Introduction
In the past two decades, the field of cancer immunotherapy evolved from a niche specialty to the frontlines of the fight against cancer. Unlike chemotherapy, immunotherapy unleashes the body’s inherent immune system by boosting it and “releasing its breaks.” Although we have come far, immunotherapy remains a crude tool, and as collateral damage, we have a new set of toxicities which are labeled as immune-related adverse events (irAEs). Several endocrine irAEs can present with symptoms that overlap with those seen in patients with advanced cancer, some of which can be life-threatening. Diagnosing and managing these conditions requires a collaborative effort between the oncologist, endocrinologist, and primary care physician.
In this chapter, we will discuss the major immunotherapeutic agents which have been approved by the US Food and Drug Administration (FDA). We describe their indications for use, mechanisms of action, endocrine toxicities associated with their use, and management of these toxicities.
Agents and Mechanism of Action
INTERLEUKIN 2 (IL-2)
Interleukin-2 (IL-2) has been used extensively in metastatic melanoma and renal cell carcinoma as monotherapy and in combination with other agents. High-dose IL-2 has a response rate of 25% in patients with renal cell carcinoma and 18% in patients with metastatic melanoma when used as monotherapy. IL-2 is associated with significant toxicities and, with the advent of better therapies, its use has largely fallen out of favor.
Mechanism of Action
IL-2, after binding to its receptor, causes phosphorylation of Janus tyrosine kinases (JAK) which leads to the activation of signal transducer and activator of transcription (STAT), phosphoinositol-3-kinases (PI3K), and SCH-MAP-RAS pathways which lead to further downstream signaling. IL-2 acts as a double-edged sword in cancer immunotherapy. It regulates both T cell expansion and differentiation into memory and effector cells, natural killer (NK) cell proliferation, and increases cytolytic activity which forms the basis of its antitumor activity. On the other hand, IL-2 also leads to the expansion of regulatory T (Treg) cells, and prolonged exposure to IL-2 leads to activation-induced cell death of T cells, which leads to suppression of antitumor immune responses.
Mechanism of Endocrine Toxicity
Thyroid dysfunction is the most common endocrine toxicity with IL-2. Autoimmune destruction is the likely mechanism. An increase in lymphocytic infiltration of the thyroid gland has been seen in patients treated with IL-2. , An increase in the levels of thyroid autoantibodies (Tab) during treatment with IL-2 has also been reported. Whether this leads to thyroid dysfunction is not clear, as a few studies have failed to show the association between increased Tab and hypothyroidism. ,
Reported Toxicities
New or worsening of thyroid function is reported in 16% to 47% of patients on IL-2 alone. , , In a study of 281 patients treated with IL-2 by Krouse et al., hypothyroidism was more common than hyperthyroidism with about 35% of patients developing hypothyroidism and 7% developing hyperthyroidism. Most patients had subclinical hypothyroidism and only a few required hormone replacement therapy. The median duration of hypothyroidism was around 60 days with an increase in its incidence seen with successive cycles of treatment. No statistical difference in incidence was seen based on age, gender, tumor type, or IL-2 dose. Similar incidences have been reported when IL-2 is used in combination with other agents. , The use of thyroid dysfunction as a predictive marker for response is controversial, with inconsistent results in several studies. , , This has been attributed to the fact that patients who respond to therapy were likely to receive more cycles of IL-2, which would increase their risk of thyroid dysfunction.
Two cases of acute adrenal insufficiency have been reported: one was due to IL-2 and another due to IL-2/tumor infiltrating lymphocyte combination therapy. , Cases of new onset insulin dependent diabetes mellitus (DM), , and changes in levels of β-endorphin, cortisol, and adrenocorticotrophic hormone (ACTH) have been reported. Transient decrease in levels of testosterone, dehydroepiandrosterone, and increase in levels of estradiol have also been reported in men treated with IL-2. These changes suggest a definite endocrine effect caused by IL-2 therapy.
INTERFERON-α (INF-α)
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INF-α2b has been used as an adjuvant treatment in patients with melanoma. It is also approved for use in renal cell cancer, Kaposi sarcoma, and chronic myeloid leukemia but, due to the advent of less toxic and more potent treatments, its use is now restricted to clinical trials.
