Immune checkpoint–blocking drugs such as ipilimumab, pembrolizumab, and nivolumab have demonstrated clinical efficacy as anticancer agents. Through modulation of immunoregulatory molecules, these novel therapeutics can produce durable cancer remissions in a variety of tumor types. As these medications are administered to an increasing number of patients, clinicians must be able to recognize and treat the associated immune-related side effects. This review summarizes the unique mechanisms of toxicity associated with immune checkpoint–blocking drugs, appropriate steps in patient evaluation, and strategies for mitigating risk and optimizing patient outcomes. Although the management of each patient receiving immune checkpoint–blockade therapy must be individualized, a conceptual framework upon which to base a multidisciplinary approach to best practices will help oncology practitioners deliver safe and effective care.
Management of Immune Checkpoint–Blockade Toxicities
Patients treated with immune-checkpoint inhibitors should be seen clinically prior to each cycle of therapy (eg, every 3 weeks for ipilimumab and pembrolizumab). The clinical visit should include a comprehensive review of systems with specific focus on common and serious toxicities, such as skin changes, diarrhea and abdominal pain, headache, fever, shortness of breath, cough, and neurologic changes. Routine laboratory testing, including hematologic profile, comprehensive metabolic panel, and TSH level, should be obtained. Any new symptoms or abnormalities in examination or laboratory test results should be evaluated prior to administration of the next dose of drug.
The diagnosis of immune checkpoint–blockade toxicity is one of exclusion. Specifically, progression of underlying malignancy, infection, and other possible causes of a particular abnormality must be ruled out prior to identifying a given toxicity as an irAE. This workup may include symptom-focused diagnostic radiologic studies and additional laboratory tests and cultures. Clinicians should feel comfortable withholding checkpoint-blockade therapy until the workup is complete.
Understanding the severity of a toxicity is key to determining the proper approach to its management. Toxicities should be graded using the CTCAE. Clinicians should consult published guidelines (eg, http://www.yervoy.com/hcp/rems.aspx) for management strategies, keeping in mind that each toxicity is different and that approaches will need to be individualized. For example, grade 1 pneumonitis is a potentially life-threatening problem, while grade 1 dermatitis generally does not require dose interruption. Guidance with regard to temporary or permanent drug discontinuation can be found in the full prescribing information for pembrolizumab and ipilimumab.[39,40] In the case of pembrolizumab, withholding the drug is recommended for grade 2 pneumonitis, colitis, nephritis, or hepatitis; any grade 3 adverse reaction; and any symptomatic hypophysitis. Pembrolizumab can be restarted with improvement of these toxicities to grade ≤ 1. Permanent discontinuation is recommended for life-threatening adverse events, including grade 3 pneumonitis, nephritis, or hepatitis; any recurrent grade 3 adverse event; or inability to reduce prednisone dosage to 10 mg daily after 12 weeks. While the inability to wean a patient from corticosteroids may be a cause for permanent drug discontinuation, many practitioners would institute a course of infliximab in the case of an ongoing high-dose prednisone requirement. Thus, the need for infliximab or alternative immunosuppression would generally be an indication for permanent checkpoint inhibitor discontinuation as well.
Grade 1 toxicities are mild, asymptomatic, or minimally symptomatic. Generally, patients with this level of toxicity are able to continue therapy with supportive care and increased monitoring. Examples of grade 1 toxicity include a mild rash or alteration in thyroid function test results. Follow-up should be tailored to the specific abnormality (eg, more frequent for pulmonary issues, less so for dermatologic issues).
Grade 2 toxicities generally require at least temporary discontinuation of checkpoint therapy. Patients should be monitored closely, and therapy can often be restarted if the toxicity improves to grade 1. However, for patients who have persistent grade 2 symptoms for at least one week, initiation of low-dose corticosteroid therapy is indicated. In general, these patients can be managed as outpatients with oral prednisone of 0.5 to 1.0 mg/kg/day or the equivalent. Patients must be monitored carefully, with strict instructions for reporting any worsening of symptoms. For grade 2 hepatic, renal, or hematologic abnormalities, laboratory monitoring every few days is recommended. As patients improve, the corticosteroid can be tapered over at least 1 month. For prolonged steroid tapers, prophylaxis against Pneumocystis jirovecii pneumonia (PCP; formerly Pneumocystis carinii pneumonia) should be considered.
