Clinical and Translational Oncology (2020) 22:213–222 https://doi.org/10.1007/s12094-019-02273-x CLINICAL GUIDES IN ONCOLOGY SEOM clinical guideline for the management of immune‑related adverse events in patients treated with immune checkpoint inhibitors (2019) M. Majem1,13 · E. García‑Martínez2,13 · M. Martinez3 · E. Muñoz‑Couselo4 · D. Rodriguez‑Abreu5,13 · R. Alvarez6 · A. Arance7,13 · A. Berrocal8 · L. de la Cruz‑Merino9,10,13 · J. A. Lopez‑Martin11,12,13 Received: 16 December 2019 / Accepted: 16 December 2019 / Published online: 28 January 2020 © The Author(s) 2020 Abstract The use of immune checkpoint inhibitors has emerged as an effective treatment option for patients with several tumor types. By increasing the activity of the immune system, they can induce inflammatory side effects, which are often termed immune- related adverse events. These are pathophysiologically unique toxicities, compared with those from other anticancer therapies. In addition, the spectrum of the target organs is very broad. Immune-inflammatory adverse events can be life threatening. Prompt diagnosis and pharmacological intervention are instrumental to avoid progression to severe manifestations. Conse- quently, clinicians require new skills to successfully diagnose and manage these events. These SEOM guidelines have been developed with the consensus of ten medical oncologists. Relevant studies published in peer-review journals were used for the guideline elaboration. The Infectious Diseases Society of America grading system was used to assign levels of evidence and grades of recommendation. Keywords Immunotherapy · irAEs · Toxicity 2 * M. Majem Department of Medical Oncology and Hematology, Hospital mmajem@santpau.cat Universitario Morales Meseguer, Murcia, Spain 3 E. García‑Martínez Department of Medical Oncology, Hospital del Mar, helenagarciam@gmail.com Barcelona, Spain 4 M. Martinez Department of Medical Oncology, Melanoma and Other Skin MariaMartinezGarcia@parcdesalutmar.cat Tumors Unit, Vall d’Hebron Hospita, Vall d’Hebron Institute of Oncology VHIO, Barcelona, Spain E. Muñoz‑Couselo 5 evamuco@hotmail.com Department of Medical Oncology, C.H.U. Insular-Materno Infantil de Gran Canaria, Las Palmas, Spain D. Rodriguez‑Abreu 6 drodabr@gobiernodecanarias.org Department of Medical Oncology, Hospital Virgen de la Salud, Toledo, Spain R. Alvarez 7 ruthalvarez21@gmail.com Department of Medical Oncology, Hospital Clínic, Barcelona, Spain A. Arance 8 amarance@clinic.cat Department of Medical Oncology, Consorcio Hospital General Universitario de Valencia, Valencia, Spain A. Berrocal 9 berrocal.alf@gmail.com Clinical Oncology Department, Hospital Universitario Virgen Macarena, Seville, Spain L. de la Cruz‑Merino 10 lucme12@yahoo.es Medicine Department, Universidad de Sevilla, Sevilla, Spain 11 J. A. Lopez‑Martin Department of Medical Oncology, Hospital Universitario, 12 jalopezmartin@gmail.com de Octubre, Madrid, Spain 12 1 Clinical and Translational Oncology, Instituto de Investigación Department of Medical Oncology, Hospital de la Santa Sanitaria Hospital, 12 de Octubre, Madrid, Spain Creu i Sant Pau, c/Sant Antoni Maria Claret 167, 13 08025 Barcelona, Spain Spanish Group for Cancer Immuno‑Biotherapy, GÉTICA, Madrid, Spain 13 Vol.:(0123456789) 214 Clinical and Translational Oncology (2020) 22:213–222 Introduction: landscape of adverse events intermediate time points. All these toxicities can become induced by cancer immunotherapies accelerated when ICIs are combined. Consequently, cli- nicians require new skills to successfully diagnose and The use of immune checkpoint inhibitors (ICI), such as manage these events properly. inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4) Several guidelines have been published [3, 7–9]; for this and programmed cell death 1 (PD-1) or its ligand, pro- reason, we will emphasize on key general points regarding grammed cell death ligand 1 (PD-L1), has emerged as effec- the management of irAEs, including severe and/or treat- tive treatment options for patients with several tumor types. ment refractory irAEs. By increasing the activity of the immune system, ICI can induce inflammatory side effects, which are often termed immune-related adverse events (irAEs). These are patho- physiologically unique toxicities compared with those from Methodology other