A major unmet need for mantle cell lymphoma is how we manage these higher-risk patients when they present to us in that fashion. What does it mean for a mantle cell patient walking in my door with proliferative 

-mutated mantle cell lymphoma? We know that, based on the data from the European mantle cell group, high-dose chemotherapy and transplants are not really likely to provide much benefit for that group of patients. Lenalidomide and rituximab may have some activity just by virtue of being a little more 

 independent. But when they’re very proliferative, it’s very hard to get a patient through that 2- or 3-month course that’s needed to realize that benefit.

We still have this population of mantle cell lymphoma that’s begging for something. We tried ibrutinib. At least in relapsed cases, we know single-agent ibrutinib is not very effective in managing this group of patients. We know that Rituxan adds a little, but most, if not all, patients progress by 6 months.

We have an ibrutinib-venetoclax trial and a ibrutinib-Rituxan-venetoclax trial that are ongoing in newly diagnosed mantle cell lymphoma patients, and it will be very intriguing to see whether there is a benefit for those who have 

 mutation, particularly if they have proliferative disease with that 

 mutation. If we can find a benefit there, that may help address this very significant unmet medical need. My own anecdotal observations are that it’s unlikely that a BTK is going to be effective in the frontline setting, even in combination with venetoclax, for these very high-risk patients. What this says is, what do we do with the ibrutinib? Even if we bring it front line, if we can get a transient response, are we now in a position where we say the next step is CAR [chimeric antigen receptor] T-cell consolidation based on some of these data that were presented as part of the ZUMA-2 trial, and hopefully as a step forward from what I hope will be FDA approval.

That’s a big question. Alternatively, you could say it’s allogeneic stem cell transplant. We don’t have a lot of data for allogeneic stem cell transplant in large part because allogeneic transplant for lymphoma is not something routinely embraced by the Medicare guidelines. The median age of mantle cell is 68 [years old]. Most of our patients will be on Medicare, so it makes it very hard to really ask and answer questions about the impact of allogeneic transplant in this particular population, let alone the safety of doing reduced-intensity transplants and the like for this group of people.

A major unmet medical need for mantle cell lymphoma remains what to do for those who present with very high-risk disease up front. A second major unmet medical need is what to do for those patients who relapse after CAR T. It’s not just diffuse large B cell now. We’re talking about bringing a CAR T-cell therapy for patients with mantle cell lymphoma. I’m absolutely excited by the 60% event-free survival at 2 years. That is phenomenal. But that still means that 40% are progressing. We need to understand what to do for those individuals. Is it going to be coming in with an alternative form of immune therapy, like an allogeneic CAR T-cell therapy or a lenalidomide or something along those lines? Are we going to see something like we see with the PD-1s, where you treat with a high-potency immune therapy and, for reasons that are less clear, you sensitize them to subsequent chemotherapy after the fact? These are all unanswered questions. But this is the other major unmet medical need in mantle cell lymphoma.

Videos

Future Directions in Mantle Cell Lymphoma

At this year’s virtual ASCO [American Society of Clinical Oncology Annual Meeting] 2020, Michael Wang and his colleagues presented an update of the ZUMA-2 data, focusing a little more on the PK [pharmacokinetics] data and really wanted to understand whether there were changes in the T-cell subsets or cytokines according to whether patients had more aggressive disease or less aggressive disease. They defined it by high proliferative rate, meaning a Ki-67 over 50% in this data set, or the presence of 

 mutation. Interestingly, they didn’t have 

 mutation for all the patients. It was mutated in 6 and nonmutated in 30, and we don’t really have the data for the others who were enrolled. Why do I mention that? You know, it’s very likely that those who have elevated Ki-67, particularly over 50%, also had a 

 mutation, so there may be some overlap in these subgroups. Because we didn’t have 

 mutation data on a lot of those with proliferative disease, it’s likely we missed it in a high number.

It is interesting to see that there were some changes in terms of the percentages of effector or effector memory or naïve T-cells. What that means in the grand scheme of things is a little harder to understand in this data set. One of the things I really liked is their focus on clinical response. Here they focused on MRD [minimal residual disease] down to 1 in 100,000 cells. They had to ask whether there were some cytokines that were more likely associated with a deeper response. There were only 5 in the MRD-negative population analyzed here—a testament to how well this works—but it also makes it hard to ask some of these questions.

They could show that having a higher interleukin-2 [IL-2], interleukin-6 [IL-6], and interferon gamma may be associated with a higher likelihood of being MRD negative. We think of interleukin-6 and interleukin-2 as just being more broadly associated with T-cell proliferation. Whether it’s the CAR T cells or native T cells—as Scott Rodig’s group from Harvard has been focusing on in the context of diffuse large B cell lymphoma plus CAR—is a little harder to tease out. This may be very important when we talk about those with 

 mutation who may have a lot of novel or neoantigens that they’re expressing in the context of MHC [major histocompatibility complex].

