Peripheral T-cell lymphoma remains one of the most challenging hematologic malignancies, marked by biologic heterogeneity, limited durable responses to frontline CHOP-based chemotherapy, and few established targeted therapies. At the Best of Hematology & Breast Cancer 2026 conference, Dr. Ning Dong of the Swedish Cancer Institute outlined critical updates in WHO classification, subtype-specific responses to HDAC inhibitors, and a newly validated prognostic model for advanced cutaneous T-cell lymphoma. She also highlighted promising phase 2 data in CD5 CAR T-cell therapy, checkpoint inhibitor combinations, and novel epigenetic approaches—offering cautious optimism for improving outcomes in this rare but aggressive group of diseases.

Dr. Ning Dong is a hematologist-oncologist at the Swedish Cancer Institute, with a particular focus on lymphoma, and has served as a principal investigator on multiple clinical trials. At the Best of Hematology & Breast Cancer 2026 conference in Seattle, Dr. Dong presented a comprehensive overview of peripheral T-cell lymphoma classification, current treatment approaches, and emerging clinical trials, with particular focus on advanced cutaneous T-cell lymphoma and novel therapies.

The transcript below has not been reviewed by the speaker and may contain errors.

HDAC Inhibitor Response in T-Cell Lymphoma Subtypes

The presentation began with a clinical question regarding which subtypes of peripheral T-cell lymphoma respond better to HDAC inhibitors. The answer highlighted that T follicular helper cell phenotype lymphomas, including AITL, respond better to HDAC inhibitors because these lymphomas are enriched in epigenetic-type mutations, making them more responsive to HDAC inhibitors and hypomethylating agents.

Overview of Peripheral T-Cell Lymphoma

Peripheral T-cell lymphoma, or mature T-cell lymphoma, is a rare lymphoma comprising only about 10% of non-Hodgkin lymphomas. It represents a quite heterogeneous group, with the most recent WHO classification identifying 34 subtypes. This rarity and heterogeneity pose significant challenges to understanding the behavior and biology of these diseases and to conducting clinical trials.

Broadly, peripheral T-cell lymphoma can be classified into four groups. The nodal type is the most common, representing about two-thirds of cases and including peripheral T-cell lymphoma not otherwise specified, AITL, T follicular helper cell lymphoma, and anaplastic large cell lymphoma. The extranodal type includes extranodal NK/T-cell lymphoma nasal type, which is more common in Asian patient populations, and enteropathy-associated T-cell lymphoma. The cutaneous type includes cutaneous T-cell lymphoma, most commonly mycosis fungoides and Sézary syndrome, as well as CD30-positive lymphoproliferative disease. The leukemic type includes adult T-cell leukemia/lymphoma, large granular lymphocyte leukemia, and T-cell prolymphocytic leukemia.

Most T-cell lymphomas are aggressive, though there are a few indolent subtypes, such as large granular lymphocyte leukemia and mycosis fungoides. Aggressive T-cell lymphomas generally have a worse prognosis and worse outcomes than their aggressive B-cell lymphoma counterparts. There are several reasons for this: biologically, they are harder to treat, they don't necessarily have a curable response to frontline combination chemotherapy, and there are not as many good novel agents available.

Current Treatment Approaches

The frontline treatment is CHOP-like combination chemotherapy, but only about 20% of patients achieve a durable response. In patients with relapsed/refractory disease who are transplant candidates, salvage chemotherapy is given to bring them to transplant. Otherwise, single-agent novel therapy or single-agent chemotherapy is attempted.

Novel agents currently in use include antibody-drug conjugates such as brentuximab vedotin, pralatrexate, romidepsin (an HDAC inhibitor), mogamulizumab (a CCR4 monoclonal antibody approved for cutaneous T-cell lymphoma in the United States and also approved for adult T-cell leukemia/lymphoma in Japan but not yet in the United States), and epigenetic modulators including HDAC inhibitors like romidepsin and belinostat, as well as hypomethylating agents. Checkpoint inhibitors are especially helpful in extranodal NK/T-cell lymphoma and cutaneous T-cell lymphoma in the refractory setting. For anaplastic large cell lymphoma, ALK inhibitors like crizotinib are approved.

Prognostic Model for Advanced Cutaneous T-Cell Lymphoma

An important presentation at ASH involved a prognostic cohort study developing a clinical model to predict prognosis in advanced cutaneous T-cell lymphoma. This was presented by Dr. Scarisbrick from the UK. The mycosis fungoides/Sézary syndrome staging system has four components: T for the extent and means of skin involvement, N for nodal involvement, M for visceral involvement, and B for blood involvement, where more than 1,000 Sézary cells in the blood constitutes the leukemic stage B2. Clinical stages are combinations of these four components.

Early-stage disease ranges from stage 1A to stage 2A, and patients with early-stage mycosis fungoides have a great outcome, with life expectancy not significantly affected. Advanced stage disease from 2B upward includes patients with skin tumors, significant leukemia cells in blood, or significant N3 disease, meaning nodes are completely replaced by lymphoma. However, there has not been a good prognostic model for patients with advanced disease.