anticancer therapies. The severity of irAEs is graded according to the Common Terminology Criteria for Adverse These SEOM guideline have been developed with the Events (CTCAE) [1, 2]. consensus of ten medical oncologists from Spanish Soci- The frequency of irAEs varies according to the spe- ety of Medical Oncology (SEOM) and Spanish Group for cific class of compounds and patient population. Grade Cancer Immune-Biotherapy (GÉTICA). Relevant studies 3–4 toxicities have been reported in 10–27% of patients published in peer-review journals were used for the elabo- receiving anti-CTLA-4, and in 7–20% of patients receiving ration of the guideline. The Infectious Diseases Society anti-PD-1/anti-PD-L1 agents [3]. Fatigue is a commonly of America grading system was used to assign levels of reported toxicity, with a frequency of 12–37% of patients evidence and grades of recommendation [10]. receiving an anti-PD-1/anti-PD-L1, and most of the times is not associated with a treatable reason [3]. These fre- General principles for the management quencies can increase significantly when these drugs are of immune‑related adverse events given in combination with another ICI or with chemo- therapy [3, 4]. Not only the spectrum of target organs is Immune-inflammatory adverse events can be life threatening very broad (Table 1) [5, 6], but also the timing and tem- [11]. Prompt diagnosis and pharmacological intervention poral evolution of the irAEs. The latter also depends on are instrumental to avoid progression to severe manifesta- the class of ICI, but, in general, skin toxicity can appear tions [V, A] [1, 7, 12]. For such purposes, sharing adequate after 2 weeks, endocrine events can have a delayed onset information with patients and their families, other treating and liver and gastrointestinal toxicities may arise at physicians (including primary care and emergency room), Table 1  Immune-related adverse events of affected organs Organ system Types of irAEs Frequent Rare or infrequent Cutaneous Rash, pruritus, vitiligo Acneiform rash, alopecia, bullous pemphigoid, papulopustular rosacea, psoriasis, Stevens–Johnson syndrome, toxic epidermal necrosis, Sweet syndrome Gastrointestinal Diarrhea, colitis, lichenoid mucositis Enteritis, gastritis, pancreatitis Endocrine Hypothyroidism, hyperthyroidism, thy- Autoimmune type 1 diabetes, primary adrenal insufficiency roiditis, hypophysitis Hepatic Transaminitis, hepatitis – Respiratory Pneumonitis Pleuritis, sarcoidosis Rheumatologic Arthralgia, inflammatory arthritis, myalgia Dermatomyositis, myositis, polymyalgia-like syndrome, Sjörgren syndrome, vasculitis Renal Increase in serum creatinine, nephritis – Ocular – Uveitis, conjunctivitis, scleritis, episcleritis, blepharitis, retinitis Neurological Sensorimotor neuropathy Aseptic meningitis, autonomic neuropathy, encephalitis, facial nerve palsy, Guil- lain–Barré syndrome, myasthenia gravis, posterior reversible leukoencepha- lopathy, transverse myelitis Hematological – Aplastic anemia, hemolytic anemia, idiopathic thrombocytopenic purpura, lym- phopenia, hemophilia Cardiac – Cardiomyopathy, myocarditis, pericarditis 13 Clinical and Translational Oncology (2020) 22:213–222 215 Table 2  General recommendations for the management of IO toxicities (3, 8) irAE Recommendation Comments CTCAE grade 1 Symptom management, usually without systemic glucocorti- Usually can continue ICI coids 2 Consider systemic glucocorticoid (Table 3) (oral prednisone, iv Withhold immunotherapy until grade 1 and prednisone methylprednisolone 1–2 mg/Kg/day) dose ≤ 10 mg If no improvement in 2–3 days, escalate glucocorticoid dose to Consider PJP prophylaxis, calcium/vitamin D. Check blood 2 mg/Kg/day glucose Once improved to at least grade 1, taper slowly (4–6 weeks) 3–4 Systemic glucocorticoid (Table 3) (oral prednisone, iv methyl- Withhold immunotherapy until G1 without corticosteroids prednisolone 1–2 mg/Kg/day) Consider PJP prophylaxis, calcium/vitamin D. Check blood If no improvement in 2–3 days, add another immune suppressant glucose (Table 3), according to specific toxicity recommendations Grade 3—consider discontinuation of immunotherapy, depending Once improved to at least G1, taper slowly (4–6 weeks) on duration and target organ (see specific guidelines) Grade 4—discontinue immunotherapy irAEs immune-related adverse