Grade 3/4 toxicities have the potential for significant morbidity and mortality. Not infrequently, patients require hospitalization for evaluation and frequent monitoring. Permanent discontinuation of the checkpoint-blockade agent should be considered. Prompt diagnostic studies, including symptom-focused imaging (eg, pituitary MRI or chest CT), cultures and/or biopsy (eg, bronchoscopy with bronchoalveolar lavage and transbronchial biopsy or flexible sigmoidoscopy with colon biopsy) should be performed in consultation with an interventional pulmonologist or gastroenterologist. When a high-grade immunologic toxicity is suspected, corticosteroid therapy should be initiated. A dosage of 1 to 2 mg/kg/day of methylprednisolone or the equivalent is generally required; however, in the case of pneumonitis, some investigators have used a higher dosage of 2 to 4 mg/kg/day. Prophylaxis against PCP should be considered. In anticipation of possible need for anti–tumor necrosis factor (TNF) agents, patients should have viral hepatitis serologies and a tuberculosis test performed. Corticosteroids should be continued at high dose until improvement of the toxicity to grade 1, at which point a prolonged taper can be initiated. In general, patients should not be rechallenged with the same immune checkpoint–blockade agent.
Special considerations for specific toxicities
This review is meant to highlight the principles underlying the evaluation and management of irAEs associated with checkpoint-blockade agents. Although an exhaustive list of possible toxicities is beyond the scope of this article, clinicians should be aware of some of the less common irAEs, which may be hematologic (eg, hemolytic anemia, thrombocytopenia), cardiovascular (eg, myocarditis, pericarditis, vasculitis), ocular (eg, blepharitis, conjunctivitis, iritis, scleritis, uveitis), renal (eg, nephritis), or pancreatic (both endocrine and exocrine pancreatitis). Management considerations regarding several of the more common or potentially serious toxicities are described in detail below.
Enterocolitis. Autoimmune enterocolitis deserves special attention, due to its relatively high frequency in patients receiving CTLA-4 blockade and the multiple facets of its management. Patient symptoms should first be graded by combining CTCAE criteria with the overall clinical picture.
Patients with mild symptoms (eg, grade 1 abdominal pain or diarrhea) should be evaluated for infection, including Clostridium difficile infection. Antidiarrheals (eg, loperamide) and supportive measures, such as increasing oral fluid intake, should be considered.
Moderate symptoms often necessitate discontinuation of therapy, an infectious workup as above, and, if symptoms do not improve within a week, initiation of low-dose oral corticosteroids (0.5 mg/kg/day of prednisone or the equivalent). If symptoms improve and the patient is requiring the equivalent of < 7.5 mg/day of prednisone, clinicians might consider cautiously restarting checkpoint-blockade therapy. Collaboration with a gastroenterologist who is familiar with the evaluation and workup of autoimmune colitis is recommended. Visual inspection of the colon, as well as pathologic evaluation of colonic biopsies, is often useful in evaluating patients with persistent or recurrent symptoms.
Patients with severe symptoms (eg, grade 3/4 diarrhea, significant hematochezia, or peritoneal signs) require discontinuation of checkpoint therapy and should be hospitalized and closely monitored. An immediate workup for infection is appropriate, and, if perforation is suspected, surgical consultation should be obtained for operative management prior to administration of high-dose systemic corticosteroids (1 to 2 mg/kg/day of intravenous methylprednisolone or equivalent). Abdominal CT scans may be instructive. In one study of patients diagnosed with ipilimumab-associated colitis, characteristic findings included mesenteric vessel engorgement, bowel wall thickening, and fluid-filled colonic distension.
