Immune checkpoint-blocking antibodies that enhance the immune system’s ability to fight cancer are becoming important components of treatment for patients with a variety of malignancies. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) was the first immune checkpoint to be clinically targeted, and ipilimumab, an inhibitor of CTLA-4, was approved for patients with advanced melanoma(1). The programmed cell death-1 (PD-1) receptor and one of its ligands, PD-L1, more recently have shown great promises as therapeutic targets in a variety of malignancies. Nivolumab and pembrolizumab recently have been approved for patients with melanoma, non-small cell lung cancer, renal cell cancer, bladder cancer, and Hodgkin lymphoma. The use of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies is associated with side effects known as immune-related adverse events (irAEs). Immune-related adverse events affect the dermatologic, gastrointestinal, hepatic, endocrine, and other systems. Doctors have to be trained how to diagnosed and treat that particular side effects.
The incidence of irAEs reported by a meta-analysis published in 2015, which included 1266 patients enrolled in 22 trials, treated with ipilimumab, showed that the incidence of all grade toxicity was 72% and grade 3-4 toxicity incidence was 25%(2).
The most important grade 4 side effects were gastrointestinal (12%), liver (7%), skin (3%), and endocrine system (3%). Immune-related adverse events generally appear in the first 12 weeks of treatment (4-11 weeks). A specific pattern of the appearance of the side effects was noted. Skin-related adverse events (AEs) can be expected after 2 to 3 weeks, gastrointestinal and hepatic AEs after 6 to 7 weeks, and endocrinologic AEs only after an average of 9 weeks(3). The early activation of T cells in lymph nodes explains the magnitude of peripheral T cell stimulation by CTLA-4 inhibitor and the multitude of adverse events, unlike PD-1 which is a negative regulator of T cells in tumor microenvironment(4).
Virtually all organs can be affected by irAEs. The most important specific site irAEs are discussed.
Cutaneous toxicity is one of the most often reported adverse event in clinical studies involving immunotherapy (both anti-CTLA4 and anti-PD L-1 antibody therapy). Skin was affected in an important proportion of the patients receiving anti-CTLA-4 therapy (44%; 95% CI; 38-49.5), but only 5% of the patients presented with high grade toxicity. No statistical difference was found between the rate of skin adverse effects depending on the dosage of ipilimumab (10 mg /kg q3w vs. 3 mg/kg q3w)(2). With anti-CTLA-4 therapy, papules (usually associated with erythema), plaques, Koebner phenomenon were mostly reported. The rash was maculopapular and intensely pruritic. The lesions were localized on the upper trunk and limbs. Head involvement seems unspecific to this type of toxicity. Pre-existent lesions (eczema, rosacea, vitiligo) were often exacerbated(2).
Histologically, a perivascular lymphocytic infiltrate extending deep into the dermis and up into the epidermis was evident.
One case report described Sweet’s syndrome in a patient undergoing ipilimumab treatment for metastatic melanoma(5).
Time of onset for skin adverse reactions was different for nivolumab (4-8 weeks) vs. pembrolizumab (23 weeks)(6). With ipilimumab, this occurred during the first month of treatment(2).
Rash, erythema, palmoplantar erythrodysesthesia, photosensitivity reaction, urticaria, vitiligo, toxic epidermal reaction were described in clinical trials involving PD-1 inhibitors(6).
Overall skin toxicity is different in patients receiving nivolumab for NSCLC vs. melanoma (12.3% in NSCLC, 40% in melanoma). One possible explanation for this could be that in melanoma the drug elicits local immune response or the fact that toxicities were reported by dermatologists in the melanoma trial and by medical oncologists in the NSCLC trial(6). However, severe skin reactions were present in very few patients no matter cancer site. For the usual doses (nivolumab 3 mg/kg q2w and pembrolizumab 2 mg /kg q3w) only 1.2% of the patients receiving nivolumab and 1.5% of the ones treated with pembrolizumab had grade 3 or higher toxicity
No biomarker was validated specifically for the cutaneous toxicity in immunotherapy. However, dosage of the circulating eosinophils before and during treatment with ipilimumab proves to be a good predictor of immune-related adverse events in general(7).Treatment for most rashes is successful with topical corticosteroids and antipruritics (e.g., hydroxyzine, diphenhydramine), and oral corticosteroid rinses and lidocaine have anecdotally been effective in patients with mucositis. More rarely, severe rashes such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported, and if suspected, hospitalization for intravenous corticosteroids, fluid, and electrolyte monitoring is required(8).