In any case, I was really glad they did this. It would be very interesting to see how this concept of looking at the cytokines as a marker for MRD positivity or negativity, given its overwhelming sensitivity for detecting residual disease, can help us better understand or predict who’s going to do well or not do well over time.

In this update they also looked at these cytokine signatures to see if they can predict for more severe neurotoxicity. In this paper, they separated into those who had no neurotoxicity, and there were about 25 folks from those who had very severe (grade 4) neurotoxicity, among which there were 6. It shouldn’t surprise folks that those who have severe neurotoxicity are likely to have higher cytokines just as a general observation. But they could show this most clearly for interferon gamma, tumor necrosis factor alpha, MCP1, soluble VCAM1, IL-2, and IL-6.

Of all these, the one that gets my attention the most, of course, is interleukin-6. We know that treating with tocilizumab for severe neurotoxicity doesn’t come with a lot of benefit. In fact, we focus on the management of those patients with steroids. But it may be relevant because this secondary elevation of IL-6 occurs as a consequence of tocilizumab. We have seen in some studies that there’s this correlation between having severe CRS [cytokine release syndrome] and having severe neurotoxicity, and it may be that in trying to treat that severe CRS with tocilizumab, we drove an interleukin-6 elevation, but that could potentially culminate in some neurotoxicity. I don’t want to make this sound definitive. This is pure speculation in this trial.

ASCO 2020: ZUMA-2 Update

When we talk about the response rate in those who’ve received BTK [Bruton tyrosine kinase] inhibitors, it’s important to know that that’s part of the eligibility for the trial. All the patients really should have come on having received a BTK and either been proven intolerant or relapsed or refractory after BTK. The overwhelming majority were relapsed or refractory, but a few who came were intolerant.

In the data that are now published in the 

, 1 of the things we can see from the subgroup analyses is the response according to ibrutinib intolerance, according to being relapsed/refractory to ibrutinib. There was a third cohort that I was a little surprised by, which is [those] not previously exposed to BTK, meaning they had some contraindication to receiving the BTK inhibitor. I don’t know much about this particular subset. The patients we enrolled had seen a prior BTK before they went on.

When we look at that particular subgroup, it is true that when you look at the confidence interval, it’s very wide, and it raises the question: Could this be a group that doesn’t benefit as much from CAR [chimeric antigen receptor] T-cell therapy? The answer is we have no idea. There were so few patients who fell into this category. One additional patient who does well and responds well would shift it way back to the right in favor of CAR T-cell therapy. I’m not really sure I can say much about how important prior BTK is to the response of CAR T.

Taking a step back, in what lymphoma and what setting do we need to argue that the response of immunotherapy is somehow dependent on prior exposure to a prior drug. Remember, when we talk about the process for CAR T, patients have to stop the ibrutinib to undergo the leukapheresis, which is where we collect those T cells for manufacturing. Then they can resume the BTK briefly during that period of manufacturing. But it’s only about 2 weeks; it’s not very long. Then they have to stop it again before starting the fludarabine and cyclophosphamide lymphodepleting chemotherapy. It’s really hard for me to believe that ibrutinib, going back roughly a month before the CAR T-cell infusion, is somehow impacting what the CAR T cells are doing.

One very interesting question that remains is, could the ibrutinib exposure prior to the leukapheresis have somehow biased the T cells in 1 way, shape, form, or another, making for a more active product? It’s a great question, and I’m not sure I can answer that. People have speculated that while ibrutinib does inhibit ITK as well as BTK, paradoxically it may strengthen TCR [T-cell receptor] signaling in those T cells, allowing for more selective binding and a better response once you have that more selective binding. I don’t think we really know or understand.

When we talk about CAR T cells, CAR T cells aren’t really acting through their TCR, right? They’re acting through the CAR. We can speculate that maybe there’s a second wave of T cells that are driven to proliferate and driven to activation following that initial CAR T-cell–mediated killing of the lymphoma. These are data that have come out of the Harvard group, Scott Rodig’s group. Others have shown that after Yescarta specifically, by day 10 they could see that the lymph nodes were actually occupied by a very high proportion of non–CAR-T transfected T cells. This would be like saying, “Oh, the CAR T is…somehow driving native T cells to see and kill mantle cell lymphoma,” and now the TCR may be more important. These are more likely to be T cells that come with the product, meaning nontransfected T cells, since we’re giving that lymphodepletion before the CAR T. And we’re talking about doing these biopsies around day 10. I say more likely, but I don’t think we know.

With all this background, it’s a simple way of saying, “Is it possible that ibrutinib somehow drives a better therapeutic response or prior ibrutinib drives a better therapeutic response?” The answer is maybe, but it’s really going to be hard to tease that out. Ultimately, until we do trials that very specifically test that, this is where we’re going to have to leave it.