Patients should continue on corticosteroids until symptoms improve, at which time a steroid taper lasting ≥ 1 month should be initiated. While patients may be concerned about corticosteroids interfering with the efficacy of treatment, one small study suggests that steroids do not affect the duration of clinical response to ipilimumab. Given the risk of narcotic bowel, opiates should be used with caution in patients with abdominal pain. Administration of infliximab (5 mg/kg) should be considered for patients who do not improve within 3 to 5 days of initiation of corticosteroid therapy.[31,43] Infliximab should be used with caution in patients with sepsis from enterocolitis. The use of infliximab for steroid-refractory enterocolitis can be generalized to most other severe autoimmune toxicities, with the possible exception of hepatitis.
Hepatitis. When patients receiving checkpoint inhibition present with liver dysfunction, a high suspicion for drug-related autoimmune hepatitis is warranted. Clinicians should rule out other causes of hepatic injury, such as viruses, metabolic or cardiovascular derangements, other medications, or tumor progression.
Grade 1 elevations in liver function laboratory values require close monitoring. For grade 2 hepatotoxicity, the immune checkpoint–blockade agent should be withheld, and corticosteroids should be promptly initiated and tapered over at least 1 month. In consultation with a hepatologist, clinicians may consider liver biopsy. Grade 3/4 hepatitis requires discontinuation of drug and initiation of high-dose corticosteroids (1 to 2 mg/kg/day of prednisone). Hospitalization should be considered, as cases of death from liver failure have been reported in patients with this level of hepatotoxicity. If a high-grade liver toxicity does not improve within 48 to 72 hours of initiation of high-dose corticosteroids, consideration of alternative immunosuppression agents is warranted. The alternative immunosuppression agent of choice is mycophenolate mofetil instead of infliximab, as infliximab can be independently associated with liver function abnormalities. One case report describes the use of antithymocyte globulin in a patient with severe ipilimumab-related hepatitis that was found to be refractory to mycophenolate mofetil. Tacrolimus 0.10 to 0.15 mg/kg/day has also been recommended by some investigators for mycophenolate-refractory hepatitis.
Pneumonitis. In a 306-patient trial of nivolumab, 3 patients died as a result of drug-related pneumonitis. Although it is relatively uncommon, pneumonitis has significant potential for morbidity and mortality, and this condition should be approached with great caution. Optimal evaluation and management of patients with suspected autoimmune pneumonitis has not been assessed in prospective clinical trials, and there is no consensus statement regarding the care of this patient population. In the case of grade 1 pneumonitis (asymptomatic radiographic changes only), immune checkpoint–blockade therapy should be withheld, and patients should be monitored closely (every 2 to 3 days) for the development of symptoms. Consultation with an interventional pulmonologist and an infectious-disease specialist is recommended. Repeat CT imaging of the chest is recommended within 3 weeks to document resolution or progression.
For patients with symptomatic pneumonitis (grade ≥ 2), patients should be monitored daily, with consideration given to hospitalization. In consultation with an interventional pulmonologist, performance of a bronchoscopy with bronchoalveolar lavage and tissue biopsies should be considered. Treatment with high-dose corticosteroids is recommended, along with empiric antibiotics, both of which can be administered while the above evaluation is underway. As with other severe toxicities, a lack of improvement after 48 to 72 hours of high-dose steroid treatment should prompt consideration of infliximab therapy. If possible, administration of infliximab should be delayed until a pulmonary infection has been reasonably excluded.
Dermatitis. An ipilimumab-associated rash should first be graded according to CTCAE. Macules/papules covering < 10% (grade 1) or 10% to 30% (grade 2) of body surface area with or without symptoms (eg, pruritus, burning, tightness) can often be managed with topical corticosteroids and oral over-the-counter antihistamines. In general, checkpoint-blockade therapy can be continued, although careful monitoring for progression of symptoms is warranted.
Grade 3 rash is characterized by macules/papules covering > 30% of body surface area with or without symptoms, as above. Oral corticosteroid administration (approximately 1 mg/kg/day prednisone or equivalent) frequently achieves symptom control. Temporary discontinuation of checkpoint therapy should be considered. Again, careful monitoring for progression of symptoms is warranted.
