Venetoclax Plus Lenalidomide/Rituximab Elicits High Response Rates in Newly Diagnosed MCL

The addition of venetoclax (Venclexta) to lenalidomide (Revlimid) and rituximab (Rituxan) resulted in a high response rate and encouraging minimal residual disease (MRD) undetectability in patients with newly diagnosed mantle cell lymphoma (MCL)—even in those with high-risk features, according to Tycel Jovelle Phillips, MD, who added that the regimen was also found to be safe.

Preliminary results from the phase 1 trial (NCT03523975) examining the triplet in previously untreated patients with MCL were presented during the 2021 ASCO Annual Meeting and demonstrated that at 3 months, 67% of 28 patients achieved a complete radiographic response (CR) with treatment, 29% experienced a partial response (PR), and 3% had disease progression. At 6 months, the CR rate was 78% among 27 patients, the PR rate was 19%, and 3% experienced progressive disease. At 9 months, 94% of 16 patients achieved a CR and 7% had a PR. At 12 months, all 12 patients had experienced a CR with the triplet.

At 3 months, 63% of 27 patients achieved MRD negativity. At 6 months, 77% of 25 patients achieved negative status. At 9 months, 94% of 16 patients had MRD negativity, and at 12 months, this rate was 92% among 12 patients.

“Although it is not a randomized study, we would hope that the data that we obtain in the expanded portion of the [the research] would compare very favorably with what has been published with some of the more intensive chemotherapeutic regimens, those including transplant,” Phillips said. “If that is the case, it provides more evidence that if [a patient] can get to an MRD-undetectable state without transplant, then there is no real need to do transplant. [Thus, we] can reduce the risk of secondary complications that come with transplant in this population.” 

In an interview with OncLive®, Phillips, a clinical associate professor, Division of Hematology and Oncology, Department of Internal Medicine at Rogel Cancer Center, Michigan Medicine, discussed the preliminary results with the novel venetoclax triplet in patients with MCL and shared future plans for an expansion of the study which will continue to evaluate the regimen in all patients except for those whose tumor harbor p53 mutations.

OncLive®: What was the rationale to evaluate the addition of venetoclax to lenalidomide and rituximab in patients with newly diagnosed MCL?

Phillips: The study was designed because we had quite a bit of interest in [another] study that was originally [done at Weill] Cornell [Medical College]. That study looked at lenalidomide plus rituximab in a patient population that was deemed to be unfit or not necessarily eligible to receive an autologous stem cell transplantation. Because of that, and because there is more recent long-term follow-up showing that [these patients] were experiencing durable responses, [we wanted] to see what we could potentially combine with that [backbone] to maybe speed up [responses].

They did report some minimal MRD data, but we wanted to see whether we could achieve a high percentage of MRD undetectability. [Additionally,] some preclinical data from a myeloma study showed some synergy between immunomodulatory drugs and venetoclax. [Based on] that [information], and the role of venetoclax in MCL, we decided to utilize that [agent] in our study. The main hope is that by giving venetoclax with another agent, we can maximize its benefit.

What is the design of the study, and what were some of the methods used?

We opened up the study to a very broad enrollment. We wanted to utilize this [regimen] as we would cytotoxic chemotherapy. All the patients who were newly diagnosed were considered to be eligible for the study, irrespective of whether we thought they were transplant eligible or ineligible. We did not exclude for any high-risk features or cytogenetic abnormalities. How we originally designed the study was very similar to that of the Cornell study. The plan was to give a 12-month induction of lenalidomide and rituximab plus venetoclax. We started the venetoclax on day 8 at 50 mg, with the [dose] escalated weekly until it reached a maximum dose of 400 mg. We had a very prolonged dose-limiting toxicity [DLT] period of approximately 42 days because of the escalation.

Thereafter, the plan was to have response assessments every 3 months by radiographs, and [to also perform] MRD testing. The plan was to continue that for 1 year. Because very early on in the study we saw that several patients had MRD undetectable results, and [a] radiographic response within the first 3 to 6 months, we attempted to modify the study. However, the amendment [happened] a lot slower than what we anticipated. [Regardless,] the plan was to modify the protocol so that after 6 months, [if] patients were MRD undetectable and also in a radiographic remission, they could transition over to maintenance therapy.

