Novel Regimens Explored for Rare DLBCL Subtypes

Sarah Rutherford, MD.

For patients with diffuse large B-cell lymphoma (DLBCL) who have more aggressive disease and are less likely to respond to chemotherapy, it is possible that they may have 2 of the rarer DLBCL subtypes that require different treatments, according to Sarah Rutherford, MD.

The subtypes—double-hit lymphomas and double-protein expressor lymphomas—are in 5% to 10% of all patients with DLBCL. Currently, an ongoing, multicenter phase I clinical trial is exploring a novel regimen of venetoclax (Venclexta) plus dose-adjusted EPOCH-R in patients with these lymphomas who harbor translocations in MYC, BCL-2, or BCL-6 (NCT03036904).

OncLive: Please provide an overview of your presentation on DLBCL.

Rutherford, an assistant professor of medicine, Weill Cornell Medicine/New York-Presbyterian Hospital, discussed these rare DLBCL subtypes, ongoing research to improve outcomes for these patient populations, and the potential role of chimeric antigen receptor (CAR) T-cell therapy during an interview at the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies.Rutherford: I focused on the most aggressive cases of DLBCL, which are called double-hit lymphomas. Then, there is another category called double-protein expressor lymphomas. My focus and research is with these more difficult-to-treat diseases and coming up with novel strategies to try to improve the cure rates.

Can you discuss the features of each of these subtypes and highlight the prevalence of them?

First, I went over the diagnoses and the current treatment strategies. I talked about some of the clinical trials that we have opened and some other exciting treatments that we have planned for the future. As a background, DLBCL is the most common type of non-Hodgkin lymphoma and also the most common type, overall, of lymphoma. It is an aggressive disease that is usually cured in about two-thirds of patients using R-CHOP. For that other one-third of patients who are not cured, there have been strategies over the last 10 years or so to try and figure out what is different about those patients and what can we do to get them cured, as well.

Some chromosome changes that can occur in some of these patients with lymphoma, causing these people to have more aggressive disease, make it not as responsive to chemotherapy. The 2 chromosome changes are called MYC and BCL-2. There is another one called BCL-6 that can also be involved. When 2 of those are rearranged, they are called double-hit lymphomas.

How are these rarer lymphomas currently treated and what novel strategies are being explored?

Then, the other category that is talked about is double-protein expressor lymphomas. Those are the same as MYC and BCL-2, but they are not rearranged; they have an increased expression of them. They are not quite as difficult to cure as the double-hit lymphomas, but they also are more aggressive disease. The standard treatment for DLBCL is R-CHOP. It is given for 6 treatments over about 4.5 months. That is the standard for DLBCL. For these double-hit lymphomas, based on a bunch of retrospective studies, there really isn’t a prospective study that has looked specifically at that patient population. It makes up about 5% to 10% of patients with DLBCL—so fairly small numbers there.

The data suggest that giving more intense treatment rather than R-CHOP is often used, which is dose-adjusted EPOCH-R. It is given usually in the hospital over 5 days and is called an infusional chemotherapy. It is given continuously over that time period. At this point, that is what we use at Weill Cornell Medicine and at many other academic institutions. Many hospitals throughout the country are using that regimen.

We are using it as a backbone to study investigational drugs for clinical trials. Right now, our hospital, along with several other institutions in the country, is running a clinical trial of dose-adjusted EPOCH-R plus venetoclax. This is a BCL-2 inhibitor and is a targeted oral drug, which is FDA approved for a couple of other diseases, such as chronic lymphocytic leukemia. We are combining it with the dose-adjusted EPOCH-R in all patients with DLBCL who meet the criteria in order to find the dose that is best tolerated with this chemotherapy regimen.

CTL019 has shown promise in DLBCL. Could CAR T-cell therapy also be effective in those specific populations?

Subsequently, we are planning to do a clinical trial with Alliance for Clinical Trials in Oncology that we work closely with, for the same combination in the double-hit and double-protein expressor population. We are very excited about that. That is a good question. The standard for DLBCL, at this point, is to treat with 1 of these R-CHOP or similar chemotherapies upfront. If the disease comes back, there is usually a second type of chemotherapy given and a couple different regimens that are standard for that, followed by an autologous stem cell transplant. However, these also have less favorable outcomes.

Therefore, the CAR T cells have come in and have been another option for that same patient population. For the double-hit lymphomas and the double-protein expressor lymphomas, CAR T-cell therapies are particularly promising. There have been recent data showing that autologous transplant in the double-hit population is not as effective as we hoped it was.

When you think of the future of DLBCL, what does it look like?

In the setting where a CAR T-cell therapy option was available—at this point, they are all on clinical trials—that would be an ideal next treatment for someone with double-hit lymphoma. We have had some patients who have been able to go on to that type of trial at Weill Cornell Medicine. Because DLBCL tends to be very responsive to chemotherapy, it is hard to imagine a time when chemotherapy won’t be part of the treatment. However, there are some targeted agents—ibrutinib (Imbruvica) and lenalidomide (Revlimid), to name a few—which have shown promising results in clinical trials. Some have been studied as a single agent and some in combination with chemotherapy. Therefore, certainly in the relapsed/refractory setting, we are going to see more targeted agents.

What do you hope that community oncologists took from your lecture to apply to clinical practice?

It may be that ultimately, there is a combination of targeted agents with chemotherapy as a standard frontline treatment for DLBCL. I hope that this will lead to an increase for two-thirds of a cure rate closer to 100%. It is important that particular tests are sent for all patients that are diagnosed with DLBCL and [we test for] the chromosome changes I mentioned: MYC, BCL-2, BCL-6. There is a cytogenetic study that can be done. It helps us to be able to identify these patients with the double-hit disease, which we would then treat with a more aggressive chemotherapy regimen.

Also, the pathologists do immunohistochemistry staining for MYC, BCL-2, and BCL-6 to help identify double-expressor lymphomas. That second population, the double-expressor lymphomas, are not treated differently. At this point, at most institutions, we should be able to figure out which patients fall in these different categories with the hope that we will be able to target better and improve the outcomes of these patients with more aggressive therapies in the future.