Mechanism of Action
INF-α acts by binding to its receptor on the cell membrane and phosphorylating the intracellular domain along with JAK and tyrosine kinase 2, which are attached to it. This leads to further activation and dimerization of STAT which translocate to the nucleus and leads to the expression of the interferon-regulated genes. INF exerts its anticancer action by (1) inducing apoptosis of tumor cells; (2) inducing activation, proliferation, and cytotoxic activity of dendritic cells, NK cells, CD4+ and CD8+ T cells, and B cells; and (3) decreasing the immunosuppressive action of myeloid-derived suppressor cells and Treg cells.
Mechanism of Endocrine Toxicities
Thyroid dysfunction is common with the use of INF-α. Autoimmune thyroiditis (which is mediated by increase in MHC-I expression in thyroid tissue, switching of the immune response to the Th1 pathway, activation of other mediating immune cells, and release of other cytokines) is the likely mechanism, but direct effects of INF-α on thyroid tissue have also been implicated. In-vitro experiments have shown that INF can inhibit thyroid function by a decrease in iodine uptake and secretion of thyroxine.
Reported Toxicities
Thyroid dysfunction can present as Hashimoto’s thyroiditis, Graves’ disease, presence of thyroid antibodies with no clinical disease, and destructive thyroiditis, which presents with biphasic thyroiditis leading to thyrotoxicosis followed by hypothyroidism and resolution. Between 2% and 10% of patients develop hypothyroidism, with a median time of 4 months after beginning therapy, and nearly 60% of these patients will have persistent hypothyroidism. The presence of thyroid autoantibodies is a risk factor for the development of thyroid dysfunction, and prior autoimmune thyroid disorder has been associated with severe hypothyroidism.
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New onset insulin dependent diabetes has also been reported and is associated with high titers of pancreatic autoantibodies with almost all patients requiring insulin even after cessation of treatment. INF-α also causes an increase in the levels of cortisol and adrenocorticotrophic hormone. The effect of INF on sex hormones is unclear. A study in men treated with INF showed a decrease in total and free testosterone and dehydroepiandrosterone-sulphate (DHEAS), and showed a correlation between low testosterone and loss of libido. Another study, however, showed no significant changes, highlighting the need for further investigation.
IMMUNE CHECKPOINT INHIBITORS (ICIS)
In the past decade, ICIs have revolutionized cancer therapeutics. Three classes of ICIs have been approved by the FDA:
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Ipilimumab, an anti-cytotoxic T lymphocyte antigen (CTLA)-4 antibody was the first ICI to be approved for use in melanoma. Tremelimumab is another anti-CTLA-4 which has shown some activity in melanoma, mesothelioma, hepatocellular carcinoma, and colorectal carcinoma but has not received FDA approval for any indication to date.
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Another class of drugs alters the programmed death (PD)-1/programmed death ligand (PDL)-1 pathway. Nivolumab and pembrolizumab are drugs that bind to PD-1. Both are approved for use in melanoma; non–small-cell lung cancer (NSCLC); and head and neck squamous cell, urothelial, and renal cell cancers. Nivolumab is also approved for use in hepatocellular and colorectal carcinomas with high microsatellite instability (MSI) or mismatch repair defects, and pembrolizumab is approved for use in gastric carcinoma and solid tumors with high MSI or mismatch repair defects. Cemiplimab is another PD-1 inhibitor which is approved for advanced squamous cell carcinoma based on it’s activity in a phase II trial.
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Atezolizumab (used in NSCLC and urothelial cancer), avelumab (used in Merkel cell carcinoma and urothelial cancer), and durvalumab (used in urothelial carcinoma) bind to PD-L1 and have been approved by the FDA. Recently, PD-L1 agents have also shown benefit with chemotherapy (triple negative breast cancer) and as maintenance therapy (small cell lung cancer, NSCLC and urothelial carcinoma).