Gastrointestinal and hepatic toxicity
The second most common side effect of ipilimumab after dermatologic toxicity is represented by colitis. Diarrhea appears in days to weeks after treatment initiation with an average time of 6-7 weeks after treatment initiation in approximately 30% of patients. Grade 3-4 colitis occurs in 3-5% of cases with its most feared complication represented by intestinal perforation(1,9,10).
The amplitude off this side effect is dose-dependent, with 25% and 6% of diarrhea of all grades and grade 3-4 colitis appearing for ipilimumab 3 mg/kg q3w versus 39% and 6% for ipilimumab 10 mg/kg q3w, respectively(11).
Endoscopic evaluation shows inflammatory changes and ulceration of the mucosa involving mostly the descendent colon, but the entire colon may be affected, gastritis and colitis being also described. Clinical trials show no benefit for prophylactic corticosteroids in preventing bowel inflammation and till now there are no predictive markers for gastrointestinal toxicity(12). When these findings are observed endoscopically, steroid treatment is usually necessary. Histologically, enterocolitis is characterized by lymphocytic, neutrophilic or combined leukocytic and neutrophilic infiltration in the lamina propria, with crypt abscesses and granulomas found in various percentages. A typical clinical presentation with sudden diarrhea appearance, no infectious etiology and prompt steroid response does not require endoscopic examination or biopsy to confirm the enteritis, unless the symptoms persist. Grade 1 and 2 diarrhea (according to CTAE v4.0) management is symptomatic, but if it persists, ipilimumab must be delayed and oral steroid initiated. Intravenous steroids are indicated for tenacious symptoms or grade 3-4 severity and in refractory cases other immunosuppressive drugs as infliximab and mycophenolatemofetil should be considered(13,14).
A significant correlation of enteritis with objective clinical response rate (ORR) was found for ipilimumab immunotherapy in metastatic renal cell carcinoma (35% of patients with colitis vs. 2% of those who did not develop colitis had an ORR, p=0.016)(15).
Unlike ipilimumab, anti-PD-1 antibodies pembrolizumab and nivolumab have less gastrointestinal toxicity (13-20% of patients) with grade 3-4 colitis in 1% of cases. The incidence of grade 3-4 enteritis is higher with increased dose (pembrolizumab 10 mg/kg q3w)(16).
The combination therapy with ipilimumab and nivolumab increases the risk of enteritis compared to ipilimumab and nivolumab alone (44% vs. 33% vs. 19%, respectively) and was the most frequent adverse event that led to treatment discontinuation(17).
Liver disorders, reported in about 5% of the patients, are among the most common immune-related adverse events (irAEs) to ipilimumab, next to dermatitis, enterocolitis or endocrinopathies(1,18,19,20). These translate into elevations in serum liver transaminases, aspartate aminotransferase (AST), alanine transaminase (AST), total bilirubin and inflammatory hepatitis, generally in 6 weeks from the drug administration(20). A differential diagnosis should exclude non- autoimmune hepatitis, by checking baseline viral serologies before ipilimumab administration, this treatment not being recommended while patients present with active hepatitis B or C. Furthermore, a reduced alcohol consumption or acetaminophen intake, that could increase liver enzymes, should be advised(21).
Liver function tests elevations in patients may be associated with symptoms of hepatotoxicity (jaundice, right upper quadrant pain, vomiting) or may be completely asymptomatic; many patients have other nonspecific symptoms (fever, malaise). Liver metastases could represent another cause of elevated serum liver tests, this being assessed by radiological imaging or even a liver biopsy, if needed. A double-blind randomized phase III study showed an improved survival in patients with metastatic melanoma, but also higher transaminitis when ipilimumab was associated with dacarbazine, the adverse events being linked to dacarbazine alone(22).