event, CTCAE National Cancer Institute Common Toxicity Criteria for Adverse Events, ICI immune-checkpoint Inhibitor, PJP Pneumocystis jiroveci pneumonia Table 3  Main characteristics of immunosuppressive agents recommended in IO toxicity management Therapy Common schedules irAE Corticosteroids Oral/IV prednisone 0,5—2 mg/kg/day From grade ≥ 2 irAEs, in any toxicity IV methylprednisolone 1–2 mg/kg/day Anti-TNFα Infliximab 5 mg/kg once every 2 weeks CRT, especially in colitis, pneumonitis, myocarditis Anti-IL6 Tocilizumab 8 mg/kg iv once per month CRT, alternative to anti-TNFα, especially in myocarditis Anti-IL1 Anakinra 100 mg once per day or canakizumab CRT, alternative to anti-TNFα, especially in myocarditis 300–600 mg once every 8 weeks Mycophenolate mofetil 500 mg orally twice a day CRT, especially in hepatitis, and myocarditis Anti-CD20 Rituximab 375 mg/m2 iv once weekly for 4 weeks Multirefractory toxicity, especially in SLE, Sjögren syndrome, nephritis, encephalitis and others Immunoglobulins Immunoglobulins iv 400 mg/kg per day, 5 days GBS, MG, encephalitis and other neurological irAEs Plasmapheresis Several courses as needed GBS, other neurological irAEs CRT​corticosteroid refractory toxicity, SLE systemic lupus erythematosus, GBS Guillain–Barré syndrome, irAEs immune-related adverse events, ATG​antithymocyte globulin pharmacists, and nurses is essential. Patients should be A] [7] (Table 3). Dose adjustments of ICIs are not recom- instructed on how to act or when to consult, and contact mended [7]. No prophylactic role has been demonstrated for persons should be defined. Managing irAEs frequently steroids [II, D] [13]. involve other specialists, such as dermatologists, gastroen- terologists, neurologists, endocrinologists, and others, who should become aware of these toxicities [12]. Patient selection and baseline assessments As shown in Table 2, grade 2 irAEs usually require with- holding ICI and close monitoring, and to decide if systemic Baseline assessments are recommended before starting treat- corticosteroids (prednisone, initial dose of 0.5 to 1 mg/kg/ ment to rule out susceptibility to develop irAEs. These include a day, or equivalent) should be initiated [V, A] [7]. For most complete patient and family history, general physical condition, of the grade 1 irAEs, ICIs can be continued, with some concomitant herbs and medication. Baseline laboratory tests exceptions (e.g., neurologic or cardiac toxicities) [7]. Grade may include complete blood counts, renal, liver and pancreatic 3–4 irAEs must be treated with high-dose corticosteroids functions tests, hormonal axis tests and viral serologies [V, C]. (prednisone 1 to 2 mg/kg/day, or methylprednisolone IV 1 Due to ICI mechanism of action, several groups of to 2 mg/kg/day) [V, A] [7]. Once initiated, corticosteroids patients have been excluded from clinical trials, including should be tapered over 4–6 weeks. If there is no improve- patients with chronic infectious diseases (hepatitis B and ment after 48–72 h, consider other immunosuppressors [V, C, HIV), transplant recipients or patients with autoimmune 13 216 Clinical and Translational Oncology (2020) 22:213–222 diseases. These challenging patients should be managed by Clinical presentation Hepatitis induced by ICIs appears multidisciplinary teams and followed up closely [V, A]. ICIs approximately 6–8 weeks after initiation of therapy and usu- appear to be relatively safe in patients with autoimmune dis- ally consists of an asymptomatic elevation of transaminases. eases [14] [V, B], as well as in chronic viral hepatitis [III, Severe hepatotoxicity involving liver injury with jaundice, B]. HIV infection should not be a contraindication for ICI, and other signs and symptoms of hepatic failure is not fre- although patients with low CD4 counts should be monitored quent. closely for efficacy and immune reconstitution [III, B]. ICIs have very high risk of causing post-transplant complications Diagnosis Initial workup includes a blood test with serum and organ rejection [V, A]. Ipilimumab appears to have supe- transaminases, bilirubin and prothrombin time [V, A], rior safety in this setting [V, B]. Anti-PD-1/PD-L1 therapy as well as the exclusion of other causes of transaminase can result in spontaneous abortion in pregnant women and increase such as infectious