T-Cell Lymphoma Options Burgeoning With Ongoing Clinical Trials

Steven Horwitz, MD

Though T-cell lymphoma is a more rare hematologic malignancy, researchers are exploring therapies such as brentuximab vedotin (Adcetris) to improve outcomes for these patients.

For example, the double-blind, randomized, multicenter, phase III ECHELON-2 trial is comparing brentuximab vedotin plus doxorubicin, prednisone, and cyclophosphamide (CHP) with standard CHOP as a potential frontline treatment for patients with CD30-positive mature T-cell lymphomas (NCT01777152). The primary endpoint is progression-free survival (PFS) with an estimated completion date of December 2017.

“Now, there's this constant stream of clinical trials adding to standard therapy or instead of standard therapy,” says Steven Horwitz, MD, who lectured on T-cell lymphoma during the 2016 OncLive® State of the Science Summit on Hematologic Malignancies. “For a patient who is interested, there probably is access to something new or different if they want to try something different from the standard.”

OncLive: Can you provide an overview of your research with T-cell lymphoma?

What are some current clinical trials that are happening in relation to T-cell lymphoma?

Horwitz, an associate attending physician at Memorial Sloan Kettering Cancer Center, sat down for an interview during the meeting to discuss standard initial therapy for patients with T-cell lymphoma with a look ahead to what the community can expect next in the field.Horwitz: In my presentation, I discussed T-cell lymphoma, and highlighted what some of our standard initial approaches are, as well as some of the newer data that do not yet modify our standard approach—but maybe they will on the horizon. I also went into some newer data in relapse diseases, including a couple of subtypes, some things that were published this past fall, and a couple of more relevant abstracts from the 2016 ASH Annual Meeting that may be practice relevant, if not totally practice changing.In terms of the upfront setting, a trial that is accrued now but we are waiting on data, is adding brentuximab vedotin to standard combination chemotherapy. This is the ECHELON-2 study, which adds brentuximab to CHP, which is a combination of doxorubicin, prednisone and cyclophosphamide. That was randomized in a double-blinded fashion against CHOP plus placebo.

It's a study with more than 400 patients, which is by far the biggest for a prospective randomized study we have in T-cell lymphoma. It's going to give us a lot of very good quality data. It just finished accrual within the past month, so data will likely be out within the next year or 2. That's probably the next thing that has the best chance of really improving, or stepping up standard of care, in patients with anaplastic large cell lymphoma, and perhaps across the board in any of the CD30-expressing T-cell lymphomas. That's pretty exciting.

What abstracts from the 2016 ASH Annual Meeting could be practice changing?

Another new, ongoing study is looking at the addition of lenalidomide (Revlimid) to standard combination chemotherapy. There is another study adding romidepsin (Istodax) upfront. As we get results from those studies within the next couple of years, we are going to have a wave of studies saying, "Is something really better than CHOP?" or, "Is adding 1 of these newer drugs really making a difference for some subset of the patients?"There were not a ton of studies in T-cell lymphoma. There was a randomized study called the ALCANZA study, which randomized patients with cutaneous T-cell lymphoma that expressed CD30. They defined it in that study as 10% or greater. There were a couple phase II studies about brentuximab vedotin that looked promising, but this was a randomized study where, in rare diseases like T-cell lymphoma, we have very few randomized studies against standard treatments. In this case it was bexarotene or methotrexate.

There was a 100-patient study done in the United States, Europe, and Australia—really powerfully in favor of brentuximab vedotin. Therefore, the overall response rate was much higher—about 68% for the single agent—which recapitulates the small phase II studies, so there wasn't really regression in a multicenter setting.

There’s another study of the drug in which the responses were at least 4 months durable, which was the primary endpoint. That was significantly better for brentuximab vedotin. The PFS is more than 4 times better, so that drug in a big, international study looked a lot better than a lot of the other standard therapies we commonly use.

