The toxicity profile of immune-based therapies has in the past typically been related to the dose and schedule of the administered therapy. Toxicity increased as the dose and frequency of administration increased and, in general, resolved upon withdrawal of treatment in hours to days without additional intervention. This pattern is seen with interferon-α (IFN-α) approved for the treatment of hairy cell leukemia at low doses (3 million international units [IU] three times weekly) and for the adjuvant therapy of high-risk melanoma at high doses (20 million IU daily five times for 4 weeks). Interleukin 2 (IL-2) is approved for the treatment of metastatic melanoma and renal cell cancer. Other members of the interleukin and cytokine families including the unapproved agents—tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 21 (IL-21), and interleukin 15 (IL-15)—show similar toxicity patterns. In contrast, the new class of immune therapy agents produce side effect profiles that are more idiosyncratic in nature, frequently require administration of immunosuppressive agents for resolution, and can take weeks or even months for resolution. Irreversible damage with the need for lifelong hormone replacement therapy beyond thyroid hormone is observed. These agents show significant therapeutic activity and predominantly consist of monoclonal antibodies directed at cell surface signaling molecules such as CTLA-4, PD-1, and PD-L1. The toxicities of immune-based therapy will be discussed in this chapter with a focus on the organ affected.

IFN-α produces side effects that can be divided into acute and chronic categories.¹ The acute toxicities include flu-like symptoms with fever, chills, myalgias, headache, anorexia, nausea, vomiting, diarrhea, and fatigue. These typically occur within hours of administration of the initial dose, and most abate despite continued administration, a phenomenon termed tachyphylaxis. Their severity is related to the dose and schedule of treatment. Systemic symptoms can be managed with nonsteroidal anti-inflammatory drugs (acetaminophen should be avoided due to its potential for complicating hepatic toxicity), antiemetics, and fluid hydration either orally or intravenously. With continued administration of IFN-α, a spectrum of chronic
dose-limiting fatigue and anorexia occur usually in association with depression. Weight loss is frequently observed with the high-dose IFN-α regimen. IL-2 produces a similar side effect profile with fever and chills that may require meperidine for control, nausea, vomiting, diarrhea, and fatigue. High-dose IL-2 should be administered by experienced practitioners in an inpatient setting with access to cardiac monitoring and the ability to deliver hemodynamic support.² IL-2 causes a capillary leak syndrome due to endothelial cell injury. This increased vascular permeability results in fluid overload with the development of ascites, pulmonary edema and pleural effusions, and renal dysfunction. Systemic side effects are unusual with immunomodulatory monoclonal antibody therapy, but as they are foreign proteins, they can produce allergic reactions that will prevent further therapy. These tend to be rare. More commonly, infusion reactions will occur as with other therapeutic antibodies such as rituximab. Infusion reactions are rare with ipilimumab, nivolumab, and pembrolizumab, but occur commonly with the unapproved antibodies directed at PDL1. Pretreatment with diphenhydramine and acetaminophen is recommended to prevent or ameliorate these effects.

Cardiac events, with the exception of hypotension, are unusual with IFN-α therapy but can produce cardiac ischemia in those who are susceptible. Intravenous fluid administration during the high-dose IV phase of the induction regimen for melanoma therapy should be used. Hypotension is frequently a dose-limiting toxicity of IL-2 and is managed by judicious use of intravenous fluids. We tended to avoid its use because of the associated capillary leak syndrome that minimized its effectiveness. We instead managed patients with pressors to avoid weight gain, edema, and pulmonary toxicity that can be associated with IV fluids. Because of the ability of β-agonists to precipitate cardiac arrhythmias, α-adrenergic agonists are recommended for the management of hypotension. It is advisable to perform cardiac stress testing in any patient over the age of 50 years to identify patients who are poor candidates for the therapy. Myocarditis can occur during or following discontinuation of IL-2 and can be fatal.³ Cardiac events are rare with agents that target CTLA-4 and PD-1, but cardiomyopathy and myocarditis have been reported.⁴ Interestingly, the PD-1 knockout mouse develops cardiomyopathy in a strain-specific manner owing to the development of antibodies to troponin I.⁵

Reduction in blood counts is almost universally seen with high-dose IFN-α with high-grade toxicity in 25% to 60% of patients. Granulocytopenia is the most common reason for dose reduction. Neutropenia is rarely associated with fever, but should be managed as with any febrile neutropenic patient. Hematologic toxicity is responsive to dose
reductions and administration of filgrastim. Rare cases of thrombotic thrombocytopenic purpura have been observed and require permanent discontinuation.⁶,⁷ IL-2 produces thrombocytopenia and anemia, which may be dilutional in origin, but decreased production is also a likely mechanism. Granulocyte migration defects occur during IL-2 therapy and are associated with infectious complications.⁸ The use of antibiotic prophylaxis significantly reduced the incidence of catheter-related sepsis but antibiotics may participate in the coagulopathy that sometimes accompanies IL-2 administration by eliminating vitamin K-producing bacteria. Use of vitamin K supplementation, particularly in patients who are eating very little, may be warranted. Hematologic toxicity is rare with the antibodies directed at cell surface signaling molecules, but autoimmune hemolytic anemia, thrombocytopenia, and granulocytopenia have been reported.

