The heterogeneous nature of peripheral T-cell lymphoma (PTCL) has long complicated treatment development, with therapies that show activity in one subtype often proving less effective in others. Now researchers at Memorial Sloan Kettering Cancer Center (MSK) are using a growing molecular understanding of these diseases to guide the development of more targeted and rational treatment strategies.
PTCL is a group of rare aggressive lymphomas, representing approximately 5-10% of all non-Hodgkin lymphomas in Western populations. The most recent World Health Organization classification in 2022, includes more than 30 distinct PTCL subtypes. PTCL not otherwise specified (PTCL-NOS) is among the most common nodal subtypes, along with angioimmunoblastic T-cell lymphoma (AITL, now classified as part of a larger group called nodal T-follicular helper cell lymphomas [nTFHL]), and anaplastic large cell lymphoma (ALCL).
While PTCL subtypes arise from post-thymic mature T cells and natural killer cells, there is a growing understanding of divergent underlying molecular pathobiology. This is the foundation for a number of new therapies and rational treatment combinations that are improving survival for patients with these rare lymphomas.
While prognosis of PTCL varies depending on subtype, it is generally poor, with a 5-year survival rate of approximately 30% to 40%. Outcomes are particularly dismal for patients with relapsed/refractory (R/R) disease.
Traditionally, these lymphomas were treated with therapies “borrowed” from B-cell lymphomas, including commonly used regimens like CHOP, or ICE. However, the poor outcomes with these approaches have led to better understanding of these diseases and development of novel targeted agents for T-cell lymphomas. “Cytotoxic chemotherapy is not always the best option,” said Jasmine M. Zain, MD, a lymphoma specialist at MSK. “We are trying to understand several factors that drive the biology of these diseases by investigating the genetic pathways that are dysregulated in each of these cancers.”
Dr. Zain and her fellow clinician-scientists at MSK are using what they observe clinically in patients with PTCL to better understand the biology underlying these diseases and guide new therapeutic approaches.
Understanding the Biology Behind PTCL
While developing new approaches, researchers at MSK are studying why some patients respond to targeted therapies, while others do not, as well as how resistance develops over time. These findings are helping investigators refine biomarker strategies, which ideally will guide drug selection going forward.
One of the findings is that the immune system can have a huge impact on disease biology as well as responses to treatment. They believe that inflammatory signaling and immune-system crosstalk driven by malignant T- cells may help explain differential responses to treatments. Another observation about T -cell lymphoma patients is that they can be very sick but do not have a huge tumor burden as seen in other lymphomas. This can also be explained by the dysfunctional immune response that underlies the pathophysiology of this disease.
“If you’re looking for the ground state truth, look to the patient,” said Santosh Vardhana, MD, PhD, who is a lymphoma specialist at MSK. Dr. Vardhana’s laboratory focuses on understanding the biology of these tumors. There is a “divergence between a PET scan of a patient with T-cell lymphoma compared with B-cell lymphoma — you might think that patients with T-cell lymphoma are not that sick because they usually don’t have huge burdens of disease compared with Hodgkin or Burkitt’s Lymphoma .”
“You very rarely see patients with huge golf ball- or grapefruit-sized lesions. But if you look at the patients, they’re unbelievably sick,” said Dr. Vardhana. This growing understanding of PTCL as both a malignant and immunologically active disease is helping shape the development of targeted therapies and rational combination strategies.
Peripheral T-Cell Lymphoma Diversity
The challenge in treating peripheral T-cell lymphoma is that it’s not a single disease; there are multiple subtypes.
“T-cells are diverse. They fill many different roles. That’s why you have so many different T-cell lymphoma subtypes,” said Dr. Vardhana.
This heterogeneity of PTCL poses a major therapeutic challenge. “There’s clearly a portion of these T-cell lymphomas that almost behave as more rapidly proliferative lymphomas … and then there are other ones that produce a lot of their morbidity through inflammatory crosstalk,” said Dr. Vardhana.
“Each subtype has unique biologic and diagnostic features. Now we’re starting to understand that their molecular mechanisms are also different, and this has guided the new therapies we are testing in clinical trials, ” said Dr. Zain.
Novel Agents
MSK’s lymphoma research program is investigating an array of new treatments informed by the biology of PTCL subtypes, including DR-01, an anti-CD94 monoclonal antibody, PI3K inhibitors, EZH2 inhibitors, and JAK/STAT inhibitors.
Anti-CD94
Cytotoxic T-cell lymphomas are very rare T-cell lymphomas with very poor prognosis. “This is a heterogeneous group with different clinical presentations. However, they share a common cell of origin, the cytotoxic compartment cell , and these all express CD94,” said Dr. Zain. These include aggressive NK-cell leukemia (ANKL), extranodal NK/T-cell lymphoma, nasal type, hepatosplenic T-cell lymphoma (HSTCL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), enteropathy-associated T-cell lymphoma (EATL), gamma delta T-cell lymphoma (γδ TCL), and T-cell large granular lymphocytic leukemia (T-LGLL).
