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INTRODUCTION — Checkpoint inhibitors, immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis for patients with advanced melanoma and are likely to significantly improve the treatment of advanced disease in a number of other malignancies.
The primary targets for checkpoint inhibition include:
●Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) – Multiple antibodies against PD-1 and PD-L1 are in development and have shown great promise in multiple malignancies. Nivolumab and pembrolizumab, both of which target PD-1, and atezolizumab, avelumab, and durvalumab, all of which target PD-L1, have been approved in various indications (eg, melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck cancer, urothelial carcinoma, Hodgkin lymphoma, Merkel cell carcinoma, as well as microsatellite instability-high or mismatch repair deficient [dMMR] solid tumors).
●Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) – Ipilimumab, an anti-CTLA-4 antibody, is approved for use in patients with advanced melanoma, based upon a significant improvement in overall survival. Another anti-CTLA-4 antibody (tremelimumab) is under development.
Despite important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs) or, occasionally, adverse events of special interest [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 corticosteroids, tumor necrosis factor-alpha antagonists, mycophenolate mofetil, or other agents can be an effective treatment in most cases.
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 upon clinical experience, since no prospective trials have been conducted to guide the treatment of irAEs. The majority of data are derived from patients with advanced melanoma who were treated with ipilimumab, nivolumab, and pembrolizumab.
The rationale of immunotherapy and the efficacy of checkpoint inhibitors are presented separately. (See "Principles of cancer immunotherapy" and "Immunotherapy of advanced melanoma with immune checkpoint inhibition" and "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'PD-1 blocking antibodies'.)
GENERAL APPROACH TO TOXICITY MANAGEMENT
Dose modifications and immunosuppressive therapy — General guidelines for the management of immune-related adverse events (irAEs) caused by checkpoint inhibitors are incorporated in the US Food and Drug Administration (FDA) Risk Evaluation and Management Strategies for ipilimumab . These guidelines are incorporated into recommendations for specific toxicities below. Although the side effects of anti-programmed cell death receptor 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) monoclonal antibodies appear to be less severe than with ipilimumab, a similar approach is expected to apply to other immune checkpoint inhibitors as they become available.
In general, treatment of moderate or severe irAEs requires interruption of the checkpoint inhibitor and the use of corticosteroid immunosuppression. Treatment is based upon the severity of the observed toxicity:
●For patients with grade 2 (moderate) immune-mediated toxicities, treatment with the checkpoint inhibitor should be withheld and should not be resumed until symptoms or toxicity is grade 1 or less. Corticosteroids (prednisone 0.5 mg/kg/day or equivalent) should be started if symptoms do not resolve within a week.
●For patients experiencing grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with the checkpoint inhibitor should be permanently discontinued. High doses of corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, steroids can be gradually tapered over at least one month.
In the authors' experience, patients who will benefit from corticosteroids generally do so within days. If symptoms do not clearly improve, particularly after approximately three days with intravenous steroids, our approach is to administer infliximab (5 mg/kg) rather than continue with a prolonged course of high-dose IV corticosteroids. If symptoms persist after the first infliximab dose, a second dose of infliximab (5 mg/kg) can be repeated two weeks after the initial dose.
The approach to the management of specific toxicities is discussed in the individual sections below.
Impact of immunosuppression on efficacy — The need for immunosuppressive therapy to manage irAEs does not appear to affect the response to checkpoint inhibition with either anti-PD-1 antibodies or ipilimumab.
●Anti-PD-1 antibodies – IrAEs are significantly less frequent with the anti-PD-1 antibodies compared with ipilimumab.
In an analysis of 576 patients with advanced melanoma treated in four clinical trials, 24 percent received immunosuppressive therapy for the management of treatment-related adverse events . There was no significant difference in the objective response rate between those who received immunosuppressive treatment and those who did not (29.8 versus 31.8 percent). The median duration of response was not reached in those with immunosuppressive therapy, compared with 22 months in those not requiring immunosuppressive therapy.
●Ipilimumab – The most extensive data with ipilimumab come from a single-institution experience that analyzed the incidence of irAEs and treatment outcomes in 298 melanoma patients treated with ipilimumab (3 mg/kg) outside of a clinical trial setting . IrAEs were seen in 254 patients (85 percent), and 103 patients (35 percent) required corticosteroids. Anti-tumor necrosis factor-alpha therapy was used in 29 cases (10 percent) who did not respond promptly to corticosteroids.
The median overall survival was 16.5 months, and the estimated two-year survival rate was 39 percent for the entire cohort. Overall survival was the same in patients who had an irAE compared with those without an irAE, and there was no difference between those requiring corticosteroids and those not requiring immunosuppressive therapy. The time to treatment failure, defined as the need for alternative therapy or death, was 5.7 months for the entire cohort. As with overall survival, there were no significant differences between those with and without an irAE or between those treated with corticosteroids and those not receiving corticosteroids.
