Toxicities associated with immune checkpoint inhibitors

INTRODUCTION — Immune checkpoint inhibitors (ICIs), also known as checkpoint inhibitor immunotherapy, are immunomodulatory antibodies that are used to enhance the immune system. These agents have substantially improved the prognosis for patients with many advanced malignancies.

The primary targets for checkpoint inhibition include (table 1):

●Programmed cell death receptor 1 and programmed cell death ligand 1 – Multiple antibodies against programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have been approved by the US Food and Drug Administration (FDA) or are in development and have shown great promise in multiple malignancies. Nivolumab, pembrolizumab, cemiplimab, dostarlimab, and retifanlimab, all of which target PD-1, and atezolizumab, avelumab, and durvalumab, all of which target PD-L1, have been approved for various indications.

●Cytotoxic T lymphocyte-associated antigen 4 – Ipilimumab and tremelimumab, anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies, are approved by the FDA, with others in development.

Despite important clinical benefits, ICIs are associated with a unique spectrum of side effects known as immune-related adverse events (irAEs) [1,2]. IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. IrAEs are believed to arise from general immunologic enhancement, and temporary immunosuppression with glucocorticoids, tumor necrosis factor-alpha antagonists, mycophenolate mofetil, or other agents can be an effective treatment in most cases. Although rare, fulminant and even fatal toxicities may occur with ICIs [3]. Therefore, prompt recognition and management of irAEs is important.

The side effects of the checkpoint-blocking antibodies targeting the PD-1 and PD-L1 receptors and CTLA-4 are reviewed here. The management approach to irAEs is presented based on clinical experience, since no prospective trials have been conducted to guide the treatment of irAEs. Principles of cancer immunotherapy are presented separately. (See "Principles of cancer immunotherapy".)

GENERAL PRINCIPLES — The American Society of Clinical Oncology (ASCO) organized a multidisciplinary panel that reviewed the literature and proposed both general guidelines and organ-systems-specific recommendations for the management of adverse events associated with ICIs [4]. The general approach is outlined in this section, and more specific recommendations are discussed below for the various toxicities. Our approach is consistent with those recommendations and those of the Society for Immunotherapy of Cancer [5].

Dose modifications and immunosuppressive therapy — In general, treatment of moderate or severe immune-related adverse events (irAEs) requires interruption of ICIs and immunosuppression with glucocorticoids. Patients should be carefully monitored during treatment for initial evidence of grade 1 adverse events. Treatment is based on the site of the irAE and the severity of the observed toxicity:

●Grade 1 irAEs – For most patients with grade 1 irAEs (asymptomatic or mild symptoms), immunotherapy may be continued, and patients may be closely monitored for worsening irAEs and/or managed symptomatically.

●Grade 2 irAEs – For most patients with grade 2 (moderate) immune-mediated toxicities (excluding endocrinopathies), treatment with immunotherapy should be withheld and should not be resumed until symptoms or toxicity is grade 1 or less. Glucocorticoids (prednisone 0.5 mg/kg/day or equivalent) should be started if symptoms do not resolve within one week.

•Grade 2 endocrinopathies – An exception is for patients who experience immune-mediated endocrinopathies but do not require immunosuppressive therapy. In such patients, depending upon the severity of symptoms, immunotherapy may be withheld until hormone replacement is initiated. Immunotherapy may subsequently be resumed once acute symptoms have resolved and (in the event of adrenal insufficiency or hypophysitis) patients are receiving adequate adrenal glucocorticoid replacement. (See 'Endocrinopathies' below and 'Retreatment after prior toxicity' below.)

●Grade 3 or 4 irAEs – For patients experiencing grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with immunotherapy is usually permanently discontinued. High doses of glucocorticoids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, glucocorticoids can be gradually tapered, typically over at least four weeks (table 2).

●Refractory toxicity – In the authors' experience, patients who will benefit from glucocorticoids generally do so within days to a week. If symptoms do not clearly improve or worsen on steroids, our approach is to administer an additional immunosuppressive agent. Examples of available agents include infliximab, vedolizumab, and mycophenolate mofetil, among other options.

The management of specific toxicities is discussed in the individual sections below.

Impact of immunosuppressive agents on immunotherapy efficacy — For patients who have required glucocorticoids or other immunosuppressive therapy, most data suggest that efficacy of the ICI is not impacted [6,7]. However, some studies suggest that either early use of corticosteroids (within two months) or second-line immunosuppressive therapy (in addition to corticosteroids) is associated with worsened survival outcomes [8,9]. Additionally, for patients being evaluated for retreatment with immunotherapy after experiencing an irAE, the concurrent use of immunosuppressive therapy is associated with reduced efficacy of immunotherapy. (See 'Retreatment after prior toxicity' below.)

Relationship between immunotherapy toxicities and efficacy — Most data suggest that irAEs are associated with either improved efficacy of immunotherapy (such as favorable response rates and prolonged survival [6,10-26]) or similar efficacy, compared with those without irAEs [7,27-30]. Although most clinicians commonly associate irAEs with treatment-related toxicity, the presence of an irAE is also a sign that the immune system is sufficiently activated to hopefully additionally target the patient's cancer. Therefore, management of irAEs should entail the minimum amount of immunosuppression needed to control symptoms and, in certain cases, holding therapy without initiating immunosuppression (eg, select immune-mediated endocrinopathies; asymptomatic hepatitis or pancreatitis). (See 'Dose modifications and immunosuppressive therapy' above and "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy".)

Predictive biomarkers of immunotherapy toxicity — The optimal biomarker to predict the risk of irAEs and as an aid in the early identification of such complications remains to be defined. In retrospective observational studies, biomarkers associated with higher risk of developing irAEs include clinical characteristics (eg, female sex [31]), germline and somatic genetic features, specific microbiome compositions [32], and circulating biomarkers [33].

Combining or sequencing immunotherapy with other therapies — In a variety of tumors, ICIs are being either combined or sequenced with other systemic agents (eg, chemotherapy, targeted therapies) and other treatment modalities (eg, radiation therapy [RT], allogeneic stem cell transplant) [34]. Such combinations result in varied toxicity profiles [35]. Clinicians should assess and treat the toxicities associated with each individual agent and remain aware of the potential for development of novel toxicities.