In [the] maintenance [setting], whether it was after cycle 6, 9, or 12, the dose of lenalidomide [would be reduced] by half, and then venetoclax and rituximab [would be continued]. We planned for the treatment regimen to sequentially stop. [As part of the maintenance treatment,] venetoclax would continue for 1 year only, lenalidomide would continue for 2 years, and then rituximab for 3 years. Every year in maintenance, the patients would stop treatment [with 1 agent] and eventually be off all therapy.

The MRD testing was done in cycles 3, 6, 9, and 12. After the first year, the MRD testing will be done yearly. We [are also performing] PET/CT scans until patients are considered to be PET negative, and then they will transition over to regular CAT scans for radiographic disease assessment.

What were some of the key findings that were presented during the 2021 ASCO Annual Meeting?

We saw a very high overall response rate [ORR]; only 1 of the 28 patients enrolled did not respond. In terms of the durability of response, we did not see any clinical relapses in the patients, except for the few patients who harbored p53 mutations. As I said, we opened up the study to all patients irrespective of risk. As such, we had a fair number of patients that were considered to be high risk by the Mantle Cell Lymphoma International Prognostic Index score. We had patients who had some complex cytogenetics, a fair number of patients with 17p deletion, patients with p53 mutations, [and those with] blastoid and pleomorphic variants. [We also] had several patients with high tumor burden at baseline.

[Of] the 5 patients with p53 mutations, 2 achieved very durable responses [with this approach]. One [of those patients] does have a mutation [for which] we are unsure of the significance, and the others have more traditional p53 mutations. Only 1 of those patients was able to obtain undetectable MRD [status], and that patient remains in remission. [In terms of the] other 3 patients, 1 did not respond [to treatment] at all, 1 had a CR by PET scan but was still MRD positive and relapsed 3 months after the negative PET scan, and 1 had a PR, was not MRD negative, and then subsequently relapsed.

For our study, MRD undetectability was [defined as] 10-6, so it was a little bit different from flow cytometry and quantitative PCR. We did concurrently conduct flow cytometry on all the patients at the University of Michigan, which was 24 of the 28 [enrolled on the study]. Of those 24 patients, we did have some discordance between the flow cytometry and the MRD testing by adaptive assay, but our flow cytometry testing was approximately 10-4, so it was not as sensitive as the adaptive assay.

Of the 23 patients who did not have a p53 mutation, none relapsed. [Most recently,] we have 23 of 28 patients still on study. We did have 2 patients come off [of the study because of] other medical issues, but they were still in remission at the time of coming off study.

As far as the MRD testing, of those who have completed at least all of induction, we have only 1 patient who is still MRD positive. That patient has a very weird test, [in that their] MRD test is neither positive nor negative; it is considered to be equivocal. We do not really know what that means, but that patient is still clinically in remission. All the other patients who have completed at least 1 year of therapy are MRD negative. We have several patients who have already completed their course of venetoclax and are now just on the lenalidomide and rituximab portion of the maintenance. Those patients also remain in remission.

What was the safety profile of this approach?

As far as adverse effects [AEs] go, we did notice a few patients seemed to have a bit more thrombocytopenia than we had anticipated. In a fair number of those patients, we have stopped [treatment with] venetoclax and they are continuing with just lenalidomide and rituximab. Dose reductions and dose modifications were mostly due to AEs, which we attribute to venetoclax. We do believe that the [addition of the] agent accelerated the time to response in our patients and did deepen their responses, but it did add a bit more toxicity.

What are the clinical implications of these data?

We have a good start based on what we have. Obviously, as this study matures and if the data hold, this regimen could be something that could be considered up front. [Moreover, the approach] may still be fairly cost effective in this patient population, given that we don’t plan to continue any of these agents indefinitely; they all have a finite treatment period.

What are the next steps for this research?

The biggest next step for us is just [seeing] more maturation of the data. We are very excited about being able to expand the study and enroll another 50 patients, so we can enhance some of the clinical data that we have.

The other thing is that there is still [an unmet need] for these more high-risk patients, such as those with p53mutations. As such, we are planning a second study utilizing a lenalidomide plus venetoclax backbone, [where we will] add something different besides rituximab to see whether we can make a difference in these p53-mutated patients. Currently, that is the group of patients that has the biggest need and does not have anything [available to them right now] to help them achieve durable responses.

Reference

1. Philips TJ, Danilov AV, Bond DA, et al. The combination of venetoclax, lenalidomide, and rituximab in patients with newly diagnosed mantle cell lymphoma induces high response rates and MRD undetectability. J Clin Oncol. 2021;39(supp 15):7505. doi:10.1200/JCO.2021.39.15_suppl.7505