disease, liver metastasis, con- should be avoided [15] [V, A]. comitant drugs or alcohol intake [V, A]. Liver biopsy [V, C] may be needed in case of severe or corticosteroid-refractory hepatitis and may help to dismiss other causes of liver toxic- Specific recommendations ity or tumor infiltration. Management of frequent toxicities Management See Fig. 2 [V, A]. A multidisciplinary man- agement is essential in the treatment of hepatic toxicity. Management of gastrointestinal toxicity Management of endocrine events Epidemiology Gastrointestinal toxicities are among the leading causes of immune-related adverse effects of ICIs. Epidemiology Endocrine AEs occur in 10% of patients The frequency with anti-CTLA-4 of diarrhea is 23–33% and receiving ICIs [33]. Hypophysitis is more frequent with anti- 3–6% for grade 3–4 colitis, [16, 17] and with anti-PD-1/ CTLA-4 and thyroid dysfunction with anti-PD-1/PD-L1 PD-L1 the frequency of diarrhea is 11–19% and 1–4% for drugs. Other uncommon irAEs include primary adrenal grade 3–4 colitis [18]; the frequency of the combination insufficiency, Graves’ disease, Graves’ ophthalmopathy and anti–CTLA-4 and anti-PD-1/PDL1is up to 45%, grade 3/4, autoimmune diabetes mellitus. 9–11% [19]. Clinical presentation Endocrine toxicities usually present Clinical presentation The median onset of diarrhea is with nonspecific symptoms that make them difficult to approximately 6–8 weeks after initiation of therapy and 1/3 suspect and many of them are irreversible due to the per- of patients have concurrent enteritis [12, 20]. manent damage of the affected gland [34]. The most com- mon are those affecting the thyroid gland, which are usually Diagnosis Diagnosis is based on duration, severity, grade ≤ 2. These occur due to a transient inflammation of and presence of alarm features that may require hospital the gland, which can present with overproduction of thyroid admission [21]. Patients should undergo a complete blood hormone (hyperthyroidism) or underproduction (hypothy- count, serum electrolyte profile, serum albumin and serum roidism). C-reactive protein. Stool analyses for enteropathogens and Clostridium difficile toxin analysis should be carried out [20, Diagnosis and treatment See Fig. 3 [V, A]. Hyperthyroid- 21]. Abdominal imaging is not routinely required in patients ism usually does not need active treatment, although it may with grade 1–2 diarrhea. In severe cases, abdominal CT may evolve to hypothyroidism. Hypothyroidism is usually a per- be indicated to rule out complications [22]. Flexible sigmoi- manent condition that needs levothyroxine substitution for doscopy or colonoscopy should be performed in patients life. Hypophysitis can affect one or several of the pituitary with bloody diarrhea or those with persistent ≥ grade 2 diar- axes with or without a pathological image in the MRI. The rhea [23] [IV, D]. steroid axis is the most frequently affected permanently [35]. In these patients, any additional stress can cause an Management See Fig. 1 [3, 24–28] [V, B]. acute adrenal crisis, seriously threatening patient’s life and requiring urgent treatment. For grade ≥ 3 toxicity to seek Management of hepatic toxicity [29–32] endocrinology consultation is recommended. Epidemiology It has been described in 5–10% (1–2% grade 3) of patients receiving monotherapy and in 25–30% (15% grade 3) of patients receiving combination of ICIs. 13 Clinical and Translational Oncology (2020) 22:213–222 217 Fig. 1  Management of gastrointestinal toxicity Management of pneumonitis Diagnosis Patients should undergo a chest CT scan as chest X-ray may fail to identify about 25% of cases of pneumoni- Epidemiology Pneumonitis occurs predominantly in tis [38]. Several patterns of radiological presentation have patients receiving anti-PD-1/PD-L1 alone or combination been reported, being cryptogenetic organizing pneumonia with anti-CTLA-4 [36]. The incidence is higher in patients the most frequent [36]. with lung and renal cell cancer, suggesting that chemo- therapy-induced lung inflammation, previous radiotherapy, Management Treatment of incidental radiographic pre-existing lung disease or smoking may contribute to the changes is controversial, and most guidelines suggest delay- occurrence of this toxicity [37]. ing treatment until radiographic improvement or resolution [V, C]. For grade 2 pneumonitis, treatment with oral steroids Clinical presentation Pneumonitis can mimic other symp- is indicated (prednisone 1 mg/kg/day) and ICIs should be toms encountered in cancer patients including dyspnea and withheld [V, B]. Grade ≥ 3 pneumonitis requires hospitali- nonproductive cough. Fever and chest pain are less com- zation and treatment with I.V. steroids (methyl/prednisolone mon. 2–4 mg/kg/day), and ICIs should be permanently discontin- 13 218 Clinical and Translational Oncology (2020) 22:213–222 HEPATOTOXICITY GRADE 1 GRADE 2 GRADE 3 GRADE 4 AST or ALT 3-5x ULN and/or AST or ALT >ULN to 3 x ULN and/or Bilirrubin 1.5 -3x ULN and/or AST or ALT 5-20x ULN and/or AST or ALT >20 x ULN and/or Bilirrubin >ULN to 1.5x ULN and/or GGTor FA 2.5 - 5x ULN Bilirrubin 3-10 xULN and/or Bilirrubin > 20x ULN and/or GGT or FA >ULN to >2,5x ULN GGT or AF 5-20 GGT or FA >20x ULN Hold ICIS Continue ICIs Laboratoty Work up** Permanently discotinue ICIs Laboratoty monitoring every Discontiue (Hold) ICIs Supportive monitoring every 3 days care* HOSPITALIZATION 2 weeks Laboratoty Immediate IV 2 mg/kg/day Improvement monitoring Improvement or Work up** methylprednisolone daily mantained grade Yes No 1 Laboratoty Work up** 1 week monitoring daily Recover Hepatology consult Yes No grade 1 and/or hospitalization Start steroids 0.5- Hepatology Continue See 1mg/kg/day consult Start steroids 1- ICIs ICIs grade 2 2mg/kg/day resumption Improvement Improvement Improvement Yes No Consider liver Yes No biopsy Continue See steroids until grade 3 > 3 days Yes No Continue Consider grade 1*** steroids until liver biopsy Continue steroides Start additional grade 1*** Grade 1 until grade 1*** immunosuppressive Start additional agent**** Steroids Grade 1 immunosuppressive Grade 1 tappering agent**** >4 weeks Steroids tappering Steroids >4 weeks tappering > 4 ICIs resumption weeks when prednisone equivalent < 10 Consider ICIs resumption mg/daily when prednisone equivalent < 10 mg/daily Fig. 2  Management of hepatic toxicity. *Supportive care: avoid alco- metastasis. ***If steroids therapy if required > 2 weeks consider pro- hol and hepatotoxic drugs. Supportive treatment in case of symptoms. phylactic antibiotic. ****Additional immunosuppressive medications **Workup: review concomitant medications, herbs, dietary supple- include mycophenolate mofetil, tacrolimus, antithymocyte globulin, ments, homeopathic. Liver function test, prothrombin time, albumin, or cyclosporine serology hepatitis, autoimmune and iron studies, investigate new ued [V, B]. A bronchoscopy should be performed to exclude life-threatening syndromes are suspected. Skin biopsy and a infectious etiologies before starting immunosuppression. review by dermatologist may also be indicated. Infliximab and/or cyclophosphamide should be considered for refractory pneumonitis [3, 7–9]. Management ICIs can be maintained in grade 1–2 toxici- ties, interrupted in grade 3 and permanently discontinued in Management of cutaneous adverse events [39, 40] grade 4 [V, A]. Symptomatic treatment with systemic anti- histamines, high to very high strength topical steroids, and Epidemiology Cutaneous side effects are common under topical moisturizers is indicated in all grades [V, A]. High- ICIs (anti-CTLA-4: 43–45%, anti-PD-1/PD-L1: 35%), and dose steroids are indicated in grade ≥ 3. Other immunosup- may be serious and dose limiting. Cutaneous adverse events pressive drugs may be needed in steroid-refractory cases [V, appear later with anti-PD-1/PD-L1 than with anti-CTLA-4 A]. or combination. Management of less frequent toxicities Clinical presentation The most frequently reported cuta- neous adverse events are maculo-papular rash, pruritus Management of neurological toxicity and vitiligo. Exacerbation of psoriasis or psoriasiform and lichenoid reactions has also been reported. Epidemiology and clinical presentation The incidence of neurological complications varies from 2–4% [1, 41, 42]. Diagnosis Careful physical examination of the skin and Moderate AEs have been reported in 6–12% (dizziness, mucosal areas is required. Blood tests may be helpful if headaches, sensory neuropathies, etc.), whereas severe 13 Clinical and Translational Oncology (2020) 22:213–222 219 Hypophysitis Autoimmune Diabetes Primary Hypothyroidism Primary Hyperthyroidism