●Immunotherapy plus chemotherapy – Details on the efficacy and toxicity of immunotherapy plus chemotherapy in non-small cell lung cancer are discussed separately. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'PD-L1 low (<50 percent) or unselected tumors'.)

●Immunotherapy plus targeted therapy – For certain tumors, such as lung cancer, some combinations of immunotherapy with targeted therapies (either administered concurrently or close together) have been associated with serious and even potentially life-threatening toxicities. Accordingly, given the long half-life of ICIs, we do not combine immunotherapy with targeted therapies outside of a clinical trial, unless the safety of the combination has already been demonstrated.

The combination of immunotherapy with agents targeting the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) pathways have been associated with life-threatening irAEs (eg, pneumonitis, hepatitis) in patients with advanced non-small cell lung cancer. This is discussed separately. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Immune-related toxicities with EGFR TKI after immunotherapy' and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Efficacy of other approaches'.)

For other tumors, such as renal cell carcinoma, the combination of targeted therapy and immunotherapy has been more successful. Details on the efficacy and toxicity of immunotherapy plus antiangiogenic therapy targeting the vascular endothelial growth factor (VEGF) pathway in advanced renal cell carcinoma are discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma".)

In patients with metastatic melanoma, ICIs and BRAF plus MEK inhibitors have also been safely combined [36-41] and have regulatory approval in this setting. Further details on these combinations are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Is there a role for combined immunotherapy and targeted therapy?'.)

The combination of ipilimumab with BRAF and MEK inhibitors is not used in clinical practice because it has resulted in severe toxicities such as hepatotoxicity, rash, colitis, and intestinal perforation [36,37,42]. The individual efficacy of these agents in melanoma is discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

●Radiation therapy followed by immunotherapy – Data suggest that immunotherapy can be safely used after completion of radiation therapy in most cancers. As an example, in one observational study of 16,835 patients with cancer treated with various ICI regimens, the sequential use of immunotherapy within 90 days following RT was not associated with significantly increased rates of irAEs, compared with those who did not receive RT prior to immunotherapy [43].

●Allogeneic stem cell transplant after prior immunotherapy – The role of allogeneic stem cell transplantation after prior immunotherapy is discussed separately. (See "Treatment of extranodal NK/T cell lymphoma, nasal type", section on 'Relapsed or refractory disease' and "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

SYSTEMIC ADVERSE EVENTS

Fatigue — Fatigue is among the most common side effects seen, with an estimated overall frequency of 16 to 24 percent for the anti-programmed cell death receptor 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) agents [1] and approximately 26 percent in those treated with combination immunotherapy [44] However, the fatigue is generally mild, and severe fatigue is rare as a side effect of these agents. When fatigue is present, it is important to exclude thyroid, pituitary, and other endocrine disorders, such as primary adrenal insufficiency. Fever, chills, and infusion reactions have also been described, but these are also rare.

Infusion-related reactions — Mild infusion-related (grade 1 and 2) side effects have been reported in up to 25 percent of patients treated with agents that inhibit PD-1 or PD-L1. These infusion-related reactions are reported most commonly with avelumab, a PD-L1 inhibitor. For patients treated with avelumab, premedication with acetaminophen and an antihistamine is indicated during the first four cycles, and subsequently as needed [45]. We discourage premedicating or managing infusion-related reactions using glucocorticoids, because such reactions often improve with antihistamines alone. (See "Treatment of recurrent and metastatic Merkel cell carcinoma", section on 'Avelumab'.)

Immunotherapy is discontinued permanently for patients who experience life-threatening (grade 4) infusion reactions. The reported incidence of high-grade infusion-related reactions due to immunotherapy is rare (less than 2 percent). (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Agents targeting the programmed cell death receptor'.)

Management recommendations are summarized in the American Society of Clinical Oncology (ASCO) guidelines table (table 3) [4].

Cytokine release syndrome — Cytokine release syndrome (CRS) is an acute systemic inflammatory response syndrome characterized by fever with or without multiple organ dysfunction mostly described with chimeric antigen receptor (CAR)-T cell therapy. CRS has also been observed with ICIs, such as nivolumab [46,47]. The management of CRS in patients treated with ICIs and other antibody-mediated therapies is discussed separately. (See "Cytokine release syndrome (CRS)", section on 'Bi-specific antibody-associated CRS'.)

DERMATOLOGIC AND MUCOSAL TOXICITY — Cutaneous immune-related adverse events (irAEs) are the most common toxicity associated with ICIs. While the most common clinical manifestation is an inflammatory skin reaction, other presentations exist such as immunobullous disease, vasculitis, neutrophilic dermatoses, and, rarely, severe cutaneous drug reactions. The management of cutaneous irAEs is based upon severity and impact on the patient's functional status.

Further details on the clinical presentation, diagnosis, and management of cutaneous irAEs are discussed separately. (See "Mucocutaneous toxicities associated with immune checkpoint inhibitors".)

DIARRHEA/COLITIS — Diarrhea and colitis are the most frequently reported gastrointestinal immune-related adverse events (irAEs) in patients undergoing treatment with ICIs. Further details on the clinical presentation, diagnosis, and management of ICI colitis are discussed separately. (See "Immune checkpoint inhibitor colitis".)

HEPATOTOXICITY — Hepatotoxicity is a frequent complication of ICIs. Further details on the clinical presentation, diagnosis, and management of hepatotoxicity from ICIs are discussed separately. (See "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy".)

PNEUMONITIS

Epidemiology — Pneumonitis is an uncommon but potentially severe or fatal complication of treatment with ICI therapy [48-53], with an overall incidence of approximately 5 percent [50]. The incidence of ICI pneumonitis is lower in patients treated with an anti-programmed cell death receptor 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) monoclonal antibody (3 percent) versus those treated with an ICI combination that includes an anti-CTLA-4 antibody (10 percent) [50]. ICI pneumonitis is also more common in patients with lung cancer [54,55].

