Efficacy and Safety of Venetoclax, Lenalidomide, and Rituximab for Newly-Diagnosed MCL

Tycel Jovelle Phillips, MD, a clinical associate professor of hematology, medical oncology, and internal medicine, at University of Michigan Health, discusses the safety and efficacy of venetoclax (Venclexta), lenalidomide (Revlimid), and rituximab (Rituxan) in patients with newly diagnosed mantle cell lymphoma (MCL).

According to Phillips, of the 5 patients with MCL harboring a p53 mutation, 2 had durable remissions. However, in the overall population, of the patients who completed induction therapy, only 1 patient remains micro residual disease (MRD) positive. Of the 28 patients included in the study, 23 remain on the study combination. Of the 5 that came off treatment, 2 came off for other medical reasons but were still in remission.

The safety profile of the triplet regimen was tolerable; however, rates of thrombocytopenia were higher than expected. Based on adverse events (AEs) it seems that most of the toxicity can be attributed to venetoclax. However, patients are not expected to stay on study drugs indefinitely after the treatment course ends. 

0:08 | I think some of the key things we found is that we did have a very high overall response rate. We only had 1 of the 28 patients who really did not respond. As far as the durability of response, what we saw is we did not have any clinical relapses in the patients except for the few patients we had who had P53 mutations. So, as I said, we opened up the study to all patients irrespective of risk. So, we had a fair number of patients considered to be high risk. We had patients who had some complex cytogenetics. We had a fair number of patients who had 17P deletion as well as patients with p53 mutations. And we did also have blast holding pleomorphic variant. And we had several patients with high tumor burden at study started.

0:55 | So, what we saw, again, of the 5 patients we had with P53 mutations, we have basically 2 out of those 5 have very durable responses. One does have a mutation, that we are unsure the significance. Of the 4 who have more traditional p53 mutations, only 1 of those patients were able to obtain an MRD undetectable test, and that patient still remains in remission. The other 3 patients, 1 did not respond at all. One had a complete remission by PET but was still MRD positive and relapse 3 months after the negative PET scan. One had a partial response. Again, it was not MRD negative, and then subsequent did relapse. And for our study MRD undetectable negative was considered to be if you were 10-6. So, it's a little bit different for flow cytometry and quantitative PCR. We do concurrently conduct flow cytometry on all the patients at the University of Michigan, so that was 24 to 28. Of those 24 patients, we did have some discordance between the flow and the MRD testing by adaptive, but our flow testing was probably 10-4, who was not as sensitive as what it was for the adaptive assay. So again, from that, like I said, of the 23 patients who did not have a p53 mutation, again, we had none of those patients’ relapse. As of currently, we have 23 of 28 patients still on study. We did have 2 patients that did come off for other medical issues. But they were still in remission from the mantle cell lymphoma at the time of coming off study.

2:30 | I think as far as the MRD testing, as of right now, of those who've completed at least all of induction, we have only 1 patient who is still MRD positive, and that patient has a very weird test. His MRD test isn't really positive or negative, it's considered to be equivocal. So, we don't really know what that means. But that patient is still clinically in remission. All the other patients who have completed at least a year therapy are all MRD negative. We have several patients now who have already completed their course of venetoclax and are just on R2 portion of the maintenance. And those patients also remain in remission.

3:07 | So, I think as far as response assessment, as I said, I think moving forward, as I mentioned before, we do have plans to expand the study. We will focus more so on those patients who are p53 negative as far as the mutation to enroll into the trail. As far as adverse events and side effects, we did notice in a few patients that they seem to have a bit more thrombocytopenia than we anticipated, not necessarily sure of etiology of that. And a fair number those patients, which is about 4 patients, we have stopped the venetoclax in those patients and they just continue on the R2. As far as dose reductions and dose modifications, most of that based on due to AEs, we attribute to the venetoclax which is a good and a bad. We do think venetoclax accelerated the time to response in our patients and did deepen the response, but it did add a little bit more toxicity to the patients. I do feel like we have a good start based on what we have, obviously, as this study matures and if the data holds that this regimen could be something that begins considered upfront and still be fairly cost effective in this patient population. And given we don't plan to continue to use these medications indefinitely and they will have a finite treatment period.