Toxicity Management, Considerations for Bispecifics: ICANS and Infections

By Thomas Martin, MD, Ajai Chari, MD, Ajay Nooka, MD, FACP, Angela Dispenzieri, MD - Last Updated: October 12, 2023

A roundtable discussion, moderated by Thomas Martin, MD, Blood Cancers Today Associate Editor, of the University of California, San Francisco, focused on bispecific therapeutics for the treatment of multiple myeloma. Dr. Martin was joined by Ajay Nooka, MD, MPH, FACP; Ajai Chari, MD; and Angela Dispenzieri, MD.

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In the next segment of the roundtable series, the panel continues the conversation around toxicity management for bispecific agents, particularly ICANS and infections.

Watch the next segment in this series.

Dr. Martin: Let’s talk a little bit about ICANS [immune effector cell-associated neurotoxicity syndrome] because I’ve previously thought that ICANS really doesn’t happen with bispecifics, but I’ve changed my tune a little bit. What do you think? Have you seen much ICANS, Angela?

Dr. Dispenzieri: With the bispecifics, not so much, but I’m not doing the inpatient service, so I just have patients that are coming back to me. I’m not the best to answer that question actually. But it doesn’t seem to be, is kind of as I read it.

Dr. Martin: Yes, it doesn’t seem to be as big of a deal, certainly. How about in your experience Ajai?

Dr. Chari: I think part of it is a learning curve too and recognition. I think early in the phase I dose escalations, we didn’t see it much because we weren’t looking for it. Then when you add in the mini mentals and you’re waking up people at 3:00 AM and having them do these crazy assessments, you’re picking up a little bit of changes. Some of that is in the setting of fever. To your earlier point, is it delirium or is it ICANS? Does it matter? If they’re all getting dexamethasone and it usually resolves. I think in general, bispecifics probably don’t have an ICANS rate of more than 10%. It’s typically low grade and I think self-limited. It’s not as concerning I think as the CAR-Ts.

Dr. Martin: What do you guys think in terms of, so for CRS [cytokine release syndrome] with bispecifics, do you worry about it after cycle one or cycle two, do you worry about CRS at all? They’re outpatient. Are you seeing any CRS, any late CRS? Anything that you worry about?

Dr. Chari: I’ll make a couple of points. One is we did this natural experiment during COVID-19, right. New York being the epicenter, we had a lot of patients on bispecifics that we had to hold because there was no vaccine and a lot of these patients were in remission. Our policy was if you’re in remission, we’re skipping drug. If you’re actively progressing or active disease, we continue. When you do the hold, the vast majority of patients did not have CRS with re-titration upward. The protocol mandated that you have to re-step up. But I think currently the protocol say if you hold, REMS [Risk Evaluation and Mitigation Strategies] program says 28 days, some of the protocols allowed 35 days before you re-step up. But I would just say if you’re taking a break in a patient for adverse event/toxicity, whatever, if they have bulky disease, I probably would be a little cautious and watch closely because they could have it again when you activate those T cells.

I think we also need to be mindful of infections for another cause of fever. Also, I have had a couple of patients with hemophagocytic lymphohistiocytosis, which bulky disease patients on bispecifics. I would say that’s another subgroup that you need to be aware of. Then lastly, when we’ve seen some combination strategies, when you particularly add certain drugs, you get these weird fevers, not just during step up. I think that’s when I’ve seen it. But just monotherapy, I usually have not seen CRS by itself.

Dr. Martin: Well you brought it up, infections, because that’s the other big thing, right? When we see the long-term data upwards of 70% to 80% of patients are having some infections during their therapy for bispecific. A lot of that is in the first few months when they’re neutropenic, etc., but also continues over time. Ajay, what are you doing for prophylaxis for patients, for infections, for bispecifics?

Dr. Nooka: We have a standing order as discussed by the entire myeloma group. Everybody that gets a BCMA-targeted therapy will get IVIG [intravenous immunoglobulin] on a monthly basis irrespective of the IgG levels, irrespective of whether the patient has an infection or not. We also use the Pneumocystis jirovecii pneumonia prophylaxis; we also use the antiviral prophylaxis. We don’t use antibacterial prophylaxis until there’s a need for, there’s a trigger for initiating an antibacterial prophylaxis.

