T-Cell Lymphomas: Where We Are and Where We Are Going

Key Takeaways

• T-cell lymphoma classification continues to be refined based on increasing knowledge of the underlying biology.
• Patient participation in clinical trials that investigate novel therapies targeting epigenetic mechanisms, the immune system response, and others based on the underlying biology is key for improving outcomes in T-cell lymphomas.
• To learn about expert insights into current and upcoming strategies to improve outcomes for patients with T-cell lymphomas, register now for our ASH 2022 symposium

Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), are heterogeneous diseases that include up to 15% of non-Hodgkin lymphomas. Our understanding of T-cell lymphoma biology is improving, which has led to a revised classification system. The changes reflect a deeper understanding of the molecular aberrations or molecular derangements that are underpinning different subtypes of T‑cell lymphomas. The classification continues to be refined with a better knowledge or recognition of the underlying biology, which is starting to translate into how we approach patients. 

Optimal management of T‑cell lymphomas continues to be an area of some unmet need. For aggressive PTCL, we mostly consider CHOP-like combination chemotherapy. Modifications to that approach have included adding brentuximab vedotin. The ECHELON-2 phase III study in frontline PTCL that evaluated CHOP compared with brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone demonstrated continued overall survival benefit at 5 years of follow-up.

Investigational areas on the horizon include epigenetic targets, PI3K inhibition, or JAK-STAT pathway inhibition. Histone deacetylase inhibitors and demethylating agents are finding places in current treatments. Some of those alternatives are making their way into the frontline treatment setting. Due to overexpression of the EZH2 epigenetic modifying gene in most T-cell lymphomas, EZH1/2 inhibitors are under investigation in PTCL. Valemetostat, a dual EZH1/EZH2 inhibitor, has shown response in several PTCL subtypes. It has received approval in Japan for relapsed/refractory adult T-cell leukemia/lymphomas.

CTCL is a heterogenous group of malignancies resulting from accumulation of T-cells in the skin. Systemic therapies are used when patients have nodal or visceral involvement. We are starting to understand the role of some immunotherapies. Epigenetic agents may have effects on the tumor microenvironment, which may sensitize tumors to checkpoint inhibitors or cellular therapy. There are emerging data in CTCL with checkpoint inhibitors and novel antibody approaches targeting CCR4 and KIR₃DL₂. Mogamulizumab, a monoclonal antibody targeting CCR4, demonstrated improved progression-free survival compared with vorinostat in the phase III MAVORIC trial.

Other immune mechanisms are just in the early stages of understanding in T‑cell lymphomas. There have been early data evaluating targets to the CD47 pathway, either targeting CD47 or targeting SIRP α, interrupting that pathway to try to stimulate an immune response against the lymphoma. Cell therapy for T‑cell lymphoma or using T‑cells to fight T‑cell malignancies, is turning out to be a more complicated problem than what we have seen with CD19 targets in B‑cell lymphoma. There are trials underway evaluating novel targets, including CD5, CD70, and PCR β, which is one of the constant regions of the T‑cell receptor. We are still trying to understand whether autologous T‑cells against T‑cell malignancies—or other sources of cells such as allogeneic T‑cells, natural killer cells, or other effector cells—are better at targeting T‑cell lymphomas. There are different strategies under investigation, but the data are in the exploratory phase. The breadth of efforts underway trying to target these diseases is very exciting to me as someone who cares for patients with T‑cell lymphoma. I have real optimism for the future. 

Upcoming Live, In-Person/Virtual Symposium on T-Cell Lymphomas
Want to learn more about T-cell lymphoma management? Register to join me; Pamela B. Allen, MD, MSc; and Kerry Savage, MD, MSc, either in person or virtually for our upcoming symposium, “Advances in the Treatment of T-Cell Lymphomas: A Forum for Data and Case Discussion,” at the American Society of Hematology annual meeting on Friday, December 9, 2022. We will discuss the molecular and phenotypic workup for T-cell lymphomas, as well as planning frontline treatment for PTCL and CTCL subtypes, considering emerging new data with novel targeted therapies. We also will provide clinically relevant insights on how to improve outcomes for patients with relapsed/refractory PTCL and CTCL subtypes based on our experiences.

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