Tycel Phillips, MD, Associate Professor, University of Michigan, Ann Arbor, Michigan, discusses how the combination of venetoclax, lenalidomide, and rituximab in patients with newly diagnosed mantel cell lymphoma (MCL) induces high response rates and minimal residual disease (MRD) undetectability. The data were presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Transcript

Hi, my name is Dr. Tycel Phillips. I'm an associate professor at the University of Michigan and Ann Arbor, Michigan.

We used the data from the Cornell Group, Dr. Jia Ruan, who led a study with that group looking at R2, which is lenalidomide-rituximab, in patients with newly diagnosed mantle cell lymphoma who were either ineligible or who declined to have an autologous stem cell transplantation.

The initial data from that study was impressive. More so, the long-term follow-up that these patients were remaining in remission was the catalyst that led us to try to see if we could possibly add in a third drug overall to see if we can improve some of the outcomes in this patient population.

When we made the decision, we based it partly on some preclinical data that showed there was some synergy between lenalidomide and venetoclax. That was the reason why we decided to use that as a partner to the R2 combination.

What we wanted to do in this situation, which was a little bit different from what they did in the original Cornell studies, we wanted to open the study up to all patients and not just those who were thought to be ineligible for transplant.

We had a broad inclusion criteria, so we enrolled all patients, irrespective age or fitness, into the study. The goal was to enroll 28 patients. We did consent 30 patients, but two patients, one was withdrawn from the study before they even received any treatment. We had one patient who unfortunately passed away before they started our dose DLT period.

Including those two, we enrolled 28 patients into the study. Within the study, they received rituximab on day 1, 8, 15, and 22 on the first cycle, and then day 1 of even cycles thereafter.

The lenalidomide was started on day 1 at a dose of 20 milligrams. They were dosed days 1 through 21, with 7 days off. With the venetoclax, we started that on day 8, with a dose of 50 milligrams and escalated it weekly.

We went from 50 to 100 to 200 to our planned maximum tolerated dose of 400 milligrams. Because of the escalation portion, we did have a more prolonged DLT period. Our DLT period for the study was 42 days to see if there was any dose-limiting toxicities with the combination.

Our original plan was to give these patients this treatment for up to a year, at which point, at the one-year mark, we would determine if patients were either both in a radiographic beaming by imaging by PET CT and molecular remission, which we used the adaptive next-generation sequencing assay to look for what we consider MRD detectability.

Patients who are in remission, both radiographic and molecularly, will be transitioned to what we consider our maintenance phase. Those patients who did not necessarily have an MRD-undetectable test but were on a radiographic remission would have the option of going into maintenance. Anybody with progressive disease will come off.

Early on, we saw quite a high level of MRD undetectability by the assay, which looked to detect evidence of the cancer up to 10−6 in peripheral blood. Because of that, we did subsequently try to amend the protocol to allow for the transition to maintenance after cycle 6 instead of cycle 12.

With the maintenance phase, what we did was we reduced the dose of lenalidomide by half, and then the plan was to, every year, lose a drug. After the first year, venetoclax would stop. After the second year, lenalidomide would stop. Then, they would have one more year of Rituxan, and then that drug would stop. The patients will be off all treatment no later than four years after starting.

As far as the initial results, we were quite pleasantly surprised that we noticed responses across a broad range of clinical characteristics that we see in mantle cell lymphoma, but we did not find that age, fitness, proliferation rate, as measured by Ki-67, 17p deletion, the extent of disease, or anything that's as far as cytogenetics that early on played a part in clinical response.

The only thing that we noticed is that we did not have durable responses in patients with a known p53 mutation. Within the study, we had five patients with a known p53 mutation. Of those five patients, three patients have already come off studies. Those are the only three progressive diseases that we've noticed in the 28 patients that we enrolled in the study.

Two patients with those mutations still are on treatment. Both of those are MRD-negative and in a radiographic remission, but one of those patients has a p53 mutation of uncertain significance. The other one has a more classical p53 mutation.

As of right now, I would say it's still probably a bit premature to know exactly how we can apply this information into a clinical setting.

Our hope is that we will continue to follow these patients out, and because we plan to expand this study to enroll another cadre of patients, we'll continue to roll over the patients in this initial cohort. We'll be able to get more long-term follow-up.

The hope is that within next three years or so, if these patients are still in remission and they're still molecularly and radiographically in remission, there's absolute growing evidence that we still continue to get long-term good outcomes in this patient population without cytotoxic chemotherapy and also without the use of autologous stem cell transplantation.

That will be what I would hope will come out of this, but again, like I said, I won't know if that's going to be the outcome until we can have more time.

As of right now, the longest patients on study are going into their third year of treatment. We still have at least another 48 months before we, even with the earlier patients, get some sense of what their five-year progression-free survival is.

We've amended this protocol to make some adjustments from what we saw from the initial 28 patients. With the second part, we will plan to enroll another 50 patients, but we will make some adjustments to the induction phase that will shorten the induction for those patients who have obtained a very good response early on.

It'll more so parallel what we see with chemotherapy, whereas the patient will get about six months of treatment, and then they will go into what we consider to be a maintenance phase.

That will help us get a better idea of whether, with these oral agents, we can match it up with what we normally do with cytotoxic chemo and also, whether we can actually stop these drugs.

Most of the studies where we do these non-cytotoxic treatment regimens with some of these oral medications, the treatments are either given indefinitely or they give them together with chemo or some sort of chemo consolidation. We're not doing that.

The hope is that with this next set of patients, the shorter timeframe that we can accomplish a few goals.

A, matching up with chemo, and B, obviously, another purpose of shortening treatment duration is to reduce any toxicities that will come from these medications, because with anything we give, there are always going to be some toxicities that occur.

We also did make one caveat. We are going to exclude patients with p53 mutations from the next cohort of 50 patients. For that patient population, we are opening up the second study that will modify that a bit. We think will be a bit better for this more high-risk patient population. Hopefully, give us better outcomes.

We'll have two basically conjoined studies, one for patients we don't consider to be ultra high-risk, and then one for what we consider to be ultra high-risk patients.

The biggest thing is that hopefully, with more time, we'll have more information to further add to the growing field of evidence that we have with some of these oral medications. It's still at least a couple of years away.