Diffuse Large B-Cell Lymphoma Overview: An Aggressive Heterogenous Disease


A panel of oncologists talks about diffuse large B-cell lymphoma, what patient and disease factors one should take into account when thinking about DLBCL.


Kami Maddocks, MD: Hello. Welcome to this OncLive® Peer Exchange titled “Navigating New Treatment Options in Relapsed/Refractory Diffuse Large B-Cell Lymphoma.” I’m Kami Maddocks, a professor of clinical internal medicine in the division of hematology at The Ohio State University. Joining me today in this discussion are 4 of my colleagues. Would you each please introduce yourselves?

Jason Westin, MD: Hi, I’m Dr Jason Westin from [The University of Texas] MD Anderson Cancer Center. I’m the director of lymphoma clinical research and the section chief for aggressive lymphomas.

David Miklos, MD, PhD: Hi, I’m David Miklos, and I’m the chief of blood marrow transplantation and cellular therapy at Stanford University.

Richard T. Maziarz, MD: I’m Richard Maziarz, the director of transplantation cell therapy at Oregon Health & Science University.

Grzegorz S. Nowakowski, MD: Hi, I’m Greg Nowakowski. I’m a professor of medicine and oncology at Mayo Clinic in Rochester, Minnesota, and I oversee our aggressive lymphoma program.

Kami Maddocks, MD: Thank you all for being with us. Today, we’re going to discuss a number of topics pertaining to the use of novel agents in relapsed or refractory diffuse large B-cell lymphoma. We’ll discuss CD19-directed chimeric antigen receptive [CAR] T-cell therapy and other available agents; the latest research in the field, including from the 2021 ASH [American Society of Hematology] Annual Meeting; and the impact of recent clinical trials on sequencing and treatment selection. Let’s get started on our first topic. Dr Nowakowski, hopefully you can start us off. I’d like you to describe how a patient with diffuse large B cell lymphoma presents. What things are you worried about or thinking about? What clinical lymphoma-related factors are you looking at?

Grzegorz S. Nowakowski, MD: Thank you, Dr Maddocks. It’s important to remember that diffuse large B-cell lymphoma is the most common lymphoma both in the United States and worldwide. This is an aggressive lymphoma, which means that a lot of patients will present with fairly rapidly progressive disease. This typically involves lymph nodes, but also can involve external sites in different organs. Patients can also present with organ dysfunction as well, depending on where the pressure from the adenopathy or the masses is appearing. Therefore, although it’s not a true medical emergency, I’m calling it a semi-emergency. These patients have to be evaluated promptly. Effort has to be made to get them to therapy as quickly as we can, and ideally on clinical trials. Because as we’ll hear later, there are a lot of exciting developments in this field, and this is our opportunity to benefit patients who present with this disease.

It’s also important to remember that this disease mostly affects older people. The median age in the United States is 67. A number of patients can present with organ dysfunction, or borderline performance status. As we’re thinking about the available treatments, those are important factors to take into account. At this year’s ASH meeting, there was a joint symposium—educational and scientific—focused on clinical trials and how we can do better in accruing patients for clinical trials. A colleague of mine, Dr [Thomas] Witzig, gave a very interesting talk that focused on who’s left behind in regard to diffuse large B-cell lymphoma. It was about how older patients and some patients with organ dysfunction are left behind [in] our clinical trials, and how we can be more inclusive in treating those patients.

The other interesting thing about diffuse large B-cell lymphoma is that in the outcomes, it’s an extremely heterogeneous disease. There are some just patients who are cured and some who aren’t. We have a number of clinical predictors, like IPI [International Prognostic Index], trying to estimate patient prognosis, but they’re all imprecise clinically. We have patients in our clinic with very high IPI scores who I really worry about, and they get standard chemotherapy and do beautifully and have complete response and it never comes back. But unfortunately, we also see patients who have very little disease and low IPI scores, and the disease surprisingly becomes refractory very quickly. They require multiple lines of therapy, and many unfortunately succumb to the disease.

There’s a huge heterogeneity in the clinical course, and we’re understanding more about the molecular underpinnings of diffuse large B-cell lymphoma. Historically, we describe 2 subtypes of diffuse large B-cell lymphoma: ABC [activated B-cell] and GCB [germinal center B-cell]. The ABC is B receptor driven, and GCB is more epigenetic regulation driven. This is moving more into complex molecular classifications, where we’re recognizing many molecular clusters. Some of those clusters could be subject to specific targeting for targeted agents based on that signaling, which we now understand better and better.

However, this ASH meeting was revolutionary for diffuse large B-cell lymphoma. We’re seeing more changes than we have in the last 20 years. Molecular subtype diagnostic approaches are moving faster, and it makes sense, because most of the approaches we’ll be discussing today are agnostic to cell of origin on molecular subtype because of the targets where they’re present.

The other interesting thing is that those diagnostic approaches are allowing us to capture patients earlier on. One of the big barriers in both GCB and ABC classification using more sophisticated molecular models, or all the clusters that were recently described by various groups, is that it takes time. Because it’s an aggressive lymphoma and we’re trying to initiate therapy right away in those patients, we frequently don’t have time to perform these molecular assays. They can be performed later on, but this makes designing the clinical trials or potential therapies a little more difficult in this setting.

This was an amazing ASH meeting for diffuse large B-cell lymphoma. With all the new treatments, I hope we’ll make a dent in the survival of this lymphoma. Because in the last 20 years, we didn’t see much of a dent. But now with the approval of multiple therapies and moving to second and now frontline setting, we’ll see a change.

Transcript edited for clarity.

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