Adverse Reactions Associated With Ipilimumab
The toxicities associated with ipilimumab differ from those typically seen with cytotoxic chemotherapy, and they create unique challenges in diagnosis and clinical management. CTLA-4 plays a critical role in native immune tolerance to self antigens, and the ability of ipilimumab to exacerbate autoimmunity in experimental models is well established.[22,23] Hence, the majority of adverse events reported in clinical trials are immune mediated—the so called “immune-related adverse events (irAEs),” which are consistent with the mechanism of action of ipilimumab.[6,14,31,40] These irAEs affect a range of organs, but the skin, gastrointestinal tract, and endocrine glands are most commonly involved. Antinuclear antibodies (ANA) have not been associated with irAEs, and they have no diagnostic value in this setting, since many patients with melanoma have baseline elevations of ANA titers. We have summarized the reported immune- and nonimmune-related adverse effects of ipilimumab in Table 2.
These irAEs are dose-dependent, schedule-related, and cumulative.[12, 31, 32, 41] Grade 3/4 immune-related adverse events have been reported in 20% to 30% of patients in various clinical trials. Most irAEs are manageable and generally reversible with corticosteroids; however, life-threatening side effects and treatment-related mortality have been reported in most published trials. Additional immunosuppression is sometimes necessary.[41-45] Up to 50% of treatment-related deaths were associated with irAEs. Close clinical and laboratory monitoring is required for early detection and timely initiation of treatment with immunosuppressive therapies. Long-term residual irAEs requiring treatment have been reported at 2-year follow-up in phase III trials—primarily dermatologic effects (rash, vitiligo, and pruritus), colitis/diarrhea, and endocrine-related adverse events.
Diarrhea and colitis. Diarrhea and colitis have been reported in 10% to 35% of study patients and are the most commonly seen grade 3/4 toxicities in the majority of clinical trials. Most patients with colitis present within 2 weeks of starting treatment, although time of onset varies considerably. Diarrhea and colitis often have a rapid onset and can be potentially life threatening when they result in bowel perforation and septicemia. Many refractory or severe cases of colitis have required diverting ileostomy or partial/complete colectomy. Reported mortality in patients in whom colitis develops is as high as 5%. Patients with colitis often have other gastrointestinal manifestations, including apthous ulcers, esophagitis, gastritis, and jejunitis. Colonoscopic evaluation usually reveals diffuse inflammation and ulceration (Figures 1A and 1B). Biopsies of the involved mucosa usually show diffuse infiltration of inflammatory cells, primarily CD4+ T cells (Figure 1C). Histologically, colitis resulting from treatment with ipilimumab shows variable patterns of inflammation that do not correlate with the clinical course.[42-45] Patterns of inflammatory bowel disease with crypt abscesses and diffuse mucosal ulceration are commonly seen (Figure 1D).
Colitis should be managed with bowel rest and supportive care, as well as high doses of corticosteroids and/or infliximab(Drug information on infliximab) (an anti-TNFα antibody), as detailed below. In cases with a prolonged clinical course and infliximab-refractory disease, features of epithelial cell apoptosis similar to those seen in gastrointestinal graft versus host disease (GVHD) have been reported.
Table 3 outlines the management of ipilimumab-related diarrhea and colitis. Patients who require corticosteroids should be started on 1 mg/kg of methylprednisolone(Drug information on methylprednisolone) or prednisone(Drug information on prednisone) twice daily, and the corticosteroids should be gradually tapered over 30 days or longer. Rapid tapering can lead to relapse and increase complications. Patients with continued symptoms beyond 1 week of initiation of corticosteroids, relapse of symptoms after initial response, or partial response to corticosteroids are considered steroid-refractory.[42,44] Steroid-refractory colitis should be treated with infliximab at a dose of 5 mg/kg.[41-45] Infliximab usually has a rapid onset of action, and a response is typically seen within 1 to 3 days.[42,45] Many patients require additional doses of infliximab at 2-week intervals (use the dose and schedule approved by the FDA for inflammatory bowel disease).[42,47] Bowel rest with parenteral nutrition is required in severe cases, along with supportive care, including hydration, close monitoring for electrolyte imbalance and bowel perforation, and prophylactic antibiotics. In patients with infliximab-refractory colitis, tacrolimus(Drug information on tacrolimus) and rapamycin have been used successfully. Although anecdotal reports have suggested no adverse outcome, the impact of the use of infliximab or other immunosuppressive agents on opportunistic infections remains largely unclear. Ongoing follow-up of patients enrolled in various clinical trials will be crucial for streamlining management of this potentially life-threatening adverse event.
Use of budesonide(Drug information on budesonide) to prevent colitis in patients receiving ipilimumab was studied in a phase II clinical trial. Prophylactic use of budesonide did not affect the rate of grade 2 or higher diarrhea, which occurred in 32.7% of patients who received budesonide and in 35.0% of patients who did not receive it. Symptomatic residual colitis and diarrhea requiring treatment for up to 2 years have been reported by Hodi and colleagues.
Hepatitis. Hepatitis or transaminitis has been reported in 2% to 20% of patients treated with ipilimumab.[29,35] Asymptomatic rises in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually seen; isolated increases in bilirubin are uncommon. Liver biopsies usually reveal histopathology of autoimmune hepatitis with diffuse lymphocytic infiltrates and ballooning degeneration. For grade 3 liver toxicity (AST and ALT more than five times the institutional upper level of normal), ipilimumab should be discontinued, and oral corticosteroids for a 30-day course or longer are warranted. Patients with grade 4 enzyme elevations require inpatient admission and intravenous corticosteroids. Severe hepatitis leading to fatal liver failure resulting from delay in initiation of corticosteroid treatment has been reported.
