clinicaltrials.gov, NCT04546399, NCT04730349).

As ICI use continues to increase,4  there is an urgent need for clinicians involved in the care of these patients to recognize ICI-associated immune-related adverse events (IRAEs). In adults, grade 3 to 4 IRAEs develop in 40% of patients treated with combination ICIs (anti-PD-1 and anti-CTLA-4),9  which can manifest as immune-mediated destruction of multiple tissues (eg, skin, gut, endocrine organs, lung, heart, nervous system). IRAEs can have a significant clinical impact including interruption of cancer treatment, permanent organ dysfunction, hospitalization, and even premature death.

It is now well-recognized that immune responses in children differ from that in adults.10,11  The development of spontaneous type 1 diabetes mellitus (T1DM), for example, occurs more frequently in the pediatric population (34.3 cases per 100 000 persons) compared to adult population (18.6 cases per 100 000).12  Whether distinct IRAE patterns will be seen in pediatric patients, however, remains unknown. Here we report a pediatric patient with hepatic cancer undergoing ICI treatment who presented with a potentially life-threatening IRAE.

The patient is a 14-year-old female with fibrolamellar carcinoma (FLC) who developed altered mental status in the setting of fatigue, polyuria, polydipsia, and headache for 1 week. The patient was found to have a blood glucose level of >900 mg/dL, pH of 6.9, serum bicarbonate level <5 mEq/L, β-hydroxybutyrate level of 14.2 mmol/L, and a serum osmolality level of 334 (nL 275–295). Physical exam showed BMI of 18.6 with no evidence of acanthosis nigricans. Family history was negative for autoimmune disease or diabetes. She was diagnosed with severe diabetic ketoacidosis (DKA) and admitted to the pediatric ICU.

Eight months prior, the patient was diagnosed with FLC. She underwent a right hepatic lobectomy for a 14-cm liver mass and received 6 cycles of systemic therapy with nivolumab (anti-PD1), pegylated interferon α, and capecitabine.13  After the initiation of therapy, monitoring laboratory data showed normal serum blood glucose levels, electrolytes, and thyroid function up to 4 weeks before DKA presentation. An elevated random serum blood glucose level of 221 mg/dL was noted at the time of her sixth cycle of nivolumab and pegylated interferon α, 2 weeks before onset of DKA.

Laboratory evaluation during her hospitalization for DKA revealed a low c-peptide level and glycated hemoglobin (HbA1c) of 9.0% (compared to an average of 13.1% in new-onset T1DM patients who present with DKA).14  Autoantibodies for diabetes were negative [Table 1]. The patient was treated over the course of 3 days with intravenous insulin and fluids. With resolution of her DKA, she transitioned to subcutaneous insulin and was discharged. C-peptide repeated 2 weeks later remained undetectable. Her cancer treatment has been monitored by the immune response evaluation criteria in solid tumors (iRECIST) criteria and has been stable. She has continued on immunotherapy and remains insulin-dependent.

TABLE 1

Laboratory Values

ParameterAt DKA2 Weeks After DKAReference
HbA1c 9.0% — — 
C-peptide 0.2 <0.2 1.1–4.3 ng/mL 
GAD antibody <5.0 — 0–5.0 IU/mL 
Insulin autoantibody <0.4 — 0.0–0.4 U/mL 
IA-2 antibody <7.5 — <7.5 U/mL 
ZnT8 antibody 11 — <15 U/mL 
ICA antibody, IgG — <1:4 <1:4 
TSH 0.35 1.3 0.3–4.7 mcIU/mL 
Free T4 0.5 1.2 0.8–1.7 ng/dL 
Cortisol (8AM) 12 — 8–25 mcg/dL 
Corticotropin 17 — 4–48 pg/mL 
21-hydroxylase antibodies Positive — Negative 
ParameterAt DKA2 Weeks After DKAReference
HbA1c 9.0% — — 
C-peptide 0.2 <0.2 1.1–4.3 ng/mL 
GAD antibody <5.0 — 0–5.0 IU/mL 
Insulin autoantibody <0.4 — 0.0–0.4 U/mL 
IA-2 antibody <7.5 — <7.5 U/mL 
ZnT8 antibody 11 — <15 U/mL 
ICA antibody, IgG — <1:4 <1:4 
TSH 0.35 1.3 0.3–4.7 mcIU/mL 
Free T4 0.5 1.2 0.8–1.7 ng/dL 
Cortisol (8AM) 12 — 8–25 mcg/dL 
Corticotropin 17 — 4–48 pg/mL 
21-hydroxylase antibodies Positive — Negative 

DKA, diabetic ketoacidosis; GAD, glutamic acid decarboxylase; IA-2, islet antigen 2; ZnT8, zinc transporter 8; ICA, islet cell cytoplasmic. —, no data.

