Dr Mehta-Shah Discusses the Treatment Paradigms for T-Cell Lymphomas

Neha Mehta-Shah, MD, MSCI, Assistant Professor of Medicine, Washington University, Siteman Cancer Center, St. Louis, Missouri, discusses various treatment paradigms for T-cell lymphomas, including primary cutaneous T-cell lymphomas and peripheral T-cell lymphomas.

Transcript

My name is Neha Mehta-Shah. I'm an assistant professor of medicine at Washington University in St. Louis affiliated with the Siteman Cancer Center, and I specialize in the treatment and clinical trials for lymphomas, with a special interest in T-cell lymphomas.

T-cell lymphomas comprise of a number of different entities. About half of those are ones we called primary cutaneous T-cell lymphomas, and the other half are called peripheral T-cell lymphomas. The treatment paradigm is quite a bit different for these. Patients who have cutaneous T-cell lymphomas are treated for the hope of improving their symptoms and their symptom burden, and allowing for control of their disease, but they're generally not cured without something like allogeneic transplant. Whereas the peripheral T-cell lymphomas are initially treated for curative intent, and they are often treated with 6 cycles of CHOP-based therapy or something similar, and then there are decisions made about the use of consolidative transplant in that patient population, but the paradigm is quite a bit different.

Among the peripheral T-cell lymphomas, the most common are peripheral T-cell lymphoma not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma. While we've always known that these are different diseases histologically, it used to be thought that they, for the most part, behaved relatively similarly clinically. As we're learning more about the biology of these diseases, we're learning that their mechanisms are quite a bit different from each other and that certain diseases are more sensitive to certain treatments than others.

I'm hoping that in the future, at some point, we'll be treating peripheral T-cell lymphoma NOS, differently than angioimmunoblastic T-cell lymphoma. We've already made those strides with anaplastic large cell lymphoma, but that is the way the treatment is evolving.

For the people with peripheral T-cell lymphomas were not cured with their initial therapy, which unfortunately often represents the majority of patients, their median survivals’ only 6 to 10 months has been shown in multiple series. They can be cured with an allogeneic transplant. For patients who are candidates for transplant both from having a donor status, their comorbidities, age, and then importantly, their disease status, we recommend sending those patients to allo because we've shown in a US series, and now there is analysis from the CIBMTR in combination with the European bone marrow transplant registries, that continue to show that almost a half, 40 to 50 percent of patients, can be cured with an allo if they're eligible for an allo, and so we consider that strongly for that population.

There's a number of agents that are in development for peripheral T-cell lymphomas. It's important to highlight these because they're rare diseases.

Clinical trial participation is critical to the development of novel therapies and the approval of novel therapies in these diseases that are often more orphan diseases. Treatment at academic centers that have access to these treatments can improve patient outcomes, or we believe that they can.

Some of these agents that are relatively far along in their development are drugs like duvelisib and tenalisib, which are PI3-kinase inhibitors.

Duvelisib is approved for CLL and follicular lymphoma (FL). The registration study for duvelisib called PRIMO is currently finishing with hopes of achieving FDA approval in the near future.

The important thing about these novel agents is that their response rate seems to be superior to the agents that we have currently available that are currently FDA approved. Drugs that are currently FDA approved for peripheral T-cell lymphomas include belinostat, pralatrexate, and romidepsin, which is NCCN Compendium listed now, which all have response rates in the 20 to 30 percent range.

Brentuximab, the antibody-drug conjugate to CD30, has a higher response rate, especially in anaplastic large cell lymphoma, but for patients who don't have CD30 expression, their response rate is 20 to 30 percent.

Drugs like duvelisib have shown an overall response rate (ORR) of about 50 percent range or higher with some very durable remissions, and 20 to 30 percent of patients achieving a complete remission (CR).

Those family of drugs are very promising. There's studies of combinations of PI3-kinase inhibitors including PI3-kinase inhibitors plus each JAK inhibitors like romidepsin. (There are also) studies of using PI3-kinase inhibitors with PD-1 inhibitors. I think that those are all very exciting in our treatment landscape.

