Clinical Trials Exploring Novel Options for T-Cell Lymphoma

Jia Ruan, MD, PhD

Long-term outcomes for T-cell lymphoma remain suboptimal, explains Jia Ruan, MD, PhD. However, ongoing studies are investigating exciting regimens—including additions to the standard CHOP regimen—that could have the potential to change practice for these patients.

For example, a phase III study is looking at the efficacy and safety of the HDAC inhibitor romidepsin (Istodax) combined with CHOP chemotherapy versus CHOP alone in patients with untreated peripheral T-cell lymphoma (NCT01796002). The randomized study, which is expected to enroll 420 patients, is using progression-free survival (PFS) as its primary endpoint and will be completed in July 2019.

OncLive: What did you discuss in your lecture on T-cell lymphoma?

Ruan, an associate professor of Hematology/Oncology at Weill Cornell Medicine/NewYork-Presbyterian Hospital, shared some of the ongoing work in the field of T-cell lymphoma and the unanswered questions investigators are still facing for these patients in an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies.Ruan: I see a lot of patients in our group for non-Hodgkin lymphoma (NHL) and there is 1 distinct subtype, which is T-cell lymphoma. It is not a very common subtype, it is in about 5% to 20% of patients with NHL. But, it is quite heterogeneous and also very difficult to treat. The long-term outcomes for patients with T-cell lymphoma remain suboptimal. For example, the studies generally state that it is a 5-year survival rate of about 20% to 30%, which certainly has room for improvement.

We are delivering not only standard of care, but also looking at options of clinical trials. For example, can we intensify our induction chemotherapy or can we incorporate novel biological agents so that we can improve effectiveness? We need to especially try to improve complete remissions (CRs) for patients with T-cell lymphoma.

How does T-cell lymphoma present, and what are the characteristics of it?

Subsequent to that, patients could have options to move on to consolidative bone marrow transplant or they can consider maintenance strategies in order to remain in remission longer. Peripheral T-cell lymphoma, the most common subtype, includes angioimmunoblastic T-cell lymphoma or anaplastic large cell lymphoma. Patients with those diseases can present with very symptomatic lymphadenopathy, which is swelling of lymph nodes. They may have some fevers, constitutional symptoms like weight loss, and also a significant proportion of those patients may have skin rash and inflammatory symptoms.

Diagnosis of T-cell lymphoma can be challenging. It requires a very specialized hematopathologist—one who definitively diagnoses T-cell monoclonalities. It needs to be differentiated, excluding other types of NHL or Hodgkin lymphoma.

What ongoing research is looking at different backbones or other biological agents?

Overall, the chemotherapy responsiveness of T-cell lymphoma tends to be more resistant. You can sort of get glimpses of that based on historical data; with the most common therapy, CHOP, we expect overall response rates (ORRs) in the 60% to 80% range and only half of them are in CR. That basically suggests that we should be looking at alternative therapies, either chemotherapy with a different backbone or incorporating biological agents that are much more specific for T-cell lymphoma. A significant amount of research is ongoing; there are more studies focusing on incorporating novel agents into CHOP. This is because physicians do have a lot of experience with CHOP and it is widely accepted. For example, there are phase III studies ongoing or in the process of waiting for data maturation incorporating an HDAC inhibitor, romidepsin. Adding romidepsin to CHOP compared with standard CHOP. Those are being performed globally, primarily in Europe. I do believe that the study has completed accrual and we are just waiting for data maturation.

Romidepsin alone has very significant clinical activity in the relapsed setting. One would assume that when you move earlier into the frontline setting, the efficacy should be quite considerable. We do have data coming from a phase I study that seem to support that.

We certainly also understand that when you combine 2 different modalities—chemotherapy plus biologic agents—you also anticipate more toxicities. In this particular combination, there are more hematologic toxicities, such as anemia, thrombocytopenia, and neutropenia. However, all of those are manageable by supportive care. The key question is, do you achieve higher CR rates and achieve higher PFS? I hope that, eventually, will translate to overall survival.

That is 1 of the examples. The other is combining biologic agents but, this time, it’s anti-CD30 therapy. We have an antibody-drug conjugate called brentuximab vedotin (Adcetris). The study is comparing the addition of adding brentuximab vedotin to a CHOP variant, which is CHP—without vincristine, just to minimize neurotoxicity. We are comparing that combination with conventional CHOP. This study is done primarily in the United States; it is a multi-institutional phase III study that is going well and has completed accrual. I am optimistic and hopeful, as we are waiting for the study outcomes.

The earlier study with the same combination, but in the phase I setting, seems to suggest that the ORR and CR rates are much higher than CHOP alone. Those data seem to withstand the test of time, because they are reports of long-term remission rates as well as survival rates. Those are in the range of 3 years and they do see fairly significantly longer PFS, OS, as well as maintaining remission status. Those are compared with historical control.

Is there any potential with immunotherapy or chimeric antigen receptor T-cell therapy in T-cell lymphoma?

Therefore, the phase III study will provide more definitive answers on whether adding a targeted biological agent can change the chemotherapy or treatment sensitivity of the underlying disease, bringing improved response rates, as well as survival to patients. Immunotherapy is of great interest—not only to our patients, but to medical oncologists. Its application in T-cell lymphoma remains to be seen. Immunotherapy implies that you want to activate and mobilize T cells and, in return, they would essentially bring your malignant process under control and eliminate that. In the case of T-cell lymphoma, it remains to be elucidated as to whether the particular interactions—for example, PD-1/PD-L1—have an impact on the malignant T cells. Do they eliminate those compartments and simultaneously activate normal T cells so that they can move in and eradicate whatever that residual process might be? It is a lot more complex in T-cell lymphoma, and it is very preliminary.

We do have some early evidence. For example, there is a very rare type of T-cell lymphoma called NK/T-cell lymphoma. It generally presents with extra nodal disease and is quite chemotherapy resistant, but is sometimes sensitive to radiation therapy. In patients who have relapsed/refractory disease, including those who failed or relapsed after prior autologous stem cell transplantation in a retrospective cohort of a study that only included 7 patients in Asia, the ORR was 100%.

What are the key takeaways for community oncologists to have from this lecture?

Therefore, it probably speaks to the biology that those T cells are expressed in a high amount of PD-1. When you target PD-1, that may play a role in terms of eradicating those malignant T cells and possibly also activate normal cells. It remains exciting, but a lot of work, especially preclinical work or animal studies, needs to be done. Whenever we talk about T-cell lymphoma, it is collaboration and education to both patients and also our community oncologists. This is because it is a disease in which, for the majority of cases, it is hard to say, “it is easily curable.” We have a lot of difficulty in terms of achieving very high remission rates or durable remission.

For those reasons, when patients come to our clinic, we want to emphasize that we are in it for the long haul. We like to have a long-term plan. We like to start with a very effective induction therapy, followed by possibly consolidation with various options.

We would like to convey that to the community oncologist, for whom it’s important to educate that this is not an easy disease. It doesn’t really hurt to have a referral to centers where there are physicians, including oncologists, pathologists, and radiation oncologists that work together, trying to come up with a long-term plan and a treatment—a strategy so that patients can expect and also adjust their schedules and a life course for that.