Front-Line Treatment of DLBCL

Transcript:

Kami Maddocks, MD: Let’s move on to our next topic, the treatment of these patients when they present with newly diagnosed diffuse large B-cell lymphoma. Dr Westin, when a patient presents to your clinic, how are you approaching treatment in the frontline setting? Does everybody get the same treatment? Do some of the factors that Dr Nowakowski talked about play into how you decide to treat a patient? How do you approach these patients?

Jason Westin, MD: Thank you, Dr Maddocks. This is unfortunately not as big of a dilemma as we’d like. We’d love to have multitudes of answers and lots of options for our patients when they come to our clinic with newly diagnosed diffuse large B-cell lymphoma. Unfortunately, at least up until the most recent ASH [American Society of Hematology Annual Meeting], the NCCN [National Comprehensive Cancer Network] guidelines have said to use R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone], and then the discussion is, “How many cycles? And do you use radiation therapy?” That’s despite a multitude of biological discoveries in terms of what drives the underpinnings of the lymphoma, and prognostic systems, including the IPI [International Prognostic Index], NCCN-IPI, the EFS24 [event-free survival at 24 months]. All these are different, beautiful systems that we put together to try to tease out the patients who are going to do well with R-CHOP and those who aren’t. But unfortunately, we haven’t done a great job of figuring out what the alternative would be.

The 50303 trial randomized patients with large cell lymphoma to receive either R-CHOP or dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin], with the hope that patients with more aggressive disease with worse prognostic features would do better with the more intensive chemotherapy. Unfortunately, that large randomized trial showed that dose-adjusted R-EPOCH and R-CHOP were very similar in terms of their outcomes. Perhaps the patients with higher IPI scores might have done better with dose-adjusted R-EPOCH, but the study wasn’t powered to look at subgroups in that particular way.

We do know that there are some groups of patients with diffuse large B-cell lymphoma in whom we could de-escalate their therapy. Patients who have a low IPI score and localized disease, stage I or II, were evaluated in the FLYER trial. It was specifically looking at younger patients. It was evaluating the potential use of 4 cycles of R-CHOP vs 6 cycles of R-CHOP, the default standard. In my practice, with patients who have localized disease and a low IPI score, we’ll sometimes consider them for less chemotherapy, for 6 cycles vs 4 cycles.

Of course, potential use of radiotherapy is sometimes explored when someone has localized disease, perhaps 3 cycles of R-CHOP followed by radiotherapy. But usually that’s starting R-CHOP and seeing how the patient tolerates it. If the patient is doing very well, then there’s no need to change horses in midstream and use radiotherapy, especially with the FLYER data. If the patient isn’t tolerating it well and wants to get out of there and not get any more chemotherapy, then looking for de-escalation strategies, including possible use of radiotherapy, are appropriate. But for the vast majority of our patients, when they hit the door, using R-CHOP for a large cell lymphoma is still king in 2021, despite CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] originally being described by some of my colleagues at [The University of Texas] MD Anderson [Cancer Center] nearly 45 years ago in 1976 in the first paper describing the doses we use today of CHOP.

That being said, this year’s ASH had some really important updates, including the POLARIX trial. The POLARIX trial randomized patients with an IPI score of 2 to 5 to receive either R-CHOP or polatuzumab [Polivy], the antibody-drug conjugate targeting CD79b, along with R-CHP [rituximab, cyclophosphamide, doxorubicin, prednisone], taking out the vincristine. Basically, it’s polatuzumab vs vincristine, along with the other agents in R-CHOP. This trial showed a statistically significant improvement in progression-free survival [PFS] of 2 years of 6.5%. Although everyone wishes that were a much larger improvement, it’s a positive randomized phase 3 trial. Now we get to debate the economics of this. Is the cost-benefit ratio worth it? But at the end of the day, it’s a positive randomized phase 3 trial, and we could take up all our time having a good debate about whether this is practice-changing across the board or if we’ll get into subsets.

Other patients in whom I would consider not using R-CHOP would be the so-called double-hit or high-grade B cell lymphoma with MYC and BCL2 or BCL6 translocations. We saw an update this year at the ASH meeting from the cooperative group study looking at dose-adjusted R-EPOCH with or without venetoclax [Venclexta], presented by Dr [Jeremy] Abramson. This trial found that the addition of venetoclax to dose-adjusted R-EPOCH was prohibitively toxic, with a number of toxic deaths that occurred on study. I wouldn’t try to get too creative off a clinical trial. If you have a patient with double-hit, using dose-adjusted R-EPOCH would be appropriate, but I wouldn’t try to incorporate novel targeted agents into that regimen without safety data.

Lastly, people talk about the question of maintenance. This has been applicable in many other types of lymphoma, including indolent lymphoma, as we often discuss maintenance, although that’s becoming increasingly controversial in the COVID-19 era. But for patients with diffuse large B-cell lymphoma, maintenance hasn’t been a strategy that’s worked well. Many patients have considered this, but their results are often the same, with no survival difference.

