Moving Beyond R-CHOP in Large Cell Lymphoma

Loretta J. Nastoupil, MD

Patients with large cell lymphomas have a standard approach of R-CHOP; however, those who fall under the activated B-cell-like (ABC) subtype are not likely to respond well to the regimen.

Alternative treatments for these patients are being investigated, such as the regimen of rituximab (Rituxan), etoposide phosphate (Etopophos), prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (R-EPOCH). Researchers are anticipating phase III results comparing R-EPOCH with R-CHOP, explains Loretta J. Nastoupil, MD, who shared updates in large cell lymphoma during the 2016 OncLive State of the Science Summit on Treatment of Hematologic Malignancies.

Combination regimens with R-CHOP are also being explored, including 1 with lenalidomide (NCT02285062) and 1 with ibrutinib (Imbruvica), a BTK inhibitor that has shown promise in chronic lymphocytic leukemia (NCT01855750).

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In an interview with OncLive, Nastoupil, an assistant professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, discussed these ongoing clinical trials and how practitioners can better identify high- and poor-risk patients with large cell lymphomas.Nastoupil: In terms of what is exciting or coming out in the next few months to 1 year in untreated large cell lymphomas, there are a number of randomized studies that are looking at building off of the backbone of R-CHOP. They are, essentially, introducing targeted agents or agents that we think might have higher efficacy in the historically considered poor-risk group, which is the ABC or non-germinal center large-cell lymphoma.

Going forward in the next 5 to 10 years in this space, what do you see on the horizon?

Historically, though somewhat controversial, we think that that might be a group that may not do as well with R-CHOP therapy. This is exciting and very promising that we might have alternative therapies that will enhance the efficacy. I briefly touched upon data looking at R-CHOP plus the addition of lenalidomide and R-CHOP with the addition of ibrutinib (Imbruvica). We think we are going to be promising options for patients of the non-germinal center subtype.That’s a great question. We have struggled over the past 10 years to really improve upon R-CHOP. We still consider that to be the standard of care for the majority of patients.

We are doing a little bit better of a job in terms of identifying high-risk patients who we fear will do poorly with R-CHOP. What we have not clearly established is what the preferred alternative is for those patients. In my opinion, I still think those patients should be considered for clinical trials where they may have access to agents where we think hold promise, but we’re still awaiting the randomized study to see if there’s truly a better option than R-CHOP.

We are still struggling with the patients who are chemorefractory in terms of identifying alternative approaches that hold promise, but also will demonstrate improvement in survival. There are more promising options in the non-germinal subtype, based on the molecular profiling that’s been done, which demonstrates that there might be targeted agents that may be effective. What has been slightly disappointing is the duration of response may not be as adequate as we had hoped.

Can you expand on the ongoing studies that you’re excited to see the results of?

What seems to be promising at this time is the CAR (chimeric antigen receptor) T-cell therapy, particularly for those who are chemorefractory, but it does come with associated toxicities. Identifying the proper patient, and providing therapy that we think will be effective in minimizing or doing a better job managing the toxicity, is still the goal.There will be a large randomized study that will be presented at this upcoming ASH Annual Meeting, which is a randomized trial of R-CHOP versus dose-adjusted EPOCH-R, which most recently has been touted as a possibility of overcoming R-CHOP. There will be a lot of interest in terms of whether there are various subgroups that might respond to 1 regimen versus the other. We have all been waiting a long time for the results, so the general consensus is that it’s probably going to be no different than R-CHOP.

That study will be coming out and could impact practice patterns. For instance, at our institution, we have a patient who is higher risk and we worry may not do well with R-CHOP. The default is leaning toward dose-adjusted EPOCH-R. This may shake things up a little bit if it truly is a negative study and shows that it is not a better option for those patients.

There are randomized studies coming out looking at R-CHOP plus drug X. Again, there’s R-CHOP plus lenalidomide versus R-CHOP. There’s R-CHOP plus ibrutinib versus R-CHOP. Those studies are promising and we anticipate that they might be beneficial—particularly for the non-germinal center subtype.

In terms of the relapse setting, we are still moving forward with salvage chemotherapy, high-dose therapy, and autotransplant for those who respond to chemotherapy. However, there is a huge unmet need for patients who are chemorefractory.

How do you identify a patient who is at high risk?

Again, we are exploring targeted agents, but that’s an area of exploration that we’ve not had promising outcomes. CAR T-cell therapy seems to be the most promising at this point. There’s a select patient population that has access to the CAR T-cell studies, and for those who fail that therapy, there are very limited options that hold promise.That’s a great question. There are different ways to identify a patient who you think may do well or do poorly with our standard treatment. There is the International Prognostic Index (IPI) risk calculator that still puts patients into low, intermediate, or high risk. We have struggled for a long time to identify better options for the high-risk population. There are 2 subtypes: germinal center and ABC.

The most effective way to classify those patients is based on gene expression profiling, which is usually reserved for clinical trials. In the clinical setting, we are usually deferring to immunohistochemistry to classify them. Outside of a clinical trial, that doesn’t necessarily help us choose who might do better with something other than R-CHOP.

Right now, we probably have the most promise in identifying poor-risk patients in altering therapy are those who are double hit. They have a translocation in 14;18, so BCL-2 or BCL-6, or they might have Myc translocation or overexpression. Those are the patients we clearly know are not well suited for R-CHOP and should have an alternative therapy.

What do you hope community oncologists will take away from your presentation today?

What should that alternative be? In retrospective studies, we’ve identified dose-adjusted EPOCH-R as our preferred approach to those patients, and there are still unanswered questions as to whether or not they should proceed with consolidation in the form of a transplant or another therapy once they achieve that first remission.That’s a great question. What I hope to confer is that we are still doing many studies to try and build upon or improve upon R-CHOP. As of right now, it is still the standard of care. The patients who we feel are probably not well suited for R-CHOP are the double hits. Oftentimes, these behave very aggressively. Sometimes, the Ki67 might be elevated. We know more often than not that they are of the germinal center subtype. These are patients that we routinely check for the Myc translocation, Bcl-2, and Bcl-6.

In the community setting, that may not be done regularly. Any patients with a high IPI might be one that you want to refer for a clinical trial because, historically, the outcomes have not been as good with the standard therapies.

There’s still unanswered questions about those that we call double expressers, so they may not actually have the translocation but have protein overexpression of both Myc and Bcl-2. Again, for those patients, we don’t know what is the optimal therapy. We think they may not do as well with R-CHOP, but we don’t know what is the preferred therapy.

In my mind, those are the patients who really should be considered for clinical trials. We have a number of studies that are ongoing at our institution and other centers where they may have access to more novel targeted agents. That would be my preferred approach.

How would you describe the future in this space?

Secondly, [we must consider] those who fail chemotherapy. If they are refractory or they have an early relapse, we know—based on prospective data—which of those folks are going to likely do poorly with additional lines of chemotherapy. I would generally consider referral to a center where they can have access to clinical trials or more novel therapy.Right now, it is a very exciting time in diffuse large B-cell lymphoma because we have a number of randomized studies that are either finishing up or still enrolling. In terms of access to novel therapies, it would be a good time to consider referral to a trial because, oftentimes, community physicians believe that frontline large cell lymphoma is not the most appropriate time to refer someone for a clinical trial.

There are a number of options out there that may be better than the standard of care, so worthy of consideration. Again, for those who are refractory or failing salvage therapy, we clearly know that those outcomes are quite poor and those patients absolutely should be referred for consideration of a trial.