1. Nalley, Catlin

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NEW YORK CITY-As immunotherapy gains wider use in oncology, there is growing concern regarding the management of immunotherapy-related adverse events (irAEs).

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"When we talk about immunotherapy, we are really referring at this point to PD-1 axis or CTLA-4 inhibitors," noted Scott N. Gettinger, MD, Associate Professor of Medicine, Yale Cancer Center, New Haven, Conn. "There are other immunotherapies that are approved, but currently there are at least 10 tumor types that have indications for PD-1 axis inhibitors, including any solid tumor that has mismatch repair deficiency."


Tumor types indicated for PD-1 axis inhibitors, such as pembrolizumab or nivolumab, include, but are not limited to, melanoma, non-small cell lung cancer, renal cell carcinoma, and head and neck cancer.


"These [agents] are here to stay and we need to get familiar with immune-related toxicities," said Gettinger, during his session, "How I Manage Immunotherapy-Related Adverse Events," at the Chemotherapy Foundation Symposium, held Nov. 8-10.


General Management

While there can be exceptions, Gettinger noted, "Generally, if a patient presents with a moderate or severe adverse reaction (grade 2 or higher), we would hold immune checkpoint inhibitors."


Oncologists should then begin interventions by trying supportive therapies, such as loperamide or hydroxyzine. "If this doesn't work or the patient presents with more severe toxicity, you will treat them one of two ways depending on whether the infected organ's function can be supplemented.


If it can be, the next course of action is hormone replacement (i.e., insulin, levothyroxine, hydrocortisone, and testosterone). If not, the patient would receive high-dose steroids and other immunosuppressive agents. This approach often requires prolonged steroid taper (1-3 months), which is associated with a risk of opportunistic infections, according Gettinger. Oncologists should consider sulfamethoxazole-trimethoprim and voriconazole in these cases.


"The real question is," Gettinger stressed, "do we re-challenge?"


Noting a high-risk of recurrence, he said oncologists should consider this question on a case-by-case basis. For example, if a provider is treating a patient who has grade 3 or 4 hepatitis, who has been undergoing immunotherapy for 5-6 months, and is responding to treatment, Gettinger suggests that therapy is held and the patient is treated for the toxicity. "After they recover, I would watch them and if, for instance, their disease recurs a year or two later, then we would have a discussion of whether or not it is worth it to start treatment again."


Important to note, Gettinger said, "One thing that we have learned over the last few years, or even more, is that treatment with immunosuppressive agents does not clearly comprise efficacy.


"That was a major concern, but data suggests this is not the case," he continued. "So don't be shy about giving steroids to your patients who develop these toxicities."


Event-Specific Approaches

Focusing on specific irAEs, Gettinger offered attendees a closer look at management techniques for these types of toxicities.


Dermatologic/Mucosal Toxicity: These are the most common irAEs, according to Gettinger. Often patients present with pruritus or a maculopapular rash. These toxicities can often be controlled by mild topical emollients or corticosteroids.


"If we can't control with these agents or the patient gets worse, for severe toxicities we will use oral corticosteroids (1-2 mg/kg prednisone)," Gettinger explained, noting that at that point a dermatology consultation is in order. In addition, if a patient is not responding to oral therapies, a biopsy should be considered. This approach should also be taken if there is any indication of a more serious toxicity, such as Stevens Johnson syndrome.


Endocrinopathies: These toxicities are also relatively common and for the most part steroids and other immunosuppressive therapies should not be utilized, according to Gettinger. One of the most common toxicities in this group is thyroiditis, which is often indicated with low TSH early and rarely symptomatic. Gettinger recommends the use of a beta-blocker. Thyroiditis often progresses to high TSH and when it gets above 10 a supplement is initiated. "In terms of this toxicity, we generally continue the immune checkpoint inhibitor," said Gettinger. "If the patient is more severe, we would resume therapy after resolution." Other endocrinopathies include hypophysitis/adrenalitis and diabetes mellitus/diabetic ketoacidosis.


Pneumonitis: "[This toxicity] is of particular concern in my patients who have lung cancer," noted Gettinger. It is not uncommon to find evidence of the toxicity via imaging, but the patient is asymptomatic. The question is, "What do you do? Often if it is mild, we will follow the patient and continue therapy, and if they develop any symptoms we will act on it," he explained. If a patient presents with grade 2, is symptomatic, but does not require oxygen, immune checkpoint inhibitors should be halted and steroids initiated.