Hepatic toxicity associated with high-dose IFN-α can be lethal if therapy is not interrupted when liver damage occurs, and it is critical that liver function tests (LFTs) be followed closely while on therapy. Similarly, IL-21 produces hepatic toxicity that can be fatal. This represents a major obstacle to the clinical development of IL-21 where treatment has been restricted to patients with normal LFTs and is interrupted for grade 2 (greater than three times the ULN values) transaminitis. The standard IFN-α regimen for adjuvant melanoma treatment consists of a 1-month induction with 20 million IU (MIU)/m² administered intravenously 5 days weekly for 4 weeks followed by 10 MIU/m² administered three times weekly for 11 months, for a total of 1 year of therapy. The majority of patients are unable to complete the regimen as initiated. Elevated transaminases occurred in over half of patients and 14% to 29% developed grade 3 or higher transaminitis.⁹,¹⁰,¹¹,¹² IFN-α should be held for grade 3 transaminitis and the dose reduced for continued treatment. The mechanism of hepatic damage due to IFN-α may be related to the induced downstream cytokine signaling with a complex array of cytokines and interleukins interacting to produce toxicity.

Liver function test abnormalities occur almost universally in patients treated with high-dose IL-2 (600,000 IU IV q8 hours for up to 15 doses), with about 40% of patients developing grade 3 (five times ULN) or greater transaminase elevation with 20% showing fivefold to tenfold or greater elevation of bilirubin levels.¹³,¹⁴ IL-2 is typically administered without dose interruption despite grade 3 elevations of transaminase levels even in conjunction with significant bilirubin elevation. Decreased hepatic synthesis contributes to the drop in albumin and clotting factor levels that can produce a coagulopathy. As with most other IL-2 toxicities, hepatic toxicity resolves completely upon therapy discontinuation. Liver biopsy findings in patients treated with IL-2 are rare due to its almost universal resolution without
intervention. In the one reported case, acute multifocal hepatitis with necrosis and acute pericholangitis was observed.¹⁵ The effects of IL-2 in man predominantly produce cholestatic changes rather than cytotoxic effects, in contrast to rodents, in which a cytotoxic effect is primarily observed.¹⁶,¹⁷ The potential mechanisms for toxicity in man include endothelial cell injury with induction of capillary leak and bile stasis, induction of cytokines in response to IL-2 administration, or direct effect of activated lymphocyte populations on hepatocytes. IL-2 produces hepatic toxicity that is atypical when compared with that induced by other immunotherapy agents in its complete reversibility.

Hepatitis is relatively rare with the new class of cell surface-signaling molecules ipilimumab,¹⁸ tremelimumab,¹⁹ nivolumab,²⁰ and pembrolizumab.²¹ Liver function tests should be monitored before administration of every dose of these therapies, and is typically held for grade 2 elevations of the transaminases. Ipilimumab and tremelimumab target CTLA-4, and the former is FDA-approved for the treatment of metastatic melanoma at a dose of 3 mg/kg administered at 3-week intervals for four doses. At this dose, 2% of patients developed severe, life-threatening, or fatal hepatitis in the pivotal approval study of ipilimumab, and tremelimumab had a 1% incidence of severe hepatic toxicity. It most frequently occurs at 8 to 12 weeks after initiation of therapy, but can occur at any time following initiation of therapy. Imaging studies and pathology specimens are available in only a small number of cases.²²,²³ Imaging studies were normal or showed mild hepatomegaly, periportal edema, and periportal lymphadenopathy. Pathology specimens may show either injury to hepatocytes (acute hepatitis pattern) or injury to the bile ducts (biliary pattern). The histologic changes observed with ipilimumab-related hepatitis are similar to those with acute viral and autoimmune hepatitis, and distinguishing these can be difficult for the latter. Recurrence of hepatitis is highly likely with reexposure to ipilimumab, occurs rapidly upon retreatment, and should therefore be avoided. Whether administration of agents targeting PD-1/PD-L1 interaction is safe in this setting is unknown at this time. Hepatitis usually presents as asymptomatic elevation of the transaminases with or without bilirubin elevation, but can be associated with fever. Hepatitis occurs more frequently when ipilimumab is combined with other agents and can produce dose-limiting toxicities in these combinations. With the addition of dacarbazine, severe hepatic toxicity increased in frequency and occurred in 20% of patients. The number of doses of ipilimumab administered were reduced in this trial.²⁴ Hepatic toxicity was also markedly increased in frequency when combined with vemurafenib²⁵ and ended attempts to combine these agents. Both pembrolizumab and nivolumab have been associated with hepatitis, but its frequency is lower than that observed with ipilimumab, and hepatitis requiring therapy is lower and may respond more rapidly to intervention. Hepatitis caused by these agents should be distinguished from other causes
of liver inflammation, particularly viral hepatitis and other liver disorders, and is managed with steroid therapy. Hepatitis may be steroid refractory but has been responsive to treatment with mycophenolate mofetil (CellCept: Genentech, South San Francisco, CA). Infliximab should be avoided because of its risk for hepatotoxicity. The time course of resolution of hepatitis can be prolonged despite steroid and CellCept therapy, sometimes for months.