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Managing T-Cell Lymphomas
Characterizing and Managing T-Cell Lymphomas: An Expert’s Review of Current Clinical Practice

Released: October 14, 2021

Expiration: October 13, 2022

Steven M. Horwitz
Steven M. Horwitz, MD
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Overall, aggressive T-cell lymphomas total approximately 9000 new cases per year in the United States alone. The WHO classification describes approximately 30 subtypes of T-cell lymphoma that are sometimes conceptually divided into 4 groups based on their clinical manifestations: nodal, extranodal, leukemic, and cutaneous. In this commentary, I provide a brief overview of T-cell lymphomas management using biomarkers for clinicopathologic characterization and targeted therapy.

Initial Patient Presentation
T-cell lymphoma is an uncommon, but heterogenous disease with almost 30 different disease subtypes that are often defined by their clinical presentation. T-cell lymphomas are often defined and subdivided by their sites of presentation. Cutaneous T-cell lymphomas (CTCLs) present primarily or exclusively in the skin, and patients are usually in their 50s-70s, although these do occasionally present in young adults or even children. Other types of T-cell lymphoma characterized by their sites of involvement include nasal natural killer (NK)/T cell lymphoma, which primarily presents in the nasopharynx, and hepatosplenic T-cell lymphoma, primarily affecting the liver and spleen, as the name suggests. And finally, there are the relatively more common subtypes of peripheral T cell lymphomas (PTCLs): PTCL–not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma usually present in the lymph nodes. Patients with these types of PTCL usually come in with swollen nodes.

Workup and Biomarker Characterization of T-Cell Lymphomas
The initial diagnosis requires tissue biopsies with an adequate sample collection—fine needle aspirates are insufficient—to understand and subclassify a T-cell lymphoma. Once assessed as predominantly a T-cell– or NK/T-cell–derived lymphoma, pathologists further characterize the tumor. For example, is it a follicular helper T-cell lymphoma (TFH)? TFH lymphomas are a group of diseases with CD4 positive T-cells originating from T-cells of the germinal center identified by the expression of certain immunohistochemical markers. These often originate from a follicular helper T-cell, which tends to have recurrent mutations and epigenetic modifiers such as TEK2, DNMT3A, or IDH1/2, for which epigenetically targeted drugs appear to be particularly active. Or is it a T-cell lymphoma derived from cytotoxic T-cells or γδ T-cells that originate from the innate immune system with different biology and characteristic patterns?

The initial workup for T-cell lymphomas requires expert hematopathology review or dermatopathology review, as these are quite uncommon diseases. It is also worth noting that many of these entities are defined by their clinical presentation as well as pathology. It can be challenging for pathologists to make these diagnoses in the absence of clinical information. Communication between the hematologist/oncologist/dermatologist seeing the patient and the pathologist can be very helpful in assigning the most accurate diagnosis. An example is anaplastic large cell lymphoma (ALCL). If an ALCL presents in lymph nodes, it is usually an aggressive, systemic, and potentially life threatening disease typically treated with chemotherapy plus the CD30-targeted antibody–drug conjugate brentuximab vedotin. A similar histologic appearance, with highly mitotic, clonal, CD30-expressing cells, can present as spontaneously regressing small skin papules called lymphomatoid papulosis, which generally requires no therapy. Consequently, in looking at the sample under the microscope in isolation, it may be difficult to distinguish between those two. This is an example where understanding the clinical picture may be useful or even essential for the pathologist to assign the best diagnosis and then lead us to the best therapy for the patient.

Therapy Selection Based on CD30 Expression
In T-cell lymphomas with strong CD30 expression such as ALCL, and even in those with a low level of expression in tumor cells including CTCL and other types of T cell lymphomas, we often use anti-CD30–targeted therapy, brentuximab vedotin, with high rates of responses with this agent. This is an example where the presence of a biomarker, even at low levels, is indicative of a likelihood of response to brentuximab vedotin.

