ASH 2024 | AEs physicians should look out for when treating R/R DLBCL with bispecific antibodies

Bispecific antibodies that are currently in routine clinical use include epcoritamab and glofitamab, which have both been approved for relapsed/refractory diffuse large B-cell lymphoma after two prior lines of treatment, and there’s really a class effect in terms of side effects that we see across both agents, and not a huge amount of difference between the two. And the key side effects are cytokine release syndrome, which essentially begins with a fever but can progress to a sepsis-like syndrome, and then there’s a lower chance of neurological side effects, which is really much, much lower than what we would expect with, for example, CAR T-cell therapy. So in practical terms, the most common side effect to think about is cytokine release syndrome. Cytokine release syndrome occurs in roughly half of patients who are receiving glofitamab treatment, a little lower in patients who are receiving epcoritamab treatment. The timing is different. So with glofitamab, it’s the first exposure to the drug, and with epcoritamab, it’s the first target dose, which is the third dose of the drug that is given. So understanding the timing of the CRS is really important in physicians who are using this. In practical terms, in most patients, it’s low-grade, it’s a fever, and it responds to corticosteroids, or if it becomes more advanced and goes to grade two CRS, will respond well to tocilizumab. Most patients can be treated on an outpatient basis, but in certain regions, prophylactic hospitalization is recommended in certain situations for patients at higher risk. We’re evolving an understanding of who is going to develop cytokine release syndrome. In some ways, it’s pretty simple. The way I think about it is that cytokine release syndrome is due to T-cell activation. It’s a direct consequence of the mechanism of action. All of these agents mitigate it by using step-up dosing and corticosteroids as pretreatment. It’s pretty clear across all the agents that dexamethasone is now the corticosteroid of preference. And so that’s one thing, if you’re choosing a corticosteroid, use dexamethasone. And then it’s pretty clear that across these agents, the risk factors are very similar. The more disease a patient has, the more antigen they have, the more T-cell activation they’re likely to see. So a patient with high burden disease or comorbidities that may make their tolerance of a fever more problematic are the ones that you need to think about keeping a bit closer to your day centre or having the capacity to admit if a fever develops. We know that patients with circulating disease also have a higher risk. Bone marrow involvement also likely has a higher risk. There have been publications of risk scores from Roche in particular that reinforces that idea that disease burden is really the key risk factor that we need to be aware of. But just like any other treatment, you also have to think about the patient and their circumstances and their comorbidities, kidney function, general performance status, and so forth in terms of their ability to tolerate cytokine release syndrome. There are some great guidelines that have been published by Jennifer Crombie and Lorenzo Falchi in The Blood that help physicians understand how to prepare for giving bispecific antibodies and how to mitigate and treat these side effects with some very clear recommendations that were developed through a consensus of investigators and clinicians who work both in community oncology-based settings, but also academic settings. And those consensus recommendations were brought together really through a very broad collaboration of different treatment settings. So I’d highly recommend taking a look at that. Now, in terms of other important side effects of the bispecifics, well, B-cell depletion is an on-target effect. And so all patients should have prophylaxis against complications of B-cell depletion, including Bactrim prophylaxis or prophylaxis against PCP pneumonia. And also I use prophylaxis against reactivation of herpes zoster with regular valacyclovir or acyclovir. And I think that should be routine in patients receiving this treatment, it certainly has become my routine. Cytopenias do occur, we do see immune-mediated cytopenia. It’s not the kind of neutropenia you get after cytotoxic chemotherapy. It’s more an immune-mediated cytopenia. It doesn’t usually lead to febrile neutropenia and it responds well to G-CSF practically. One of the less well-reported side effects that I’ve seen a few cases of is colitis. And I have seen colitis after several bispecific antibodies. It’s probably an in-class effect. We don’t know much about the mechanism of that. It’s fairly infrequent, less than one percent probably, and usually responds to steroids and in many cases you can re-expose the patient. COVID-19 is an important consideration. In my region, we strongly recommend use of the COVID-19 vaccine in patients who are receiving these sorts of treatments. In vaccinated patients, it’s usually manageable to manage a patient through their COVID-19 before recommencing a bispecific once you’re confident that their infection is not progressing with any complications such as pneumonitis. They’re the main things that you need to think about with a bispecific antibody. It’s all pretty manageable. Sometimes you see site-related reactions with the subcutaneous formulations, but compared to managing chemotherapy, this is something hematologists can do with confidence. It’s certainly no more complicated than managing a patient with R-CHOP, for example, or GEMVIN or GEMOX. Bispecific monotherapy is relatively straightforward; it’s just a different profile from what we’re used to.

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