Ranjit Nair, MD, is an Associate Professor and Center Medical Director in the Department of Lymphoma/Myeloma at MD Anderson Cancer Center in Houston, Texas. A specialist in T-cell lymphomas, he leads translational research efforts focused on PI3K-directed therapy, HDAC and PD-1 inhibitors, antibody-drug conjugates (ADCs) and cellular approaches to this historically underserved group of malignancies.

Introduction: The Perpetual Challenge of a Rare and Heterogeneous Disease

Peripheral T-cell lymphomas are among the most challenging malignancies in hematologic oncology. They are rare, accounting for approximately 10 to 15% of all lymphomas, and they encompass twenty-five to thirty distinct entities with different biology, immunophenotype, molecular drivers, and outcomes. They are frequently misdiagnosed, with cases initially read as reactive processes, skin conditions, or other hematologic malignancies not uncommon. Their prognosis, outside of a few specific subtypes, has not meaningfully improved over three time periods spanning 1999 to 2015 despite multiple lines of therapy.

A 66-year-old patient at our center presented with a whole-body rash after a viral illness. Two skin punch biopsies showed a superficial perivascular lymphohistiocytic infiltrate interpreted as reactive. He developed pelvic lymphadenopathy, was biopsied at an outside hospital, and was diagnosed with Langerhans cell histiocytosis. He came to MD Anderson for a third opinion. The final diagnosis: nodal T-follicular helper (TFH) cell lymphoma, stage IVB. This case, spanning many months from first symptom to correct diagnosis, illustrates the diagnostic challenge that defines this field.

Classification: A Field in Rapid Evolution

The WHO 2022 classification has substantially reorganized how we think about T-cell lymphomas. The major practical changes:

PTCL-NOS is shrinking: What used to be the largest single category is increasingly being reclassified as our understanding of biology improves. Two molecularly defined subgroups within PTCL-NOS are now recognized: GATA3-driven tumors (worse outcomes, median survival less than one year) and TBX21-driven tumors, which fare somewhat better.

The TFH umbrella is expanding: Angioimmunoblastic T-cell lymphoma (AITL) has been reclassified under the broader category of nodal T-follicular helper lymphomas. Approximately 10 to 15% of PTCL-NOS cases are being reclassified into this group. TFH lymphomas arise from adaptive T-cells with CD4+ phenotype and have a distinct biology that informs treatment, including sensitivity to epigenetic and JAK/STAT pathway targeting.

ALCL subtypes are better characterized: Anaplastic large cell lymphoma (ALCL) now has defined genetic subtypes within the ALK-negative category: DUSP22-rearranged (approximately 30%), TP53-positive (2 to 8%), and triple-negative. DUSP22-rearranged ALCL behaves distinctly, with minimal STAT3 activation and low PD-L1 expression. Though once considered to have a better prognosis, accumulating data indicate that outcomes may be less robust than initially reported. Consequently, while consolidation transplant is highly considered in peripheral T-cell lymphomas, its utility in this specific subtype remains undefined.

Site matters: The same histologic name does not imply the same disease. Cutaneous ALCL has approximately 90% ten-year survival. Nodal ALCL is aggressive. Breast implant-associated ALCL is a distinct entity with its own management considerations.

The practical implication: an experienced hematopathologist and core biopsy versus excision decisions are critical. Clinical correlation, site of disease, and immunophenotyping (CD2, CD3, CD4, CD8, CD30, CD56, ALK-1, TCR status, and key transcription factors) together with molecular testing define the diagnosis. Increasingly, we also consider tumor microenvironment, particularly metabolic tumor volume by PET, as a prognostic tool beyond IPI.

Frontline Treatment: Setting the Stage

CHOP and the Role of Etoposide

For most nodal PTCL, CHOP-based therapy remains the backbone. The German data established that the addition of etoposide (CHOEP) significantly improved three-year EFS to 75% versus 51% in patients aged 60 or younger with normal LDH, though the benefit was most pronounced in ALK-positive ALCL. For AITL and PTCL-NOS, the benefit was less clear.

BV-CHP: The New Standard for CD30-Positive Disease

ECHELON-2 established brentuximab vedotin (BV) plus CHP (cyclophosphamide, doxorubicin, prednisone, with vincristine replaced by BV) as superior to CHOP in previously untreated CD30-positive PTCL, with PFS and OS benefits. Patients required at least 10% CD30 expression, and the study was enriched for ALCL (approximately 75%).

