Familiarity With Adverse Effects of Checkpoint Inhibitors Urged

Roxanne Nelson, BSN, RN

November 07, 2018

The introduction of immune checkpoint inhibitors has dramatically changed the treatment of a number of cancer types, but because these drugs are quite different from those that were used before, clinicians are now having to manage a whole new spectrum of adverse effects.

Because the use of these agents is growing, "knowledge of their adverse effects is important for physicians in multiple clinical disciplines," say Douglas B. Johnson, MD, of Vanderbilt University, Nashville, Tennessee, and colleagues. They highlight the most common side effects that physicians who are not oncologists are likely to encounter in practice in an article published online in JAMA.

Adverse effects with these agents can affect a wide range of organs, they note. The most common ones affect the skin, the gastrointestinal tract, the lungs, endocrine organs (thyroid, adrenal gland, pituitary gland), and musculoskeletal, renal, nervous, hematologic, cardiovascular, and ocular systems.

Overall, autoimmune events are generally dose-dependent with anti–CTLA-4 regimens, such as ipilimumab (Yervoy, Bristol-Myers Squibb), but not with the many checkpoint inhibitors that act on the programmed cell death pathway, the anti–PD-1/PD-L1 drugs such as nivolumab (Opdivo, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck & Co), and many others that are now available.

Adverse events most commonly will occur during the first 12 weeks of therapy, but patients may experience them up to 6 months after treatment has been stopped, the authors point out.

Most effects are acute events and will generally respond to treatment with steroids after 1 to 7 days. They are usually managed with low-dose glucocorticoids (prednisone, 0.5 mg/kg) for mild reactions and high-dose glucocorticoids (1-2 mg/kg) for more severe events.

In about 10% of patients, adverse events will recur after steroid treatment has ended, and about 5% of patients who are receiving anti-PD-1 monotherapy will need to be hospitalized, the authors note. The combination of anti-CTLA-4/anti-PD-1 immunotherapies increases the risk for adverse events, and hospitalization may be required for up 36% of patients receiving this combination.

If patients do not improve after 3 to 7 days of steroid therapy, then disease-specific, second-line immunosuppression, such as with infliximab (multiple brands) or mycophenolate mofetil (Cellcept, Roche Palo Alto), should be considered, the authors write. They also point out that because checkpoint inhibitors have only been commercially available since 2011, long-term adverse events have not been characterized.

Specific Adverse Events

The most common events are those related to the skin. They occur in up to 30% of patients and include pruritus, acneiform rash, and toxic epidermal necrolysis. Mild inflammation may be managed effectively with topical steroids and antihistamines; persistent or more severe cases may require high-dose systemic steroids, the authors note.

Blisters or mucosal involvement are rare (<1%); their occurrence suggests a bullous disorder or Stevens-Johnson syndrome and requires prompt dermatology evaluation and treatment with high-dose steroids.

Colitis is another common adverse event. It occurs in approximately 25% of patients treated with ipilimumab and in fewer than 5% of patients treated with anti–PD-1/PD-L1 monotherapy. Symptoms include watery diarrhea, which occurs in more than 90% of patients, and abdominal discomfort and lower gastrointestinal bleeding, observed in up to 20% of patients.

Mild to moderate colitis (<6 additional stools per day vs baseline) can usually be managed with hydration and antidiarrheal medication. Severe diarrhea (>6 additional bowel movements per day vs baseline) or mild to moderate cases that persist for longer than 5 to 7 days require high-dose steroids (1-2 mg/kg/day). In patients with peritoneal signs, dehydration, electrolyte imbalances, or very frequent (>10-15 per day) high-volume stools, intravenous steroids and hospital admission should be considered. This side effect may be life threatening, the authors warn.

Less common adverse events include pneumonitis, which is also potentially life threatening and occurs in 2% to 5% of patients; hypophysitis (pituitary inflammation), which occurs in up to 10% of patients treated with anti–CTLA-4 therapy but rarely with other types of agents; and hepatitis, which is also more prevalent with anti-CTLA-4 agents (10%) but is seen in only in 1% of those receiving anti‐PD1/PD‐L1 agents.

Inflammatory myocarditis occurs in fewer than 1% of patients but is associated with a high risk for death (20% to 50%). It often presents with concurrent skeletal muscle myositis and can be fulminant or smoldering. Neurotoxicities are quite rare (<1%) but can be severe and may present as Guillain-Barré syndrome, myasthenia gravis, and encephalitis.

The management of these less common events is dependent on their presentation and severity, the authors comment.

The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have recently developed joint guidelines for assessing and managing side effects of the checkpoint inhibitors.

The authors' disclosures of relevant financial relationships are listed in the original article.

JAMA. 2018;320:1702-1703. Abstract

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