Bruton Tyrosine Kinase Inhibitors

 In regard to the ZUMA-2 trial, there are a lot of things that are really important to know. One is that this trial really took on a very high-risk group of patients. The eligibility required that patients be either BTK [Bruton tyrosine kinase] intolerant or refractory. That means there are patients who came on the trial who didn’t respond at all to the BTK, and there are some who came on and relapsed within a short time or potentially a long time being on the BTK. But as others have heard me talk about in the past, when we see that BTK-relapse or BTK-refractory patient, they’re usually very proliferative, aggressive, and difficult to rescue. That was also seen on this trial when we look at the Ki-67, which was greater than 50% in a large percentage of these patients. We were all seeing 

 mutations in a high proportion of patients who were enrolled on this trial.

This is typical of this population, and it also captures all the things that we hate most about mantle cell lymphoma. These are all the same things that make treatment with any drug, whether it is Revlimid, Velcade, you name it. You combine that 

-mutation status with a highly proliferative disease, and we struggle. We really struggle.

The fact that Gilead [Sciences] chose to invest in this space was a very meaningful step forward, not just because they were willing to do it but because it worked. They treated this subgroup of patients with a cell dose of 2 x 106 cells/kg, and with this dose, they were able to show a 93% overall response rate. The majority—about two-thirds—were complete remissions. This is hitting it out of the park as far as I’m concerned. This is a space where we’re lucky to see anything, let alone complete remissions.

Adding to the response rates, we also have the published durability of response. When we look at it at 1 year, and even as far out as 2 years, the curve seems to be plateauing around 60%. That means we’re not only getting a high efficacy, but we’re seeing that these responses are durable over time. I’ve not seen anything like this in this population of mantle cell lymphoma, so I’m very encouraged by the data.

A Look at ZUMA-2 Trial

Hi, I’m Dr Bijal Shah from the Moffitt Cancer Center in Tampa, Florida. I’m an associate professor in the Department of Malignant Hematology, where I focus on the treatment of mantle cell lymphoma.

The prognosis for patients with relapsed/refractory mantle cell lymphoma is still somewhat of a challenge, especially when we talk about advanced relapses, where we’re saying that they’ve relapsed after 2, 3, 4, 5 lines of therapy. A nice review by Anita Kumar and her colleagues at Memorial Sloan Kettering [Cancer Center] was performed, and they show what we’ve all experienced in practice, which is this notion of diminishing returns with each subsequent line of therapy. If we get about 5 years from the first line, we’re going to get 2½ years from the next line, 1 year from the next line, 6 months, and so on. Essentially, when we say specifically, “Let’s fast-forward to the third-line-and-beyond setting,” we’re talking about a median PFS [progression-free survival] of somewhere around 3 to 6 months, again diminishing with each line. When we talk about survival, it’s also dropping off dramatically. We’re talking about a median overall survival once we get into that third-line setting of around 2 years. When we talk about fourth line, it’s more along the lines of about a year and so on. We really are running into considerable difficulties when we talk about the treatment of multiple relapsed and refractory mantle cell [lymphoma].

Kite Pharma–Gilead Sciences submitted to the FDA a request for CAR [chimeric antigen receptor] T-cell therapy approval in mantle cell lymphoma. There are a couple of things to know about this particular CAR T. It’s made a little differently. It’s not called Yescarta, the product that’s currently approved for diffuse large B-cell [lymphoma]. This 1 is currently going by the name KTE-X19. I’m not sure what the official brand name will be. KTE-X19 is unique in that there’s a separation step involved before the CAR T cells are manufactured. Normally, when we talk about treating a patient with diffuse large B-cell lymphoma, we just collect the T cells, and if there are other cells in the product, they can go into the manufacturing. When we talk about KTE-X19, we’re actually very purposefully separating out the T cells from the rest of the product before manufacturing. That process of isolating the CD4 and CD8 T cells does make the product unique, and that change in manufacturing does require a different moniker for the product.

In terms of the priority review, when Kite-Gilead launched the trial, they had already been working with the FDA. This is something where the process is dating back to around 2016, when the trial was getting off the ground and they began having conversations with the FDA to ask what it would take to commercialize this product. What we’re seeing in terms of the BLA [biologics license application] and the rapid turnaround for that BLA is a reflection of all the things that happened beforehand. Certainly, the data we’ve seen are very encouraging and all support that priority review. We’re expecting an answer in August. I’m keeping my fingers crossed. We certainly, as I alluded to earlier, need new therapies for higher-risk variants of mantle cell lymphoma, and the data that we’re seeing coming out of this particular trial suggest this could be a very powerful adjunct.

Bijal Shah, MD, Moffitt Cancer Center

Articles

Future Directions in Mantle Cell Lymphoma

ASCO 2020: ZUMA-2 Update

Bruton Tyrosine Kinase Inhibitors

A Look at ZUMA-2 Trial

An Introduction to Mantle Cell Lymphoma & KTE-X19