The one study that’s of interest for maintenance is the REMARC trial, which evaluated older patients we wouldn’t consider for stem cell transplant if they were to relapse after R-CHOP. It randomized them to receive either placebo or lenalidomide [Revlimid]. Although the lenalidomide dose was somewhat toxic and the majority of patients needed to have either significant dose reductions or cessation, there was a significant improvement in progression-free survival in that patient population. We’ll talk later in the session about the use of CAR [chimeric antigen receptor] T cells, which potentially could be used in patients who are between that age and 60. Therefore, that population might have options. It’s something to think about if you have a patient who wouldn’t be able to get aggressive chemotherapy if they were to relapse.

Kami Maddocks, MD: Thanks, Dr Westin. That was an excellent summary. You brought up a good point about Dr Abramson’s study. It can be tempting to be more aggressive with treatment or combine these novel agents, but that showed that it’s important to know that using these outside a clinical trial—or even the novel agents themselves—can add toxicities. Dr Miklos, do you have the same approach? Are there patients in whom you use something other than R-CHOP in the frontline setting?

David Miklos, MD, PhD: Those who know me know that I’m really the bone marrow transplant and the intensive patient treater. I came to this with the development of CAR Ts and other cellular therapies. I have to admit that I enjoy the interest of the polatuzumab addition upfront, whether or not that’s going to be accepted, having heard so much criticism of the cost of CAR T. I look forward to that vigorous debate. But we’ve been blessed by what Dr [Tom] Frei and his colleagues at [The University of Texas] MD Anderson [Cancer Center] put together over 50 years ago, his combinatorial therapy. There will be improvements, including improvements in patient care that make a big difference, not just the drugs. That’s one of the ASH talks I saw as well.

In upfront therapy, we’ve been blessed by R-CHOP. Maybe polatuzumab will play a role. Maybe we’ll see T-cell engagers come upfront as a more intelligent or effective targeted therapy than Fc binding of a monoclonal antibody. But it will remain a combinatorial chemotherapy–targeted therapy. There’s some excitement about the use of CAR T in high-risk patients, and they’re all excited for the ZUMA-12 study, presented by Sattva S. Neelapu, MD. It’s a very small study of patients who had high-risk features and had shown early indications of poor response at a 2-month, 2-cycle PET [positron emission tomography] CT scan.

There’s a lot of debate in the field about the prognostic value of a 2-month PET scan in large cell lymphoma. Therein lies the weakness of the study, but it was an amazing series of patient results. We saw greater than 70% CR [complete response] rates in these patients who hadn’t had earlier chemotherapy, and we believe that might implicate the benefits of the fresh T cell, the Fit T cell, the T cell not damaged by chemotherapy. I’m sure I’ll get my thunder and lightning in a minute here to talk about the randomized control trials of the CAR Ts and second line, and I hesitate to say this, but there are some data that suggest that first-line might be up for discussion for CAR T in the future.

Kami Maddocks, MD: Dr Nowakowski, you’ve treated lot of large cell lymphoma and have been involved in a number of these other frontline trials. Do you have a different approach in any patient population?

Grzegorz S. Nowakowski, MD: Yes. Citing the clinical trial, we have patients who have double-hit lymphoma defined by translocation of MYC and BCL2 or BCL6. That’s the population that clearly does worse, but it appears that they do better with escalated therapies, like dose-adjusted EPOCH-R, CODOX-M/IVAC [cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine], or [INAUDIBLE]. We don’t have a randomized study that supports this approach, but looking at the results of the phase 2 studies and observational studies, this appears to be the case.

We’ll see in the future how many other attempts there will be to move the bar in this population. This is a population that’s treated differently. There are also patients at a very high risk of CNS [central nervous system] relapse later on, who occasionally may receive methotrexate prophylaxis. At this year’s ASH, the controversy continued regarding how effective this strategy is in preventing CNS relapse. When we debate this, in patients who we may perceive to be high-risk by traditional measures, there are still some sites like testicular or adrenal involvement that are associated with such a high risk that we’ll typically add methotrexate prophylaxis for those patients.

The last point I’d like to make goes back to what Dr Westin said. The POLARIX study is very important. The difference is more or less in progression-free survival, but it has moved the bar. We could have a long discussion for the whole meeting, as Dr Westin pointed out. Is it more benefit in high-risk patients? Is it more driven by ABC [activated B-cell], which we have seen in the subgroup analysis?

The bottom-line is the POLARIX study demonstrated that we can change or improve R-CHOP. For the last 20 years, this has been a debate. R-CHOP cures only about 60% of patients, and there were dozens of randomized studies constantly trying to improve on that. Prior to that, there was only 1 randomized phase 2, which potentially showed some signal benefit, but this was only a signal-seeking phase 2 study. This is a phase 3 study that shows that the idea that you can never improve on R-CHOP might not be warranted, and we have a chance to improve upfront therapy. Would it be more [INAUDIBLE] driven? Would it be using bispecifics, some immune therapies, or maybe even CAR-T consolidation in our extremely high-risk patients? We’ll figure it out. But the first-line therapy can be improved, and I’m sure it will improve in ongoing studies.

Kami Maddocks, MD: The POLARIX data are very exciting. It’s the first time that we’ve seen this. There are people in whom we’re hoping for a bigger PFS benefit or an overall survival benefit. It’s probably too early to see that because of the therapies that we’ll talk about in regard to relapse, but nevertheless, it’s exciting.

Transcript edited for clarity.