Opportunistic infections in immunosuppressed patients — Prolonged immune suppression is typically used to treat immune-related adverse events (irAEs). Thus, these patients may be at risk for the development of unusual or opportunistic infections.
The most extensive data come from a single-institution series of 740 patients treated for advanced melanoma . 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 corticosteroids or infliximab. The incidence of serious infections was lower in those treated with nivolumab and pembrolizumab alone compared with ipilimumab or ipilimumab plus nivolumab, but this may have reflected the lower incidence of serious side effects necessitating immunosuppression.
We generally follow National Comprehensive Cancer Network (NCCN) guidelines for the prevention and treatment of cancer-related infections , which recommend considering Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole, atovaquone, or pentamidine for patients treated with 20 mg of prednisone equivalent daily for at least four weeks. The role of prophylactic antiviral or antifungal medication in these patients requires further study.
Pre-existing autoimmune disorder or prior immune-related toxicity — There are only limited data on the safety and efficacy of checkpoint inhibitors in patients with an underlying autoimmune disorder or a major irAE from prior ipilimumab immunotherapy. Since both cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD-1) have an important role in maintaining immunologic homeostasis, there is theoretical concern that therapeutic blockade of these receptors could lead to exacerbations of underlying autoimmune conditions or prior immune-related toxicity.
Given the life-threatening nature of the malignancies that patients face and the potential benefits of these checkpoint-blocking antibodies, clinicians should discuss the possible benefits and risks of immunologic checkpoint blockade with their patients. Retrospective data suggest that patients with pre-existing autoimmune conditions or irAEs due to ipilimumab can safely receive anti-PD1 therapy, experiencing a similar rate of irAEs that can usually be managed without need for permanent discontinuation of drug therapy.
Anti-PD-1 agents — The available evidence indicates that anti-PD-1 agents (pembrolizumab, nivolumab) can be given safely and retain activity in patients with a pre-existing autoimmune disorder and in those who had major toxicity from prior ipilimumab therapy.
A retrospective study analyzed the outcomes from 119 patients with advanced melanoma who were treated with pembrolizumab or nivolumab at 13 academic centers .
●In the 52 patients with a pre-existing autoimmune disorder, the objective response rate was 33 percent, and 20 patients (38 percent) had a flare of the autoimmune disorder requiring immunosuppression. However, the majority of patient flares were relatively mild, and only two patients required discontinuation of anti-PD-1 treatment.
●In the 67 patients with a major irAE from ipilimumab, the objective response rate was 40 percent. Only two patients (3 percent) had a recurrence of the ipilimumab irAE, while 23 (34 percent) had a new irAE.
Ipilimumab — The most extensive data come from a multicenter retrospective series of 30 patients with advanced melanoma and a pre-existing autoimmune disorder who were treated with ipilimumab . The most commonly represented autoimmune diseases included rheumatoid arthritis, inflammatory bowel disease, and psoriasis.
The efficacy of ipilimumab in this setting appeared to be similar to that in the broader experience with this agent, with 6 of 30 (20 percent) patients having an objective response. Exacerbation of underlying autoimmune conditions occurred in 8 of 30 patients (27 percent), all of which were successfully managed with corticosteroids. There was one death due to colitis; in this case, immunosuppressive treatment was delayed for approximately one week due to delayed reporting of symptoms. This patient had a prior diagnosis of psoriasis (skin-only) but no prior history of inflammatory bowel disease.
Patients undergoing allogeneic stem cell transplant after prior PD-1 therapy — Nivolumab is approved for treatment of patients with Hodgkin lymphoma that has progressed or relapsed after hematopoietic stem cell transplantation (HSCT) . Since some patients with Hodgkin lymphoma may ultimately be referred for allogeneic stem cell transplantation after PD-1 therapy, assessing toxicities of allogeneic transplantation in the setting of prior PD-1 is an important consideration in this patient population. One retrospective study of 19 patients with hematologic malignancies treated with a PD-1 inhibitor (nivolumab or pembrolizumab) and subsequently treated with reduced-intensity conditioning allogeneic transplantation has been reported . In this small heterogeneous study, the posttransplant relapse rate was favorable, but there was a higher than expected rate of severe complications, including fatal early acute graft versus host disease (GVHD) and veno-occlusive disease (VOD). A steroid-responsive febrile syndrome was also seen. Additional study in larger groups of patients is needed to determine whether prior PD-1 increases the toxicities of allogeneic transplantation.
Biomarkers associated with side effects of checkpoint inhibitors — Immunologic biomarkers are being studied as a way to assess the risk of irAEs and as an aid in the early identification of such complications.
●In one report, ipilimumab-treated patients with melanoma who developed colitis had higher on-treatment serum concentrations of interleukin 17 (IL-17) compared with those without colitis . In this study, there was also a temporal relationship between colitis symptoms and elevations in IL-17 in several patients.
