Expert Expresses Need for More Effective Treatments for Aggressive Lymphomas

Craig Reeder, MD

Treatment for patients with aggressive lymphomas needs to be intensified with more effective strategies, potentially including an infusion, dose-adjusted regimen of etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride, and rituximab (EPOCH-R), according to Craig Reeder, MD.

One highly anticipated phase III study, the results of which Reeder says are likely to be presented at the 2016 ASH Annual Meeting, is a randomized trial exploring rituximab (Rituxan) added to 2 different chemotherapy regimens: the standard R-CHOP therapy and dose-adjusted EPOCH-R in untreated patients with diffuse large B-cell lymphoma (NCT00118209).

The trial’s primary endpoint is event-free survival, while secondary endpoints include response rate, overall survival, and whether gene expression signatures are associated with survival in either treatment arm.

If findings favor EPOCH-R, Reeder says, this could prove to be a new method of administering the drugs for this patient population. Other ongoing studies are also investigating R-CHOP plus agents such as ibrutinib (Imbruvica) and venetoclax (Venclexta) in an effort to improve the efficacy of the standard regimen.

OncLive: What were the key takeaways from your discussion on aggressive lymphomas?

What other agents are being explored here?

During the 2016 OncLive State of the Science Summit on Treatment of Hematologic Malignancies, Reeder, an assistant professor of Medicine at Mayo Clinic, lectured on the unmet treatment need for patients with aggressive lymphomas. In an interview, he discussed the anticipated data on dose-adjusted EPOCH-R, novel agents that could potentially have an impact in this setting, and what he envisions as the future treatment paradigm for these patients.Reeder: I reviewed the aggressive lymphomas, including some of the classifications from the World Health Organization, including the double-hit lymphomas and the double-expresser large cell lymphomas, to try to show that we need better treatment for those subtypes of lymphoma. Hopefully, some of the new drugs that we’re adding to standard therapies, such as R-CHOP and other novel agents, are going to improve the outcomes of those high-risk patients.Drugs such as ibrutinib and venetoclax are being added to R-CHOP. There are monoclonal antibodies, such as obinutuzumab (Gazyva), instead of rituximab with R-CHOP. Those are just some of the things that are being done.

Will R-CHOP be a regimen that will always have a role in these types of lymphomas? Why or why not?

The early studies with ibrutinib and venetoclax show promise and where we are right now is in phase III trials comparing them to standard therapies. However, there are studies done with lenalidomide (Revlimid) plus R-CHOP initially done at Mayo Clinic, and those look very promising—with lenalidomide plus R-CHOP versus R-CHOP alone. The data from these trials will be interesting to see.I think so. All of the drugs have activity in lymphoma and, over the years, people have tried different combinations and have tried to add things without any real benefit. The era we have now where we have these small molecule inhibitor drugs is different than adding on additional chemotherapy drugs.

Can you provide some more detail as to what EPOCH-R is and how it’s different?

One other finding that will hopefully be presented at the 2016 ASH Annual Meeting meeting this year will be of the trial looking at R-CHOP versus dose-adjusted EPOCH-R, which is still mainly chemotherapy but it is given in a very different way—with infusion therapy. Hopefully, that trial will have some information to see if it’s better.R-CHOP, of course, is given as a bolus. All of the drugs are given in 1 day. Prednisone is given for 5 days by mouth, and that is repeated for 3 weeks. That’s kind of been the standard of care for many years.

What are the challenges in this area that should be tackled in the next couple of years?

Dose-adjusted EPOCH-R is given as an infusion of mainly the same drugs, but without the cytoxan, as it’s given as infusion. That’s for 4 days; on the fifth day, there’s a bolus of cytoxan. Rituximab, of course, is given along with that. It’s the infusion of drugs being given over a 24-hour period of time, and we think it may improve results with some of the subtypes of large cell lymphoma.One of the big challenges is the risk of CNS relapse. Certainly, some of the higher-grade B-cell lymphomas, the double-hit lymphomas, and double-expresser lymphomas have a very high risk of CNS relapse. It is very important to provide prophylaxis for these patients. The problem is, we are not sure what is the best prophylaxis.

Why is CNS relapse so common in these patients?

Looking at the future of these lymphomas, what do you envision the treatment paradigm looking like?

Typically, we have given methotrexate, but the data do not really support that being of much benefit. Other things being looked at are these higher-dose intravenous methotrexate or higher-dose cytarabine as a way of prophylaxis to prevent relapse.It’s the biology of the disease. These patients tend to relapse within the first 1 to 2 years from their diagnosis. Some of those patients have CNS involvement at the time of their initial diagnosis.I am hoping we are able to use regimens more like dose-adjusted EPOCH-R, if we see that there is benefit for these high-risk lymphomas, or one of these novel agents like lenalidomide or ibrutinib if they turn out to be much more effective.

What are the main differences between the ABC and GCB subtypes?

What are the main things that community oncologists should know about this field?

We are now able to phenotype the large cell lymphomas into the ABC type versus the GCB type, and hopefully some of these drugs will be beneficial for each of the subtypes. It will be much more tailored to individual patients and individual subtypes. Each year, we know more and more about the different classification, and that helps us pick the right regimen.That has typically been based on gene expression profiling. It’s a very tedious process and is expensive. People have gone on to using immunohistochemistry approach, to using the Hans algorithm, to phenotyping either into GCB (germinal center B-cell type) or non-GCB—what we call activated B-cell or ABC subtype. We know they have different outcomes with R-CHOP chemotherapy; GCB has a better outcome with it than the non-GCB or ABC type.We need to make sure that we recognize the high-grade B-cell lymphomas, so that we don’t miss the double-hit and double-expresser patients who have higher-risk disease just based on their International Prognostic Index score. These patients have worse outcomes, and we need to think about how we can give them more potent and effective treatments than just R-CHOP.