That is the kind of thing where we are going to say that this drug has a high response rate and some chance of complete responses, which is very different than the moderate response we get from a lot of other drugs. That is going to factor into decision-making, partly because the patients with cutaneous T-cell lymphoma are so symptomatic. Depth of response and degree of response has a big impact on quality of life. That is the one that's ready to use. It's using the same guidelines. This is the third study now looking at that drug in that setting.

The other interesting data in cutaneous T-cell lymphoma was with pembrolizumab (Keytruda), so now we’re looking at checkpoint inhibitors. We don't have a lot of data in T-cell lymphoma. This was a phase II study in mycosis fungoides and Sézary syndrome. The response rate was about 38%. A lot of the responses were durable, and people were still in remission at 6 to 12 months.

What are some of the biggest challenges that remain in this field?

This may be a new drug to be able to get access to which, in a decent-sized study, looks like it has pretty good activity. These patients who have cutaneous T-cell lymphoma move from one treatment to another. As they get further along in their course, you're often looking for new treatments. Typically, that's investigational therapy. There may be some access at checkpoint inhibition based on these data for those patients.The main problem in these systemic T-cell lymphomas is that we just don't carry enough people. We do combination chemotherapy and we add autotransplant in first remission. But even with all that, the cure rates probably don't get much above 40% or 45%. It's a disease where we need new and better therapies. It's nice to see that some of the new therapies have now moved to the frontline setting, and we'll see what those studies show. If those randomized studies are better, those will be new standards of care. If they're negative, then we are back to the drawing board.

Is T-cell lymphoma considered to be a heterogeneous disease?

We are also doing research to move beyond this one-size-fits-all approach. A lot of the drugs approved in relapse T-cell lymphoma were treated in unselected patients. In addition to finding newer and better therapies, we also want to understand whom those treatments are most likely to work in. This way, we can better select which patients are likely to benefit from which therapies, and then look at potential combinations.Because it's rare from a clinical trial-understanding standpoint, we tend to lump them together; however, there are more than 20 different subtypes. Even as we get more of an understanding of the genetics and of the disease, we see that—even with some of those top subsets—there is some heterogeneity. That's surprising. As you learn more, you start splitting these things up more and more. When you don't have very good tools and it's chemotherapy, it may not make a ton of sense to stratify. You treat everybody and see what happens.

What is it like to see these checkpoint inhibitors making their way through the hematology field?

As we have more targeted therapies—to target CD30, CCR4, and PI3K—then it's probably more important to understand where those targets are important in which patients. We need to be smarter about selecting patients to enroll on clinical trials, to understand if you're hitting those targets, and to see if it makes an impact on the disease. If not, how will we figure that out and improve those treatments?It's exciting. We're kind of late to the game. These drugs have been around for a while. In solid tumors, you are seeing some fairly durable responses in a number of diseases.

In T-cell lymphoma, there has been some concern because you are targeting things that are on the tumor cells—you're not just targeting the immune system. There's a lot of overlap between malignant T cells and normal T cells. In some early studies, it is unclear whether a patient’s disease accelerated or the treatment is just not effective. It's nice to see studies where you are seeing the majority of patients have stable or better disease. You're seeing some real, durable responses.

What are the takeaways for community oncologists to apply to clinical practice?

There was some interesting data at the ASH meeting about some other novel approaches. There are several drugs that are looking at CD47 or that pathway, which is more of a macrophage target. It may be a way of stimulating the immune system to fight tumor cells without directly stimulating T cells and getting other immune effector cells involved. There were some very early data there, but that's another strategy that is being looked at and could be relevant in T-cell lymphoma.In terms of T-cell lymphoma, there's a lot of heterogeneity. Get your stories straight. Make sure you understand the diagnosis. Clarify the goals of treatment with patients. Sometimes we hear that it's a horrible disease and it's fairly hopeless. I would say while the cure rates are not what we want, in a patient who can get an aggressive approach; they're still in the 40% to 45% range.