Clinical manifestations — Patients with ICI pneumonitis most commonly present with symptoms of dyspnea and cough (53 and 35 percent, respectively), while approximately one-third of patients are asymptomatic [50]. Most patients with ICI pneumonitis present with grade 1 or grade 2 involvement (table 4). More than half of patients with ICI pneumonitis may also present with another immune-related adverse event (irAE), such as colitis, dermatitis, or thyroiditis. (See 'Diarrhea/colitis' above and 'Dermatologic and mucosal toxicity' above and 'Endocrinopathies' below.)

The timing between initiation of ICI therapy and development of ICI pneumonitis varies, with a median of 2.8 months (range 9 days to 19 months), and occurs earlier for those treated with combination ICI therapy rather than single-agent therapy (median 2.7 versus 4.6 months) [50]. In some circumstances, pneumonitis can also present as a delayed irAE and occur more than one year after initiating therapy [56]).

ICI pulmonary toxicity may also manifest as a radiation recall pneumonitis limited to previously irradiated areas of the lung [57]. This phenomenon can occur when treatment is initiated years after radiation therapy.

Diagnosis

●When to suspect the diagnosis – The diagnosis of pneumonitis from ICI therapy should be suspected in patients on active treatment with an ICI who present with new or worsening cough, shortness of breath, dyspnea on exertion, and/or oxygen requirement. (See 'Clinical manifestations' above.)

●Differential diagnosis – Drug-induced pneumonitis is a diagnosis of exclusion. Therefore, patients with suspected ICI pneumonitis should also be evaluated for alternative diagnoses such as pulmonary embolism, infection (including coronavirus disease 2019 [COVID-19], which can mimic ICI pneumonitis), malignant pulmonary infiltration, congestive heart failure, and chronic obstructive pulmonary disease (COPD) exacerbation in those with a history of smoking (table 5). (See "Overview of acute pulmonary embolism in adults" and "Overview of community-acquired pneumonia in adults" and "COVID-19: Considerations in patients with cancer" and "Clinical manifestations and diagnosis of advanced heart failure" and "COPD exacerbations: Clinical manifestations and evaluation".)

●Diagnostic evaluation – For all patients with symptoms of ICI pneumonitis, the initial diagnostic evaluation includes physical examination and pulse oximetry. (See "Approach to the patient with dyspnea", section on 'Physical examination'.)

For patients with mild (grade 2 or lower (table 4)) symptoms, we obtain initial imaging with a chest radiograph (CXR). A CXR can be performed rapidly, and patients with normal imaging findings can often proceed with treatment if ICI pneumonitis is not suspected. In patients where there is a high index of suspicion for ICI pneumonitis (eg, persistent or progressive symptoms), we offer short-interval clinical follow-up and a contrast-enhanced computed tomography (CT) of the chest to reassess for mild or developing pneumonitis.

For patients with more severe (grade 3 or higher) symptoms or those with abnormal findings on an initial CXR, we refer to the emergency department for prompt evaluation, including a contrast-enhanced CT of the chest. A chest CT can demonstrate several radiographic patterns associated with ICI pneumonitis, although there is no one characteristic radiographic feature for this condition (figure 1). A contrast-enhanced chest CT can also assess for other potential diagnoses, such as pulmonary embolism, malignant pulmonary infiltration, or infection. In observational studies, a CXR did not detect new radiographic abnormalities in approximately one-fourth of patients with ICI pneumonitis [50,58-60].

Bronchoscopy is not usually necessary for the diagnosis of ICI pneumonitis; its use is typically reserved for patients with grade 2 or higher pneumonitis (table 4) whose diagnosis remains unclear after an initial evaluation or whose symptoms are unresponsive to a trial of glucocorticoids. A bronchoscopy can be used to assess for infection and, if necessary, obtain lung tissue to clarify the diagnosis [4,58,59]. However, the pathologic features for ICI pneumonitis are diverse and there is no one pathognomic finding. In one observational study that included 27 patients with ICI pneumonitis who underwent lung biopsy, histopathologic findings included cellular interstitial pneumonitis; organizing pneumonia; diffuse alveolar damage; or no abnormalities [50]. Interstitial inflammatory infiltrates included poorly formed granulomas or eosinophils.

Management — The management of pneumonitis is summarized in the American Society of Clinical Oncology (ASCO) guidelines table (table 5) [4]. There are no prospective clinical trials to define optimal management. Our treatment approach includes the following:

●For asymptomatic, grade 1 pneumonitis (table 4), we generally withhold drug for two to four weeks with close follow-up. If symptoms arise or there is radiographic progression, glucocorticoids are appropriate.

●Patients with grade 2 or higher pneumonitis should have their drug withheld and be treated using glucocorticoids with close follow-up. Additional immunosuppression may be used in patients with worsening of pneumonitis, with some evidence of benefit [61].

Outcomes from one observational study of 43 patients diagnosed with ICI pneumonitis provide some insight into the optimal management of this complication [50]. Overall, 15 of 17 asymptomatic patients (grade 1) were successfully managed by withholding the ICI, while 2 of the 17 and all 14 with grade 2 pneumonitis were successfully treated with glucocorticoids. All 12 patients with grade 3 or higher pneumonitis were initially treated with glucocorticoids. Five patients in this group required additional immunosuppression (infliximab with or without cyclophosphamide), but all five ultimately died. Of these five cases, infectious complications or progression of tumor appeared to be the proximal cause of death in four instances. The median starting dose of prednisone was 50 mg, and the median duration of treatment required was 68 days (range 20 to 154 days).

ENDOCRINOPATHIES — Inflammation of the pituitary, thyroid, or adrenal glands as a result of checkpoint blockade often presents with nonspecific symptoms such as nausea, headache, fatigue, and vision changes. The incidence of endocrinopathies has been difficult to precisely state due to variable methods of assessment, diagnosis, and monitoring in different clinical trials. The most common endocrinopathies are hypothyroidism, hyperthyroidism, and hypophysitis.

In a systematic review and meta-analysis that included 7551 patients in 38 randomized trials, the overall incidence of clinically significant endocrinopathies is approximately 10 percent of patients treated with ICIs [62]. The frequency of specific endocrinopathies and the relationship to different agents are discussed in this section.

The management of endocrine adverse events involving the thyroid, adrenal, pituitary, or endocrine pancreas is summarized in the American Society of Clinical Oncology (ASCO) guidelines table (table 6) [4].