"Most of the time, I admit them to the hospital for IV steroids (methylprednisolone sodium succinate 2 mg/kg), but in a compliant patient I may try as an outpatient with oral therapy," Gettinger outlined during his presentation. He recommends 1 week high-dose followed by a 4-6 week taper. "You can re-challenge for grade 2 pneumonitis," he noted. "However, I would be reluctant to because most of the patients I have did recur."


Patients with grade 3 toxicity require oxygen and must be admitted to the hospital. "IV steroids at a high-dose must be used and you may have to increase from 2 mg/kg [methylprednisolone sodium succinate] all the way up to a gram," Gettinger said. If a patient continues to have a poor prognosis, the question of a bronchoscopy arises. Utilized to rule out infection, Gettinger noted that his pathologists are reluctant to do this due to some poor outcomes, and often the decision is to continue steroids and follow the patient.


Diarrhea/Colitis: This toxicity is seen more commonly with CTLA-4 antibodies, but it can also occur in conjunction with PD-1 axis inhibitors. Anti-motility agents are the first line of defense for low-grade toxicity, according to Gettinger.


"If this doesn't work or they present with more severe toxicity, we will hold the immune checkpoint inhibitor and we will start steroids tapered over 4-6 weeks." For those patients not responding to steroids, infliximab (5 mg/kg) is the next step. Whether or not re-challenging is an option depends on the individual patients. "The rule of thumb is for grade 3 or 4 toxicities I would be very reluctant to re-challenge."


Hepatitis: This toxicity is seen occasionally among patients treated with immunotherapy agents and they are often asymptomatic. Grade 1 cases are monitored and treatment continues. For grade 2 patients, immune checkpoint inhibitors are held and if no improvement is seen in 1-2 weeks steroid treatment is initiated. Based on his experiences with patients, Gettinger believes re-challenging is an option for grade 2 cases. However, grade 3/4 patients should generally discontinue treatment and begin steroids. If there is no improvement, other immunosuppressive agents should be used. Again, taper 4-6 weeks, but this may need to be longer in some cases.


Other potential irAEs include arthritis/myositis; nephritis; pericarditis/myocarditis; and pancreatitis. "We have seen all types of neurological toxicity, such as myasthenia gravis, Guillain-Barre, and encephalitis/meningitis," Gettinger noted. "We discontinue immune checkpoint inhibitors and begin high-dose steroids and we may need plasmapheresis so we can give IVIG."


Hematologic toxicities, including aplastic anemia, hemolytic anemia, and immune thrombocytopenia purpura, have also been observed in these patients


Case Study

Gettinger ended his discussion with a number of case studies, demonstrating the real-world application of these treatment interventions.


For example, JT is a 70-year-old smoker with recurrent metastatic adenocarcinoma of the lung who received a lobectomy and adjuvant chemotherapy. He started anti-PD-L1 therapy on a clinical trial in August 2014. "Two days later, he is short of breath and reports chest pains and palpitations," Gettinger recalled. "We do an EKG in the clinic and see a flutter, so we send him to the ER to get a CT, which shows a pulmonary emboli."


The patient receives unfractionated heparin and is discharged on enoxaparin, Gettinger noted. "And then 19 days later, before he gets any other dose of immunotherapy, he presents with elevated aspartate transaminase and alanine transaminase," he continued. "We start him on prednisone for 1 week and tapered off over 3 weeks and his liver enzymes normalized."


In October 2014, the patient resumes anti-PD-L1 on trial and shows a tumor response. JT presents to the ER in February 2015, according to Gettinger, with slurred speech, facial fullness with sensation of tongue and cheek swelling, as well as fatigue. A battery of tests are conducted in the ER, included MRI, CT chest, EKG, and blood tests. "I don't think the ER was overwhelmed by his symptoms, so they discharged him to see us the next day.


"We do a TSH 98 at no detectable FT4 (< 0.10), and we start him on levothyroxine and he does well with that. In March 2015, he resumes anti-PD-L1 therapy and since then he has continued and I saw him a few weeks ago and he continues to have a sustained response."


Given the number of potential adverse events and their impact on treatment and quality of life, "early recognition and initiation of therapy are key," Gettinger concluded.


Catlin Nalley is associate editor.