Venetoclax Plus Dose-Adjusted R-EPOCH Shows Promise for Richter’s Syndrome

A multicenter phase 2 study of patients with chronic lymphocytic leukemia (CLL) who developed Richter’s syndrome, presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, evaluated the use of venetoclax plus dose-adjusted R-EPOCH.

As of the February 3, 2020 data cutoff, the study suggested that the treatment may be effective in this patient population.

In an interview with CancerNetwork®, Matthew Steven Davids, MD, MMSc, an attending physician in the Lymphoma Program of the Division of Hematologic Malignancies and associate director of the CLL Center at the Dana-Farber Cancer Institute, spoke about the phase 2 study and what the results could mean for this treatment combination moving forward.

CancerNetwork®: First off, can you explain the study design of the phase 2 study of venetoclax plus dose adjusted R-EPOCH and the results presented at ASCO?

Davids: So, in this phase 2 study we decided to test the hypothesis that we could use the BCL-2 inhibitor venetoclax as a chemosensitization strategy to help R-EPOCH chemotherapy work better for patients with Richter's syndrome, which traditionally is a very refractory population. So, the study design involves starting with a cycle of R-EPOCH. This was done to establish disease control quickly. When patients had their counts recover, we then admitted them to the hospital for a rapid venetoclax ramp up; and this was done because the traditional ramp up for CLL patients takes 5 weeks. But we know that with patients who have Richter's syndrome, they can have a very aggressive disease. So instead of doing the traditional 5-week ramp up, we actually did a 5-day ramp up, where each day the patients would go up to the higher dose of venetoclax, starting at the usual 20 milligrams and eventually getting to 400 milligrams. And as long as they didn't have any tumor lysis syndrome, then we would be able to proceed with the dosing. And so, we were able to do that actually successfully for all 21 patients who went through this combination with rapid ramp up and no evidence of tumor lysis syndrome. Once they got through that ramp up, then we kept them in the hospital and gave them a second cycle of R-EPOCH and continued the venetoclax for days 1 through 10 of that cycle. And patients could then go on to get up to 6 cycles in total of therapy with venetoclax and R-EPOCH.

So, in terms of the results so far, we've seen really excellent efficacy from this regimen. For the evaluable patients who received the combination, about two thirds have achieved complete remission. And when we compare that back to the historical results that we would get with R-EPOCH alone, that's only about a 20% rate. So, it does seem like there's some distinction there and a pretty compelling rate of complete remission. All the patients who had bone marrows checked also had undetectable MRD for CLL. So, it does seem to be very effective in controlling the CLL. And many of these were very high-risk patients who needed to move along to [allogeneic] transplant to have a hope of a long-term survival, and about half of the patients who were candidates to move on to [allogeneic] transplant were able to do that, which again is higher than we might expect from the chemotherapy alone. So, whereas historically, you know, this is a very high-risk group where we see median overall survival in the range of only 3 to 6 months, so far in our study, we've seen a median overall survival of 16.3 months.

So, this is not a controlled study. It's a single arm study, but we certainly think these look like promising results compared to the historical results we'd expect from chemo alone. We certainly did see some toxicity with this regimen, in particular cytopenia, neutropenia, and thrombocytopenia. And we saw some significant infectious complications as well, including sepsis, as well as febrile neutropenia So moving forward, in terms of the next steps for this study, we've decided to open an expansion cohort. And in this cohort, we're going to change the chemotherapy backbone and use R-CHOP instead of R-EPOCH. We're hoping that the R-CHOP will be less myelo-suppressive and lead to fewer infections. But we're continuing the venetoclax with the same schedule, thereby hopefully preserving this chemosensitization strategy. And so, we're very eager to explore this new regimen to see if we can build on the results of this initial study.

So, given these initial findings, what would you say are the overall implications of the study?

So, I think right now we don't have a standard of care for Richter's patients; we typically do start by using chemotherapy. And although our study is a small one, it is a multicenter study, we were able to replicate the results at 3 different centers. And so, I think it's reasonable to discuss the possibility of adding venetoclax to chemotherapy, such as R-EPOCH for patients with Richter's based on our results. I think as we get more patients treated that will become easier to justify in terms of the level of evidence.

This is something that we hope the [National Comprehensive Cancer Network; NCCN] actually will consider as a listing within the guidelines, because remember that Richter’s is a very rare disease. So, this is not one where I expect to see larger randomized trials, certainly not phase 3 trials. And so, this may end up being the level of evidence that we have to justify a new approach to treating Richter’s patients.

So, for patients who may not fully understand the study results, how would you explain the main highlights of the study?

Yeah, so for patients I would say that, you know, we know that using standard treatment approaches for Richter's syndrome unfortunately is not very helpful. And so, I would encourage patients whenever possible to seek out the possibility of a clinical trial. Because this is just one of many different promising new approaches looking at treatment of Richter's syndrome. For example, there's immune-based strategies like checkpoint blockade, particularly in combination with ibrutinib (Imbruvica) I think looks interesting, and other novel targets. But you know, if patients don't have access to clinical trials, then I think talking to their oncologist about the data from studies like ours where, you know, we're using an FDA approved drug for CLL, venetoclax. So, in terms of the logistics of getting the drug it should be fairly straightforward and combining it with the chemotherapy we think could be the right response and the right choice for many patients. But again, they would need to discuss that with their individual oncologist.

Are there any notable adverse events that are associated with the venetoclax combination?

So, you know, in terms of venetoclax itself, obviously the tumor lysis syndrome is something we were looking closely for, and we did not see it so that was good. We know that venetoclax on its own can cause neutropenia, and certainly that's the case with aggressive chemotherapy regimens like R-EPOCH. So, I would say we did see a bit higher rate of neutropenia and febrile neutropenia than we might expect from either drug, you know, either regimen on its own. So, I think there is some enhancement of toxicity there, as well as thrombocytopenia. So, you know, I think that as patients particularly got into the later cycles, sometimes they weren't able to get completely through the full 6 cycles. Sometimes we had to do some dose reductions. So that does speak to the aggressive nature of this regimen, particularly for CLL patients who tend to be older. Although I would say that particularly the younger patients on the trial did tolerate the chemotherapy backbone better.

Are you all planning on exploring this combination in any other cancer type?

So, in terms of the potential for this combination in other cancer types, I think that's a great question, because this is a concept, chemosensitization, that certainly could apply across different cancers. And we saw last year the publication of the CAVALLI study, which combined venetoclax with R-CHOP or G-CHOP (GA101), also known as obinutuzumab, and that also looked like a promising approach for patients with diffuse large B-cell lymphoma and follicular lymphoma. And there's other studies that are starting to look at this in other lymphoid malignancies as well, including also other myeloid cancers. And so, I think in the blood cancer domain, this is definitely a promising approach. There's no reason why this type of approach couldn't work in solid tumors either in terms of chemosensitization, although it may not be as straightforward as targeting BCL-2; we may actually need some of the other molecules in the growing toolkit of BH3-mimetic drugs that target other anti-apoptotic proteins because the dependence of different solid tumors may be very different and more heterogeneous than it is in hematologic malignancies.

Reference:

Davids MS, Rogers KA, Tyekucheva S, et al. A multicenter phase II study of venetoclax plus dose-adjusted R-EPOCH (VR-EPOCH) for Richter’s syndrome. Presented at: 2020 ASCO Virtual Scientific Program. Abstract #: 8004.