Treating Newly Diagnosed Patients With DLBCL

John Leonard, MD: Hello, and welcome to this OncLive® Peer Exchange® titled “Recent Updates on Management of Diffuse Large B-Cell Lymphoma.” I’m Dr John Leonard. Joining me in this discussion are my colleagues Dr Cyrus Khan, Dr Loretta Nastoupil, Dr Greg Nowakowski, and Dr David Rizzieri. We’re going to discuss a number of topics pertaining to newly diagnosed and relapsed/refractory diffuse large B-cell lymphoma [DLBCL]. We’ll discuss newly available agents, the latest research in the field, including data from the ASCO [American Society of Clinical Oncology] 2021 Annual Meeting and the impact of recent clinical trials on making decisions around treatment selection. Before we get started, I want to highlight the fact that a number of us have provided consulting advice along the way to different companies, and we may touch on some of their agents, so please keep that in mind over the course of today’s discussion. Let’s get to our first topic.

I want to thank everyone for joining me in this discussion. We’re going to start our first segment with systemic therapy for diffuse large B-cell lymphoma at diagnosis and first relapse. DLBCL is the most common lymphoma, accounting for about 30% of patients with lymphoma. It’s a curable lymphoma for the majority of patients, so clearly we want to cure as many patients as possible. Unfortunately, we don’t cure everyone, so we want to improve on that. We want to minimize toxicity and make therapy as acceptable and manageable for our patients. Obviously, we want to prevent patients from relapsing, so they can be cured, hopefully with their first-line therapy, and not have to get more complicated or toxic second-line therapy that often is less effective.

We’ve also had a lot of data over recent years around subsets of patients with large cell lymphoma, biomarkers, cell of origin, and other pretesting at diagnosis, trying to tailor therapy. That’s been with mixed success. In some cases they’re helpful, but in some cases, unfortunately, they’re disappointing. It seems that in some ways, the pendulum has swung back and forth around how we approach this. 

I want to start with you, Greg. You’ve been working in this area—up-front therapy of large cell lymphoma—for some time and contributed, as others and I have, to some of those. I don’t want to say they’re disappointing results, but they’re not as successful as we would like. Let’s say the glass is half-full. Tell us a little about your thoughts and your approach to newly diagnosed patients. R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is clearly the approach for most patients in practice. When do you think about something else as you approach this group of people?

Greg Nowakowski, MD: Thanks, John. It’s been nearly 20 years, and R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is still the standard of care for the majority of patients with diffuse or B-cell lymphoma. As you mentioned, if it’s still a standard, it’s not for the lack of trying to improve on R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. The initial approaches focused on escalation of chemotherapy, as it was suggested: R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride]. Substituting with a more effective antibody like obinutuzumab in the GOYA study unfortunately did not show improvement of those combinations over R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone].

Then we had a wave of approaches, as already mentioned, focused on molecular biomarkers. The ABC [activated B-cell] or non–GCB [germinal center B-cell] subtype vs GCB had been the ones targeted quite extensively for 2 reasons. No. 1, those patients typically have worse outcomes than patients with GCB subtype. More important, we also understand very well the signaling pathway in ABC diffuse or B-cell lymphoma. With many agents able to target those pathways, those were moved in combination with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and XR-CHOP [novel agent with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. We were adding them [novel agents] to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], trying to improve the outcome. 

Unfortunately, this approach has been also largely disappointing. The addition of bortezomib did not show improved outcomes over R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] alone. The same was true about BTK [Bruton tyrosine kinase] inhibition with ibrutinib. In this study, there was some benefit, and additional studies are being built on that.

Finally, lenalidomide had been studied extensively. There were recently 2 published studies, 1 called ROBUST, and 1 called E1412. ROBUST was a large phase 3 study that did not show a benefit of additional lenalidomide, specifically in ABC subtype of diffuse or B-cell lymphoma. E1412, on the other hand, did show improvement in outcome with the addition of lenalidomide to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] in all comers, but this was a smaller, randomized phase 2 study, so it is more of a signal-seeking study and therefore not necessarily changing the standard of care in this area.

Regardless of molecular subtype, a cell of origin, or even double expressor status, standard of care for the majority of patients is R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. The exception to this, in my practice, would be patients with double-hit and triple-hit lymphoma. Although there are no randomized studies showing that other therapies would be more advantageous in this area, there’s convincing evidence from retrospective studies and prospective studies, some analysis, that those patients do quite poorly with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. Typically, we use more escalated chemotherapy in those patients.

Our own practice here at Mayo Clinic, for younger patients, less than 60 years old, would be to use more of a Brocade-like therapy, with and IVAC [ifosfamide, etoposide, cytarabine]. Others use dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride], even in younger patients. In older patients, we tend to use dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride] or R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] only if they cannot tolerate any escalated therapy. As of now, with all the molecular classifiers, this would be the only subset of patients that I would not treat with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] as a standard therapy.

This year at ASCO, we saw some additional attempts to identify patients with specific subtypes that could benefit from different therapy. There was an interesting abstract from the Japanese group that looked at patients with diffuse or B-cell lymphoma overexpressing CD5, so CD5-positive diffuse or B-cell lymphoma. It’s been shown previously that those patients have poor outcomes when treated with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. They are typically ABCs. They have frequent external involvement and high propensity for CNS [central nervous system] relapse.

Therefore, the Japanese group designed a study of dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride], with high intermediate dose methotrexate sandwiched between the cycles of dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride] in this group of patients. In this abstract, they showed that their result in terms of PFS [progression-free survival] and overall survival compared favorably with historical controls. The introduction of this high intermediate dose methotrexate came in the middle of the therapy after full cycles of dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride] but before continuation of remaining cycles resulted in decrease in CNS relapse, which we typically see in those patients.

Having said so, just like with other phase 2 studies, we have to be very cautious in diffuse or B-cell lymphoma. Because those results require additional validation, those patients benefited from escalation of chemotherapy. The other interesting abstract, which we’ve seen at ASCO, goes the other way around a little. Rather than trying to focus on a specific cluster of patients, it’s looking at the more universal targeting: the abstracts from a first-line study. It’s a first-line study building on this idea of adding novel agents to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. We’ve seen it in the past, but now it’s adding novel antibody C19 tafasitamab plus lenalidomide.

We already mentioned that, based on CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], it has been shown to be potentially somewhat effective in E1412. It’s signal seeking, but this study is taking this backbone. It’s adding the antibody C19 and a second arm of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], and C19 antibody only. It’s a relatively small study, about 30 patients per arm, and the idea was to produce the safety signal and understand the potential toxicity of this combination. This work has shown that this combination is quite feasible and is being evaluated in a large, global, randomized phase 3 study. The phase 3 study design is R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] plus tafasitamab and lenalidomide vs R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] alone.

TRANSCRIPT EDITED FOR CLARITY