Mechanism of Action of ICIs
CD28 is present on the surface of naïve T cells. It binds to CD80/86 present on the surface of activated antigen presenting cells (APC) providing a costimulatory signal to the interaction between major histocompatibility protein (MHC) and the T cell receptor (TCR). CTLA-4 acts as a competitive antagonist of CD28 expressed on activated T cells and Tregs, and binds to CD80/86 providing an inhibitory signal leading to decrease in T cell activation, proliferation, and IL-2 production. There is some evidence that CTLA-4 might cause trans-endocytosis of CD80/86 leading to its degradation, thereby reducing the number of ligands for CD28. CTLA-4 also enhances the activity of Treg cells leading to more immunosuppression. Blocking of CTLA-4 using monoclonal antibodies (mAbs) was shown to increase T cell activation and proliferation in vitro and decrease tumor growth and tumor rejection in mice models. PD-1, similar to CTLA-4, is also found on the T cell surface, although, unlike CTLA-4, its action is mostly restricted to effector T cells, and peripherally in the tumor microenvironment by binding with its ligands PD-L1 and PD-L2 expressed extensively on tumor cells. This leads to apoptosis and downregulation of T-cell effector functions, which is blocked by antibodies targeting PD-1/PD-L1.
Mechanism of Endocrine Toxicity
Hypophysitis:
Although the exact mechanism has not been defined, autoimmunity is the most popularly theorized mechanism. In a murine model, CTLA-4 was seen in the murine pituitary glands at both RNA and protein levels and administration of anti-CTLA-4 mAb lead to the development of antibodies against pituitary cells, lymphocytic infiltration, and complement deposition in the pituitary: a mechanism similar to type II hypersensitivity reaction. In the same report, antipituitary antibodies were found in patients who developed hypophysitis after ipiliumumab administration, although not in the other patients without hypophysitis. In an autopsy report of a patient who developed hypophysitis with tremelimumab, high levels of expression of CTLA-4 was seen in the pituitary cells as well as signs of type II and type IV hypersensitivity reactions, ultimately leading to necrosis of the pituitary tissue. None of these changes were seen in patients who did not develop hypophysitis (although one patient had mild lymphocytic infiltration of the pituitary). Although the exact mechanism of hypophysitis with anti-PD-1/PD-L1 is not well described, it does appear to follow the patterns discussed earlier.
Thyroid dysfunction:
Genetic susceptibilities linked to HLA phenotypes or polymorphisms in CTLA-4/PD-1 genes have also been associated with the development of Graves’ disease and Hashimoto’s thyroiditis. , The current consensus is that thyroid dysfunction is due to autoimmune destruction of the thyroid gland, evidenced by several case series in which patients initially had thyrotoxicosis or subclinical hyperthyroidism before becoming hypothyroid. One case study showed that patients at the time of initial thyroid dysfunction had low nuclear uptake or a nonvascular gland on ultrasound, supporting the process of destructive thyroiditis. A recent study described the presence of PD-L1 and PD-L2 on thyroid tissue in patients who developed thyroid dysfunction with nivolumab. It is also possible that the use of PD-1 inhibitors could lead to the loss of peripheral tolerance. Antithyroid antibodies (antithyroglobulin antibodies and antimicrosomal antibodies) may have a role in the pathogenesis of thyroid dysfunction as they are found more commonly in patients who develop thyroid dysfunction but their role in the pathogenesis of ICI induced thyroid dysfunction remains questionable.
Other endocrinopathies:
Autoimmune diabetes mellitus is a rare endocrine disorder with ICI therapy, and most cases have been reported with the use of anti-PD-1 or anti-PD-L1 antibodies. Blockade of the PD-1/PD-L1 pathway using anti-PD-1 or anti-PD-L1 antibodies causes destructive insulitis and precipitates DM in nonobese diabetic mice models. It is likely that the PD-1/PD-L1 pathway maintains peripheral tolerance, which is broken down by mAbs (blocking this pathway).
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Primary adrenal insufficiency (PAI) has also been reported with ICI therapy. Polymorphism of the CTLA-4 gene has been associated with the development of this entity. , Due to its rarity, there are no studies to our knowledge which have thoroughly evaluated its pathogenesis.
