Newer Agents for DLBCL Show Potential for Earlier Use in the Course of Treatment

Jason Westin, MD

The most common frontline treatment for diffuse large B cell lymphoma (DLBCL) is cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone (CHOP). However, approximately 1 in 3 patients relapse after CHOP, and alternative therapies are still needed.

According to Jason Westin, MD, the leader of the DLBCL research team at the University of Texas MD Anderson Cancer Center, the strategies for DLBCL treatment have not changed drastically since the mid 1970’s. Additionally, more information is needed as to why patients relapse after CHOP.

For patients who are CHOP resistant, the standard of care is strong chemotherapy followed by an autologous stem cell transplant. However, according to Westin, more personalized and targeted therapies are needed.

In an interview with Targeted Oncology^TM, Westin discussed the future of DLBCL treatment in both the frontline and later-line settings, along with current unmet clinical needs.

TARGETED ONCOLOGY: Can you give a background on current treatments in DLBCL?

WESTIN: DLBCL is the most common lymphoid cancer in adults, it's diagnosed in about 30,000 people each year in the US. And the treatments of that most common lymphoid cancer have been effectively stuck in the 1970s and the 1990s. We use a combination chemotherapy approach called CHOP, which was originally prescribed in 1976. We've changed a lot in life from 1976 to now, but we're still using this old combination chemotherapy in the curative setting for lymphoma. So obviously, new approaches are needed.

What does the current DLBCL treatment landscape?

Most patients are treated with the combination chemotherapy CHOP, and that cures approximately 2/3 of patients. It's a fairly effective standard therapy. However, at least 1 out of 3 people need additional treatments, and we don't do as well in the relapse setting as we'd like. So, we're constantly trying to innovate and improve that frontline setting and get beyond the 2/3 cure rate with initial treatments, and that will take a better understanding of why those 1/3 don't respond to CHOP, and a better understanding of the biology of what makes them resistant to treatments.

Do we know anything right now about the mechanisms of resistance to CHOP?

We know some, but I argue that we don't nearly know as much as we think we do. We understand the biology in the sense of understanding which mutation is present, or what type of gene signature. But often, the actual reason as to why a given patient doesn't respond to CHOP is very poorly understood. Patients that have the same biopsy, same genetic signature, some of those patients are cured and some of those patients are resistant. And it's difficult to predict prior to therapy which of those patients are resistant.

For patients that are resistant to CHOP, what options exist for them?

The standard of care for the past 20 years for those resistant to CHOP has been strong chemotherapy followed by an autologous stem cell transplant. Beyond the second line setting right now, there are a number of FDA approved agents for patients with relapsed BLBCL, and many of those FDA approved agents are being studied in combination CHOP and rituximab [Rituxan; R-CHOP].

What clinical needs are still unmet in this patient population?

The needs that are still unmet are finding more personalized therapies, specifically for those patients who are not cured with R-CHOP. But I would argue even in those patients who are currently cured with R-CHOP, that we don't want to use 1970s, chemotherapy in 2050. We want to be able to have personalized approaches and be able to move beyond effectively sledgehammer kind of blunt force instruments and use more precision medicine. So, we clearly need to do better urgently for the folks who are currently resistant or not responsive to chemotherapy. But I'd argue in the long run we need to do better across the board.

Do you see more aggressive approaches like autologous stem cell transplant and targeted therapies moving to the frontline setting in the future? Or do you think they'll remain a second- and third-line option?

I think that CAR T cells have the potential to move to the frontline for a subset of patients, for those that are not going to be responsive to our standard treatments. I think that's an approach that has merit, to try and use a powerful weapon at an earlier time point. I don't think stem cell transplant will do that. But I do think some of the other targeted therapies, the antibody drug conjugates, the bispecific antibodies, antibodies in combination with other immune therapies do potentially have a role to play in the frontline setting.

Where do you see the DLBCL space going in the next 5 to 10 years?

Well, I'd love to say things will be dramatically different. But we could have said that at any point over the last 20 years and would have been wrong. There are multiple ongoing studies looking at ways to improve the frontline setting. But innovation is more likely in the relapse space, which then filters up to the frontline space. And I think that the CAR T-cell studies showing potential advantages in the second line will change the landscape for patients who have relapsed after R-CHOP in the next 5 to 10 years to favor using CAR T-cell therapy. I think based on having that better cure fraction in the relapse space, more innovation may be possible in the frontline space. And so therefore doing studies that are not handcuffed to the 1970s chemotherapy for fear of not giving a patient the old curative therapy and missing a potential window for cure, I think that will allow us to do more innovative studies. I've done a handful of clinical trials using targeted therapy combinations prior to chemotherapy. And what we've shown in those studies is the response rates are very high. And patients tolerate it very well. And so that's still on a clinical trial stage. But it does show the potential that these targeted treatments can work better in newly diagnosed patients and potentially forego the need for chemotherapy.

I think the R-CHOP plus combination trial designs a failure. And I think that more innovative trial designs are needed. But clinical research still remains the best weapon we have to fight cancer in general and specifically DLBCL.