Hypophysitis is the most commonly reported endocrine adverse reaction associated with ipilimumab.[14,18] Clinical manifestations of hypophysitis are probably dependent on the rapidity of onset, severity, and relative suppression of the endocrine axes (thyroid vs adrenal vs gonads). Enlargement of the pituitary gland on imaging of the brain has been reported as the earliest sign (Figure 2). Abnormalities in laboratory testing and development of clinical symptoms of hormone deficiency usually follow the radiological changes.[18,48]
Symptoms of hormone deficiency vary and include fatigue, insomnia, loss of libido, anorexia, weight loss, severe hyponatremia, profound hypothyroidism, and/or symptoms mimicking Addison disease.[48-50] Hypophysitis resulting in enlargement of the pituitary gland can present with headache, nausea, vomiting, and/or visual disturbances.[48,50] The presentation can mimic that of bleeding or edema of intracranial metastasis and requires prompt evaluation. Hence, a high index of suspicion is required to diagnose hypophysitis, since signs and symptoms can be very subtle and misleading.
Unlike most other irAEs, where treatment with corticosteroids usually leads to resolution of symptoms, endocrine dysfunction seems to have a protracted course and is irreversible in many cases. Dysfunction of the adrenal axis, whether primary adrenal insufficiency (elevated adrenocorticotropic hormone [ACTH], resulting from adrenalitis) or secondary adrenal insufficiency (low ACTH, resulting from hypophysitis), often seems to be an irreversible irAE, and long-term corticosteroids using physiologic replacement doses are required. [3,14, 18,35,40] Early treatment of subclinical hypophysitis frequently does not change the requirement for eventual hormone replacement.[18,40]
Ocular toxicities associated with ipilimumab treatment also need very vigilant clinical follow-up. Uveitis can lead to permanent vision loss and needs immediate treatment. Patients usually present with decreased visual acuity, photophobia, and painful tearing.[6,31,40] Local treatment with periocular corticosteroid injections and corticosteroid eye drops are generally effective, but systemic corticosteroids are required in severe cases.
Asymptomatic elevation of lipase/amylase and grade 4 ipilimumab-related pancreatitis have been reported. A case of severe constipation, with intestinal biopsy showing inflammation of the mesenteric plexus and accompanied by autonomic neuropathy, has been reported. Other rare side effects, such as lupus-like nephritis, aseptic meningitis, pure red cell aplasia, immune-mediated pancytopenia, and autoimmune inflammatory myopathy have been reported.
Use of Corticosteroids and Immunosuppressive Therapy
Retrospective reports suggest that there is no negative effect in terms of melanoma-related outcome when systemic corticosteroids are used to manage irAEs.[3,31,56] A subset analysis of 23 patients who had treatment response to ipilimumab revealed that corticosteroid administration had no significant effect on duration of clinical response (P = .23). Maker and colleagues have reported a similar observation; use of high-dose corticosteroids to treat irAEs had no impact on the durability of objective clinical responses. However, the safety of corticosteroids has not been established in large-scale trials, and precise algorithms for immunosuppression need to be prospectively validated.
Does Development of irAEs Portend Clinical Benefit?
Various phase I/II studies have shown that the development of irAEs, particularly grade 3 or 4 irAEs, is associated with tumor response.[3,29,32,41] Ku and colleagues reported better clinical outcome at 24 weeks in patients with irAEs than in those without irAEs (CR+PR+SD, 60% vs 22%; P < .01) and a better objective response rate in patients with grade 3 or 4 irAEs than in those with irAEs of grade 2 or lower (27% vs 6%, P < .05). Similar observations were reported by Downey and colleagues, who found that out of 50 patients in whom grade 3/4 irAEs developed, 14 (28%) experienced an objective response, with a median duration of response of 34 months. All three patients with CR had grade 3 or 4 irAEs. In subsets of patients experiencing grade 1/2 irAEs, only 8 out of 36 (22%) experienced an objective response—and all of these were partial responses, with a median duration of response of 11 months. The association between development of irAEs and the likelihood of clinical response was significant (P = .0004).
Despite these observations, a phase II study by Maker and colleagues addressing this question failed to establish a correlation between increased adverse reactions and objective response rates. The recently published phase III study did not address this phenomenon.
Ipilumumab in Central Nervous System (CNS) Disease
Most studies of ipilimumab have excluded patients with active/untreated CNS disease. A multi-center phase II study of ipilimumab monotherapy in patients with melanoma metastatic to the brain was recently reported. Ipilimumab was shown to have a similar level of activity in brain and non-CNS lesions. Out of 51 patients, 5 had a PR in CNS lesions, and an additional 6 patients showed stable disease per WHO criteria. Further follow-up of this study with survival analysis has yet to be reported. In the foreseeable future, most patients will require multimodality approaches to control CNS disease in addition to systemic treatment.
Despite the demonstrated overall survival benefit in ipilimumab-treated patients, response rates reported in various trials with ipilimumab are in the range of 5% to 15%, and durable responses are less frequent. Although the discovery of ipilimumab has shifted the paradigm for evaluating drug efficacy and reinforced hope in immunotherapy, many aspects of ipilmumab use require additional evaluation, including toxicity management, predictive biomarkers, assessment of response to therapy, and optimal use of combination therapies. Further progress in immunotherapy is likely to come from the combination of ipilimumab with other therapies, including cytotoxic chemotherapy and radiation therapy to improve antigen presentation, or with other immune-modulating agents. Moreover, studies are ongoing to assess the role of ipilimumab in the adjuvant setting and in the treatment of other malignancies.[19,20,49]
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.