●In another study, gene expression profiling was performed on whole blood samples from patients with melanoma treated in two phase II clinical trials of ipilimumab . Differences in gene expression at baseline (including immunologically relevant genes) were observed comparing patients who ultimately developed gastrointestinal toxicity with those who did not. There were increases in expression of immunologically-related genes during ipilimumab treatment that were also seen to a greater degree in patients who ultimately developed gastrointestinal toxicity.
●Other studies have examined peripheral blood counts to assess whether eosinophilia (often seen during ipilimumab treatment) is associated with adverse events. In one retrospective, multi-institution review, the degree of eosinophilia was associated with the development of an irAE during ipilimumab treatment . Additional study is necessary, but this is consistent with other series, in which skin rashes have been associated with eosinophilia .
Combined CTLA-4 and PD-1 blockade — The distinct mechanisms of action of CTLA-4 and PD-1 receptor blockade have provided the rationale for combining these two checkpoint inhibition strategies. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Combined anti-CTLA-4 and anti-PD-1 immunotherapy'.)
Combining nivolumab and ipilimumab was studied most extensively in the CheckMate 067 phase III trial . In that trial, the incidence of grade 3 or 4 toxicity with the combination was increased compared with either single agent (59 versus 21 and 28 percent, respectively, for nivolumab and ipilimumab). There were two treatment-related deaths with the combination, and one each in the nivolumab and ipilimumab treatment arms.
There were no unique toxicities attributed to the combination of ipilimumab and nivolumab that have not previously been seen with either agent alone. Side effects related to the combination of CTLA-4 and PD-1/programmed cell death ligand 1 (PD-L1) blockade were managed similarly to those arising from treatment with monotherapy. Most side effects resolved with immunosuppression within a few months, except for endocrine side effects, which typically require long-term hormone supplementation. Although many patients discontinued treatment due to side effects, the duration of treatment required is unclear. In a prior phase 2 study of the combination, 68 percent of patients who received the combination and discontinued due to toxicity had an objective response . Additionally, the progression-free survival and overall survival among patients who discontinue combination immunotherapy early appear favorable .
Whether the combination of ipilimumab and nivolumab is associated with a similar safety profile in patients with other advanced malignancies or at different dosing levels remains under investigation.
Combined immune checkpoint blocking antibodies plus targeted therapy — Personalized treatment based upon targeted therapy for specific driver mutations (eg, BRAF V600 mutations in patients with advanced melanoma) is another area of rapid advance in the treatment of advanced malignancies. (See "Molecularly targeted therapy for metastatic melanoma".)
The toxicity profile of combinations of immune checkpoint-blocking antibodies and targeted agents is just beginning to be understood. Results suggest that combinations involving targeted agents and ipilimumab may significantly increase toxicity.
●In one published prospective study, treatment of advanced melanoma with vemurafenib, a BRAF inhibitor, plus ipilimumab was associated with a high incidence of grade 3 transaminase elevations, which required abandonment of this combination as concurrent therapy . Rash was also a significant problem in this small number of patients treated with this concurrent regimen.
The irAE profile of ipilimumab in combination with BRAF inhibitors may vary with different drugs. In a separate phase I study, dabrafenib was combined with ipilimumab, and no significant safety concerns with this doublet combination were observed in a preliminary report .
Additional studies combining targeted agents with immune checkpoint-blocking antibodies, mainly anti-PD-1 or anti-PD-L1 agents, are continuing. Establishing the optimal dose and schedule will be critical to the safety and possible efficacy of combinatorial approaches if this approach is to be useful clinically. Combinations of targeted agents with PD-1 and/or PD-L1 antibodies are showing a more favorable side effect profile than combinations with ipilimumab. The first reported data on the combination of an anti-PD-1/anti-PD-L1 antibody were reported at the American Society of Clinical Oncology (ASCO) 2015 annual meeting . The PD-L1 antibody durvalumab was safely combined with both dabrafenib and with dabrafenib plus trametinib. Many additional combinations, including vemurafenib, cobimetinib, and atezolizumab  as well as dabrafenib, trametinib, and pembrolizumab , have been explored and are generally believed to be tolerable.
Ipilimumab plus GM-CSF — Granulocyte-macrophage colony-stimulating factor (GM-CSF) does not currently have a clear role in either the prevention or treatment of side effects associated with checkpoint inhibition. However, the combination is of clinical interest since GM-CSF-secreting tumor vaccines enhanced the activity of CTLA-4 blockade in preclinical models . (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Combined anti-CTLA-4 and anti-PD-1 immunotherapy'.)
The combination of GM-CSF and ipilimumab 10 mg/kg was assessed in patients with advanced melanoma in a phase II randomized study (ipilimumab 10 mg/kg plus GM-CSF versus ipilimumab 10 mg/kg alone). Interim results indicated the combination prolonged survival and was associated with fewer irAEs than ipilimumab 10 mg/kg alone . The extent to which this decrease in toxicity contributed to an improved overall survival is unclear. It is unknown whether GM-CSF results in similar effects in patients treated with the approved dose of ipilimumab (3 mg/kg).