Clinical suspicion Clinical suspicion Clinical suspicion Clinical suspicion Asthenia, constipation, dry skin, hair Palpitations, ↑stool frequency, heat Severe: Poliuria, polydipsia, polyfagia, weight loss, weight gain intolerance, sweating, weight loss Mild: Intense headache, loss, Fasting plasma glucose ≥126 Headache, fatigue, visual sypmtoms, mg/dL (7 mmol/L) asthenia, hypotension, Diagnostic Tests Diagnostic Tests amenorrhea, abdominal pain, TSH, free T4, TPOAb TSH, free T4, TPOAb, TSIAb, EKG impotence hypoglycemia, hipoNa, hyperK vomiting, hipoNa, Repeat in 4-8 weeks TSH >10mUI/l TSH 5-10mUI/l hyperK TSH <0.3mUI/l TSH <0.3mUI/l ↓ free T4 N free T4 ↑free T4 N free T4 Diagnostic Tests Diagnostic Tests Diagnosis Diagnosis Diagnosis Plasma blood glucose, electrolytes, Diagnosis Blood samples for ACTH, plasma cortisolACTH, Subclinical Hyperthyroidism Subclinical Hypothyroidism TSH, FSH, LH, IGF-1, plasma cortisol, free T4, urea, creatinine, arterial blood gases hypothyroidism hyperthyroidism prolactin, testosterone/estradiol Urine or plasma ketones Treatment Treatment No If symptomatic, Symptomatic Levothyroxine Propranolol Treatment 50 mcg/day oral 10-20mg/8h Hidrocortisone Yes 20mg/day oral Urgent, do not wait for if cortisol results: Admission, Treatment Hydrocortisone IV deficiency suspected until 100mg/8h or equivalent Levothyroxine 1l SS 0.9% in 1st hour 25-50 mcg/day results available Rule out infection oral Consider Continue Immune Checkpoint Inhibitor holding dose Omit Scheduled dose Monitoring Preferential Urgent Endocrinology consultation TSH, free T4 in 4-8 weeks Monitoring consultation Titrate for TSH in normal range: TSH, free T4 in 4 weeks 25mcg increments Confirmed Confirmed diagnosis diagnosis Treatment Switch to Once stabilized, Hypothyroidism Admission, Urgent treatment of DKA if algorithm hypothyroidism corticoisteroids tappering present, rule out infection and hormone replacement under strict Once stabilized, Insulin basal bolus survaillance by Optional Endocrinology consultation regime under strict survaillance by Endocrinologist Endocrinologist Brain MRI Residual toxicity ≤2: restart anticancer treatment Long-lasting surveillance by Endocrinologist Fig. 3  Management of endocrine toxicity. TSH thyrotropin-stimulating hormone, TPOAb anti-peroxidase antibodies, TSIAb anti-TSH receptor antibodies, SS saline solution 0.9% events (encephalitis, aseptic meningitis, inflammatory Management of cardiovascular toxicity myopathies, myasthenia gravis, Guillain–Barre syndrome, multiple sclerosis, etc.) are present in < 1% of patients. This Epidemiology and clinical presentation The incidence of incidence can be higher when ICIs are given in combina- cardiac toxicity is < 1%, although it might have been under- tion (14%), or if there is preexisting autoimmune disease reported and/or underestimated. The incidence is higher (27–38%) [1, 41, 43–45]. with the combination of anti-CTLA-4 and anti-PD-1/PD-L1 (0.27%) compared with anti-PD-1/PD-L1 alone (0.06%). A Management A neurologic consult is indicated. There is no wide range of toxicities, including myocarditis, pericarditis, standard therapy and treatment is decided according to the arrhythmias, cardiomyopathy and decrease in ventricular type and severity of the neurological event. Improvements function, have been reported [47]. have been described after discontinuation of ICIs and with systemic high-dose steroids [V, B]. Other treatments such Diagnosis and management Initial workup may include as intravenous immunoglobulin, plasmapheresis or immu- EKG, troponin, BNP and echocardiogram. Early consulta- nosuppressive agents have shown non-consistent results [V, tion with a cardiologist is highly recommended [V, B] and B]. After neurological toxicity recovery, resumption of ICIs additional testing with cardiac MRI may be indicated. High- is controversial, and risk/benefit ratio should be carefully dose steroids have been used successfully and should be taken into consideration [46]. given quickly if suspected [V, B]. Other immunosuppressive drugs such as mycophenolate, infliximab, or antithymocyte globulin may be indicated if patient does not respond to ster- 13 220 Clinical and Translational Oncology (2020) 22:213–222 oids [V, B] [3]. Infliximab in contraindicated in the presence ipilimumab [56], requiring