Treatment with ICIs can lead to multiple co-occurring IRAEs.15  Thyroid function tests showed low thyroid stimulating hormone (TSH) and low free thyroxine (FT4), and thyroid peroxidase and thyroglobulin antibodies were negative. TSH and free thryoxine normalized 2 weeks later, after resolution of acute illness, indicating likely nonthyroidal illness. Testing was negative for celiac disease. Exocrine pancreatic function was not evaluated. Corticotropin and cortisol levels were normal, and she did not have symptoms of adrenal insufficiency. However, 21-hydroxylase antibodies were positive, which are correlated with the development of autoimmune primary adrenal insufficiency (ie, Addison’s disease).16 

We report a case of a pediatric patient presenting with DKA from new-onset ICI-autoimmune diabetes mellitus (DM) and potential evidence of primary adrenal autoimmunity secondary to ICI therapy. This case highlights an emerging and potentially life-threatening diagnosis in pediatric patients. Importantly, the presentation of ICI-associated IRAEs, including autoimmune ICI-T1DM, is distinct from usual spontaneous autoimmune disease seen in childhood. First, the pace of ICI-T1DM disease progression was more rapid, consistent with what has been reported in adults with ICI-associated autoimmune DM.15  Adult patients often have hyperglycemia and low or undetectable c-peptide at presentation, but hemoglobin A1c (HbA1c) is only modestly elevated. In a case series of 91 adult patients with ICI-T1DM, the median HbA1c at diagnosis was 7.7% with a range of 5.4% to 11.4%.17  Additionally, 50% to 71% of patients with ICI-T1DM present in DKA.17,18  Together these findings suggest that patients are often critically ill at presentation, yet the average blood glucose has not been elevated for a prolonged period. Moreover, in an ICI-treated patient with evidence of hyperglycemia and hypoinsulinemia, a normal HbA1c does not exclude new-onset ICI-T1DM. Second, autoantibodies that characterize early stages of spontaneous T1DM may not be present in ICI-T1DM. Islet antibodies are positive in only 53% of patients, compared to classic T1DM, where autoantibodies are present in 80% to 95% of patients at diagnosis.17  This may reflect a rapid T-cell–mediated autoimmune attack on β-islet cells, in which autoantibodies have not developed.19  We therefore recommend that new hyperglycemia workup in ICI-treated pediatric patients include a c-peptide level to assess β cell insulin production.

Incident ICI-T1DM is relatively rare in adults (approximately 1% of ICI-treated patients).17  One other pediatric case of ICI-T1DM has recently been reported in a 12-year-old patient with Hodgkin lymphoma treated with single agent anti-PD-L1.20  Pediatric patients may be at an increased risk for ICI-T1DM, compared to adult patients, given the increased incidence of spontaneous T1DM in children compared to adults. The patient presented here is, to our knowledge, the first known case of ICI-T1DM in a patient on triple therapy with nivolumab, interferon-α, and capecitabine. Combination ICI therapy (ie, anti-PD-1 plus anti-CTLA-4) has an increased risk of IRAEs in adults, and perhaps pediatric patients. Interferon α-therapy has also been associated with the development of autoimmune DM with an estimated prevalence of 0.34%.21  Early analyses from patients undergoing triple therapy,13  as well as studies of patients being treated with checkpoint inhibitors in combination with interferon α, show high rates of IRAEs, but there are no reported cases of similar autoimmune ICI-T1DM.22,23 