Reported Toxicities
Hypophysitis
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A meta-analysis from 2018 reported that 3.2% of patients developed hypophysitis with ipilimumab. Other studies have reported a higher incidence which is probably due to higher recognition of the condition with more experience with the drug. , The incidence of hypophysitis is dose-related, with a higher incidence seen with the 10 mg/kg dose versus the 3 mg/kg dose of ipilimumab. The incidence of hypophysitis is more common in men and in elderly patients. The number of cycles received did not differ between patients who developed hypophysitis versus patients who did not. In a study by Faje et al., of 57 patients with ipilimumab-induced hypophysitis, the median time of onset was 2 to 3 months after starting therapy but can occur as early as 4 weeks or have delayed presentation. Most cases involved the anterior pituitary with several hormone axes; thyroid, adrenal, and gonadotrophic deficiencies were commonly reported, whereas growth hormone was usually unaffected. Hyperprolactinemia was rare, whereas low prolactin levels were seen in about 60% of patients. The majority of patients also had radiographic pituitary enlargement at the time of diagnosis, which was transient and resolved in most patients. Thyroid and gonadal axes recovered in about half of the patients, whereas most patients continued to have adrenal axis deficiency. Hypophysitis during treatment with ipilimumab has been associated with improved response to therapy. Interestingly, involvement of the posterior pituitary is exceedingly uncommon, although some cases of diabetes insipidus and syndrome of inappropriate antidiuretic hormone (SIADH) have been reported with ipilimumab. ,
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The incidence of hypophysitis with anti-PD-1 antibody treatment is low- a meta-analysis reported that 0.4% of patients develop hypophysitis with anti-PD-1 antibody. Another article reported the development of hypophysitis to be 0.5% to 0.9% of patients treated with nivolumab with a median time to onset of 5.5 months. With pembrolizumab, the incidence of hypophysitis was reported at 0.8% in patients with melanoma and 0.2% in patients with NSCLC with a time to onset of between 3.3 and 3.7 months. The rate of drug discontinuation due to hypophysitis was less than 1%. The incidence of hypophysitis is greatest with the combination of ICI, with 6.4% developing hypophysitis, whereas anti-PD-L1 antibodies alone cause hypophysitis in less than 0.1% of patients.
Thyroid disorders
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Barroso et al., in their meta-analysis, reported that 3.8% and 1.7% of patients developed hypothyroidism and hyperthyroidism, respectively, on ipilimumab. No difference in the incidence of hypothyroidism or thyroiditis was noticed between the 3 mg/kg and the10 mg/kg dose of ipilimumab. The onset of thyroid dysfunction commonly occurred after 2 to 4 infusions. New onset Graves’ disease, Graves’ ophthalmopathy with normal thyroid stimulating hormone (TSH) levels but elevated thyroid stimulating antibody (TSIAb), and thyroid storm have also been reported.
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Thyroid disorders are more frequently seen with anti-PD-1 therapy compared to ipilimumab. Hypothyroidism is seen in 7.0% and hyperthyroidism is seen in 3.2% of patients. The risk of hyperthyroidism with pembrolizumab is reported to be higher than nivolumab (3.8% vs. 2.3%). New onset hypothyroidism or a transient hyperthyroid state followed by recovery or hypothyroidism have been reported in many studies. , , The median time to onset of thyrotoxic phase is 3 to 6 weeks, with resolution in 4 weeks and subsequent hypothyroidism in 6 to 8 weeks.
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Compared to PD-1 inhibitors, the incidence of thyroid dysfunction with PD-L1 inhibitors is significantly lower: 3.9% of patients developed hypothyroidism, and 0.6% of patients developed hyperthyroidism. The highest incidence of thyroid dysfunction is seen with combination immunotherapy, with 13% and 8% of patients developing hypothyroidism and hyperthyroidism, respectively.
Other endocrine disorders
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Insulin-dependent DM has been reported with ICIs. The onset is variable with reported times ranging from 1 week to 12 months. Around half of the patients had antibodies against GAD or islet cells. Furthermore, an association with high-risk HLA-genotypes has been shown in some cases. Patients may have variable presentation. Some present with hyperglycemia, whereas others present with diabetic ketoacidosis (DKA). Primary adrenal insufficiency (PAI) is a rare endocrine disorder related to ICI therapy. The incidence with ICI monotherapy is around 0.7%; however, higher incidences were reported with combination therapy. Cases of transient low total testosterone levels without concurrent hypophysitis, suggesting primary gonadal failure, were identified, although most of these patients were receiving high-dose steroids for other irAEs and simultaneous measurement of sex-binding globulins was not done. Autonomous cortisol secretion has been seen in one patient treated with ipilimumab. Hypoparathyroidism leading to symptomatic hypocalcemia has been reported with ipilimumab. Cases of hypercalcemia have also been reported with ipilimumab and nivolumab, although the etiology is unclear.
