Immunotherapy: What side effects can you expect?

Published in the July 2018 issue of Today’s Hospitalist 

IMMUNOTHERAPY has not only transformed how many cancers are treated, but it’s also changed how oncologists think of cancer.

“We always thought of cancer as a sumo wrestler suppressing the immune system and that it was the failure of the immune system to detect cancer that led to metastatic disease,” said Yelena Y. Janjigian, MD, who presented an oncology update at this year’s Society of Hospital Medicine conference.

But with immune checkpoint inhibitors, “the sumo wrestler is now the immune system, suppressing cancer as the little guy.” This treatment bonanza, however, has come with one major misperception, said Dr. Janjigian, who is chief of the GI oncology service at New York’s Memorial Sloan Kettering Cancer Center: the idea that immunotherapies are benign.

“Side effects can be severe and even deadly.”

~ Yelena Y. Janjigian, MD
Memorial Sloan Kettering Cancer Center

In reality, “side effects can be severe and even deadly,” she said. “Patients may not be getting the alopecia or neuropathy they do with chemo, but they’re getting rashes, colitis and pneumonitis.” As she explains to her patients, “Immunotherapy takes the brakes off the immune system, so it disables the checks and balances we normally have to prevent autoimmune effects.”

The good news is most of these toxicities are reversible, said Dr. Janjigian—”if you treat them aggressively and quickly.”

Toxicity profiles
The FDA has approved six immune checkpoint blocking antibodies that target either the CTLA-4 receptor or the PD-1 receptor and its ligand PD-L1. According to Dr. Janjigian, these agents “are now FDA-approved for multiple cell tumor malignancies, so you will be seeing them more and more.”

The one that targets CTL-4—ipilimumab (Yervoy)— is approved for melanoma, although it’s being tested in several GI trials. As for therapies targeting PD-1 receptors, there’s nivolumab (Opdivo), which is manufactured by Bristol Myers Squibb, or “its Merck counterpart, penbrolizumab (Keytruda), the drug that cured Jimmy Carter of metastatic melanoma of the brain,” she pointed out. “These are the Coke and Pepsi of PD-1 inhibitors, and they have very similar effectiveness profiles.”

Their toxicities are also similar. The other approved agents—atezolizumab, avelumab and durvalumab— all target PD-L1 and are not used as often.

The side effects of these drugs vary, but “generally the patients who are actually responding to therapy are the ones who develop effects,” said Dr. Janjigian.

“What’s good for treating the cancer is bad for your side-effect profile.” Oncologists think about toxicities in terms of grades, with grades 1 and 2 being treated as outpatients.

But grades 3 and 4 often lead to patients being hospitalized or even sent to the ICU—and to having their immunotherapy discontinued. Patients on monotherapy with nivolumab or pembrolizumab “tend to do OK,” Dr. Janjigian said, although common side effects include diarrhea, fatigue, nausea, itchy skin and rash.

Ipilimumab, on the other hand, causes a lot of LFT abnormalities, as well as colitis and pneumonitis. Not surprisingly, combining two drugs is more toxic than one.

“The nivo plus ipi combination is where you see a lot of side effects,” she noted. She also treats many patients with gastric cancer for which pembrolizumab is FDA-approved. “But most patients don’t respond that well to monotherapy, so the majority take a combination. We start seeing a lot of side effects with those as well.”

What’s common and what’s rare
When do side effects occur? “The answer is, really any time,” said Dr. Janjigian. A study in the March 2017 Journal of Clinical Oncology looked at nivolumab and its median time to onset of different treatment-related adverse events. Those medians ranged from five weeks for skin events to 7.3 weeks for GI, 7.7 weeks for hepatic, 8.9 weeks for pulmonary, 10.4 weeks for endocrine and 15.1 for renal.

But the range of onset times around those medians was very broad. And “nivo plus ipi is given every two weeks, so usually a patient gets one dose and is already reporting some kind of side effect, either itchy skin or mild rash, at the next visit,” she said. “If patients become symptomatic or there is a really dramatic liver function abnormality, that’s when we think about admitting them.”

Asymptomatic liver function elevations are common, with “astronomically high numbers in the thousands.” Any organ system can be affected, and potentially life-threatening side effects include pneumonitis and colitis, with those patients frequently needing ICU care.

More rare but still very serious effects include interstitial nephritis (“patients can end up on dialysis”); hematologic abnormalities including thrombocytopenia and pure red cell aphasia; neurologic toxicities including encephalitis, aseptic meningitis and neuropathy; and myocarditis.

While myocarditis is rare, “it can be quite traumatic,” she noted, as evidenced by a report in the Nov. 3, 2016, New England Journal of Medicine describing two patients, each on a combination of ipilimumab and nivolumab, who died from fulminant myocarditis.

They presented with complete heart block followed by ventricular tachycardia. Autopsy revealed lymphocytic infiltration of the myocardium.

Rash is also common. “Often, the rashes feel like sandpaper, and if patients aren’t undressed, you may not notice them,” she pointed out. Rashes tend to be on the trunk or proximal limbs, rarely on the face, and vitiglio can occur as well. And while endocrinopathies are less common, they can be serious.