The presence of one IRAE should increase providers' suspicion of another. In adult patients diagnosed with ICI-T1DM, two-thirds were diagnosed with another IRAE.15  Our patient had 21-hydroxylase antibodies, raising concern for autoimmune primary adrenal insufficiency (PAI). While her corticotropin and cortisol levels were normal, she will be screened regularly for the development of adrenal insufficiency (AI). ICI-related PAI is rare,2  because AI is typically secondary to hypophysitis. Morning corticotropin and cortisol levels and serum electrolytes can help to distinguish primary from secondary AI. Imaging of the adrenal gland and pituitary can also be considered, although the absence of pituitary enhancement does not exclude ICI-hypophysitis.2  While uncommon, a recent study identified 45 cases of definite ICI-related PAI and 406 suspected cases.24  More than 90% of these cases were associated with severe complications defined as life-threatening hospitalization or physical disability; death was observed in 7.3% of cases. The pathophysiology of ICI-PAI remains unclear, because cases have been associated with adrenal antibodies, adrenal atrophy, and adrenalitis. Of 3 reported cases of ICI-related PAI with antiadrenal antibodies,2527  patients all presented in adrenal crisis and with other endocrine IRAEs (eg, thyroiditis, T1DM). Furthermore, as our case highlights, while PAI is considered exceedingly rare in adult patients, the prevalence in pediatric patients may be higher given the underlying differences in autoimmune risk and pathogenesis. Antibodies against 21-hydroxylase were not tested before ICI treatment in this patient, so the relative timing of when antibodies first appeared is unclear. Given the high morbidity and mortality associated with ICI-associated IRAEs, protocols are needed to screen for type 1 diabetes, adrenal insufficiency, thyroid dysfunction, and other IRAEs in pediatric patients before starting and while taking ICI, as has been suggested for adults.28 

This case highlights areas of continued uncertainty in pediatric patients with cancer treated with ICI. The frequency and type of biomarkers used for routine screening of IRAEs in pediatric patients remain to be defined. This will require a deeper understanding of the organs most often affected by IRAEs and median time to onset after initiation of ICI treatment, which may differ from adult patients. Should ICI treatment continue in pediatric patients with IRAEs? Current recommendations suggest that for endocrine IRAEs in adults, ICI therapy should be continued. Furthermore, the use of high-dose glucocorticoids or withdrawal of ICI treatment is unlikely to reverse permanent organ damage and may be associated with increased mortality.2931  For nonendocrine IRAEs, a number of treatment strategies are recommended and continue to evolve, with the consideration for nonsteroid therapies.28  It remains unclear whether adult guidelines can be safely extended to pediatric patients. Furthermore, it is now clear in adults that the development of IRAEs is associated with improved cancer response to immunotherapy.3234  This relationship is stronger for patients who develop multiple, higher-grade, and endocrine IRAEs.34  By stopping cancer immunotherapy for IRAEs, therefore, we may be limiting anticancer benefits. Balancing toxicity with efficacy is an ongoing challenge in ICI treatments that requires additional study of the mechanisms underlying IRAE development. It will be important that such future research include pediatric patients.

FUNDING: Dr Su receives funding from NIH grant R01DK119445 and Dr Lechner receives funding from NIH grant K08DK129829.

Drs Dasgupta and Tsay conceptualized the report, analyzed and interpreted the clinical data, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Federman, Lechner, and Su conceptualized the report, analyzed and interpreted the clinical data, and reviewed and revised the manuscript; Drs Lechner and Su contributed equally as corresponding authors; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

     
  • Anti-CTLA-4

    cytotoxic T lymphocyte associated-4

  •  
  • Anti-PD-1

    programmed cell death protein-1

  •  
  • DKA

    diabetic ketoacidosis

  •  
  • FDA

    Food and Drug Administration

  •  
  • FLC

    fibrolamellar hepatocellular carcinoma

  •  
  • HbA1c

    glycated hemoglobin

  •  
  • ICI

    immune checkpoint inhibitor

  •  
  • IRAE

    immune checkpoint inhibitor–associated immune-related adverse event

  •  
  • PAI

    primary adrenal insufficiency

  •  
  • T1DM

    type 1 diabetes mellitus

  •  
  • TSH

    thyroid stimulating hormone

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Competing Interests

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest to disclose.