Expert Describes Importance of Classifying T-Cell Lymphomas

Madeleine Duvic, MD

Novel agents being explored in the landscape of both peripheral and cutaneous T-cell lymphomas could lead to an expansion of treatment options for patients, explains Madeleine Duvic, MD.

Such burgeoning developments include an open-label phase I/II trial exploring the safety and efficacy of a chimeric antigen receptor (CAR)-pNK therapy targeting CD7 in relapsed/refractory patients with peripheral, angioimmunoblastic, extranodal natural killer, enteropathy-type intestinal, or hepatosplenic T-cell lymphoma (NCT02742727).

Additionally, the investigational agent E7777 is being tested in patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma in a phase II trial (NCT02676778). The primary endpoint of the multicenter, open-label, single-arm study is objective response rate with E7777, which is a fusion protein that combines the interleukin-2 receptor-binding domain with diphtheria toxin fragments.

OncLive: Can you provide a summary of your presentation at this meeting?

Why do you think classification is so important?

Are there any new targets being investigated currently?

In an interview with OncLive during the 2016 OncLive State of the Science Summit on Treatment of Hematologic Malignancies, Duvic, professor of Medicine and Dermatology, Blanche Bender Professorship in Cancer Research, director of the Research Fellowship Program, Department of Dermatology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, shares her insight on classification of T-cell lymphomas, potential treatments in development, and what challenges oncologists are still facing in the field.Duvic: I spoke about T-cell lymphomas—the ones that are in the nodes and the more specialized, rare cutaneous T-cell lymphomas. I looked at the classification of the lymphomas, the prognosis, and newer therapies for each of the 2 categories—the peripheral and the cutaneous T-cell lymphomas.We are moving toward personalized medicine and targeted therapies, so that if you know what markers a cancer bears on its surface, you can design a toxin-antibody to kill that cell selectively and decrease the toxicity in general. The more we know about the molecular basis for cancer in different people, the more prepared we’ll be to offer effective therapy. Rather than using big guns, we targeted small bullets.Absolutely, there are many new targets being investigated now. One of the most exciting is the CARs, or the chimeric antigen receptors, where if you know there’s a surface molecule, you can send T cells selectively to kill that cell.

What challenges would you say still exist?

Looking ahead, what do you see happening in this area in the next 5 to 10 years?

What do you hope that community oncologists in attendance took away from this presentation?

What are some things that oncologists treating this disease still may not know?

However, there are also antibodies that are being developed based on surface markers. There is a whole new area using microRNA inhibitors; microRNAs can control a lot of genes and inhibitors can regulate them. We have a new category of drugs for the peripheral T-cell lymphomas and cutaneous T-cells lymphomas, in that they are very sensitive to histone deacetylase inhibitors [HDAC]. Romidepsin (Istodax) and vorinostat (Zolinza) are approved for peripheral T-cell and cutaneous T-cell lymphomas.The T-cell lymphomas are hard because T cells keep you from getting cancer, and they fight off infection and they control the immune system. If they become malignant, they lose their ability to be killed. Then, they are the only kids left on the block or the malignant cells after we have decimated all the other T cells. Treating a peripheral T-cell lymphoma or cutaneous T-cell lymphoma leaves the patient immunosuppressed almost to the extent of a patient with AIDS. We have to find ways to be more selective in killing only the specific malignant T cells and not all of the T cells.It is my hope that we will create therapies that are less toxic and more effective. The drugs that we have now for these diseases have overall response rates in 20% to 35%, and we need drugs that have 90% efficacy. All of that happens through targeting and through basic science research.[I hope that they have] an appreciation that T-cell lymphomas are quite heterogeneous, and that not one shoe fits all. You can’t just use CHOP and then be done with it. This is because, although CHOP is effective initially, patients almost always relapse. Additionally, we are only curing a few patients with allogeneic stem cell transplant. The rest of the patients with advanced T-cell lymphomas will probably die of their disease. Therefore, we need a lot of better therapies. We need to know more about who should get what therapy.I believe that the oncologists don’t know a lot about cutaneous T-cell lymphomas and how to diagnose them. This is because they are very subtle when they appear; they look like ringworm, cirrhosis, or even eczema. Oftentimes, that results in a delay of diagnosis, which means that the patients are sicker when they first present and are harder to control.

Most cutaneous T-cell lymphomas fall into the category of mycosis fungoides, or Sézary syndrome. Patients with early onset mycosis fungoides can be treated very conservatively. They don’t need chemotherapy. In fact, if you give chemotherapy they get worse, because you are knocking out a patient’s innate immune system that can control it. Therefore, we manage it early enough with topical steroids, with phototherapy, and topical nitrogen mustard (Mustargen)—just topical agents will control them and often put them in remission for a long time.