intravitreal anti-VEGF injec- of moderate to severe heart failure. tions. Management of renal toxicity Diagnosis and management Treatment of ocular toxici- ties depends on the severity and type of toxicity. In case of Epidemiology and clinical presentation Renal toxicity is uveitis, topical steroids can be effective, and for more severe rare in patients receiving monotherapy (< 1%) but can reach toxicities, systemic steroids are indicated and discontinua- 5% when ICIs are combined together or with a platinum- tion of ICIs should be considered [V, B]. Resumption can be based chemotherapy. The most common event is acute considered in patients with grade 1–2 ocular toxicities but tubule-interstitial nephritis. in case of grade ≥ 3, permanent discontinuation should be recommended [V, B]. Diagnosis and management Renal function should be measured before every infusion of ICI and nephrotoxic Management of refractory toxicities (Table 3) drugs may be stopped in case of renal dysfunction. Presence of infection or urinary tract obstruction must be evaluated. Epidemiology of steroid-refractory high-grade irAEs is cur- ICI should be interrupted in grade ≥ 2 renal dysfunction and rently unknown. Due to the lack of validated biomarkers, treatment with high-dose steroids is recommended [V, B]. a gradual approach is advocated to manage severe irAEs, Nephrology evaluation is also recommended and a renal starting with high-dose steroids. If the latter fails, a more biopsy may be useful [V, B] [3, 48]. aggressive immunosuppression is recommended, consider- ing the introduction of cytokine-directed mAb against IL-1, Management of rheumatologic toxicity IL-6 or TNFα [11, 57]. Anti-TNFα mAb infliximab (single dose of 5 mg/kg) is the upfront recommended treatment Epidemiology and clinical presentation Incidence of rheu- for corticosteroid-refractory colitis and pneumonitis, and matologic toxicity is generally underestimated and is more mycophenolate mofetil with appropriate antibacterial and common with anti-PD-1/PD-L1. They can be grouped in antiviral prophylaxis for corticosteroid-refractory hepatitis inflammatory arthritis, myositis, and polymyalgia rheumat- [V, C], although use of anti-IL6 (tocilizumab) and anti-IL1 ica (PMR)-like syndromes [49]. (anakinra) may represent good alternatives for the previ- ous and many other irAEs in the context of a personalized Diagnosis and management A multidisciplinary approach approach with close monitorization [7] [V, D]. Immuno- would be the first measure. Comprehensive anamnesis globulins and plasmapheresis could be an option in severe including joint examination and muscle strength, autoim- and multirefractory irAEs, especially in neurological irAEs mune blood panels and inflammatory markers, and radio- [8] [IV, D]. logical assessment with plain-X ray, ultrasound and or MRI is recommended [50] [V, D]. For grade 1 events, common analgesia with paracetamol or NSAIDs is recommended. Conclusions From ≥ grade 2, referral to rheumatologist, temporary or permanent discontinuation of ICIs, steroids and biologic ICIs are an effective treatment option in several tumor types disease-modifying anti-rheumatic drugs must be considered that can induce inflammatory side effects, termed irAES. [51] [V, D]. irAEs can affect multiple organs of the body and its sever- ity can be low to life threatening. As a consequence, clini- Management of ocular toxicities cians require new skills to successfully diagnose and manage these events, and also a multidisciplinary approach may be Epidemiology and clinical presentation Ocular toxicities indicated. represent < 1% of irAEs [52] and consist of ocular inflamma- tion (uveitis, peripheral keratitis, Vogt–Koyanagi–Harada syndrome), orbital inflammation, as well as retinal and Author contributions All the authors have contributed equally to the writing of the manuscript. choroidal diseases (retinopathy, neovascularization) [53]. Previous trials have shown that patients who develop ocu- lar toxicities are more likely to present other irAEs. Uveitis Compliance with ethical standards has been reported in patients treated with anti-CTLA-4 and Conflict of interest MMT reports grants and personal fees from BMS; anti-PD-1 [54]. Idiopathic orbital inflammation has been personal fees from Astra Zeneca, Roche, MSD, Boehringer Ingelheim, described