Cytokine Release Syndrome Grading and Management Strategies in MM
Comprehensive insight on the grading system for cytokine release syndrome and available treatment strategies utilized in practice when patients with multiple myeloma develop CRS.
Transcript:
Ajai Chari, MD: That’s a great segue to CRS [cytokine release syndrome] itself. We’ve been alluding to it, but let’s hear a little more about CRS. What is it, and what is its grading?
Kiah Purcell, NP: Cytokine release syndrome is triggered by an activation of the T cell. They’re activated because that’s how the drug works. It grabs on to the myeloma cell and receptor of the T cell. It activates the T cell, which releases cytokines and causes adverse effects, such as fever, myalgia, low blood pressure, and tachycardia. That usually happens within the first week. Risk factors include bulky disease, high disease burden, high myeloma markers, a lot of disease in the marrow, comorbidities, and sepsis. Suspect it if you have symptoms, such as fever, low blood pressure, or hypoxia, or evidence of organ toxicity, such as elevated liver enzymes.
We use the ASTCT [American Society for Transplantation and Cellular Therapy] guidelines for grading. Grade 1 CRS is defined as a temperature over 38 °C. Grade 2 is temperature with hypotension, not requiring vasopressors. The hypotension responds to IV [intravenous] fluid and/or hypoxia requiring nasal cannula. Grade 3 CRS is defined as temperature and hypotension requiring vasopressors and/or hypoxia requiring high-flow nasal cannula, with nonrebreather, or venturi mask. Grade 4 is temperature with hypotension requiring multiple vasopressors and/or hypoxia with positive pressure.
Ajai Chari, MD: Now that we know what CRS is and the grading system, how does your management differ based on the grade and timing? We can start with Kiah for her perspective [at Mount Sinai Hospital], but there are some differences. It will be great to hear Robert’s perspective from his institution [St. Luke’s Cancer Institute]. How would you treat CRS?
Kiah Purcell, NP: Generally, we treat CRS earlier than a lot of the recommendations at Mount Sinai. We sometimes intervene at grade 1. Most recommendations say tocilizumab with grade 2 CRS, but we’ve given a lot of tocilizumab with grade 1. Originally, when someone first spikes a fever of over 38 °C, we might give them Tylenol to start. If the fever continues or they have any other symptoms that wouldn’t even make it grade 2—such as tachycardia if their sinus tachycardia is very high, or they seem like their blood pressure is going in the wrong direction, or they’re just not responding to Tylenol—we administer tocilizumab quite early. We’ve seen a lot fewer ICU [intensive care unit] admissions because of that.
Ajai Chari, MD: That’s great. Robert, when do you give tocilizumab?
Robert Mancini, PharmD, BCOP: I agree with Kiah. We’re moving toward earlier use of it. You showed the consensus guidelines. They say typically you give it in grade 2, but we’re starting to see more of that in grade 1, especially in the situations Kiah mentioned. There’s 1 thing that’s interesting that may be different for us. If we look at the patient we presented, that patient had elevated IL-6 levels, and that’s the target of tocilizumab. That’s what you’re neutralizing by using that medication. Unfortunately for us, IL-6 is not an in-house lab. We could grab that and send it out, but by the time we got the results, it would be way too late. Earlier use of tocilizumab is important because we can prevent these patients from progressing toward higher grades and therefore decrease the acuity of their stay. But a lot of times, if you have CRS with concomitant ICANS [immune effector cell-associated neurotoxicity syndrome], that’s another reason to throw in tocilizumab a little earlier.
Ajai Chari, MD: Just to pick your brain as a pharmacologist, the half-life of tocilizumab, which is a monoclonal antibody, is about 7 days. Some institutions believe in multiple doses of tocilizumab, but we tend to not do that unless it’s been several days because of the half-life. What are your thoughts as a pharmacist?
Robert Mancini, PharmD, BCOP: I agree with that. The half-life it says it can be this, but if you look at the [PK] pharmacokinetics of tocilizumab, it can be 2 to 3 weeks—16 days or longer. It’s concentration dependent. A lot of times with monoclonal antibodies, it’s how quickly it gets used up that may play into that eventual half-life, but it’s not cleared by the kidneys or liver like most drugs. It’s cleared by our lymph system in most situations. It tends to have a pretty long half-life.
As you’ve outlined, the consensus treatment guidelines say no more than 3 doses in a 24-hour period or 4 doses total. We don’t use that very often. If a patient doesn’t respond to that dose, we’re going to move on to something like dexamethasone, anakinra, or cetuximab or something else because it’s probably not doing enough. And the other drugs have a lot better CNS [central nervous system] penetration comparatively, so you can get some added benefit there. If the patient has a good response and that CRS comes back after 2 to 3 days, then we redose it. But I don’t see much redosing constantly within that first 24 hours.
Ajai Chari, MD: At institutions where you don’t get these cytokines, 1 of the biggest complications in relapsed/refractory myeloma—particularly when treating with BCMA-directed bispecifics, particularly when there’s cytopenia—is that there are infectious complications. In fact, we’ve had patients get them while admitted in the hospital with nosocomial viral infection. You have to do parallel processing. Don’t put all your eggs in 1 basket. You may need broad-spectrum antibiotics if the patient looks sick. If you think it’s CRS, give them a dose or 2 to stabilize and then you can peel back once the cultures are negative. That’s an important bedside pearl.
Before we go to the next case, Annel, do you have any nursing comments on this? There are symptoms, the frontline providers are called, they agree it’s CRS, and they put in an order for tocilizumab. How quickly should individuals move on this in terms of mixing the drug and hanging these drugs?
Annel Urena, RN: It should be done pretty quickly. You don’t want your patients to go more downhill. Blood pressure is still dropping, and oxygen is still dropping, so you need to monitor vitals a little more frequently and be on top of it. As a floor nurse, you’re caring for the patient, making sure you’re in contact with pharmacy: what’s the ETA from mix to the floor, to the hanging of the drug? You want as early an intervention as is possible.
Ajai Chari, MD: You highlighted the importance of communication and care coordination. As you alluded to with this case, the gratifying thing is that this works so quickly. We’ve all seen when you give the tocilizumab, dexamethasone, or whatever, these patients promptly get better.
Transcript edited for clarity.