DR-01 (dibotatug), an anti-CD94 monoclonal antibody, represents a novel approach for cytotoxic T-cell lymphomas expressing CD94 as a biologically related family.
DR-01 works by depleting target cells primarily through antibody-dependent cellular cytotoxicity. The dose-escalation portion of the phase 1/2 trial (NCT05475925), presented by Dr. Zain and colleagues at the 2024 ASH Annual Meeting, demonstrated complete and partial responses in patients with these subtypes across multiple dose levels. DR-01 was also well tolerated. The dose optimization portion of the trial is ongoing.
“The unique thing about this agent is that it’s probably the first time that a trial is being done in these specific group of lymphomas, and it’s working,” said Dr. Zain. DR-01 is under development by Dren Bio.
PI3K inhibitors
Work at MSK has helped researchers appreciate that phosphoinositide 3-kinase (PI3K) appears to play an important role in some PTCL subtypes by affecting immune responses and inflammation. A dysfunctional PI3kinase pathway has been associated with poorer outcomes in PTCL — providing investigators with a potential therapeutic target.
Duvelisib is an oral dual PI3K-δ/γ inhibitor, which has been extensively studied in PTCL in the United States. It was first evaluated in patients at MSK supported by basic science work conducted here that showed promising efficacy against T cell lymphomas.
Final results of the duvelisib PRIMO Phase 2 Trial, released in April 2026, in patients with R/R PTCL demonstrated an overall response rate of 48.0%, a complete response rate of 33.3%. Median progression-free survival was 3.4 months, and median overall survival was 12.4 months. This response rate was the highest ever seen with a single agent in RR T cell lymphomas and has helped many patients across the US and other parts of the world to achieve remission. It is now being studied in various combinations with results to come.
EZH2 inhibitors
While relatively rare in PTCL, overexpression of enhancer zeste homolog 2 (EZH2) alterations are a recognized oncogenic driver across multiple malignancies, including PTCL. EZH2 overexpression appears to contribute to tumorigenesis in some PTCL subtypes by dysregulation of genes controlling cellular growth . EZH2 inhibitors appear to turn off those genes. Researchers at MSK have been collaborating on a trial of valemetostat for patients with R/R PTCL (VALENTINE-PTCL01). The initial results are promising but patients may develop resistance. At MSK, researchers have been analyzing the genomics of biopsies from patients in whom the drug is not working or is no longer working to identify potential clues as to why the drugs didn’t work or stopped working.
“We’ve been involved in some clinical trials testing EZH inhibitors, there are patients in whom it just doesn’t work at all and then there are patients in whom it works and then it stops working,” said Zachary Epstein-Peterson, MD, a lymphoma specialist at MSK.
Combination Therapies
Combining different types of therapies is also an active area of PTCL research. Single agents often have limitations that may be overcome through combination approaches. In addition, the biologic diversity underlying PTCL suggests that multiple pathways may contribute to disease behavior, creating opportunities for therapies that target complementary mechanisms. Researchers hope these rational combinations may ultimately improve outcomes.
Increasingly, researchers are investigating pathways involved in inflammatory signaling and immune-cell communication in PTCL, including the JAK/STAT pathway.
“The JAK family of kinases primarily transduces signals from cytokines,” said Dr. Vardhana. “Cytokines are essentially what mediates the conversation between immune cells and your body.”
This rationale led to an ongoing phase 2 study at MSK evaluating the combination of the JAK1/2 inhibitor ruxolitinib and the PI3K inhibitor duvelisib in patients with relapsed/refractory PTCL.
Duvelisib is highly active in T-cell lymphoma. However, researchers observed that some patients developed hepatotoxicity during treatment.
“This was the setting where we realized interestingly that PI3 kinase inhibitors maybe mobilize the immune system to treat the cancer, but they also drive some of this inflammation,” said Dr. Vardhana. “We realized that biologically hepatotoxicity was really driven by an inflammatory response.”
In this context, adding a JAK inhibitor such as ruxolitinib may help mitigate inflammatory toxicity associated with PI3K inhibition.
“The combination is better in terms of the side effect profile because one drug tends to mitigate the side effects of the other somewhat,” said Dr. Zain. This effect was observed in an earlier study of duvelisib with romidepsin. “The response rate didn’t increase that much more with the combination, but the side effect profile got better,” she said.
While PTCL remains one of the most biologically complex and therapeutically challenging lymphoma subtypes, researchers at MSK believe that integrating clinical observation with molecular investigation is steadily reshaping the field. Increasingly, insights from patient presentation, treatment response, and resistance patterns are helping guide the development of more precise and rational therapies.
Learn more about MSK clinical trials for patients with T-Cell lymphoma.