The reasons for the decreased frequency of side effects are unclear.
Adjuvant ipilimumab — Ipilimumab has been approved as adjuvant therapy for patients with cutaneous high-risk melanoma. Efficacy results with ipilimumab in the adjuvant setting are discussed separately. (See "Adjuvant therapy for cutaneous melanoma", section on 'Ipilimumab'.)
In the European Organisation for Research and Treatment of Cancer (EORTC) 18071 trial, 951 patients were randomly assigned to either ipilimumab or placebo . Treatment using a dose of 10 mg/kg was associated with irAEs that were similar to those in the metastatic setting. Approximately 50 percent of the patients treated with ipilimumab discontinued therapy due to treatment-related adverse events, and there were five treatment-related deaths (1.1 percent) in the ipilimumab group (three due to colitis, one due to myocarditis, one due to Guillain-Barre syndrome). The rates of irAEs in the adjuvant setting appear similar to those in the metastatic setting using the same dose of ipilimumab, although endocrinopathies may be more frequent.
Adjuvant nivolumab was also shown to improve recurrence-free survival compared with adjuvant ipilimumab. In addition, adjuvant nivolumab had more favorable tolerability than adjuvant ipilimumab. Toxicities of adjuvant nivolumab appear similar to toxicities of nivolumab in the metastatic setting .
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  and approximately 40 percent in those treated with ipilimumab . 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 side effects have been reported in up to 25 percent of patients treated with anti-PD-1 or anti-PD-L1 agents. The reported incidence of severe or life-threatening infusion-related reactions has been 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'.)
For patients treated with avelumab, premedication with acetaminophen and an antihistamine is indicated during the first four cycles, and subsequently as needed . (See "Staging and treatment of Merkel cell carcinoma" and "Staging and treatment of Merkel cell carcinoma", section on 'Avelumab'.)
DERMATOLOGIC AND MUCOSAL TOXICITY
Manifestations — Dermatologic toxicity is the most common immune-related adverse event (irAE) associated with checkpoint inhibitors (table 1). Approximately 50 percent of patients treated with ipilimumab will experience rash and/or pruritus, and approximately 30 to 40 percent of those treated with nivolumab or pembrolizumab will have dermatologic complications . Alopecia has been reported in approximately 1 to 2 percent of cases . For most patients, dermatologic toxicity is the earliest irAE experienced, with onset an average of 3.6 weeks after treatment initiation (figure 1) .
Typical physical examination findings consist of a reticular, maculopapular, faintly erythematous rash on the trunk or extremities (picture 1) . Vitiligo is also seen commonly. Perivascular lymphocytic infiltrates extending deep into the dermis have been observed on histopathology . In one case, neutrophilic infiltration diagnostic for Sweet syndrome was seen . (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)
Oral mucositis and/or complaints of dry mouth appear to be more frequent with programmed cell death receptor 1 (PD-1) receptor checkpoint inhibitors than with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade. In the phase I study of nivolumab, this was observed in 6.5 percent of patients, including one case with grade 3 toxicity . Oral candidiasis remains an important consideration in the differential diagnosis, particularly if a patient has been on oral corticosteroids for management of other irAEs. In some patients, oral corticosteroid rinses and lidocaine have been effective.
Management — Most checkpoint inhibitor rashes can be treated with topical corticosteroid creams. If pruritus is a prominent symptom, oral antipruritics (eg, hydroxyzine, diphenhydramine) can be helpful. Severe rashes (grade 3/4) should be managed with oral corticosteroids, and treatment with checkpoint blockade should be held as per established management algorithms .
Severe rashes such as Stevens-Johnson syndrome/toxic epidermal necrolysis have been reported in rare cases. Such reactions typically require hospitalization, intravenous steroids, dermatologic evaluation, and vigilant monitoring to treat abnormalities in fluid and electrolyte status. Any rash that does not promptly resolve with corticosteroid creams or shows signs of blistering should be evaluated promptly by a dermatologist and biopsy considered. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)
DIARRHEA/COLITIS — Diarrhea is a common clinical complaint in patients undergoing treatment with checkpoint-blocking antibodies. Careful attention to the diagnosis and treatment of the earliest symptoms associated with gastrointestinal toxicity can decrease the risk of more severe toxicity.
The differential diagnosis of patients with diarrhea on treatment with a checkpoint inhibitor includes infections with Clostridium difficile or other bacterial/viral pathogens. Diarrhea (increase in stool frequency) is related to but clinically distinct from colitis (abdominal pain, radiographic or endoscopic findings of colonic inflammation).
The incidence of diarrhea is much higher in patients receiving cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-blocking antibodies compared with inhibition of programmed cell death receptor 1 (PD-1).