Autoimmune thyroid disease — Thyroid function should be monitored prior to each dose of an ICI. Autoimmune thyroid disease can be manifested as primary hypothyroidism secondary to a destructive thyroiditis or as hyperthyroidism associated with Graves disease.

Hypothyroidism — Most commonly, thyroid disorders present with nonspecific symptoms such as fatigue. Since these symptoms can be vague, distinguishing primary thyroid disorders from secondary hypothyroidism (typically a result of hypophysitis) is critical to a thorough differential diagnosis.

●Typically, a high thyroid-stimulating hormone (TSH) with low free thyroxine (T4) indicates primary hypothyroidism.

●A low TSH with low free T4 indicates secondary hypothyroidism and likely hypophysitis. In such patients, levothyroxine should not be administered until patients have been evaluated for secondary adrenal insufficiency and, if diagnosed, treated with cortisol replacement. (See 'Hypophysitis' below and "Treatment of hypopituitarism", section on 'TSH deficiency'.)

●Often a period of thyroiditis with transient hyperthyroidism (low TSH and high free T4) precedes longstanding hypothyroidism (high TSH and low free T4) [63]. For such patients, we do not suggest initial treatment of the hyperthyroid phase with anti-thyroid medication, since the phase is usually brief and almost invariably leads hypothyroidism. Instead, for select patients with significant symptoms attributed to hyperthyroidism, we suggest evaluating patients for the use of beta-blockers or other supportive medications. (See 'Hyperthyroidism' below.)

For patients treated with ipilimumab, nivolumab or pembrolizumab, atezolizumab, and the combination of nivolumab plus ipilimumab, the incidence rates for hypothyroidism were 3.8, 7, 3.9, and 13.2 percent, respectively [62]. There was no significant difference in incidence with nivolumab and pembrolizumab (6.5 and 7.9 percent, respectively).

Management of primary hypothyroidism typically involves replacement with thyroid hormone (levothyroxine) and endocrinology consultation.

Hyperthyroidism — Persistent primary hyperthyroidism is significantly less frequent than hypothyroidism and should be treated similarly to primary hyperthyroidism. The key to managing hyperthyroidism is to ensure it is persistent (eg, for at least two to three months) and not the initial transient hyperthyroid phase of thyroiditis that often leads to hypothyroidism. (See 'Hypothyroidism' above and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment".)

For patients treated with ipilimumab, nivolumab or pembrolizumab, atezolizumab, and the combination of nivolumab plus ipilimumab, the incidence rates for hyperthyroidism were 1.7, 3.2, 0.6, and 8 percent, respectively [62].

Hypophysitis

Clinical presentation and diagnosis — Typically, hypophysitis is manifested by clinical symptoms of fatigue and headache. The diagnosis is established by low levels of the hormones produced by the pituitary (adrenocorticotropic hormone [ACTH], TSH, follicle-stimulating hormone [FSH], luteinizing hormone [LH], growth hormone [GH], prolactin). (See "Clinical manifestations of hypopituitarism".)

Laboratory findings differentiate hypophysitis from primary adrenal insufficiency (manifested by low cortisol or inappropriate cortisol stimulation test and high ACTH) and primary hypothyroidism (manifested by low free T4 and high TSH). The diagnosis of hypophysitis is often supported radiographically by enhancement and swelling of the pituitary gland on magnetic resonance imaging of the brain (image 1) [64,65].

For patients treated with ipilimumab, nivolumab or pembrolizumab, atezolizumab, and the combination of nivolumab plus ipilimumab, the incidence rates for hypophysitis were 3.2, 0.4, <0.1, and 6.4 percent, respectively [62].

Management — In most patients, long-term supplementation of the affected hormones is necessary due to secondary hypothyroidism (treated with levothyroxine) or secondary adrenal insufficiency (treated with replacement doses of hydrocortisone, typically 20 mg each morning and 10 mg each evening). In some cases, patients can be successfully weaned from replacement steroids over time [66].

High doses of steroids are not typically needed to manage hypophysitis and have been associated with worse clinical outcomes [67]. However, for the rare patient who presents with pituitary compressive symptoms (eg, headache, double vision), a short course of high-dose corticosteroids (eg, prednisone 0.5 to 1 mg/kg daily for approximately one week) can be administered to alleviate such symptoms. (See "Treatment of hypopituitarism".)

Adrenal insufficiency — Adrenal insufficiency is a potentially life-threatening endocrinopathy which can cause dehydration, hypotension, and electrolyte imbalances (hyperkalemia, hyponatremia) and constitutes an emergency. Adrenal insufficiency is rare and has been reported in 0.7 percent of patients treated in randomized clinical trials [62].

When an adrenal crisis is suspected, intravenous glucocorticoids and immediate hospitalization is warranted. Consultation with an endocrinologist, aggressive hydration, and evaluation for sepsis are also critical. (See "Clinical manifestations of adrenal insufficiency in adults" and "Treatment of adrenal insufficiency in adults".)

Type 1 diabetes mellitus — Treatment with ICIs has been associated with acute onset of type 1 diabetes mellitus in approximately 0.2 to 0.9 percent of cases [62,68]. As examples, in several case series, patients typically presented with severe hyperglycemia or diabetic ketoacidosis; all required insulin therapy at diagnosis and remained insulin-dependent for diabetic control [68,69].

It is important to monitor glucose with each dose of immunotherapy. Patients who develop immunotherapy-induced type 1 diabetes mellitus are typically treated with insulin therapy. In contrast to other immune-related adverse events, treatment with glucocorticoids or other immunosuppressive agents is not effective in these patients, due to the almost complete destruction of the pancreatic beta cells by immunotherapy [68]. Immunotherapy-related diabetes may be suggested when the C-peptide level is low in the setting of hyperglycemia. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment" and "Management of blood glucose in adults with type 1 diabetes mellitus".)