ONCOLYTIC VIRUSES
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Talimogene laherparepvec (T-VEC) is the first oncolytic virus to receive FDA approval for intralesional use based on a phase III clinical trial which showed significant increase in durable response rate and overall response rate compared to granulocyte macrophage colony stimulating factor (GM-CSF) in melanoma, although without significant change in overall survival. Trials with the combination of T-VEC and ICIs have shown to have clinical benefit and appear to be well tolerated. ,
Mechanism of Action
T-VEC is an attenuated herpes simplex virus-1 which can encode for GM-CSF. It is capable of selective replication in tumor cells due to disrupted PRK activity (PKR is a protein which is activated in human cells when infected by a virus and prevents protein translation), and disrupted INF signaling. The replication of viruses in the tumor cell ultimately leads to cell death and release of viruses which can infect neighboring cells. Cell lysis also leads to release of tumor-related antigen and damage-associated protein, which leads to further immune response against the tumor.
Reported Endocrine Toxicities
T-VEC is well tolerated. When used as a monotherapy or in combination with ipilimumab, no endocrine toxicities were reported (although when used in combination with ipilimumab only, toxicities with an incidence more than 10% were reported). , A single case of thyroid dysfunction has been reported with concurrent use of T-VEC, although it was deemed to be not related to T-VEC use.
CHIMERIC ANTIGEN RECEPTOR CAR T-CELL THERAPY
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The FDA has approved CD19 targeting CAR-T cells for use in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B cell lymphoma (DBCL) who have relapsed after two lines of therapy. , Several other CAR-T cells targeting various other antigens on hematological and solid malignancies have undergone clinical trials with promising results.
Mechanism of Action
CAR is an antibody derived single-chain variable fragment which engages the antigen present on the target cell. CAR is attached to a CD3ζ-signaling domain within the T cell via a hingeand transmembrane domain. Further development has led to the addition of costimulatory domains to the CD3ζ-chain signaling domain in second and third generation CAR-T cells.
Reported Endocrine Toxicities
Cytokine release syndrome (CRS) and neurological adverse effects are the most common toxicities reported. , Hyperglycemia was reported as an adverse effect during treatment with CD19 CAR-T cells, although the exact etiology is not known and is may be related to corticosteroids given to treat CRS or neurotoxicity. , No other endocrine toxicity was reported.
BISPECIFIC T CELL ENGAGER (BiTE)
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Blinatumomab is the first BiTE to be approved by the FDA for use in relapsed/refractory precursor B-ALL in adults and children and has recently gained approval for use in patients with B cell precursor ALL in remission with minimal residual disease. Blinatumomab has shown promising results in phase II trials in patients with relapsed/refractory non-Hodgkin’s lymphoma.
Mechanism of Action
Blinatumomab consists of two single-chain variable fragments joined together through a linker molecule, with one fragment binding to CD3 on T cells and the other fragment binding to CD19 on B cells. The BiTE brings the T cells and tumor cells into physical proximity, leading to the formation of a transient cytolytic synapse between the two cells. The activated T cell then releases perforins and granzymes which penetrate the tumor cell leading to its apoptosis.
Reported Endocrine Toxicities
Neurological adverse events are the most common reported toxicities with BiTE therapy. In a phase II trial, hyperglycemia was reported in about 13% of patients, with about 8% of patients developing grade 3 hyperglycemia. Hyperglycemia is more common in patients over 65 years of age. It is likely related to corticosteroids given to prevent or treat neurotoxicity. No other endocrine toxicity has been reported with blinatumomab.