The PFS and OS benefits were strongest in ALK-negative and ALK-positive ALCL. For AITL, the subgroup hazard ratio was 1.41, suggesting BV-CHP may not benefit this subtype. This is a key clinical distinction that must be interpreted with caution, as the study was not statistically powered for this prespecified subgroup analysis. Given that ECHELON-2 represents the only positive phase 3 trial in frontline T-cell lymphoma in decades, BV-CHP remains a strongly considered treatment option for these patients. Ultimately, this highlights the critical need for subgroup-specific studies to better define the optimal frontline management for AITL.

In younger or fit patients with AITL who are CD30-positive, my approach is BV-CHEP: adding etoposide to BV-CHP to capture the etoposide benefit and take these patients through to autologous SCT in CR1. Response rate at end of induction was approximately 80%, and the outcomes with SCT consolidation appear quite promising. This strategy now carries a category 2A designation in NCCN guidelines.

The Role of Autologous SCT in CR1

Multiple cooperative group datasets support autologous SCT in CR1 for PTCL, with five-year OS of approximately 70% in ALCL and approximately 50% in AITL, roughly a 20% improvement over chemotherapy alone. Our institutional AITL data show PFS rates for upfront SCT versus no SCT versus SCT at relapse of 57%, 19%, and 0% respectively, a striking result that reinforces early consolidation in responding patients.

For AITL specifically, the biology of TFH-derived disease with frequent TET2 and DNMT3A mutations may make these tumors particularly amenable to epigenetic targeting.

Relapsed and Refractory Disease: Targeting Disease Biology

The Challenge

Outcomes after relapse in PTCL are dismal. In three time periods between 1999 and 2015, outcomes for relapsed/refractory PTCL did not improve. Single-agent chemotherapy produces responses measured in weeks to months, and multi-agent chemotherapy is more toxic without meaningfully better outcomes. The field has recognized that empiric approaches are insufficient and turned toward biology-directed targeting.

JAK/STAT Inhibition: JACKPOT8 and Golidocitinib

JAK/STAT pathway activation is a common driver in PTCL, particularly in AITL and TFH subtypes. Golidocitinib (AZD4205) is a selective JAK1 inhibitor that has shown activity in relapsed/refractory T-cell lymphoma in larger multicenter trials.

Our single-center JACKPOT8 experience presented at ASH 2025 included 13 patients with R/R PTCL. ORR was 53.8% with 46.1% complete responses, median PFS 37.9 months, and two-year PFS of 58.3%.

The most striking finding was a biomarker analysis: patients with TBX21-positive tumors had a 100% ORR versus 0% in TBX21-negative tumors (p=0.008). TFH subtype also showed superior responses (100% ORR) versus non-TFH (40%), though this did not reach statistical significance in this small cohort. This suggests that JAK/STAT inhibition may be most effective in the TBX21-positive and TFH-driven subtypes, exactly the populations where we now know how to select patients.

Based on this, a chemo-free frontline strategy is being explored at MD Anderson: patients with AITL and TFH-subtype PTCL receive six cycles of golidocitinib alone in the frontline setting, and if they achieve CR, continue without chemotherapy for one year. This is investigator-initiated and would not have been conceivable five years ago.

PI3K Pathway Inhibition

PI3K/AKT/mTOR pathway hyperactivation is present across many T-cell lymphoma subtypes, particularly in GATA3-positive PTCL-NOS, where PI3K-associated pathway gene expression is enriched in approximately 45% of cases.

Our single-center experience with linpersilib (a delta-selective PI3K inhibitor) in relapsed/refractory PTCL produced a 75% ORR with 50% complete responses in 12 patients.

The PRIMO study evaluated duvelisib (a delta/gamma dual PI3K inhibitor) in 123 relapsed/refractory PTCL patients, producing 48% ORR and 33% CR across the cohort. AITL performed best: 62.2% ORR and 8.3-month median PFS, substantially better than PTCL-NOS (49% ORR, 3.45-month PFS) or ALCL (15% ORR). Nineteen patients bridged to SCT on duvelisib. A phase 3 trial in TFH-subtype disease is ongoing.

