Tackling Challenging Patient Populations in DLBCL

Kathryn Kolibaba, MD

There is a misconception that diffuse large B-cell lymphoma (DLBCL) is often a more favorable diagnosis than other types of non-Hodgkin lymphoma, says Kathryn Kolibaba, MD, medical oncology/hematology, Compass Oncology, and co-chair, Hematology Research Committee, US Oncology Research.

“I don’t think everyone in community oncology understands that there are subtypes of diffuse large B-cell lymphoma, and that only a minority of patients have those favorable outcomes you hear about,” says Kolibaba. “Our efforts need to be ongoing to look for the best way to treat patients who are not germinal center B-cell (GCB) or young and healthy.”

Two recent studies that Kolibaba is involved with are assessing patients who typically have less favorable outcomes. The first, which is an ongoing dose-escalation study, is investigating the antibody-drug conjugate polatuzumab vedotin combined with R-CHOP in high-risk patients with previously untreated DLBCL. Thus far, results have been promising.

Kolibaba was also an author on the PYRAMID Trial, which examined R-CHOP with or without bortezomib (Velcade) in previously untreated patients with the non-GCB subtype of DLBCL. The study had negative results, as preliminary data suggested no significant efficacy advantage with the addition of bortezomib to R-CHOP in patients. Despite these results, much can still be learned from the trial, says Kolibaba.

OncLive: What studies in DLBCL are you currently excited about?

In an interview with OncLive, Kolibaba discusses the significance of both trials, and how she hopes the treatment paradigm for DLBCL will evolve in the future.Kolibaba: There are several. Our practice had the opportunity to participate in a phase I trial looking at high-risk patients with DLBCL, adding a novel therapy, and improving on RCHOP—all at the same time.

Polatuzumab vedotin is an antibody-drug conjugate that is being studied in DLBCL because of its wonderful results in indolent lymphoma and in the relapse diseases as a single agent. In previous studies, it has had single-agent activity in diffused indolent lymphoma, and the chief toxicities were peripheral neuropathy and some myelosuppression.

However, the myelosuppression was minimal and had a lot to do with previous lines of therapy that patients had received. Having identified peripheral neuropathy as a chief toxicity, it made sense to us to substitute vincristine sulfate (Oncovin), which we think adds very little to R-CHOP as compared to the other drugs, but does have that toxicity.

What have you found so far?

We replaced vincristine sulfate with polatuzumab vedotin in hopes that it would cause dramatic improvement in efficacy and not change or, perhaps, even improve the toxicity profile of R-CHOP. We initiated a phase I study, which allowed relapsed/refractory patients who had only a single line of therapy or untreated patients with DLBCL who were high risk. It was initially restricted to ages 60 to 80.At the 2015 ASH Annual Meeting, we presented data on 13 patients in the dose-escalation portion of the study, and 10 of the 40 who will be enrolled in the expansion. Polatuzumab vedotin was given on day 2 of the first 2 cycles of the combination therapy, and, after that, it was added in at day 1.

The PYRAMID trial also looked at a high-risk group of patients with DLBCL. Can you discuss what you learned from that trial?

We’ve really had remarkable results to date. Through PET CT scan at the end of treatment, there was a 100% PET complete response rate in patients with DLBCL who were treated at the second level or above. Dose escalation started at 1 mg/m², the second level was 1.4 mg/m², and the top level was 1.8 mg/m². Based on the results, 1.8 mg/m² was selected as the dose going forward into phase II. We are very excited about that.PYRAMID was a very important study where we were attempting to identify treatment that would be better than R-CHOP for the group of activated B-cell like (ABC) patients with DLBCL who we know does not do very well with R-CHOP.

What did you learn from the results?

Where do you hope to see the treatment paradigm of DLBCL going in the next 5 to 10 years?

In this study, the first task was to identify those patients. That had to be very inventive because we knew that many of these patients were ill and needed to be enrolled very quickly. We certified some local pathologists to do immunohistochemistry subtyping so that we could quickly enroll patients to the study. There was an effort between US Oncology Research, and other cancer centers and academic centers, to find these patients and enroll them. The study arm added bortezomib to R-CHOP and the standard R-CHOP arm was given in the usual way without any variance from standard of care.Unfortunately, there was no benefit from the addition of bortezomib to R-CHOP in the ABC-subtype. This was surprising to the investigators because, based on a phase II study, it had looked like there should be a benefit to be derived from the investigation. Despite this, we learned a lot about being able to establish diagnostic criteria across the United States in community hospitals that will allow quick accrual to a challenging study.I hope the paradigm allows us to risk stratify from the start and really match each group with a treatment that has been shown to do well for them. I expect there will be much less R-CHOP, and many other treatments will be applied.