Grade 4 skin toxicity includes Stevens-Johnson syndrome; toxic epidermal necrolysis; and rash complicated by full-thickness dermal ulceration, necrosis, or hemorrhage. These symptoms require emergent administration of high-dose corticosteroids, inpatient admission, and consultation with a dermatologist.
Pruritus often accompanies a rash and can persist even after resolution of visible skin irritation. Mild, localized pruritus can be managed with moisturizing creams, topical corticosteroids, and topical antihistamines. More intense or widespread pruritus resulting in skin changes from scratching (eg, edema, papulation, excoriations, lichenification, oozing/crusts) may require low-dose oral corticosteroids or antipruritics (eg, hydroxyzine). For symptoms that limit activities of daily living or sleep or are intense or constant, clinicians could consider prescribing gabapentin, pregabalin, mirtazapine, or aprepitant.
Endocrinopathies. Autoimmune endocrinopathies can affect any organ in the hypothalamic-pituitary-adrenal axis. Patients who have hypophysitis but who are not in adrenal crisis generally require a short course of high-dose corticosteroids (eg, methylprednisolone 1 to 2 mg/kg/day or the equivalent) to address the acute inflammation; such treatment may preserve some degree of pituitary function. Steroids should be tapered over at least 1 month, and patients should be followed by an endocrinologist, since many patients who develop endocrine deficiencies as a result of autoimmune hypophysitis do not experience restoration of normal hormonal function despite control of the initial inflammation with corticosteroids. These patients may require long-term pituitary hormone replacement.
In rare cases, an autoimmune endocrinopathy may manifest as an adrenal crisis. These patients should receive stress-dose corticosteroids (eg, hydrocortisone 100 mg IV immediately, followed by 50 to 100 mg every 8 hours) along with fluid resuscitation as appropriate.
Patients who present with hyperthyroidism may initially require treatment (eg, beta-blockers) for alleviation of symptoms. Frequently, thyroiditis resolves over time, but then patients become hypothyroid, requiring thyroid hormone replacement. Isolated, asymptomatic hypothyroidism that can be managed with thyroid replacement alone generally does not require dose interruption or discontinuation of checkpoint-blockade drugs.
The successful clinical application of immune checkpoint–blockade therapies will continue to change the way we treat patients with advanced cancers. As novel immunomodulators increasingly play a role in oncologic therapy, practitioners must have strategies and protocols in place for identifying and treating immune-related toxicities. Indeed, the National Comprehensive Cancer Network (NCCN) consensus panel strongly recommends that physicians who prescribe ipilimumab participate in the corresponding Risk Evaluation and Mitigation Strategy (REMS) program.
While guidelines and algorithms are available to assist in the management of immune-related events, a patient’s entire treatment team—in particular, nurses, who are often a patient’s first point of contact in an oncology practice setting—must be familiar with and trained to properly manage these toxicities.[49,50] Patients, too, must be educated regarding possible side effects of therapy and the need for prompt symptom reporting. To facilitate effective patient-provider communication, some practitioners elect to use a standard list of questions to screen for possible irAEs at each patient encounter.
Ongoing studies aim to identify biomarkers to help identify patients at highest risk for irAEs. For now, practitioners must maintain a high level of suspicion for checkpoint-inhibitor toxicity, must understand the common and serious side effects, and must recognize that the potential exists for irAEs to affect any of the body’s organ systems.
Financial Disclosure: Dr. Lipson has served as an advisory board member for Amgen, and has received research funding from Genentech and AstraZeneca. Dr. Teply has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Drake CG, Lipson EJ, Brahmer JR. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat Rev Clin Oncol. 2014;11:24-37.
2. Gangadhar TC, Vonderheide RH. Mitigating the toxic effects of anticancer immunotherapy. Nat Rev Clin Oncol. 2014;11:91-9.
3. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-64.
4. Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev. 2008;224:141-65.
5. Bour-Jordan H, Esensten JH, Martinez-Llordella M, et al. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev. 2011;241:180-205.
6. National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, DHHS. May 29, 2009. NIH publication # 09-7473.
7. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.
8. Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol. 2011;29:abstr 8583.
9. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700-12.
10. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046-54.
11. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (ipi) versus ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013;31(suppl):abstr CRA9007.
12. Kirkwood JM, Lorigan P, Hersey P, et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res. 2010;16:1042-8.
13. Chung KY, Gore I, Fong L, et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol. 2010;28:3485-90.
14. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134-44.
15. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014;384:1109-17.
16. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54.
17. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020-30.
18. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65.
19. Hamid O, Sosman JA, Lawrence DP, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J Clin Oncol. 2013;31(suppl):abstr 9010.
20. Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917-27.
21. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.
22. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-7.
23. Lipson EJ, Bodell MA, Kraus ES, Sharfman WH. Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma. J Clin Oncol. 2014;32:e69-71.
24. Tarhini AA, LaFramboise WA, Petrosko P, et al. Clustered genomic variants specific to patients who develop immune-related colitis after ipilimumab for prediction of toxicity. J Clin Oncol. 2014;32(suppl 5S):abstr 9024.
25. Shahabi V, Berman D, Chasalow SD, et al. Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events. J Transl Med. 2013;11:75.
26. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:5591-8.
27. Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. 2009;58:823-30.
28. Lacouture ME, Wolchok JD, Yosipovitch G, et al. Ipilimumab in patients with cancer and the management of dermatologic adverse events. J Am Acad Dermatol. 2014;71:161-9.
29. Minkis K, Garden BC, Wu S, et al. The risk of rash associated with ipilimumab in patients with cancer: a systematic review of the literature and meta-analysis. J Am Acad Dermatol. 2013;69:e121-8.
30. Kaehler KC, Piel S, Livingstone E, et al. Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. Semin Oncol. 2010;37:485-98.
31. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24:2283-9.
32. Carpenter KJ, Murtagh RD, Lilienfeld H, et al. Ipilimumab-induced hypophysitis: MR imaging findings. AJNR Am J Neuroradiol. 2009;30:1751-3.
33. Torino F, Barnabei A, De Vecchis L, et al. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist. 2012;17:525-35.
34. Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Invest New Drugs. 2013;31:1071-7.
35. Bompaire F, Mateus C, Taillia H, et al. Severe meningo-radiculo-nevritis associated with ipilimumab. Invest New Drugs. 2012;30:2407-10.
36. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro Oncol. 2014;16:589-93.
37. Bot I, Blank CU, Boogerd W, Brandsma D. Neurological immune-related adverse events of ipilimumab. Pract Neurol. 2013;13:278-80.
38. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712-7.
39. Pembrolizumab prescribing information. Available from: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed September 22, 2014.
40. Ipilimumab package insert. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf. Accessed September 22, 2014.
41. Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab-associated colitis: CT findings. Am J Roentgenol. 2013;200:W468-74.
42. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13:6681-8.
43. Pages C, Gornet JM, Monsel G, et al. Ipilimumab-induced acute severe colitis treated by infliximab. Melanoma Res. 2013;23:227-30.
44. Reuben A. Hepatotoxicity of immunosuppressive drugs. In: Kaplowitz N, DeLeve LD, editors. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier; 2013. p. 569-91.
45. Chmiel KD, Suan D, Liddle C, et al. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. J Clin Oncol. 2011;29:e237-40.
46. Tarhini A. Immune-mediated adverse events associated with ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo). 2013;2013:857519. Epub 2013 Apr 17.
47. Kaehler KC, Egberts F, Lorigan P, Hauschild A. Anti-CTLA-4 therapy-related autoimmune hypophysitis in a melanoma patient. Melanoma Res. 2009;19:333-4.
48. Lammert A, Schneider H, Bergmann T, et al. Hypophysitis caused by ipilimumab in cancer patients: hormone replacement or immunosuppressive therapy. Exp Clin Endocrinol Diabetes. 2013;121:581-7.
49. Rubin KM. Managing immune-related adverse events to ipilimumab: a nurse’s guide. Clin J Oncol Nurs. 2012;16:E69-75.
50. Ledezma B, Heng A. Real-world impact of education: treating patients with ipilimumab in a community practice setting. Cancer Manage Res. 2013;6:5-14.