Advanced-stage patients have an overall 5-year survival rate of 50%, but the stage itself is not a good predictor. For example, stage 2B patients with skin tumors do worse than stage 3 patients, and large cell transformation is associated with the worst outcome.

This international effort was led by Dr. Scarisbrick from the UK and Dr. Kim from Stanford, involving 52 sites from 19 countries across six continents in a truly impressive collaboration. The project started 10 years ago and enrolled approximately 2,000 patients. In multivariate analysis, four factors were associated with outcome and survival: age older than 60, elevated LDH, ECOG performance status, and large cell transformation.

Low-risk patients include those with zero to one risk factors, intermediate risk includes those with two risk factors, and high risk includes those with three or four risk factors. The overall survival curve stratified by risk groups showed that low-risk patients had a 5-year survival of 60%, high-risk patients 18%, and intermediate-risk patients fell in between. Patients in the intermediate or high-risk groups also had significantly worse quality of life and symptoms.

Phase 2 Clinical Trials in T-Cell Lymphoma

The presentation focused on phase 2 trials in T-cell lymphoma, noting there are no phase 3 trials currently, and skipped phase 1 trials, although several compounds showed impressive promise in phase 1 studies that may be available in the future.

CD5 CAR T-Cell Therapy

A phase 2 trial of CD5 CAR T was presented by Dr. Ira Gordon. CD5 is expressed in normal T cells and about 70% of T-cell lymphomas. The compound NP-105 is an autologous CD5-targeted CAR T product. For T-cell lymphomas, there is the issue of fratricide: tumor antigens expressed on T-cell lymphomas also exist on normal T cells, so in engineered CAR T cells, if these antigens are not removed, the CAR T cells can end up killing each other. This product prevents fratricide through internal and rapid downregulation of CD5 protein.

This phase 2 trial presented the safety run-in phase at the conference. Seven patients were enrolled, with five evaluable for efficacy. All five patients achieved complete response after CAR T, and two patients remain in remission, though follow-up was short at less than half a year. The safety profile showed the product was well tolerated in most patients with grade 1-3 cytokine release syndrome, but there was one patient who developed EBV-associated post-transplant lymphoproliferative disorder or B-cell lymphoma, a concerning post-transplant disease that was unfortunately seen in this T-cell lymphoma patient. This is an exciting and promising agent, and the study is moving on to the full phase 2 trial.

Checkpoint Inhibitor Combination Therapy

Another study was presented by a group from China combining checkpoint inhibitor with lenalidomide and chidamide for relapsed/refractory T-cell lymphoma. They recruited about 31 patients, with approximately half having AITL and the other half having a mixture of different pathologies. The overall response rate was about 60%, and progression-free survival was about one year. This is impressive considering that, for example, in a phase 2 trial of single-agent therapy, the response rate was about 37% and progression-free survival was about three months. However, this study did not separate the response or efficacy by subgroups, so future reporting with more detailed data is needed.

Adult T-Cell Leukemia/Lymphoma Treatment

The final study discussed focused on adult T-cell leukemia/lymphoma. The acute type has a dismal overall survival of about eight months even with intensive treatment. Typically, combination chemotherapy is given to bring patients to transplant, but most patients relapse quickly, even after allogeneic transplant.

Antiviral treatment with AZT and interferon has activity in adult T-cell leukemia/lymphoma. Dr. Ramos from the University of Miami conducted a phase 2 trial combining an HDAC inhibitor with antiviral therapy. The idea is that HDAC inhibitors can bring the HTLV retrovirus out of its latent state and reactivate it, which provokes host immune response through minor histocompatibility antigen expression, allowing antiviral treatment to have antitumor activity.

About 15 patients were treated, with approximately 50% showing a response. Impressively, about one-quarter of patients had a deep response, meaning they cleared their leukemia cells from blood. Two patients remain in remission. Dr. Ramos stated that this trial shows AZT-interferon-vorinostat warrants further evaluation in frontline treatment, which seems a fair assessment.

Clinical Practice Implications for 2026

In terms of treatment changes for 2026, there is no data to change practice yet. However, active screening and referral of patients to clinical trials is important because there are many interesting trials for novel products in the pipeline. The prognostic index for advanced cutaneous T-cell lymphoma is ready to be used in practice. For patients identified in the high-risk group, clinical trials should be prioritized and consideration given to bringing patients to transplant.

Future Directions in T-Cell Lymphoma

The field is moving forward with many novel agents in the pipeline. At ASH this year, several promising agents were presented in phase 1 trials, including monoclonal antibodies for large granular lymphocyte leukemia showing promising outcomes. There are ongoing CAR T studies and targeted therapies, including BTK inhibitors, being explored in T-cell lymphoma. The hope is that at some point, T-cell lymphoma can have promising targeted therapy options similar to advances seen in B-cell lymphomas.