OPPORTUNISTIC INFECTIONS

Risk with immunosuppressive therapy — For most patients with no underlying pulmonary conditions receiving glucocorticoids for less than six weeks to treat an uncomplicated immune-related adverse event (irAE), we do not suggest Pneumocystis pneumonia (PCP) prophylaxis. Although PCP prophylaxis is often administered to patients on prolonged courses of glucocorticoids for other indications, it may not be necessary for those receiving them for an uncomplicated irAE. The incidence of opportunistic infections in patients with an irAE is low in observational studies, ranging between 2 and 7 percent [70,71]. Additionally, glucocorticoids in this patient population theoretically do not induce greater immunosuppression, but rather reduce immune activation from the ICI. This approach differs from the typical use of PCP prophylaxis in other HIV-uninfected patients. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

However, prolonged immune suppression may put certain patients at risk for unusual or opportunistic infections. We offer PCP prophylaxis to patients receiving glucocorticoids for an irAE in the setting of combined chemotherapy plus immunotherapy; those with underlying pulmonary conditions receiving glucocorticoids for an uncomplicated irAE; or those with a complicated irAE (eg, those requiring longer than six weeks of glucocorticoids, or those not responsive to glucocorticoids requiring additional immunosuppressive therapy). The role of prophylactic antifungal or antiviral therapies in these patients requires further study.

●In one series of 740 patients treated for advanced melanoma [70], approximately 80 percent of patients had been treated with ipilimumab, either alone or in combination with nivolumab. Serious infections were reported in 54 cases (7.3 percent). Specific infectious etiologies were bacterial, viral, fungal, and parasitic in 46, 6, 5, and 1 cases, respectively.

These infections were predominantly seen in association with glucocorticoids or infliximab. The incidence of serious infections was lower in those treated with nivolumab and pembrolizumab alone compared with ipilimumab or nivolumab plus ipilimumab, but this may have reflected the lower incidence of serious side effects necessitating immunosuppression.

Further details on the use of PCP prophylaxis in HIV-uninfected patients are discussed separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)

LESS COMMON IMMUNE-RELATED ADVERSE EVENTS — Treatment with ICIs has also been associated with less common side effects in other organs. In some instances, these side effects have been severe or fatal.

Kidney — Acute kidney injury (AKI) is a rare but potentially serious complication of ICIs [72]. For patients with severe ICI-associated acute kidney injury (ICI-associated AKI), holding ICIs and treatment with glucocorticoids are indicated. One retrospective study suggested that patients with ICI nephritis treated with rapid glucocorticoid taper (over three weeks) had equivalent kidney recovery compared with those treated with longer glucocorticoid tapers (over six weeks) [73].

For patients whose kidney function improves, rechallenging with immunotherapy is a reasonable strategy. In one observational study of 429 patients with ICI-associated AKI, among the subset of patients who were subsequently rechallenged with immunotherapy, approximately 84 percent did not develop recurrent ICI-associated AKI [74]. (See 'Retreatment after prior toxicity' below.)

The estimated incidence of ICI-associated AKI is approximately 1.5 to 5 percent [75-77]. The most common reported underlying pathology is acute tubulointerstitial nephritis (image 2), but immune complex glomerulonephritis and thrombotic microangiopathy have also been observed [74,78-80].

The management of kidney toxicities is summarized in the American Society of Clinical Oncology (ASCO) guidelines table (table 7) [4].

Exocrine pancreas — The clinical presentation, diagnosis, and management of exocrine pancreatic toxicities associated with ICIs are discussed separately. (See "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy", section on 'Exocrine pancreas'.)

Neurologic — A wide range of neurologic syndromes have been associated with checkpoint blockade involving ipilimumab and programmed cell death receptor 1 (PD-1) pathway inhibitors [81-83]. Case series suggest that neurotoxicity occurs in approximately 1 to 14 percent of patients, with the highest rates associated with the use of combined immunotherapy using nivolumab plus ipilimumab [84-86]. As an example, in a review of approximately 9000 patients, the incidence of neurologic immune-related adverse events (irAEs) was 4 percent with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, 6 percent with PD-1 inhibitors, and 12 percent with combined CTLA-4 and PD-1 inhibition [87].

The most common symptoms are headache and peripheral sensory neuropathy. Neurologic complications associated with more severe toxicity include Guillain-Barré syndrome [88,89] and myasthenia gravis [1,90]. In some cases, myasthenia gravis may co-occur with inflammatory myositis and myocarditis and is associated with high fatality rates [91]. (See 'Cardiovascular toxicity' below and 'Rheumatologic and musculoskeletal' below.)

Other reported severe neurologic complications include posterior reversible encephalopathy syndrome [92], aseptic meningitis [93,94], enteric neuropathy [95], transverse myelitis [96], pancerebellitis [97], autoimmune encephalitis [98], and cranial and peripheral neuropathies. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Checkpoint inhibitor-associated neuropathies'.)

Neurologic irAEs typically develop within three months of starting ICI therapy, although the time of onset may vary [99]. Serious neurologic irAEs should be treated with glucocorticoids, even when the non-immunotherapy-induced version of the same neurologic disorder is not typically managed with glucocorticoids (such as Guillain-Barré syndrome). Consultation with neurology is indicated to consider additional treatment, such as plasmapheresis and intravenous immunoglobulin. Early recognition and intervention are key to reducing severity and duration of toxicity. As an example, in one observational study of 35 patients treated for neurologic irAEs, symptoms resolved in 26 patients (75 percent), with a median time to resolution of approximately one month [85].

The management of patients with immunotherapy-related neurologic toxicity is summarized in the ASCO guidelines table (table 8) [4].

Neurologic toxicities associated with other molecularly targeted and biologic agents are discussed separately. (See "Neurologic complications of cancer treatment with molecularly targeted and biologic agents".)

Cardiovascular toxicity — Cardiotoxicity may develop in the absence of a history of significant cardiac risk factors. Cardiac irAEs include myocarditis, pericarditis, heart failure, arrythmias, and vasculitis [100,101]. Venous thromboembolism may also be seen, although its relationship to ICIs is less clear.

●Myocarditis – The time to onset was variable, but fatal myocarditis has been reported after a single treatment with the combination of nivolumab plus ipilimumab [102]. Observational studies also suggest that the incidence of myocarditis is higher in patients treated with the combination immunotherapy compared with single-agent immunotherapy [103].

