Monitoring and Managing CRS, ICANS, and Infections With Bispecifics

CancerNetwork® spoke with Ralph V. Boccia, MD, FACP, founder of The Center for Cancer and Blood Disorders, clinical associate professor at MedStar Georgetown University Hospital, and medical director of the International Oncology Network Clinical Research Program, about monitoring and managing toxicities in patients receiving bispecific antibodies in the outpatient setting. Boccia walked through the home monitoring tools, virtual visits with advanced practice providers (APPs), and grade-based escalation his practice uses for cytokine release syndrome (CRS), including prophylactic dexamethasone and tocilizumab (Actemra). He also explained how his team assesses immune effector cell–associated neurotoxicity syndrome (ICANS) with the Immune Effector Cell–Associated Encephalopathy (ICE) score, and he discussed infection risk, the rationale for monthly intravenous immunoglobulin (IVIG), and why time-limited therapy may help patients recover immune function.

CancerNetwork: What tools help monitor adverse events in the outpatient setting, such as remote monitoring kits, virtual visits, or remote triage?

Boccia: The first thing we need to do is monitor the patient’s neurologic status and the potential for CRS. Monitoring a patient for CRS is easy. At the very basic level, they have to have a thermometer, a sphygmomanometer to take their blood pressure, and an oxygen saturation device. Those are the 3 key things the caregiver needs to monitor the patient, and they record all those things. We also give them dexamethasone, so they have dexamethasone at home. If they develop a fever and it doesn’t seem like infection is what’s going on, they take their Tylenol and their dexamethasone, and then we monitor them over time. Sometimes we’re giving prophylactic dexamethasone, most of the time, and other times we’re also giving prophylactic tocilizumab, especially to our patients receiving myeloma bispecifics. That can go a long way toward blocking CRS, or at the very least limiting it to grade 1. That’s what we do for prophylaxis.

Then we see the patients in the clinic on the day after their step-up dose. Often, they come in and get some IV fluids; sometimes they get more steroids. They’re monitored for several hours, then sent home, and at the end of the day they get a telehealth visit, often with the APP, to go over how they did when they got home. On the third day, and often the fourth day, we’re often just doing 2 virtual visits. You can see the patient, look at the recordings the caregiver has made, and determine whether you need to see them face to face or, if worse comes to worst, meet them at the hospital. That’s how we manage and monitor.

If a patient develops grade 1 CRS, which is just a fever, a temperature of 100.4 °F or more, we’ll often try to manage that at home. If the fever doesn’t break in 24 hours, they come into the office, and we’ll often give them tocilizumab if they haven’t had it already. If we can’t break it, or if they have grade 2 CRS, meaning maybe they’re a little hypoxic or their blood pressure is a little soft and they still have the fever, then we’ll bring them into the office. We’ll often give them tocilizumab, we’ll always give them steroids, and we’ll give them IV fluids and monitor them with a little low-flow oxygen. Most of the time, by the end of the day, we’ve broken it. If we haven’t, they often go to the hospital, and that’s when we’ll admit them, because we don’t want them to be an outpatient with grade 3 CRS. That’s our outpatient strategy, and it’s worked well.

Right now, we also use a device that remotely monitors temperature. It’s a simple patch that goes on the arm, transmits to a monitor and then to a portal, and we can see it on the phone. Currently, that’s all we’re using because, as I said earlier, all CRS is heralded by a fever. That’s what you mostly need to know, because the caregiver can take the blood pressure and pulse and tell you. That said, we’re also now looking at companies that provide a more robust suite of services that can include all 3 of those measurements and have remote monitoring health care providers. They’re usually nurses who have worked with T-cell therapy themselves, who can take the calls and report back to the physicians if it’s anything other than something very simple. There are now services that basically have people on call to take those calls.

We’ve talked a lot about CRS, but how do you assess for ICANS?

Boccia: There’s a tool called the ICE score, and we go through the ICE score each time. It’s a scoring system out of 10, where basically 10 means you have none of the features. It assesses mental clarity, being able to write, and understanding the date and time, so whether patients are oriented or not. It’s being able to repeat things when you give them a task, and often it’s the same things every day. It’s watching them write to see how they write. All these things add up to a score, where the higher the score, the better they’re doing, and the lower the score, the worse they’re doing. ICANS can range from a confusional state or lower levels of consciousness all the way to loss of consciousness or even seizures, and those can be scary if patients have them.

With bispecifics, that’s extraordinarily rare. The incidence of ICANS with bispecifics is on the order of 5% or less, and most cases are grade 1, which sometimes is just a little fogginess, you might say. It’s with CAR T that the more significant ICANS can occur, and the frequency is higher, just as it is for CRS.

What infection risks do you see with bispecifics, and how effective is immunoglobulin replacement? Do you give prophylactic IVIG from cycle 2 on, perhaps on the same day as the bispecific?

Boccia: Probably the most common toxicity we need to manage in patients treated with bispecifics is infection. If you look at the data across all the bispecifics for multiple myeloma and lymphoma, roughly 75% will get a grade 3 or 4 infection, so almost everybody gets some infection. They’re usually respiratory infections. If you look at these patients’ immunoglobulin levels, they’re generally very low, often under 500, depending on how long they’ve been on therapy and what they had before. That’s because almost all the drugs we use in this space cause depletion of B cells, which make antibodies. The other thing is that the helper T cells, the CD4 counts, go very low, almost to AIDS-level CD4 counts.

These patients need some sort of prophylaxis, and the field has gotten to the point where the recommendations and guidelines suggest that, no matter what the immunoglobulin G level is, all patients should have monthly IVIG. That will reduce the incidence of infections by more than 50%. That’s another reason that we like time-limited therapy: it allows B-cell recovery and antibody levels to go back to a more normal range, so patients won’t need IVIG forever.