Pharmacological Management of Toxicities
INTERLEUKIN-2
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Thyroid dysfunction is commonly reported with IL-2 therapy. Krouse et al. based their recommendations on a study of 281 patients treated with IL-2 which proposed that TSH and free T4 (FT4) levels should be measured at regular intervals during treatment with IL-2. In patients who develop moderate and severe hypothyroidism, thyroid hormone replacement should be started, and further IL-2 therapy should be withheld for 2 to 4 weeks. Therapy should be continued for about a year after finishing IL-2 therapy or until thyroid dysfunction resolves. In this study, patients also developed mild and transient hyperthyroidism, which did not require any treatment.
INTERFERON (INF)-α
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Fatigue and depression are common adverse effects of INF therapy and may mimic symptoms of hypothyroidism. Before starting therapy with INF, TSH, and FT4 should be measured. Positive titer of thyroid peroxidase (TPO) Ab prior to treatment is associated with higher risk of developing thyroid dysfunction during treatment with INF. Thyroid function should be checked every 8 to 12 weeks during treatment. Thyroid hormone replacement should be initiated in patients who develop hypothyroidism and should be continued until treatment completion, although in patients who have positive antithyroid antibody titers, lifelong replacement may be required. Patients who develop destructive thyrotoxicosis can be managed with β-blockers, although patients who have uncontrolled symptoms may require withdrawal of INF and recheck of thyroid function in 4 to 6 weeks. Patients with Graves’ disease can be managed with antithyroid drugs, although patients with severe disease may need radioiodine ablation. In these cases, INF should be withheld until thyroid function normalizes postablation.
IMMUNE CHECKPOINT INHIBITOR
Thyroid Dysfunction
Hypothyroidism
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A high index of suspicion is necessary as several symptoms of hypothyroidism overlap with those of advanced cancer. Patients present with fatigue, weight gain, hair loss, leg swelling, constipation, and depressed mood. Rarely, patients present with myxedema coma. Biochemical diagnosis requires the presence of high TSH with a low T4 level. In cases of subclinical hypothyroidism, T4 levels will be normal. TSH and FT4 should be obtained at the start of therapy and then every 4 to 6 weeks for the whole duration of treatment. In patients with a biochemical diagnosis of hypothyroidism, thyroid antibodies should also be obtained.
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Treatment is not indicated for patients with grade 1 toxicity and ICI should be continued. Patients should be monitored clinically along with regular monitoring of TSH and FT4 levels. , Hormone replacement should be initiated for patients with grade 2 toxicity, and ICI may be withheld until replacement produces adequate levels. In patients with no risk factors, a complete replacement dose of 1.6 µg/kg per day can be initiated, whereas elderly patients or patients with cardiovascular risks should be started on a lower dose of 25–50 µg/day. Levels of TSH should be rechecked in 6 to 8 weeks for adequacy of the replacement, and once stable, the thyroid function can be evaluated annually or with clinical change. Patients with TSH levels persistently greater than 10 mIU/L should be treated similarly, even if asymptomatic, as these patients have higher risk of coronary heart disease (CHD) events, CHD mortality, and total mortality. ,
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Patients with grade 3 or higher toxicity generally need hospitalization for treatment. In these cases, further ICI therapy should be withheld until symptoms resolve. Hormone replacement should be carried out as in grade 2 patients. , Intravenous levothyroxine should be used in patients who present with myxedema coma. For patients with adrenal insufficiency and hypothyroidism, adrenal hormones should be replaced before thyroid hormone replacement is started as replacement of thyroid hormone in patients with adrenal insufficiency can precipitate an adrenal crisis.
Hyperthyroidism
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Thyrotoxicosis/hyperthyroidism usually presents with symptoms such as palpitations, anxiety, weight loss, diarrhea, and heat intolerance. Cases of thyrotoxic storm as initial presentation have also been reported. Biochemical diagnosis is made by detecting increased T4 or T3 in the setting of a suppressed TSH. Hyperthyroidism can be caused by two different mechanisms: autoimmune destruction of the gland leading to release of thyroxine hormone, and Graves’ disease. Thyroid stimulating immunoglobulin or thyroid hormone receptor antibodies, TPO antibodies, and a nuclear iodine uptake scan should be obtained in patients with suspected Graves’ disease, because these can help differentiate the clinical syndrome from thyrotoxicosis due to autoimmune thyroiditis. Use of Doppler ultrasound of the thyroid gland is not well defined.