●Diarrhea of any grade was reported in approximately 30 percent of patients treated with ipilimumab for melanoma, but severe (grade 3/4) diarrhea occurred in less than 10 percent of cases . The incidence of diarrhea appears to be dose-dependent. In a phase II dose-finding study, the rate of severe diarrhea was higher at the 10 mg/kg dose than with 3 mg/kg (10 versus 1 percent) .
In clinical trials of ipilimumab for melanoma, significant colitis was reported in approximately 5 percent of patients [28,37]. Endoscopic findings have revealed mucosal edema with biopsies demonstrating neutrophilic, lymphocytic, or mixed neutrophilic-lymphocytic infiltrates (picture 2) [38,39].
●Diarrhea/colitis appears to be less frequent with PD-1 blockade than with CTLA-4 blockade, with grade 3/4 immune-mediated colitis seen in approximately 1 to 2 percent of cases [35,40,41].
Patients who had significant diarrhea/colitis during CTLA-4 blockade have subsequently been treated with PD-1 blockade using nivolumab without developing diarrhea/colitis . However, additional clinical experience is needed to clarify the safety of PD-1 blockade in patients who had significant diarrhea/colitis from prior treatment with CTLA-4 blockade.
Management — Patients being treated with a checkpoint inhibitor should be counseled on the importance of maintaining oral hydration if diarrhea develops. If symptoms persist for more than three days or increase and no infectious causes are identified, prompt assessment and use of oral or intravenous corticosteroids are required.
●Mild (grade 1 (table 2)) symptoms (fewer than four stools per day over baseline) can be managed symptomatically. Some clinicians feel that the American Dietary Association colitis diet and anti-motility agents (loperamide or oral diphenoxylate atropine sulfate) can be helpful for mild symptoms. Budesonide may be helpful in the early treatment of mild noninfectious diarrhea symptoms that persist but do not escalate after two to three days of dietary modification and anti-motility agents.
●Colonoscopy may be helpful if grade 2 symptoms (increase of four to six stools per day over baseline) or greater occur or in situations where the diagnosis is unclear. Treatment should be initiated if colitis is observed.
●For patients with severe or life-threatening enterocolitis (grade 3/4, increase of seven or more stools per day over baseline or other complications), treatment with ipilimumab should be permanently discontinued. High doses of corticosteroids should be given.
●If patients do not improve with intravenous corticosteroids after approximately three days on IV steroids, infliximab at a dose of 5 mg/kg once every two weeks is typically recommended [43-45]. The dose and schedule of infliximab in this setting is based upon experience treating patients with inflammatory bowel disease . In cases refractory to infliximab, mycophenolate may be needed. (See "Infliximab in Crohn disease".)
●In very rare cases, colitis can result in bowel perforation, potentially requiring colostomy.
Prophylactic treatment with the matrix-release corticosteroid, budesonide is not recommended for the prevention of diarrhea/colitis. This approach was studied as a way to reduce the incidence and/or severity of diarrhea in a double-blind, placebo-controlled phase II study . The rates of diarrhea were similar in both study arms.
Manifestations — Elevations in serum levels of the hepatic enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) can be seen with both cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD-1) blockade. Most episodes are asymptomatic laboratory abnormalities, but occasionally patients have an associated fever. Rarely, elevations in total bilirubin are seen as well, usually in association with a prolonged period of AST and ALT increase. Among patients that develop liver-related toxicities, the most common time of onset is 8 to 12 weeks after initiation of treatment, although early or delayed events may also be seen (figure 1) .
The reported rates of AST and ALT elevations with CTLA-4 blockade have varied in different trials and study populations but typically are less than 10 percent [37,48,49]. In the pivotal phase III study of ipilimumab as monotherapy at 3 mg/kg for patients with advanced melanoma, the rate of elevated AST/ALT was only approximately 1 to 2 percent with no reported grade 3/4 events . On the other hand, hepatotoxicity is more common with the nivolumab plus ipilimumab combination, with approximately 20 percent of patients experiencing grade 3 AST and ALT elevations with the ipilimumab 3 mg/kg and nivolumab 1 mg/kg combination and <5 percent grade 3 with the ipilimumab 1 mg/kg, nivolumab 3 mg/kg combination .
In the large phase I studies of PD-1-blocking antibodies, the rates of hepatitis are less than 5 percent and grade 3/4 toxicity is rarer [41,51]. The frequency of liver-related laboratory abnormalities, especially grade 3/4 events, may be more common in combination with other agents such as dacarbazine or vemurafenib . (See 'Combined immune checkpoint blocking antibodies plus targeted therapy' above.)
Radiographic findings are not typically seen in patients with abnormal liver function tests. However, computed tomography (CT) scan may show mild hepatomegaly, periportal edema, or periportal lymphadenopathy . Biopsies of some patients with hepatotoxicity have demonstrated severe panlobular hepatitis with prominent perivenular infiltrate with endothelialitis. A primary biliary pattern with mild portal mononuclear infiltrate around proliferated bile ductules has also been reported [53,54].