Similarly, there's an EZH2 inhibitor called belinostat that is also in a phase 2 registration study opened in the US and internationally, and that drug similarly has shown up to a 60 percent response rate in the initial studies in T-cell lymphomas, including rare T-cell lymphomas like acute T-cell lymphoma leukemia, which is often very hard to treat. Those are 2 of the agents that are currently in development that are in Phase 2 studies. There are multiple others that are in development or in earlier stages of development as well.

The key is that, until now, the understanding of these diseases was relatively limited. Over the last 10 years or so, there's been considerable efforts to better understand the biology, which has led to unique insights into which drugs would be effective in this patient population and a resurgence of research in T-cell lymphomas which had previously been very hard to do research in.

In the frontline setting, for peripheral T-cell lymphomas, the most important approval, which is now a couple of years outdated, is the approval of brentuximab in the frontline setting. Brentuximab vedotin is an antibody-drug conjugate to CD30. While it can be expressed in many T-cell lymphomas, it's expressed in 100 percent of cases of anaplastic large cell lymphoma.

There was a randomized, double-blind, double-dummy study of brentuximab CHP, so CHOP minus vincristine versus CHOP. That study had demonstrated not only a progression-free survival (PFS) benefit to brentuximab-based therapy in this patient population, but it also showed an overall survival (OS) benefit. That's the first study ever in T-cell lymphomas to show an OS benefit. The key is that most of these patients had anaplastic large cell lymphoma.

The European mandate had required that over 70 percent of these patients had anaplastic large cell lymphoma, and they make up the majority of the study. As a result, the effectiveness in other T-cell lymphoma subsets is less robust. That discussion for me happens on a case-by-case and patient-by-patient basis, but it's important to understand that, but in anaplastic large cell lymphoma, brentuximab vedotin-CHP should be the standard of care for all patients.

We are conducting a US intergroup study currently that recently opened with the support of the NCI and BLOG and the ALLIANCE and ECOG, of looking at combinations in the setting of patients who were CD30 negative or CD30 less expressing. Patients who would not have been eligible for ECHELON-2, they have CD30 expression less than 10 percent. Those patients are being randomized to either CHOP or CHOEP based on their age, so the standard chemotherapy backbones, or those agents with either duvelisib or with CC-486, which is an oral version of azacytidine.

The reason we're doing that is because there are early signs that some of those drugs may work preferentially in T-cell lymphomas that have what we call a T-follicular helper phenotype. Angioimmunoblastic T-cell lymphoma has that phenotype, but they're also subsets of peripheral T-cell lymphoma not NOS, or T-follicular helper peripheral T-cell lymphomas that also have that phenotype. These seem to be genetically similar in their gene expression profiles, similar in their immunohistochemistry, and we think represent a common biology. The drugs like azacytidine have shown early promising activity in that patient population. Similarly, with duvelisib, there have been some signs that that might be more effective in patients with Tfh phenotype diseases. Patients in this study are going to be stratified by their Tfh phenotype as well to help us better understand that. If you had the opportunity to participate in that study, we think that's also an important study to look forward to.

There's a lot of topics that are really exciting. The question of if there's a way to improve frontline therapy for T-cell lymphomas is very exciting, and determining if there are biomarkers that predict for long-term remissions. We know the majority of our patients will respond to chemotherapy, but many of patients’ relapse. Even by their end of treatment, they have initially had a response, and then they have progression. How to figure out who those patients are, and early identification would be instrumental in trying to improve on their care. You could imagine that one day, in T-cell lymphoma there could be some adapted approach based on either PET or cell-free DNA or tumor metabolic volume or any number of things, and all those are currently being investigated as tools.

The other area very much interest is the role of an autotransplant in first remission. There is considerable data that shows that outcomes and studies where they've used consolidated autotransplant look superior to studies where that has not been the standard approach. This has been seen in registry studies as well in patients treated for the intent-to-transplant in first remission versus not. It will be very hard to do a randomized study in that population, but as we gain more and more data to compile that information, that is definitely an active question, especially in the era of brentuximab CHP-based therapy in which patients should go on to a transplant following that. Some of that work is being done currently by others, including Carrie Savage who's working on that.