John Leonard, MD, Discusses the Lymphoma Treatment Landscape

John P. Leonard, MD, Weill Cornell Medicine, New York Presbyterian Hospital, discusses the complex landscape and management of patients with lymphoma, as well as hot topics in hematologic malignancies, including the use of monsunetuzumab therapy, a bispecific antibody.

Transcript

I'm John Leonard from Weill Cornell Medicine and New York-Presbyterian Hospital in New York. I'm a physician and hematologist-oncologist, professor of medicine here, as well as senior associate dean.

There are a number of different types of lymphoma. The landscape and the management of lymphoma is quite complex, depending on the type that one is talking about. Most lymphomas are non-Hodgkin lymphomas (NHLs), and most of those are B-cell NHLs. They tend to fall into a couple of different categories.

The most common type of lymphoma, diffuse large B-cell lymphoma (DLBCL), has traditionally, for a number of years, been treated with R-CHOP chemoimmunotherapy as an outpatient. There are some subsets of patients, a small subset of patients, that some individuals consider using the infusional regimen dose-adjusted E-POCH. The majority of patients are treated with R-CHOP as an upfront therapy.

If they relapse, they traditionally have been treated with more aggressive chemotherapy and autologous stem cell transplantation in a number of different settings. For the group of patients that relapse, are not candidates for a more aggressive approach. If they relapse, we have a number of new drugs and modalities that have been recently approved.

We have several different CAR-T cell constructs that can be meaningful, give durable responses for a number of patients, although not the majority of patients. CAR-T cells are used in a number of different situations in the relapse setting.

We have also in DLBCL, relatively recent approvals for a number of different drugs, loncastuximab, which is an antibody-drug conjugate. We have tofacitinib, which is an antibody given in combination with lenalidomide. We also have polatuzumab used in combination with particularly bendamustine-rituximab in the relapse setting. Then we also have selinexor, which has been an oral agent that's also been approved. We have a number of different options in the DLBCL setting particularly for relapse patients.

The other big category of B-cell lymphomas is follicular lymphoma (FL). FL is typically treated either with single-agent, rituximab, sometimes treated with obinutuzumab, a newer anti-CD20. Often is treated with chemoimmunotherapy of various types, whether it's been the bendamustine-rituximab, CHOP-rituximab, other combinations. In the relapse setting, we have a number of different possibilities as well. Some of the same agents, we have PI 3-kinase inhibitors. We have tazemetostat and EZH2 inhibitor. There are lots of different agents that are available for the lymphomas and really very much of a patient-specific approach with physicians looking at their patients and trying to sort out what the best strategy is.

Then in mantle cell lymphoma (MCL), which is the third major category, we have a number of different chemoimmunotherapies that are out there. We have BTK inhibitors that are approved for mantle cell lymphoma and are useful. We also have CAR-T cells that are approved in that setting. Again, MCL continues to evolve as well. Additionally, we have Hodgkin's lymphoma. We have T-cell lymphoma, marginal zone lymphoma (MZL). It has many other different subtypes. For many of these cases, a similar regimens are available and used.

What's coming up as far as new data is, I think, going to be focused around the ASH meeting and what we're expecting to come later this year. The approvals we've touched on some of them with new approvals of new drugs, CAR-T cells have been approved also in follicular lymphoma, as well as other settings. We reference some of the other drugs in the relapse setting that have been approved recently.

I would say that 2 of the areas that we're expecting to see more data on in the near future, one is the use of polatuzumab as part of upfront treatment of DLBCL, swapped into the R-CHOP regimen, and then also randomized trials that have looked at CAR-T cells as part of second-line therapy rather than third-line therapy.

Both of those types of treatments we've heard about through press releases that positive trials are out there, we've not seen the data yet, and we're certainly enthusiastic about seeing those at ASH and elsewhere. Those are data that may change the standards of care for some subsets of patients with lymphoma in the near future.

Hot topics have been at recent meetings, the Bruton's tyrosine kinase inhibitors. We have newer BTK inhibitors. That first was ibrutinib. We have acalabrutinib and zanubrutinib approved for certain situations. There are several others that are investigational at this point that might be available before long. We'll see what the data show.

We know that from several randomized trials that these newer BTK inhibitors appear to have at least similar or in some cases even better efficacy than ibrutinib. They have a better tolerability profile in some ways, particularly cardiac toxicity and cardiac arrhythmias, atrial fibrillation. That's been a big area these days.

BTK inhibitors have been used and studied in chronic lymphocytic leukemia (CLL) and in MCL, as well MZL. The treatment of those diseases with BTK inhibitors is evolving.

The BTK inhibitors are also being used in more settings. We have data and looking at them earlier in the course of the disease. That's interesting particularly in MCL where that's being looked at extensively.

The other big area that's getting a lot of attention is the bispecific antibodies. We have several different bispecific antibodies. They have different constructs. One of those is mosunetuzumab, we have odronextamab, we have epcoritamab, and others out there as well.

The idea is that these are engaging the tumor cell in one fashion typically through CD20. They're engaging T-cells in another arm of that—glofitamab is one other that I didn't mention that's also of interest—they engage T-cells by a CD3.

The concept there is that instead of giving him an infusion of CAR-T cells that are ex-vivo manipulated, these are essentially treating the patient with a way to off the shelf, engage the T-cells from the patient. We know that these can be effective particularly in FL, and DLBCL particularly can be useful in patients where other treatments aren't working.

They are, in some ways, kind of a “CAR-T cell light” in that they work through engaging T-cells and activating T-cells in a little bit different way. They do have some of the same side effects of CAR-T cells but are easier because they're off-the-shelf and can be used potentially even as outpatient therapies much less cumbersome.

They may not be as effective as CAR-T cells. They are approaching the same ballpark with a little bit less toxicity. These agents are all sorting their way through different clinical trials and are very exciting. We're going to see more and more data using them earlier in the course of the disease. We'll see where those go but that may be a next generation of engaging or activating T-cells that is likely to have an impact on patients. Perhaps, some of these will be approved in the near future.