Management — Hepatic function (transaminases and bilirubin) should be monitored prior to each dose of ipilimumab . When a patient has an elevated AST and/or ALT, exclusion of viral or other drug-induced causes of hepatitis is important.
If no other etiology is obvious, then prompt treatment with corticosteroids following an established algorithm is the next step . Hepatitis may persist for quite some time and may require prolonged or repeated corticosteroid tapers (a minimum of three weeks treatment is suggested) and/or additional immunosuppression.
●Grade 2 hepatic toxicity – AST or ALT >2.5 times the upper limit of normal (ULN) but ≤5 times the ULN, or total bilirubin >1.5 times the ULN but ≤3 times the ULN. Treatment with the checkpoint inhibitor should be withheld.
●Grade 3 or greater hepatic toxicity – AST or ALT >5 times the ULN, or total bilirubin >3 times the ULN. Treatment should be permanently discontinued.
●In rare cases, elevations in AST and ALT are refractory to corticosteroid therapy, and mycophenolate mofetil (500 mg every 12 hours) may be an additional medication to administer concurrently with corticosteroids. The use of antithymocyte globulin therapy has also been described .
Infliximab should not be given to patients with elevated AST/ALT since infliximab itself carries a risk of hepatotoxicity.
PNEUMONITIS — Pneumonitis is an uncommon but potentially severe or fatal complication of treatment with checkpoint inhibitor immunotherapy [57-61]. Drug-induced pneumonitis is a diagnosis of exclusion, and alternative diagnoses, including infection and malignancy, need to be excluded.
Manifestations — The clinical spectrum of pneumonitis is illustrated by a series of 43 patients who developed pneumonitis after being treated with an anti-programmed cell death receptor 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) monoclonal antibody, either alone or in combination with an anti-Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent . Melanoma and non-small cell lung cancer were the most common malignancies treated in this series.
Key observations included the following:
●The overall incidence of pneumonitis was 5 percent (43 patients out of a total of 915 treated with checkpoint blockade), including 3 percent of those treated with anti-PD-1 or anti-PD-L1 monotherapy and 10 percent of those treated with a combination that included an anti-CTLA-4 antibody. The incidence of pneumonitis was similar in patients treated for melanoma and non-small cell lung cancer.
●The duration of treatment prior to the development of pneumonitis was variable, with a median of 2.8 months (range 9 days to 19 months), and was earlier for those treated with combination rather than monotherapy (median 2.7 versus 4.6 months). The most common presenting symptoms were dyspnea and cough (53 and 35 percent, respectively), while one-third of patients were asymptomatic.
●There were no characteristic radiographic or pathologic features that were associated with pneumonitis due to checkpoint inhibitor immunotherapy (figure 2). Chest computed tomography (CT) was the preferred imaging modality, and routine chest radiography did not detect a new radiologic abnormality in almost one-fourth of cases.
●Of the 43 patients diagnosed with pneumonitis, 31 (72 percent) had either grade 1 or grade 2 involvement (table 3). Overall, 37 of 43 (86 percent) improved by simply withholding additional checkpoint inhibition or treating with immunosuppression, while five (0.5 percent of the total population) worsened and died, despite therapy. Of these five cases, infectious complications or progression of tumor appeared to be the proximal cause of death in four instances.
Pulmonary toxicity may also manifest as a radiation recall pneumonitis limited to previously irradiated areas of the lung . This phenomenon can occur when treatment is initiated years after radiation therapy.
Management — The outcomes from the 43 patients diagnosed with pneumonitis provide some insight into the optimal management of this complication .
Overall, 15 of 17 asymptomatic patients (grade 1) were successfully managed by withholding the checkpoint inhibitor, while 2 of the 17 and all 14 with grade 2 pneumonitis were successfully treated with corticosteroids. All 12 patients with grade 3 or higher pneumonitis were initially treated with corticosteroids. Five patients in this group required additional immunosuppression (infliximab with or without cyclophosphamide), but all five ultimately died. The median starting dose of prednisone was 50 mg, and the median duration of treatment required was 68 days (range 20 to 154 days).
There are no prospective clinical trials that have defined the optimal treatment approach. Based on the observations in this series, our empiric approach to treatment includes the following:
●For asymptomatic, grade 1 pneumonitis (table 3), we generally withhold drug for two to four weeks with close follow-up. If symptoms arise or there is radiographic progression, corticosteroids are appropriate.
●Patients with grade 2 or higher pneumonitis should have their drug withheld and be treated using corticosteroids with close follow-up. Additional immunosuppression may be used in patients with worsening of pneumonitis, although the benefit of this approach is uncertain.
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 checkpoint inhibitors . The frequency of specific endocrinopathies and the relationship to different agents are discussed in this section.
Autoimmune thyroid disease — Thyroid function should be monitored prior to each dose of a checkpoint inhibitor. 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, and a low TSH with low free T4 indicates hypophysitis. Occasionally, thyroiditis with transient hyperthyroidism (low TSH and high free T4) may be followed by more longstanding hypothyroidism (high TSH and low free T4).