There are several treatment algorithms that have been developed and proposed for helping solving hepatic adverse events(23).
For liver function tests (LFTs) or bilirubin elevation more than or equal 2 times the baseline, increased monitoring every 1-3 days should be included, along with clinical examination and autoimmunity work-up for serum antinuclear antibody (ANA), smooth muscle antibody (SMA), antimitochondrial antibodies, antisoluble liver antigen/liver pancreas antibodies or anti-liver-kidney microsomal-1 antibodies. If LFTs continue raising greater than 5 times the normal value, patient admission into hospital for evaluation, hepatology consult and stopping or even permanent discontinuation of ipilimumab should represent the first steps of the management algorithms. After starting at least 120 mg of methylprednisolone per day, daily LFTs and bilirubin should be advised until stable or improved values for at least 3 days in a row. If there is an inadequate response, in severe cases, immunosuppressive agents should be added and if there is still no answer in 5 to 7 days, then tacrolimus at 0.10-0.15 mg/kg/day has to be the administered drug. Continuing close monitoring, if no improvement is seen in another 5 to 7 days of infliximab single dose at 5 mg/kg should be considered. Further blood tests should be carried on every day for at least 2 weeks until the LFTs is stabilized(24). Hepatic irAEs rates seen with PD-1 inhibitors can be observed in less than 5% of cases, having a moderate to low severity (grade 1-2) and mainly consists of asymptomatic transaminase elevation. Time to adverse events debut varies according to the specific administered drug or the tumor site, as follows: 25 weeks in lung cancer patients and 4 weeks in melanoma patients for nivolumab, and 19 weeks for pembrolizumab(25,26,27).
In combination trials using ipilimumab and nivolumab, the liver toxicity of all grades was reported in 30% of patients, and grade 3-4 toxicity was reported in 18% of patients(28,29).
Endocrine disorders of any grade associated with anti CTLA-4 and anti-PD-1 therapy have been observed in up to 10% of all treated patients. These endocrine toxicities, that are in general autoimmune-mediated, mostly affect the thyroid gland, resulting in grade 1-2 hypothyroidism (4-8%) and hyperthyroidism (2-3%), as well as less commonly in acute thyreoiditis (1%). Uncommonly, hypophysitis (0.2-1%), hypopituitarism (0.1-0.2%), and type 1 diabetes mellitus (0.1%) may occur and their median time to onset is varying from 4 to 18 weeks (median: 11 weeks)(30).
Symptoms that may indicate endocrine dysfunction include unusual headaches, extreme tiredness, weight gain or weight loss, changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness, dizziness or fainting, hair loss, feeling cold, constipation, and a deeper pitch of the voice.
Thyroiditis is often painless and asymptomatic. Hypo- and hyperthyroidism secondary to thyroiditis were rare, up to 5.6% in clinical trials. One case reported bilateral Graves’ ophtalmopathy with high thyroperoxydase and thyroglobulin antibodies after two cycles of ipilimumab therapy. If hyperthyroidism occurs, symptomatic treatment with b-blockers and anxiolytics should be initiated. No antithyroid drugs are necessary, except in the case of Graves’ disease(31). Corticosteroids do not seem to provide benefit. Hyperthyroidism resolves spontaneously and evolves into hypothyroidism that should be treated with hormone-replacement therapy.
Lymphocytic hypophysitis is a rare inflammatory condition of the pituitary gland whose pathogenesis is probably autoimmune and has been reported in 1-6% of patients involved in ipilimumab trials. The presenting symptoms are headache, nausea, vertigo, and behavior change, visual disturbances such as diplopia, and weakness, which occur at an average of 6 weeks after initiation of therapy. Magnetic resonance imaging scans with gadolinium and selective cuts of the pituitary can show enlargement or heterogeneity and confirm the diagnosis. If hypophysitis is suspected, pituitary, thyroid, adrenal and gonadal status (serum morning cortisol, adrenocorticotropic hormone [ACTH], free triiodothyronine [T3], free thyroxine [T4], thyroid-stimulating hormone [TSH] and, if possible, testosterone in males and follicle-stimulating hormone, luteinizing hormone, and prolactin in females have to be tested(32).