High-dose corticosteroids (ie, prednisone 1 to 2 mg/kg/day) have been used to treat cardiac complications, but symptoms may progress in some cases despite aggressive therapy. Immediate transfer to a coronary care unit or, if available, cardiac transplant unit should be considered for patients with elevated troponin or conduction abnormalities. Concurrent skeletal muscle involvement (myositis) may also complicate therapy, as diaphragm involvement may lead to respiratory failure.

Patients without an immediate response to high-dose corticosteroids should be treated promptly with cardiac transplant rejection doses of steroids (methylprednisolone 1 g every day) and the addition of either mycophenolate, infliximab, or antithymocyte globulin. Abatacept [104] or alemtuzumab may be used as additional immunosuppression in life-threatening cases.

The management of ICI-associated myocarditis and other ICI-related cardiovascular toxicities is summarized in the ASCO guidelines table (table 9) [4].

●Acute pericarditis – The management of acute pericarditis associated with the use of ICIs is discussed separately. (See "Pericardial disease associated with cancer: Management", section on 'Immune checkpoint inhibitor-associated pericarditis'.)

Hematologic — Various hematologic irAEs have been described in patients treated with ICIs. These include immune thrombocytopenic purpura, autoimmune hemolytic anemia, hemophagocytic lymphohistiocytosis, red cell aplasia, neutropenia, acquired hemophilia A, and cryoglobulinemia, among others [105-117]. As with other irAEs, the standard approach is initial glucocorticoid treatment with the addition of other immunosuppressive agents if symptoms are glucocorticoid refractory. The management of common hematologic toxicities is summarized in the ASCO guidelines table (table 10) [4].

Select hematologic irAEs are discussed below:

●Immune thrombocytopenic purpura – Immune thrombocytopenic purpura (ITP) is likely the most common hematologic irAE, although it occurs in approximately 1 percent of patients treated with ICIs. Peripheral blood smear and routine work-up for thrombocytopenia should be performed to rule out other rare causes of thrombocytopenia, including thrombotic thrombocytopenic purpura. Spontaneous resolution is common in mild cases. While glucocorticoids are effective for more severe cases of ITP, the addition of other immunosuppressive agents may also be necessary (such as intravenous immunoglobulin, thrombopoietin receptor agonists, and rituximab) [111,112]. Further details on the management of ITP are discussed separately. (See "Initial treatment of immune thrombocytopenia (ITP) in adults" and "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults".)

●Autoimmune hemolytic anemia – Autoimmune hemolytic anemia (AIHA) has been associated with the use of multiple immunotherapy agents (eg, atezolizumab, nivolumab, pembrolizumab, and ipilimumab) [113,114]. The treatment approach to immunotherapy-induced AIHA is similar to that of AIHA due to other drugs, which includes holding immunotherapy and initiation of glucocorticoid-based therapy. One observational study demonstrated that patients with immunotherapy-induced AIHA may have a negative direct antibody test (DAT), and most patients also resume immunotherapy without recurrent AIHA [115]. Further details regarding the diagnosis and management of this general condition are discussed separately. (See "Drug-induced hemolytic anemia".)

●Hemophagocytic lymphohistiocytosis – Hemophagocytic lymphohistiocytosis (HLH) has been reported in patients receiving immunotherapy with nivolumab, ipilimumab, and/or pembrolizumab [116,117]. This is a rare but potentially fatal syndrome of excessive immune activation resulting in multi-organ failure, including cytopenias and bleeding. Further data are needed to confirm the association of either the PD-1 pathway or CTLA-4 inhibition with the development of HLH. Details regarding the treatment of HLH are discussed separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Eye — CTLA-4 blockade with ipilimumab has been associated with eye inflammation, which can be manifested by episcleritis, conjunctivitis, uveitis, or orbital inflammation. The incidence is less than 1 percent, and symptoms can include photophobia, pain, dryness of the eyes, and blurred vision.

Intraocular inflammation (uveitis) following treatment with pembrolizumab or nivolumab is a rare but clinically important event described in approximately 1 percent of treated patients. Although the available data are limited, the risk of eye disorders may be aggravated when drugs of both ICI classes are combined. (See "Ocular side effects of systemically administered chemotherapy", section on 'Anti-PD-1 and PD-L1 agents'.)

An ophthalmology consultation is recommended, and treatment with topical glucocorticoids (eg, 1 percent prednisolone acetate suspension) may be helpful. Oral glucocorticoids can be used for severe (grade 3/4) or refractory cases. The management of eye toxicity is summarized in the ASCO guidelines table and discussed in detail separately (table 11). (See "Ocular side effects of systemically administered chemotherapy", section on 'Ipilimumab'.)

Rheumatologic and musculoskeletal — A wide range of rheumatologic toxicities has been observed with ICIs. These include myositis, inflammatory arthritis, salivary gland dysfunction (sicca syndrome), and vasculitis, among others [118-122]. The incidence of these side effects has not been clearly determined. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy".)

Myositis can also be seen with ICIs and is occasionally severe/fatal. Given the possibility of severe cases, Health Canada issued a safety alert urging recognition and management of myositis [123]. Patients who have significant myositis should be evaluated for myocarditis since these syndromes commonly manifest together. (See 'Cardiovascular toxicity' above.)

The management of musculoskeletal toxicities is summarized in the ASCO guidelines table (table 12) [4].

RETREATMENT AFTER PRIOR TOXICITY — Retreatment with ICIs may be safely offered to most patients with significant immune-related adverse events (irAEs) during initial treatment that consists of either a cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor and/or a programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor [124-131].

The choice to retreat is dependent on multiple factors, including the severity and nature of the initial irAE, its degree of responsiveness to systemic immunosuppression, and the availability of alternative treatment options. Clinicians should also provide a careful risk-benefit discussion to patients who are candidates for retreatment.

Data are limited on the specific patient populations who should not be offered retreatment with ICIs, and clinical judgment is necessary. As examples:

●Patients who survive a frequently fatal irAE (eg, myocarditis) are not routinely offered retreatment.

