Clinical Pearls on the Management of Immune-Related Adverse Events Affecting the CNS

Educational Impact Challenge The goal of is to discuss the identification and management of immune-mediated neurologic adverse events related to treatment with immune checkpoint blockade therapy.

We are going to talk about immune-mediated adverse events (imAEs) today. There are a lot of general issues that are worth discussing. What is an imAE? It occurs when there is loss of immune tolerance to self-antigens. You see tissue damage that is associated with inflammatory T-cell infiltrates which can involve any organ system. imAEs are mostly mild to moderate and almost always reversible. They can, however, be life-threatening and they do represent a new type of oncologic emergency. Most of us in the field believe that the benefits of therapy clearly outweigh the potential risks, particularly when imAEs are recognized early and treated quickly and appropriately.

Most imAEs occur during the first 3 to 4 months of therapy. However, these events can occur late. For example, I have seen one episode at month 47, 4 years into treatment during the maintenance phase of ipilimumab therapy. Each imAE has different kinetics of onset and some of them can wax and wane, particularly colitis. Moreover, you can also see multiple imAEs within the same patient over a particularly long period of time. Corticosteroids and other immunosuppressants can be used to manage virtually all imAEs. However, one should think about the fact that prolonged steroid tapers are usually required.

General Management of imAEs[3-5] The management of these events is the responsibility of all healthcare providers involved in the team taking care of cancer patients who are receiving drugs such as checkpoint inhibitors. The emergency department (ED) clinicians are often the first responders, yet they may not have an extensive level of experience in managing these events. Early reporting by patients with close monitoring and early intervention by the healthcare team is critical to the successful management of these imAEs. It is important for the team to provide thorough and continuous patient education about the signs and symptoms of these imAEs. Again, one critical thing for the practitioner who uses these immunotherapies is to always assess for the signs and symptoms of imAEs before giving each immunotherapy treatment. It is very important for the practitioner giving these drugs to know the management algorithms specific to each one of these imAEs. It is also important to know the safety profiles of the immunosuppressants that we use to deal with these side effects. It is very important to be aware of, to monitor for, and to manage the toxicities of the drugs that you use to suppress the side effects of our immunotherapies. For example, with steroids, opportunistic infections, hyperglycemia, and diabetes can be significant complications, and you need to be on the lookout for them.

Neurologic im

Neurologic imAEs are relatively infrequent with cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) antibodies alone, but they are more frequent when they are used in combination. There is a possible underestimation of neurologic imAEs due to lack of recognition or underreporting. Presentations can vary enormously as the nervous system is quite a complex organ. You can have symptoms that are as variable as numbness and tingling, foot drop, localized muscle weakness, generalized ascending motor weakness, diaphragmatic weakness that impacts respiratory function. You can also have symptoms that are more localized to the central nervous system (CNS), with headache, seizure, altered mental status, and syncope all possibly being seen.

Experience With Neurologic imAEs[6-8] In terms of our experience with neurologic imAEs, in a published compilation of 59 trials totalling over 9000 patients, the overall incidence of neurologic imAEs was about 3% in patients receiving anti-CTLA-4 antibodies, 6.1% in patients receiving anti-PD-1 antibodies, and 12% in patients receiving a combination. Incidence of grade 3 and 4 imAEs was about 1% with all antibodies. From the experience at the Royal Marsden Hospital, the rate of neurologic imAEs was about 2.8%. In the EORTC trial, neurologic imAEs were reported at a rate of about 4% in the adjuvant ipilimumab arm. Most neurologic events were mild; headache and peripheral sensory neuropathy were the most common.

Variety of Neurologic imAEs[4,5] There has been a wide variety of neurologic events reported so far. We have seen myasthenia gravis (MG)-like syndrome, Guillain-Barré syndrome (GBS), limbic encephalitis, aseptic meningitis, peripheral neuropathy, isolated facial nerve palsy, enteric neuropathy, transverse myelitis and transverse myeloradiculitis, and also posterior reversible leukoencephalopathy syndrome

in dealing with any neurologic disease. Some of the key things that we need to rule out include: processes such as hypophysitis, which we would see with an acute endocrinopathy; stroke, which can take many different forms and it is important to always consider with any new onset focal neurologic symptoms; CNS metastases as well as leptomeningeal disease, which have become key things that have to be differentiated when we are thinking about neurologic imAEs; and paraneoplastic syndromes, infections, and metabolic derangement, which must also must be considered

When we see these patients and we suspect a neurologic imAE, especially a moderate-to-severe one, we have to withhold the checkpoint inhibitors. Often, we will empirically treat with antibiotics. If there is any thought that there is either a clinical or a subclinical seizure, we will give an anticonvulsant. I tend to jump on these folks with high-dose steroids. We will give methylprednisolone, 2 mg/kg/d. If this is indeed agreed to be a bona fide neurologic imAE, we are looking at a prolonged steroid taper over 6 to 8 weeks. This is not a grade 3 colitis that is going to go away in a couple of days and be treated with a month of steroids. We will give a long steroid taper. The other issue is: in many of the syndromes such as MG or GBS, often neurologists will use intravenous immunoglobulin (IVIG) or plasmapheresis. As oncologists, we have experience using the immunosuppressants, but it is not obvious to us when we should use IVIG or plasmapheresis.

It is quite difficult and it really becomes more of an art than a science in many cases. IVIG is generally more first line for GBS. Plasmapheresis is used more when there is a crisis. Especially with a myasthenic crisis, plasmapheresis would be your first treatment option. Other immunosuppressants such as mycophenolate, tacrolimus, azathioprine, or rituximab also can be considered in grades 3 and 4 imAEs that do not resolve within 48 hours with steroid treatment

the most important thing is having a good multidisciplinary team involved with the patient. Patients are often in the hospital, so you should have access to a pain management team, which will be relevant in one of the cases we talk about. Occupational therapy (OT), physical therapy (PT), and speech therapy should be available for patients who have severe side effects, such as MG and GBS.

You have to treat these neurologic imAEs as if they had occurred in isolation from immunotherapy. It is shocking how they literally recapitulate the actual diseases that occur idiopathically or spontaneously. You have to get your neurologists involved early. You need to have a multidisciplinary team and talk to them everyday -- especially if they are in the hospital and there is a hospitalist where you are not directly taking care of the patient. That hospitalist may not have a lot of experience with these side effects. In my experience at the hospitals I have worked at, I have to talk once or even twice a day to the inpatient team and the patient needs to be in the loop. At the end of every day, I am talking with that patient.

Concluding Remarks

In summary, imAEs of a neurologic origin are not that uncommon. Get the neurology consult involved early. Even though there is a broad differential, you have think about an imAE as the etiology and think about the possibility of treatment with steroids.