Dr. Martin: Like a febrile neutropenia…

Dr. Nooka: Like a febrile neutropenia. We have routinely monitored our viral panels like we have the same group as a transplant group. Allogeneic transplants, we routinely use the CMV [cytomegalovirus] monitoring, adeno-monitoring, EBV [Epstein-Barr virus] monitoring. We have used the same kind of a platform for the bispecifics on a weekly basis to evaluate whether these patients are at a higher risk for viral activations. If not, we always can go back and change our process. It is all building upon what you’re learning from your patient population for the betterment of the care that you give.

Dr. Martin: For viral reactivations, any pearls about viral activations? Are you seeing any CMV disease or any other viral specific-driven disorders?

Dr. Nooka: In our first 50 patients we have not seen any, which brought the discussion back to, so should we do all these? But the real experience from the clinical trials from other institutions show that there is some amount of viral reactivation. The problem why we didn’t have the baseline incidence of viral reactivation is it’s not uniformly done across all the studies. It makes us very not comfortable making a decision without the data. I think right now as we see in the cohort of patients that we treated, we didn’t see any, makes it easier for us to make a decision moving down the line.

Dr. Dispenzieri: The hard thing though, we know in the autologous setting, we don’t monitor for CMV reactivation, but you get it and it’s not disease. We don’t treat it unless somebody’s actually symptomatic. I mean I think we’re learning a lot about you monitor it, but are you going to treat it if you see the reactivation and everything?

Dr. Chari: We actually have a paper coming out very shortly in Blood Cancer Journal where we looked at about 40 BCMA patients where we did see CMV monitoring, and the reactivation rate was about 20%. Included were two, one was pneumonitis, and one was esophagitis. I think it’s real. You may not be seeing it perhaps because you’re giving the IVIG, which we also do, but this was before we learned about that. I agree with all of your recommendations. We haven’t been doing EBV and adenovirus unless they’re febrile or have a cytopenia or some adverse event.

But the CMV, I think because the reason to monitor it also is you may want to hold the drug until you get several time points, right? Because the CMV could be rising like this, or it may rise and then fall. But before you hit that next dose of the BCMA bispecific, it’d be nice to have that comfort of like, this is just low level viremia that’s going to get controlled. Because if you’re going to give the drugs, guess what, you’re now adding to cytopenias and costs with the antivirals. I think CMV viremia is an area that we need to understand better.

Dr. Martin: I think we probably all agree that IVIG prophylactically is actually very important for this therapeutic, which is great. Also I think one of the take home points are if somebody is demonstrating signs of infection, if they’re having fever or symptoms, we have to look not just at bacterial and fungal possibilities, but the viral possibilities and the reactivations do occur. We have a couple of patients at UCSF [University of California, San Francisco] that had severe anemias, and so we check parvovirus and lo and behold their parvovirus is really quite high and they responded really well to high-dose IVIG. But that is one of the things that happens with these bispecifics. You really have to be on top of infectious disease.

Dr. Chari: The two other quick points I would make about IVIG is number one that the IgG dropping is just a pharmacokinetic issue, right? Incidence of severe hypogamma is a hundred percent on BCMA bispecifics, and it doesn’t necessarily improve when you stop the drug. It paralyzes the immune system for quite a while. Vaccinating people prior to BCMA therapy I think is super important. Then giving the IVIG as soon as you can get it approved. Then the last thing is I would say we have a growing group of patients with CKD [chronic kidney disease], in whom IVIG created problems, either created worsening azotemia or albuminuria. We’ve decided to give fluids for those patients and then not use actual weight, but ideal body weight and try to not dose as frequently, maybe just keep tolerate a little bit lower peak. But I think we haven’t been using IVIG in these kinds of patients as much as we are now. I think historically the low osmolarity was pretty safe, but things just we’ve learned.

Dr. Martin: Very interesting.

Post Tags:Myeloma Talq
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