Andre Goy, MD, MS: Diffuse large B-cell lymphoma [DLBCL] is an aggressive lymphoma with heterogeneous disease biology. Although much progress has been made since the advent of chemoimmunotherapy, patients with relapsed or refractory DLBCL who are particularly ineligible for transplant or who don’t respond to high-dose therapy and transplant, have limited treatment options and a poor prognosis.

In this OncLive® Peer Exchange discussion, I am joined by a panel of experts in the field of lymphoma. We will discuss the latest advances in the treatment of DLBCL, including novel therapies for disease subtypes.

I am Andre Goy, the chairman and director of the John Theurer Cancer Center, and chief of the division of lymphoma at Hackensack University Medical Center in New Jersey.

Joining me today on my left is Dr Julio Chavez, assistant member of the lymphoma section of the department of malignant hematology at the Moffitt Cancer Center in Tampa, Florida;

Also on my left is Dr Nathan Fowler, associate professor in the department of lymphoma and myeloma division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas;

On my first right, Dr Kami Maddocks, associate professor of medicine in the division of hematology at The Ohio State University in Columbus, Ohio;

Dr Peter Martin, associate professor of medicine and the chief of the lymphoma program at Weill Cornell Medicine in New York, New York;

And finally, Dr Grzegorz Nowakowski, associate professor of medicine and oncology at the Mayo Clinic in Rochester, Minnesota.

Thank you, and let’s begin.

In the field of lymphoma, every year we are very excited to come to ASH [the American Society of Hematology annual meeting], my friends and colleagues, and see what’s new. Every year there are new options for our patients. In the field of large cell lymphoma, I think the way to start is to talk about how we manage newly diagnosed large cell lymphoma. We all are very aware now of the distinction of the ABC [activated B-cell] and GCB [germinal center B-cell] subtypes since 2000. But there has been a lot of progress, and I would like Grzeg to summarize what matters in the subtyping of diffuse large B-cell lymphoma that has an impact on treatment.

Grzegorz S. Nowakowski, MD: Exactly. Diffuse large B-cell lymphoma is clinically heterogeneous. We know that about 60% of the patients are cured with induction frontline therapy. However, about 40% of the patients will relapse relatively quickly after therapy, and the majority of them will unfortunately succumb to the disease. We now understand that those differences in the outcome and presentation are actually due to heterogeneity and molecular makeup of diffuse large B-cell lymphoma. Traditionally, we recognized 2 major subtypes, the activated B-cell subtype and GCB subtype, or germinal center B-cell subtype. GCB was associated with better prognosis than ABC DLBCL. ABC DLBCL has been associated with activation of the B-cell receptor signaling pathway, and worse prognosis. Because of this, there was interest in developing clinical trials targeting the ABC subtype for diffuse large B-cell lymphoma. Unfortunately, most of those attempts failed to show significant improvement in the outcomes of those patients.

There are multiple reasons for that, including some issues with the trial designs and in how those patients were identified. There may be some issues with delaying the entering of patients in the clinical trials. But the bottom line so far is that we’re unable to necessarily improve the outcome of patients with the ABC subtype of diffuse large B-cell lymphoma, unfortunately.

But I think if you look at this, the major underlying reason could also be that those subtypes, GCB and ABC, are not uniform. There are some clusters of subtypes within those. There are a number of technologies that can identify those. Gene expression profiling, now this is improving, and people are now describing super GCBs or of patients having double-hit signature within the GCB subtype. There’s increasing recognition that some of the patients with the ABC subtype are overexpressing MYC and BCL2, which is also an adverse prognostic factor. But more recently, we also discovered that there are different molecular profiles in those patients if you look at DNA.

The driving mutations in GCB and ABC appear to be different. We knew it for a long time. But now if you look at the actual association of those mutations with the outcomes within those subtypes, and how we can cluster the lymphoma, it’s different.

Recently there have been 2 papers published. There’s 1 from Margaret Shipp, MD, by Bjoern Chapuy, MD, PhD, and another…. Both identified these new molecular clusters of large diffuse B-cell lymphoma. So this has been a major development of our understanding of the molecular underpinning of lymphoma.

Moving this to the clinic could be a challenge. It took us 10 years to discover ABC and GCB before we even started doing the trials using this in real time. Those technologies are still not clinically immediately ready. But with the progress in molecular technologies and mutation analysis, we would expect that those new classifications will have a major impact on how we think about diffuse large B-cell lymphoma, and what therapies could change the outcome in those molecular clusters.

Transcript Edited for Clarity