Advancements, future research in diffuse large B-cell lymphoma treatment
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Treatment regimens for diffuse large B-cell lymphoma have seen many recent advancements, thanks in large part to the development of targeted agents.
To learn more, Healio spoke with Christine Ryan, MD, senior hematology-oncology fellow at Dana-Farber Cancer Institute.
Healio: What have been some promising advances in the treatment of diffuse large B-cell lymphoma?
Ryan: The field of diffuse large B-cell lymphoma has seen tremendous advancements in the recent years, and that really comes from development of targeted agents. For example, now we have chimeric antigen receptor T cells targeting CD 19, we have bispecific antibodies that target CD 20, there's tafasitamab [Monjuvi; MorphoSys, Icyte] targeting CD 19, and we have polatuzumab vedotin [Polivy, Genentech], which is targeting CD 79 B. So, what's very striking is that these are targeting cell surface markers and that's been a major advancement in the field and in effectively treating diffuse large B cell lymphoma.
Healio: What factors are taken into consideration when developing a treatment plan for patients with diffuse large B-cell lymphoma?
Ryan: In many ways, it depends if we're talking about first-line therapy vs. second- or third-line therapies. Very broadly, we think about patient factors — so, things like age, and of course age is just a number — but coming along with that are overall functional status, other medical comorbidities and baseline organ function, with particularly key components being renal function as well as cardiac function. Then, as we think about the later lines of therapy, we also need to take into account a patient’s functional status at that point in time after having relapse disease, and if there are any lingering side effects from a prior treatment regimen.
Healio: What role does immunotherapy play in diffuse large B-cell lymphoma treatment?
Ryan: When we think about immunotherapy broadly, it involves harnessing the power of a patient’s own immune system to target their cancer, and immunotherapy in DLBCL right now encompasses, in part, both CAR-T and bispecific antibodies. An area of active research is potentially incorporating CAR-T as earlier-line therapy. One trial that is particularly interesting in this space is the ZUMA-12 trial, which specifically targets high-risk patients either with double hit lymphoma or a high IPI score. Basically these patients start with R-CHOP, and then for those who have achieved less than a complete response, they transition immediately to axi-cel [Yescarta; Kite Pharma/Gilead Sciences. So, we could be seeing much more of a response-adapted treatment approach like that, with the opportunity for CAR-T to be moved even more upfront in patients who potentially demonstrate that they have chemo-refractory disease initially.
Healio: So, you see an expanded role for immunotherapy in the future of this treatment?
Ryan: Yes, definitely. And bispecific antibodies like glofitimab [Genentech], epcoritimab [DuoBody-CD3XCD20; Genmab, AbbVie], and others, are very much coming on the heels of CAR-T as an additional wave of immunotherapy. These are antibodies that engage the lymphoma cell with a CD20-binding domain, and at the same time with a CD3-binding domain engage T cells, which are the effector cells of the immune system in targeting that lymphoma cell. These agents are what we call an off-the-shelf therapy. So, whereas CAR-T requires manufacturing of an individual patient's own T cells, these do not require that step. But of course, they have their own considerations, with some requiring step-up dosing and inpatient administration, etc.
Healio: What challenges exist in treating patients with relapsed or refractory diffuse large B-cell lymphoma? How can these be managed?
Ryan: I would say that relapsed/refractory disease in the post-CAR setting really remains an area of unmet need, as well as an area of open investigation. Especially with the advancements of CAR-T now moving into earlier lines of therapy and two of the constructs FDA approved for a second-line therapy, more and more, we're now going to be seeing patients who potentially relapse after that CAR-T and the question is what is the most effective treatment in that setting? In terms of how these patients can be managed, bispecific antibodies are a very exciting new class of agents that are really taking the field by storm, and I'm sure we're going to see much more data at ASH this year as well.
Healio: What would you like to see future research focus on in relation to diffuse large B-cell lymphoma?
Ryan: There are a few main areas of unmet need. Especially as CAR-T moves more into the second line for many patients, the question of what to treat patients with following CAR-T really remains. And while there are many other targeted therapies that have efficacy, often the responses are not thoroughly durable. So, continuing to investigate treatments that are going to have durable remissions is key. One other area for diffuse large B cell lymphoma that would be a very important area of research is in our more elderly patients. And that obviously encompasses a broad group, not just based on age, but also patients with other medical comorbidities or just underlying medical issues where they may not be able to receive as intensive therapies. For many of these patients, the standard of care has been R- mini-CHOP, which is basically R-CHOP but with reduced dosages. I think a question will be can these immunotherapies also be effectively used in our older patients? And similarly, can they achieve durable remissions?
For more information:
Christine Ryan, MD, can be reached at email: ChristineRyan@dfci.harvard.edu.
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