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No intervention is indicated in patients with grade 1 toxicity. , Assessment of thyroid function should be done every 2 weeks to assess for new hypothyroidism or persistent hyperthyroidism. Grade 2 hyperthyroidism can be managed symptomatically with β-blockers and supportive care. , Further ICI therapy may be withheld. The role of corticosteroids is controversial as it is not recommended in the American Society of Clinical Oncology (ASCO) and Society for Immunotherapy of Cancer (SITC) guidelines, although European guidelines recommend the use of prednisone 0.5 mg/kg followed by a taper in patients with painful thyroiditis. , , ICI therapy should be withheld for grade 3 or higher toxicity and hospitalization is indicated in patients with severe symptoms. , In addition to treatment indicated for grade 2 toxicity, prednisone 1–2 mg/kg, which is tapered over 1 to 2 weeks, should also be used. Graves’ disease should be considered in patients who have persistent hyperthyroidism longer than 4 to 6 weeks. , Patients with Graves’ disease will need antithyroid medications to decrease thyroxine production. Antithyroid medications have no role in autoimmune thyroiditis. Patients who developed ophthalmopathy have been treated successfully with prolonged steroid taper with/without canthotomy. ,
Hypophysitis
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Headache and fatigue are the most common presenting symptoms of hypophysitis, , but patients can have nausea, vomiting, confusion, anorexia, temperature intolerance and weight loss as well. Patients may present with adrenal crisis as well, a life threatening condition with shock, confusion and electrolyte abnormalities. Symptoms due to mass effect are rare and visual impairment is uncommon as optic structures are rarely involved. In patients in whom hypophysitis is suspected, morning cortisol and ACTH, TSH, and FT4, and electrolytes should be obtained. , Gonadal hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and MRI of the brain with pituitary cuts can be considered depending on the symptoms of the patients.
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ICI-induced hypophysitis is diagnosed by detecting low ACTH and cortisol, low TSH and FT4, low gonadal hormones, and low FSH/LH. Posterior pituitary involvement may also present with hyponatremia. Radiographic enlargement of the pituitary is seen in the majority of the cases and resolves in almost all cases. Radiographic enlargement of the pituitary on MRI may precede biochemical or clinical onset of disease. A proposed diagnostic criterion includes: ≥1 deficiency of pituitary axis (TSH or ACTH deficiency required) with MRI findings or ≥2 axis deficiency (TSH or ACTH deficiency required) accompanied by headache.
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Patients with grades 1 and 2 toxicity can be managed with hormone replacement of the deficient axis: hydrocortisone orally 10–20 mg in the morning and 5–10 mg in the early afternoon and levothyroxine based on patient’s weight should be started. In patients with deficiency of gonadal hormones, treatment is usually considered in the outpatient setting after consultation with an endocrinologist. Monitoring of thyroid hormone replacement should be evaluated with FT4 levels because TSH levels are inaccurate in patients with central hypothyroidism. In patients presenting with grade 3 toxicity or higher or associated with severe headaches and vision loss, pulse dose therapy with prednisone 1–2 mg/kg, or equivalent, daily tapered over 1 to 2 weeks should be considered, followed by hormone replacement as in grade 1 toxicity. Long-term high-dose steroids (over 3–12 weeks) has not been shown to reduce either residual hormone deficit or time to resolution of symptoms. ICI therapy should be withheld until patients are on a stable dose of replacement hormones.
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In patients presenting with hypotension, sepsis should always be ruled out. Hormone replacement should be started in critically ill patients who have a high suspicion of hypophysitis even before biochemical diagnosis is made. In patients suspected with adrenal insufficiency, corticosteroids should be started prior to other hormone replacement, especially before thyroid hormone replacement to prevent precipitation of adrenal crisis. The majority of patients will need long-term hormone replacement therapy. Although immunosuppressants like mycophenolate have been frequently used in other irAEs, their use in ICI mediated hypophysitis is not well described.