For symptomatic hypophysitis and for any grade 3 to 4 endocrinopathy, the ipilimumab dose should be held, and an initial dose of methylprednisolone 1 to 2 mg/kg intravenously should be given. This should be followed by prednisone 1 to 2 mg/kg orally once per day with gradual tapering over 4 weeks and replacement of appropriate hormones as the steroid dose is tapered. Usually, after a few days, the symptoms improve, and a reduction of the swelling and heterogeneity of the pituitary gland can be observed radiologically.
Adrenal crisis is the most urgent form of endocrinopathy. Patients who have an adrenal crisis might have severe dehydration, hypotension or shock, for which immediate hospitalization is required. Intravenous corticosteroids with mineralocorticoid activity (e.g., methylprednisolone) should be initiated and the possible presence of sepsis or infection should be investigated(33).
Other side effects
Neurologic toxicity is rare, less than 1%, in patients presented with myasthenia gravis-like syndrome, Guillain-Barré syndrome, peripheral neuropathy or encephalitis(34). Numbness, tingling, foot drop, and localized muscle weakness, or generalized ascending motor and diaphragmatic weakness are the main complains. Work-up includes labs tests and brain MRI, neurology consultation, EMG if appropriate. When toxicity exceed grade 2, high-dose corticosteroid administration with a prolonged taper is used, and consider rapidly moving to immunoglobulin (infliximab) if grades 3-4 toxicity and without resolution of symptoms within 24-48 hours.
The main immune-related respiratory adverse reaction that has occurred with severity of grades 3-4 in up to 1.6% of patients is pneumonitis. Pneumonitis itself is a usually non-infectious lung inflammation with interstitial and alveolar infiltrations. Clinical characteristics include a dry, unproductive cough, tachypnoea and dyspnoe, tachycardia, cyanosis and fatigue, seldom fever and chills, in the chronic form interstitial fibrosis with collagenous thickening of the alveolar septa 6-9 months after exposure. The diagnostic procedures include lung function test with blood gas analysis and imaging technique mainly with thoracic CT scans showing diffuse, patchy ground-glass attenuation and centrilobular nodules with areas of air-trapping(6). Pneumonitis that is symptomatic is more common with PD-1 antibodies at 1-2% of cases and in patients with lung cancer. High dose steroids with at least 45-60 day tapers with starting doses of at least 1-2 mg/kg are required, and infliximab at 5 mg/kg if without relief in one week
Other irAEs reported with less frequency are pancreatitis, uveitis, nephritis or arthritis and red cell aplasia.
The combination with ipilimumab and nivolumab is associated with higher toxicity, more rapid onset, longer duration, slower resolution, more hepatitis, more multiple irAEs are seen(29). A higher proportion of patients who received the combination experienced at least two grade 2-4 AEs across organ categories during treatment.
An algorithm for withhold immunotherapy includes four to six stools per day over baseline or more, blood or mucus in stool, diffuse rash over less than 50% of skin surface, AST or ALT >2.5 to ≤5×ULN and/or total bilirubin >1.5 to ≤3×ULN, moderate neurologic symptoms, including muscle weakness, motor or sensory neuropathy, but with no impact on activities of daily living, endocrine signs or symptoms of dysfunction, including: fatigue, headache, mental status changes, abdominal pain, hypotension, abnormal thyroid function tests and/or clinical chemistries. Reasons for permanently discontinuation of the treatment include seven or more stools per day over baseline, severe or life-threatening enterocolitis, signs of bowel perforation, life-threatening dermatitis, including generalized exfoliate, full-thickness dermal ulceration, ulcerative or bullous dermatitis, skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, AST or ALT >5×ULN and/or total bilirubin >3×ULN and inability to taper corticosteroid dose to 7.5 mg prednisone per day without symptoms reemerging.
Immunologic checkpoint inhibition targeting CTLA-4 and PD-1/PD-L1 has dramatically improved the care of patients with many advanced malignancies. The treatment is associated with specific transient irAEs, but irAEs occasionally can be severe and fatal, and only rapid diagnosis and management of side effects can improve outcome without compromising the effıcacy of immune checkpoint inhibition.