For patients treated with ipilimumab, nivolumab or pembrolizumab, atezolizumab, and the combination of ipilimumab plus nivolumab, the incidence rates for hypothyroidism were 3.8, 7.0, 3.9, and 13.2 percent, respectively . 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. For cases of acute thyroiditis, a short period of high-dose steroids (1 mg/kg of prednisone or equivalent) may be helpful, but there is little strong evidence to suggest that this prevents longer term thyroid dysfunction.
Hyperthyroidism — Persistent primary hyperthyroidism is significantly less frequent than hypothyroidism and should be treated similarly to primary hyperthyroidism. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment".)
For patients treated with ipilimumab, nivolumab or pembrolizumab, atezolizumab, and the combination of ipilimumab plus nivolumab, the incidence rates for hyperthyroidism were 1.7, 3.2, 0.6, and 8 percent, respectively .
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 also supported radiographically by enhancement and swelling of the pituitary gland (image 1) [64,65].
For patients treated with ipilimumab, nivolumab or pembrolizumab, atezolizumab, and the combination of ipilimumab plus nivolumab, the incidence rates for hypothyroidism were 3.2, 0.4, <0.1, and 6.4 percent, respectively .
Management — When hypophysitis is suspected, a course of high-dose corticosteroids (1 mg/kg of prednisone daily) given during the acute phase may result in reversal of the inflammatory process in some cases and prevent the need for longer term hormone replacement.
In most patients, however, long-term supplementation of the affected hormones is necessary due to secondary hypothyroidism (treated with levothyroxine) or secondary hypoadrenalism (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 . (See "Treatment of hypopituitarism".)
Adrenal insufficiency — The most critical endocrinopathy is adrenal insufficiency, 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 .
When an adrenal crisis is suspected, intravenous corticosteroids 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 checkpoint inhibitors has been associated with acute onset of type 1 diabetes mellitus in approximately 0.2 percent of cases . As an example, in a series of five cases, patients presented with severe hyperglycemia or diabetic ketoacidosis; all required insulin therapy at diagnosis and remained insulin-dependent for diabetic control .
It is important to monitor glucose with each dose of immunotherapy. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment" and "Management of blood glucose in adults with type 1 diabetes mellitus".)
LESS COMMON IMMUNE-RELATED ADVERSE EVENTS — Treatment with checkpoint inhibitors 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 is a rare complication of checkpoint inhibitor immunotherapy. Discontinuation of checkpoint inhibitor immunotherapy and treatment with corticosteroids are indicated for patients with severe renal injury. The most common reported underlying pathology is acute tubulointerstitial nephritis, but immune complex glomerulonephritis and thrombotic microangiopathy have also been observed [68,69].
The most extensive data come from a series of 13 patients who underwent kidney biopsy at seven centers and from a review of multiple large clinical trials .
●The estimated incidence of any-grade acute kidney injury was 1 to 2 percent in patients treated with a single agent (ipilimumab, nivolumab, pembrolizumab) and approximately 5 percent in those treated with the combination of nivolumab plus ipilimumab. The incidence of grade 3 or 4 acute kidney injury was less than 1 percent with single agents and 1.7 percent with the combination of nivolumab plus ipilimumab.
●Renal toxicity was diagnosed a median of 91 days after initiation of checkpoint inhibitor immunotherapy (range 21 to 245 days). The median peak serum creatinine was 4.5 mg/dL. Two patients required transient hemodialysis, and two patients remained on hemodialysis at the time of publication.
●Pathology from the renal biopsies revealed acute tubulointerstitial nephritis in 12 cases and thrombotic microangiography in one patient (image 2).
●Checkpoint inhibitor immunotherapy was discontinued in all 13 patients. Eleven patients were treated with corticosteroids, and among these 11, nine patients improved. One patient with thrombotic microangiopathy did not improve, despite glucocorticoids, and another patient transiently improved but then worsened. Two additional patients did not receive immunosuppression and did not recover renal function.
Exocrine pancreas — Monitoring serum amylase and lipase in asymptomatic patients is not recommended unless pancreatitis is suspected clinically. Corticosteroid treatment is not indicated in patients with modest asymptomatic elevations in serum amylase and lipase, as long as there are no other signs or symptoms of pancreatic inflammation.
Elevated levels of serum amylase and lipase have been reported in many patients in trials of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD-1) blockade (approximately 10 to 15 percent grade 3/4), but these laboratory findings do not fulfill the criteria for acute pancreatitis and most of these patients are asymptomatic. The clinical significance of elevated amylase/lipase in the absence of associated symptoms remains unknown [70,71]. (See "Clinical manifestations and diagnosis of acute pancreatitis".)
Immune-related pancreatitis has been reported in a patient treated with CTLA-4 blockade . In this patient, who already had a prior history of gallstone pancreatitis, abdominal symptoms were accompanied by laboratory evidence of elevated amylase and lipase.