Primary Adrenal Insufficiency (PAI)
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PAI, like secondary adrenal insufficiency, presents with nausea, abdominal pain, anorexia, and fatigue and hypotension. Laboratory testing often reveals hyponatremia, hyperkalemia and hypoglycemia. Notably, hyperpigmentation is exclusively seen in PAI compared to patients with secondary adrenal insufficiency, who can have similar presenting complaints. Symptoms of PAI mimic those of disease progression, and requires a high index of suspicion on the clinicians part for diagnosis. In patients with suspicion of PAI, 8:00 a.m. serum cortisol and ACTH levels and serum electrolytes should be obtained. Patients with PAI will have low serum cortisol with high ACTH levels. Plasma renin and aldosterone levels should also be obtained as PAI, unlike secondary insufficiency, will also cause mineralocorticoid deficiency. In patients with an indeterminate result, a cosyntropin test should be obtained. Cortisol level of less than 18 µg/dL at 30 or 60 minutes post-250 µg IV cosyntropin is diagnostic of PAI. Abdominal CT can help to rule out metastasis or hemorrhage as a cause of PAI. Patients should also be evaluated for underlying infection.
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Further treatment with ICI should be withheld in all cases of PAI until the patient is clinically stable. Expert endocrinology consultation is recommended for patients with suspected PAI. Patients with grade 1 symptoms can be started on a maintenance dose of steroids (prednisone 5–10 mg daily or hydrocortisone 10–20 mg in the morning and 5–10 mg in the afternoon). Fludrocortisone (100 µg/day) will be required in patients with mineralocorticoid deficiency. Patients with grade 2 symptoms will initially need a higher dose of hydrocortisone or equivalent steroid, which can be tapered to maintenance dose as patient’s clinical status improve. Patients with higher than grade 3 toxicity should be given IV hydrocortisone 100 or 4 mg dexamethasone along with adequate fluid resuscitation. Dexamethasone is preferred in cases where the diagnosis is unclear as it does not interfere with cosyntropin stimulation testing. The dose of hydrocortisone should be tapered to maintenance dose as patient’s clinical condition improves. Blood cultures and appropriate imaging should be obtained in these patients to rule out sepsis. Further treatment with ICI should be withheld until the patient is on adequate hormone replacement.
Diabetes Mellitus (DM)
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Patients on ICIs can present with worsening of DM or with new onset of insulin-dependent DM. Patients can be asymptomatic or present with symptoms of polyphagia, polydipsia, weight loss, dehydration, and fatigue, or even present in diabetic ketoacidosis (DKA). Blood sugar should be checked at baseline and at regular intervals while patients are on treatment with ICIs. , Low levels of insulin and C peptide can help differentiate type 1 from type 2 DM. , In patients with suspected type 1 DM, antiglutamic acid decarboxylase (GAD) 65, anti-insulin and anti-islet cell antibodies can be measured, although antibody negative cases have been reported in the literature.
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Patients with new diagnoses of diabetes should be screened for DM type 1. Patients with grade 1 toxicity can continue with ICI therapy, and oral hypoglycemic medications can be started in patients with DM type 2. In patients with grade 2 toxicity, oral hypoglycemic medications can be up-titrated or patients can be started on insulin if diagnosed with type 1 DM or if the subtype is unclear. Patients with more than grade 3 toxicity will need insulin therapy and an endocrinology consult irrespective of the subtype. In this setting, ICI therapy should be withheld until blood sugars are controlled. Steroids have not shown any benefit in checkpoint induced DM. The role of other immunosupressive agents is not well defined, however, a case of checkpoint induced DM successfully treated with infliximab has been reported.
CAR T-CELL THERAPY AND BiTE THERAPY
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Hyperglycemia is frequently seen with both CAR T-cell therapy and with BiTE therapy; however, this is likely due to use of corticosteroids to prevent and treat neurotoxicity and CRS. Patients should be closely monitored with regular blood sugar monitoring, especially if they are diabetic. Insulin-based regimens are preferred due to risk of acute kidney injury, with CRS associated with both therapies. Patients who develop DKA should be managed on established protocols.
Non-Pharmacological Management
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Medical alert bracelets should be provided to patients with primary and secondary adrenal insufficiency. Patients should be made aware of the need to increase steroid dosage with concurrent illness. Similarly, doses should also be increased prior to any major surgery, in consultation with an endocrinologist. Patients with thyroid dysfunction and diabetes are at a higher risk of CHD, and risk factor for CHD should be optimized.
References
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