Key opinion leaders provide their perspective on the optimal management of high-risk chronic lymphocytic leukemia with novel therapeutic agents.
Sonali M. Smith, MD: One of the toughest complications or progressions of CLL [chronic lymphocytic leukemia] is if a patient develops Richter syndrome. I’ll turn to Ryan to tell us a little about venetoclax-based regimens for patients who have Richter.
Ryan W. Jacobs, MD: Richter syndrome is a tough situation to manage in a lot of patients. Unfortunately, clinical trial data to guide us aren’t significant. We did have a poster presentation looking at the use of venetoclax in various forms to treat Richter syndrome. It had venetoclax with chemotherapy, venetoclax with BTK [Bruton tyrosine kinase], venetoclax with anti-CD20, and venetoclax monotherapy. Responses were there, but outcomes were poor overall. There were some interesting data to report. Perhaps venetoclax can help us address these difficult-to-treat patients. There’s a lot of interest in looking at venetoclax with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]in the frontline setting or R-EPOCH [rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin hydrochloride].
Sonali M. Smith, MD: Not all Richter syndrome is the same. There’s some heterogeneity, but that’s something to keep our eye on. John, what do you think about venetoclax in high-risk patients defined by deletion 17p? Are there any data there?
John N. Allan, MD: Yeah. As you may be aware, venetoclax had its first approval in relapsed/refractory patients with deletion 17p. This is based on a New England Journal of Medicine paper published many years ago, I believe in 2014 or 2015, demonstrating the activity of monotherapy venetoclax in patients with this high-risk feature deletion 17p. This study has recently reported with up to 6 years of median follow-up for these patients. We now have a good sense of how patients do with high-risk features with long-term follow-up, getting monotherapy venetoclax. At the 6-year mark, this study shows that response rates are high in general. Over 80% or so of patients are responding, but most of those are PRs [partial responses]. About 20% of patients are achieving a CR [complete response]. This is in contrast to the initial report, which was under 10% of these patients.
There seems to be some deepening. Progression-free survival is about 2 years. That’s the expectation seemingly in these high-risk patients: to get progression-free survival of 2 years. But overall survival still looks very good, with a median being met around this 6-year mark. There are patients achieving MRD [minimal residual disease] negativity. Close to a third of patients achieved an MRD-negative state in peripheral blood with monotherapy. These are patients we sometimes don’t see anymore because these were 17p patients who didn’t have BTK inhibitors. In fact, most of these patients were unexposed.
That said, response rates are good. If you did get a complete remission in this study, these patients had remarkable progression-free survivals: 5-plus years. If you do have very sensitive CLL, you’re going to do phenomenally well. That said, even in patients with high-risk disease, the median mileage that we get is almost 2 years. That’s meaningful with a monotherapy approach. This put venetoclax on the map. With this study, we’ve got 6 years of follow-up. These are impressive data, and they’ve greatly informed us of how we use this drug and the expectations set forward, particularly in relapsed high-risk disease.
Sonali M. Smith, MD: What about the noncovalent inhibitors for Richter syndrome? Nicole, what do you think?
Nicole Lamanna, MD: Obviously we’ve had some data presented at this meeting as well, looking at pirtobrutinib in this setting. It’s small numbers. This truly is an unmet need in CLL. All of us always try to bind together and enroll our patients in clinical trials because we need better therapies for this group. This was a study that has about 80 patients with pirtobrutinib in this setting. The overall survival was still short. It was about 13 months, but it’s a young study. The median survival of patients with Richter, when we look at older studies, is anywhere from 6 to 18 months. There were some complete remissions on this study.
It’s also a potential bridging for other therapies. That’s important. When we think about giving R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or R-EPOCH [rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin hydrochloride] to these patients, many of them are heavily pretreated, [so we have to consider the] toxicities of those chemoimmunotherapy strategies. With something like pirtobrutinib, the toxicities are relatively minor, so that’s a very good therapy. Even though it might not be a long-lasting therapy—the response durations might still be inadequate for what we’d like for patients with Richter—many of those patients were bridged. Actually, 6 of them went on to get an allogenic [stem cell] transplant, so they might be good bridging potential for other alternative therapies with much less toxicity using some of the strategies we’ve used previously for patients with Richter.
Transcript edited for clarity.