in relation to ipilimumab [52, 55]. Choroidal neo- Takeda, and Bayer; non-financial support and other from Astra Zen- vascularization has been reported in a patient treated with eca, MSD, Boehringer Ingelheim, and other from Takeda, outside the 13 Clinical and Translational Oncology (2020) 22:213–222 221 submitted work; EGM reports grants and personal fees from Roche, anti-CTLA-4 antibody ipilimumab in patients with meta- Astra Zeneca, MSD, BMS, Pfizer, and Pharmamar, outside the submit- static melanoma after prior anti-PD-1 therapy. Br J Cancer. ted work; MMG reports personal fees and non-financial support from 2016;114(10):1084–9. Roche, and non-financial support from Pfizer, outside the submitted 7. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, work; AA reports personal fees and other from BMS, MSD, Roche, Caterino JM, et al. Management of immune-related adverse events Novartis, Merck, Sanofi, Amgem, Pierre Fabre, outside the submitted in patients treated with immune checkpoint inhibitor therapy: work; AB reports personal fees and non-financial support from BMS, American society of clinical oncology clinical practice guideline. MSD, Roche, Novartis, Sanofi, Merck-Pfizer, personal fees from Pierre J Clin Oncol. 2018;36(17):1714–68. Fabre and Incyte, outside the submitted work; LC reports grants and 8. Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, personal fees from BMS, Roche, MSD-Merck, Amgen, personal fees Dadu R, et al. Managing toxicities associated with immune check- from Pierre Fabre, Novartis, and grants from Celgene, outside the sub- point inhibitors: consensus recommendations from the society for mitted work; JAL reports grants, personal fees, non-financial support immunotherapy of cancer (SITC) toxicity management working and others from BMS-Celgene, MSD, Novartis-GSK, Roche and Pfiz- group. J Immunother Cancer. 2017;5(1):95. er, grants, non-financial support and others from Astra-Zeneca, and 9. Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand non-financial support and others from Amgen, Bayer, Daichi-Sankyo, P, Bhatia S, et al. Management of immunotherapy-related tox- Chobani, Pierre Fabre, personal fees, non-financial support and others icities, Version 1.2019. J Natl Compr Cancer Netw JNCCN. from Pharmamar, and non-financial support from Merk-Serono during 2019;17(3):255–89. the conduct of the study; EM, DR and RA have nothing to disclose. 10. Dykewicz CA. Summary of the guidelines for preventing oppor- tunistic infections among hematopoietic stem cell transplant Ethical approval The current study has been performed in accordance recipients. Clin Infect Dis. 2001;33(2):139–44. with the ethical standards laid down in the 1964 Declaration of Hel- 11. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, sinki and its later amendments. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. Informed consent Not applicable. 2018;4(12):1721–8. 12. Weber JS, Kahler KC, Hauschild A. Management of immune- related adverse events and kinetics of response with ipilimumab. Open Access This article is licensed under a Creative Commons Attri- J Clin Oncol. 2012;30(21):2691–7. bution 4.0 International License, which permits use, sharing, adapta- 13. Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, tion, distribution and reproduction in any medium or format, as long et al. A randomized, double-blind, placebo-controlled, phase as you give appropriate credit to the original author(s) and the source, II study comparing the tolerability and efficacy of ipilimumab provide a link to the Creative Commons licence, and indicate if changes administered with or without prophylactic budesonide in were made. The images or other third party material in this article are patients with unresectable stage III or IV melanoma. Clin Can- included in the article’s Creative Commons licence, unless indicated cer Res. 2009;15(17):5591–8. otherwise in a credit line to the material. If material is not included in 14. Pantuck M, McDermott D, Drakaki A. To treat or not to treat: the article’s Creative Commons licence and your intended use is not patient exclusion in immune oncology clinical trials due to pre- permitted by statutory regulation or exceeds the permitted use, you will existing autoimmune disease. 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