Epigenetic Modifiers
We also have several epigenetic-modifying agents for use in T-cell lymphoma. These include HDAC inhibitors (eg, belinostat, romidepsin, and vorinostat), and we see emerging data for hypomethylating agents (decitabine and azacytidine), as well as the EZH 1/2 inhibitor valemetostat. In the studies of these agents, we see an association of response with the presence of mutations, as opposed to directly targeted therapy. In angioimmunoblastic T-cell lymphoma, for instance, we see high rates of epigenetic alterations, mostly methylation of DNMT3A and TEK2. There is a correlation between this subtype and a higher response to HDAC inhibitors. We don’t know yet whether we are directly targeting the genetic alterations in the tumor per se, but we associate those patterns of gene alterations with a greater likelihood of response to HDAC inhibitors. Similarly, with EZH inhibitors, there are some investigational drugs with preliminary data showing responses in T cell lymphoma. However, unlike in B cell lymphomas, we less often see mutations in EZH genes, but we know based on biology that EZH1 and EZH2 genes are important for germinal center T-cells, and this may explain the association of response to EZH inhibitors in some subtypes of T-cell lymphoma.

Treatment Options for PTCL
There is a proportion of patients with PTCL—the most common systemic subtypes—who can potentially be cured with combination chemotherapy such as cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or CHOP/etoposide, often followed by autologous stem cell transplant. This is a standard approach or the most commonly used upfront approach. Previous and ongoing studies in the frontline management of PTCL have evaluated a combination of standard combination chemotherapy plus targeted therapy. The phase III ECHELON-02 study combined brentuximab vedotin plus cyclophosphamide/doxorubicin/prednisone vs CHOP in adult patients with previously untreated CD30-positive PTCL and demonstrated a significant reduction in the risk of disease progression of 29% and improvement in overall survival, leading to FDA approval for this indication. A nonrandomized phase Ib/II study evaluated the HDAC inhibitor romidepsin plus CHOP in previously untreated PTCL, showing an overall response rate of 74% and 1-year estimated progression-free survival of 64%, and led to the initiation of a confirmatory phase III study of romidepsin plus CHOP vs placebo plus CHOP in 421 patients with previously untreated PTCL (NCT01796002). That confirmatory study failed to meet its primary endpoint of progression-free survival, resulting in the FDA’s withdrawal of the accelerated approval for the PTCL indication, but romidepsin is still approved for CTCL.

At the 2021 American Society of Hematology (ASH) annual meeting, data will be reported for a phase II study of oral azacitidine (CC 486) plus CHOP in patients with previously untreated PTCL (NCT03542266). The primary endpoint of that study is complete response rate after cycle 6 at 18 weeks by the Lugano criteria. Moreover, chemotherapy free options, including with epigenetic modifying agents, are also being explored, but data remain preliminary and it is unclear whether these approaches are curative.

Choosing Initial Therapy for Difficult-to-Treat Subtypes
However, there are subtypes of T-cell lymphomas that are not cured with chemotherapy. CTCLs tend to be chronic and more indolent. They can respond to chemotherapy, but patients can experience significant toxicity from treatment and their disease ultimately relapses. For these patients, we often think about milder or maintenance type approaches first, which may include HDAC inhibitors, brentuximab vedotin, retinoids, and anti-CCR4 monoclonal antibody mogamulizumab, or other approaches, often in combination with skin-directed therapy, all of which can lead to durable but noncurative responses. Aggressive and frequently chemotherapy-refractory lymphomas, including HTLV 1–associated T-cell lymphomas, hepatosplenic T-cell lymphomas, and NK/T-cell lymphomas, are often managed with intensive chemotherapy approaches. In many of these entities, we often look to bridge to an allogeneic stem cell transplant at first remission for these patients with chemotherapy refractory disease. There is an unmet need for patients whose disease is not currently cured with the combination of chemotherapy and targeted therapies and for patients with less aggressive chronic lymphomas, where novel options are needed with improved activity, better disease control, and fewer toxicities that would make them ideal for long term use.

ASH Satellite Symposia on T-Cell Malignancies
Want to learn more about T-cell lymphoma management? Join me, Barbara Pro, MD, and Francine Foss, MD, at the upcoming ASH 2021 satellite symposium, titled “Addressing Clinical Challenges in T-Cell Lymphomas Through Biomarker-Driven Therapy.” We will discuss the molecular and phenotypic workup for T-cell lymphomas, planning frontline treatment for PTCL and CTCL subtypes, emerging new data for novel targeted therapies in the frontline management of T-cell lymphomas including key insights on optimal management recommendations for individualizing targeted therapy, and strategies for sequencing therapies and prioritizing therapies for our patients. We will also discuss how to improve outcomes for patients with relapsed or refractory PTCL and CTCL subtypes.

Your Thoughts
What are your challenging cases in treating patients with PTCL? I encourage you to answer the polling question and join the conversation in the discussion box below.

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