●Similarly, retreatment is discouraged in those actively receiving glucocorticoid doses equivalent to prednisone 10 mg daily or higher for treatment of an initial irAE, as the concurrent use of glucocorticoids is associated with reduced efficacy of immunotherapy [132]. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Impact of steroids on efficacy of immunotherapy'.)

●Data are also limited for the oncologic benefits of retreatment in those experiencing an initial irAE, particularly in those who have had a complete or sustained response to the initial regimen and do not require further intervention. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'What is the optimal duration of immunotherapy?'.)

For patients who are candidates for retreatment with ICIs, dose reductions are not recommended with retreatment, as this approach has not been assessed in clinical trials. The optimal choice of agent also varies based on clinical practice. Patients who experience severe toxicity from an initial regimen containing a CTLA-4 inhibitor are generally offered retreatment with single-agent PD-1 or PD-L1 inhibitors rather than rechallenging with a CTLA-4 inhibitor.

In studies of patients who are retreated with various classes of ICIs (table 1), the rate of recurrent irAEs for PD-1 or PD-L1 inhibitors ranges between 18 and 55 percent; however, a majority of these irAEs are mild and managed successfully with immunosuppressive therapy [124,126-129,133]. In patients with irAEs from combination PD-1 plus CTLA-4 inhibition, approximately 20 percent had recurrence of irAE with resumption of single agent PD-1 inhibitors [127]. In contrast, retreatment with CTLA-4 inhibitors are associated with the highest rates of recurrent irAEs (up to 88 percent in one study [124]).

The approach to resuming immunotherapy after ICI colitis and ICI hepatitis are discussed separately. (See "Immune checkpoint inhibitor colitis", section on 'Resuming immune checkpoint inhibitors' and "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy", section on 'Resuming immunotherapy after prior toxicity'.)

PATIENTS WITH VULNERABILITIES TO IMMUNOTHERAPY TOXICITIES

Pre-existing autoimmune disease — In patients with pre-existing autoimmune disease, there are limited data on the safety and efficacy of ICIs [30,134]. Such patients were excluded from clinical trials evaluating immunotherapy due to concerns about exacerbating underlying autoimmune disease or immune-related adverse events (irAEs) [135]. Observational studies suggest that most patients with autoimmune disease can safely receive ICIs [30,126,136-141]. However, compared with those without autoimmune disease, these patients may be at higher risk for specific irAEs (eg, immune-mediated colitis in those with inflammatory bowel disease [IBD], cardiovascular irAEs [142]) or discontinuing immunotherapy due to irAEs [30]; they may also be at high risk for developing an exacerbation of their underlying autoimmune disorders [126,135-137,139,143].

Clinicians should offer such patients a cautious risk-benefit discussion prior to initiating immunotherapy and evaluate various factors including the effectiveness of immunotherapy for the underlying malignancy; performance status and comorbidities; and type and severity of the autoimmune condition. Patients should also be evaluated for contraindications to immunotherapy (eg, poorly controlled autoimmune disease, active immunosuppression using the equivalent of prednisone 10 mg daily or higher) that require alternative therapies for their cancer [144]. Immunotherapy should be used with extreme caution or avoided in patients with potentially life-threatening autoimmune conditions [145]. We also recommend discussion of treatment options with both the patient and the clinician responsible for treating their autoimmune condition before determining a specific plan of action. Further details on the general approach to managing irAEs in patients with specific autoimmune disorders are discussed separately. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy", section on 'General principles of evaluation and management' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Defining immunotherapy eligibility'.)

In a prospective observational cohort study of 4367 patients with advanced melanoma, 415 patients (10 percent) with autoimmune disease were identified [30]. This cohort included 227 patients with rheumatologic disease (rheumatoid arthritis, systemic lupus erythematosus, and others); 143 patients with endocrine disease (hypo- or hyperthyroidism, Graves disease); 155 patients with IBD; 8 patients with "other" autoimmune conditions, and 20 with multiple autoimmune conditions. Of note, patients with autoimmune disease and active immunosuppression were more likely to receive alternative initial therapy (eg, BRAF plus MEK inhibitors) rather than immunotherapy.

Among the 55 percent who received immunotherapy (228 patients), the incidence of grade ≥3 irAEs was similar to that seen in a cohort of patients with advanced melanoma and no autoimmune disease, regardless of the choice of immunotherapy (30 percent each for a cytotoxic T lymphocyte-associated antigen 4 [CTLA-4] inhibitor; 17 versus 13 percent for a programmed cell death receptor 1 [PD-1] inhibitor; and 44 versus 48 percent for combination immunotherapy). Among those treated with PD-1 inhibitors, patients with autoimmune disease were more likely to discontinue immunotherapy due to irAEs compared with those without autoimmune disease (17 versus 9 percent). Patients with IBD treated with PD-1 inhibitors were more likely to develop immunotherapy-induced colitis (6 of 31 patients [19 percent]) versus those with other (non-IBD) autoimmune diseases (3 percent) and those without autoimmune disease (2 percent), which is consistent with prior studies [135]. However, data on acute flares of patients' pre-existing autoimmune condition were not reported.

Objective response rates and overall survival were similar for those with and without autoimmune disease, although this could be biased by the imbalance of baseline treatment characteristics between the two groups. The impact of other immunosuppressive agents (eg, infliximab or vedolizumab) on clinical outcomes is not known. In addition, approximately one-third of the study population was comprised of patients with thyroid disease (for whom there is less concern regarding irAEs). However, this study did not include patients with more rare, potentially fatal autoimmune conditions/irAEs (eg, myositis, myasthenia gravis, and Guillain-Barré syndrome) [3]. (See 'Relationship between immunotherapy toxicities and efficacy' above.)

Older adult patients — Data suggest that ICIs have similar efficacy and toxicity in older adults as in younger adults, and that chronologic age alone should not preclude the use of these agents [146-150].