“When the antibodies affect the thyroid,” Dr. Janjigian said, “patients present with either primary or secondary adrenal insufficiency.”

Diagnosis and management
When patients are admitted, “it’s often a diagnosis of exclusion,” Dr. Janjigian explained. You need to rule out infections, reactions to other medications or metabolic causes.

One big problem is that “all these patients are somewhat immune-compromised and frail at baseline, so you have to dig deep and rule out other causes before you call it immune-related.” If you’ve ruled out everything else, “the answer is usually some immune-related side effect. When in doubt, give steroids.”

Another problem: “Cancer patients are used to getting diarrhea, so they tend to blow it off and not even report it,” she said. “But if you get diarrhea from ipi, you can die.” In her practice, she tells patients that communication is their first line of defense.

General management of immune-mediated adverse events includes high-dose corticosteroids (prednisone of 1 to 2 mg/kg/d or equivalent) tapered slowly over a month or more, once toxicity resolves to grade 1 or less. “Another inhibitor we commonly use is the TNF blocker infliximab,” she said. “That usually does the trick when steroids aren’t helping.”

Can patients resume therapy?
Once symptoms resolve, patients will want to know: When can they resume immunotherapy?

“The answer is to just have the oncologist be the bad guy,” Dr. Janjigian said. While patients who develop endocrinopathies can frequently restart treatment, “we don’t restart immunotherapy in patients with symptomatic liver function abnormalities, pneumonitis or colitis, or with anyone whose side-effect grade reached 3 or 4.”

To try to help patients steer clear of side effects, Dr. Janjigian tells them to avoid alcohol, as well as foods with too much fiber or grease, and to not take Tylenol. “That comes in with a mild LFT bump that can potentiate autoimmune effects.”

She also praises patients when they report symptoms: “We want them to call often so we can manage these before they get too sick,” she said. But “we can’t predict who will experience immune-mediated adverse reactions.”

And be prepared to have patients resist having their symptoms treated. “You’ll hear, ‘I don’t want to die of cancer and I can bear these side effects, so don’t suppress my immune system,’ ” Dr. Janjigian said. “But data suggest that if their immune system isn’t active, giving them steroids won’t affect the efficacy of the drug.” If their cancer progresses, “it’s not because they got steroids,” she added. “It’s because the cancer became resistant to that particular line of therapy.”

Phyllis Maguire is Executive Editor of Today’s Hospitalist.

Managing specific effects
AT THIS SPRING’S Society of Hospital Medicine conference, Yelena Y. Janjigian, MD, chief of the GI oncology service at New York’s Memorial Sloan Kettering Cancer Center, spoke about treating adverse and immune events that can occur with immunotherapies and land patients in the hospital. For patients hospitalized for a potential side effect (except for those with endocrinopathies), physicians need to discontinue the immunotherapy. Dr. Janjigian gave the following management tips for specific side effects:

• Diarrhea: Check for other causes including C. diff and ova and parasites, and latent TB. For patients having only four additional stools above their baseline, “consider symptomatic management with Imodium and budesonide,” said Dr. Janjigian. “Anything above that, I would use prednisone” (1-2 mg/kg/day or equivalent). Above seven additional stools, “consider IV steroids as well” (methylprednisolone or equivalent at 1-2 mg/kg/day).

And if symptoms don’t improve within 72 hours, administer infliximab at 5 mg/kg as well as IV fluids and pneumocystitis prophylaxis.

• Rashes and itching: Use topical steroids. Systemic interventions include selective H1  and/or H2 blockers, hydroxyzine 25 mg PO every six hours as needed, and prednisone 5-10 mg every 8-12 hours as needed.

“Basically, for anything above topical steroids, I refer to the dermatologist,” Dr. Janjigian said, adding that “some of these rashes can linger because the immune system is activated, even when immunotherapy is withdrawn.” One of her patients, who completed her immunotherapy course and was cured of metastatic disease, is still dealing with a chronic rash a year later.

• Persistent cough: Consult pulmonary and infectious diseases and get a STAT bronchoscopy with lavage and tissue biopsies. Also, consider empiric antibiotics and/or corticosteroids.

To manage biopsy-proven pneumonitis, monitor X-ray changes, give 2-4 mg/kg of solumedrol for severe symptoms or hypoxia, get a bronchoscopy, and taper steroids slowly over several weeks. “Often, symptoms flare again after the steroids.”

And consider prophylaxis for opportunistic infectious such as Bactrim for pneumocystis pneumonia. Also consider prophylaxis in patients on 20mg of prednisone for at least four weeks.

• Headache/fatigue/depression: Consider an MRI of the pituitary. Then consider high-dose (1 mg/kg/d) prednisone if patients are in acute phase of adrenal insufficiency, then hydrocortisone replacement (such as 20 mg in a.m., 10 mg in p.m.). Collaborate with an endocrinologist to individually adjust hydrocortisone dosing.