Neurologic — A wide range of neurologic syndromes have been associated with checkpoint blockade involving ipilimumab and anti-PD-1 agents . Case series suggest that neurotoxicity occurs in approximately 1 to 3 percent of patients .
Cases of Guillain-Barre syndrome are particularly notable , and one case resulted in a treatment-related death in a postsurgical adjuvant study of ipilimumab . (See "Adjuvant therapy for cutaneous melanoma", section on 'Ipilimumab'.)
Other reported neurologic complications include myasthenia gravis , posterior reversible encephalopathy syndrome (PRES) , aseptic meningitis , enteric neuropathy , transverse myelitis , and autoimmune encephalitis. (See "Paraneoplastic and autoimmune encephalitis".)
Serious neurologic immune-related adverse effects (irAEs) should be treated with corticosteroids. Consultation with neurology is indicated to consider additional treatment such as plasmapheresis and intravenous immunoglobulin.
Cardiotoxicity — Cardiotoxicity may develop in the absence of a history of significant cardiac risk factors and may be associated with a more general myositis as well as other irAEs.
The time to onset was variable, but fatal myocarditis has been reported after a single treatment with the combination of nivolumab plus ipilimumab . In pharmacovigilance studies, the incidence of myocarditis was higher in patients treated with the combination of nivolumab plus ipilimumab compared with nivolumab alone (0.27 versus 0.06 percent).
High-dose steroids 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. The early institution of cardiac transplant rejection doses of steroids (methylprednisolone 1 g every day) and the addition of either mycophenolate, infliximab, or anti-thymocyte globulin should be considered in patients without an immediate response to high-dose steroids.
Hematologic — Red cell aplasia, neutropenia, thrombocytopenia, acquired hemophilia A, and cryoglobulinemia have been described in patients treated with checkpoint inhibitors [82-88]. As with other irAEs, the standard approach is initial corticosteroid treatment with addition of other immune-suppressing agents if symptoms are steroid-refractory.
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. An ophthalmology consultation is recommended, and treatment with topical corticosteroids (eg, 1 percent prednisolone acetate suspension) may be helpful. Oral corticosteroids can be used for severe (grade 3/4) or refractory cases. (See "Ocular side effects of systemically administered chemotherapy", section on 'Ipilimumab'.)
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 checkpoint inhibitor classes are combined. (See "Ocular side effects of systemically administered chemotherapy", section on 'Anti-PD-1 and PD-L1 agents'.)
Rheumatologic and musculoskeletal — A wide range of rheumatologic toxicities has been observed with checkpoint inhibition immunotherapy. These include inflammatory arthritis, salivary gland dysfunction (sicca syndrome), and inflammatory myositis, among others [89-91]. The incidence of these side effects has not been clearly determined.
●Immunologic checkpoint inhibition agents targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD-1) receptor are having a dramatic impact on the care of patients with advanced melanoma and are rapidly being explored as therapy for other malignancies. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition".)
●Treatment is associated with immune-related adverse events (irAEs) that typically are transient but occasionally can be severe or fatal. The most common and important irAEs are dermatologic, diarrhea/colitis, hepatotoxicity, and endocrinopathies, although other sites can also be affected. (See 'Dermatologic and mucosal toxicity' above and 'Diarrhea/colitis' above and 'Hepatotoxicity' above and 'Endocrinopathies' above and 'Less common immune-related adverse events' above.)
●Rapid identification of irAEs and prompt initiation of local or systemic immunosuppression can optimize outcomes. Side effects are more common with the anti-CTLA-4 antibody ipilimumab than with the anti-PD-1 agents (nivolumab, pembrolizumab) or anti-programmed cell death ligand 1 (PD-L1) agents (atezolizumab, durvalumab, avelumab). The combination of nivolumab plus ipilimumab is associated with more toxicity than either agent alone. (See 'General approach to toxicity management' above.)
●In general, treatment of moderate or severe irAEs requires interruption of the checkpoint inhibitor and the use of corticosteroid immunosuppression . Treatment is based upon the severity of the observed toxicity (see 'General approach to toxicity management' above):
•For patients with grade 2 (moderate) immune-mediated toxicities, treatment with the checkpoint inhibitor should be withheld and should not be resumed until symptoms or toxicity is grade 1 or less. Corticosteroids (prednisone 0.5 mg/kg/day or equivalent) should be started if symptoms do not resolve within a week.
•For patients experiencing grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with the checkpoint inhibitor should be permanently discontinued. High doses of corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, steroids can be gradually tapered over at least one month.
•If corticosteroids are not effective in treating immunotherapy-related diarrhea after approximately three days, infliximab (5 mg/kg) may be considered. Infliximab should not be given to patients with immune-mediated hepatitis.
●Frequent and consistent communication between patients, caregivers, and the clinical team is vital to successful irAE management.
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