A meta-analysis of nine randomized trials that compared nivolumab, pembrolizumab, or atezolizumab with chemotherapy or targeted therapy in solid tumors (non-small cell lung cancer, melanoma, renal cell carcinoma, head and neck cancer) analyzed efficacy in 5458 patients [146]. There was a consistent overall survival advantage for immunotherapy across all trials (hazard ratio [HR] 0.69, 95% CI 0.63-0.74), and there was no difference between those <65 years (HR 0.68, 95% CI 0.61-0.75) and those ≥65 years (HR 0.64, 95% CI 0.54-0.76). An analysis of progression-free survival based on age was available in four trials. There was no significant difference between the two age cohorts (HR 0.73, 95% CI 0.61-0.88, and HR 0.74, 95% CI 0.6-0.92, respectively). However, limitations of this meta-analysis include the potential lack of applicability to those with an impaired performance status or significant comorbidity, the limited number of patients 75 years or older, and the lack of relative toxicity data in the older adult population versus younger patients.

Another retrospective study in approximately 900 patients age 80 years or older treated with ICIs showed similar efficacy and severe toxicity rates compared with younger patients [149]. Of note, the oldest population (≥90 years old) frequently discontinued therapy due to irAEs, even though these were often low grade.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of toxicities due to checkpoint inhibitor immunotherapy".)

SUMMARY AND RECOMMENDATIONS

●Definitions – Immune checkpoint inhibitors (ICIs), also known as checkpoint inhibitor immunotherapy, are antibodies that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death receptor 1 (PD-1), and programmed cell death ligand 1 (PD-L1). (See 'Introduction' above.)

•ICIs are widely used in the treatment of various types of cancer.

•Despite important clinical benefits, ICIs are associated with a unique spectrum of side effects known as immune-related adverse events (irAEs).

●Impact of immunotherapy agent on irAEs – IrAEs are more common with agents that target CTLA-4 (ipilimumab, tremelimumab) than agents that target PD-1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab) or PD-L1 (atezolizumab, durvalumab, avelumab (table 1)). The combination of nivolumab plus ipilimumab is associated with more toxicity than either agent alone. (See 'General principles' above.)

●Common irAEs – Although many sites can be affected, the most common and important irAEs are:

•Dermatologic (see "Mucocutaneous toxicities associated with immune checkpoint inhibitors")

•Diarrhea/colitis (see "Immune checkpoint inhibitor colitis")

•Hepatotoxicity (see "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy", section on 'Hepatotoxicity')

•Pneumonitis (see 'Pneumonitis' above)

•Endocrinopathies (see 'Endocrinopathies' above)

●Less commonly affected sites – Less commonly affected sites include the kidney, exocrine pancreas, central nervous system, cardiovascular, hematologic, eye, and rheumatologic and musculoskeletal systems. (See 'Less common immune-related adverse events' above.)

●Treatment approach – Rapid identification of irAEs and prompt initiation of immunosuppression can optimize outcomes. In general, treatment of moderate or severe irAEs requires interruption of ICIs and immunosuppression with glucocorticoids. Treatment is based on site of the irAE and the severity of the observed toxicity (see 'General principles' above):

•Grade 1 irAEs – For most patients with grade 1 irAEs (asymptomatic or mild symptoms), immunotherapy may be continued, and patients may be closely monitored for worsening irAEs and/or managed symptomatically.

•Grade 2 irAEs – For most patients with grade 2 (moderate) immune-mediated toxicities, treatment with immunotherapy should be withheld and should not be resumed until symptoms or toxicity is grade 1 or less. Glucocorticoids (prednisone 0.5 mg/kg/day or equivalent) should be started if symptoms do not resolve within one week.

-Grade 2 endocrinopathies – For those with grade 2 immune-mediated endocrinopathies, immunotherapy may be withheld until hormone replacement is initiated and subsequently resumed once acute symptoms have resolved and (in the event of adrenal insufficiency or hypophysitis) patients are receiving adequate adrenal glucocorticoid replacement.

•Grade 3 or 4 irAEs – For patients experiencing grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with the immunotherapy is usually permanently discontinued. High doses of glucocorticoids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, glucocorticoids can be gradually tapered over at least one month.

•Refractory toxicity – If glucocorticoids are not effective, our approach is to administer an additional immunosuppressive agent (eg, infliximab, vedolizumab, mycophenolate mofetil, among other options).

●Communication – Frequent and consistent communication between patients, caregivers, and the clinical team is vital to successful irAE management.

●Immunotherapy plus other agents – Immunotherapy in combination with other systemic agents may result in varied toxicity profiles. Clinicians should assess and treat the toxicities associated with each individual agent and remain aware of the potential for development of novel toxicities. (See 'Combining or sequencing immunotherapy with other therapies' above.)

●Indications for PCP prophylaxis – For patients with no underlying pulmonary conditions receiving glucocorticoids for less than six weeks to treat an uncomplicated irAE, we suggest observation rather than pharmacologic Pneumocystis pneumonia (PCP) prophylaxis (Grade 2C).

We offer PCP prophylaxis to patients receiving glucocorticoids for an irAE in the setting of combined chemotherapy plus immunotherapy; those with underlying pulmonary conditions receiving glucocorticoids for an uncomplicated irAE; or those with a complicated irAE (eg, those requiring longer than six weeks of glucocorticoids or additional immunosuppressive therapy). (See 'Opportunistic infections' above.)

●Pre-existing autoimmune disease

•In patients with pre-existing autoimmune disease receiving immunotherapy, limited observational data suggest a similar incidence of overall irAEs compared with those without autoimmune disease, but a potentially higher risk for developing specific irAEs (eg, immune-mediated colitis in patients with inflammatory bowel disease) and/or discontinuing therapy. (See 'Pre-existing autoimmune disease' above.)

•Although data suggest that most patients with autoimmune disease can safely receive immunotherapy, clinicians should offer a cautious risk-benefit discussion prior to initiating therapy, evaluate for contraindications (eg, poorly controlled autoimmune disease, active immunosuppression) that require alternative therapies, and involve the clinician treating the patient's autoimmune condition.

●Retreatment after prior toxicity – Retreatment with ICIs may be safely offered to most patients with significant irAEs during initial treatment with immunotherapy, after a risk-benefit discussion. The choice to retreat is dependent on multiple factors, including the severity and nature of the initial irAE, its degree of responsiveness to systemic immunosuppression, the clinical response to the initial immunotherapy regimen, and the availability of alternative treatment options. (See 'Retreatment after prior toxicity' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jedd Wolchok, MD, PhD, who contributed to earlier versions of this topic review.