Dual JAK/PI3K Inhibition

The combination of ruxolitinib plus duvelisib, evaluated in a phase 1 expansion study, produced an overall ORR of 41% in 49 patients across PTCL, CTCL, and T-PLL. In AITL/TFH subtypes, the ORR was 79% with 65% CR, numerically superior to either agent alone. This combination deepens CR rates in the TFH-biology-driven population and raises the question of whether this can be moved to frontline. The Alliance A05912 phase 2 trial is examining CHOP/CHOEP plus duvelisib versus CHOP/CHOEP alone versus CHOP/CHOEP plus azacitidine in untreated PTCL excluding ALCL and NK/T-cell lymphoma.

Epigenetic Targeting in AITL: Azacitidine

AITL is characterized by mutations in TET2, DNMT3A, and IDH2 (epigenetic regulators) in addition to the defining TFH immunophenotype. A small frontline study of azacitidine alone in AITL produced a 75% response rate, all complete responses, particularly in TET2-mutated patients.

The randomized phase 3 data adding romidepsin to CHOP in AITL/TFH subtypes were negative overall, but the TFH subgroup analysis showed a PFS signal that was not seen in non-TFH disease. These data support the biological rationale for epigenetic targeting specifically in TFH-biology disease, and ongoing combinations are being investigated.

EBV-Directed Therapy: Nanatinostat

For EBV-positive T-cell lymphomas, which include a significant proportion of AITL cases, EBV reactivation strategies represent a novel approach. Our patient, described earlier, eventually underwent autologous stem cell transplantation in first complete remission (CR1). Unfortunately, his disease relapsed quickly thereafter. He subsequently enrolled in a clinical trial evaluating nanatinostat (an HDAC inhibitor that reactivates EBV lytic cycle) combined with valganciclovir, which then kills EBV-reactivated cells. He completed twelve cycles, achieved a complete response, came off therapy, and remains in complete remission at last follow-up.

Cellular Therapy: MB105 CD5-Directed CAR-T

At ASH, our group presented data on MB105, a CD5-directed CAR-T product for T-cell lymphomas. CD5 is expressed on the majority of T-cell lymphoma subtypes. The safety run-in of five patients showed that all achieved complete response. Three events occurred: two progressive disease with CD5-negative escape clones, and one patient developed an EBV-positive DLBCL (addressed by amending the protocol to include rituximab prophylaxis). This is an early proof of concept for a cellular therapy approach in T-cell lymphoma, a disease where autologous CAR-T faces the fundamental challenge that the target antigen may be expressed on the patient's own normal T cells used for manufacturing.

For Patients

If you have been diagnosed with a T-cell lymphoma, the most important early steps are ensuring the diagnosis is confirmed at a center with experienced hematopathologists, and discussing your case at a multidisciplinary tumor board that includes T-cell lymphoma specialists. These are rare diseases where the subtype, determined by immunohistochemistry, molecular testing, and clinical features, determines the treatment approach.

For patients with CD30-positive disease including ALCL, a treatment approach incorporating brentuximab vedotin is now standard. For AITL and TFH-subtype lymphomas, clinical trials exploring JAK inhibitors, PI3K inhibitors, and combination approaches are available and represent some of the most promising options currently under investigation. Ask specifically about clinical trials at the time of your first relapse, as this is a field where enrolling on a trial is often the best available option.

Key Takeaways

PTCL is highly heterogeneous; WHO 2022 classification has substantially reorganized subtypes, with TFH lymphomas (AITL, nodal PTCL-TFH) now recognized as a unified biology-driven group, and PTCL-NOS stratified into GATA3 and TBX21 molecular subtypes.
BV-CHP is now the standard frontline treatment for CD30-positive PTCL; benefit is strongest in ALCL; subgroup hazard ratio for AITL favors caution (HR 1.41 for BV-CHP in this subtype).
BV-CHEP (adding etoposide) for young AITL patients targeting SCT in CR1 is a practical strategy with approximately 80% induction response rate; now category 2A in NCCN.
Autologous SCT in CR1 improves outcomes across nodal PTCL subtypes; AITL data from multiple groups are most compelling; DUSP22-rearranged ALK-negative ALCL may not benefit.
Golidocitinib (JAK1 inhibitor): 53.8% ORR in relapsed PTCL, 100% ORR in TBX21-positive patients; chemo-free frontline strategy in TFH disease under investigation.
PI3K inhibition: linpersilib 75% ORR in small PTCL cohort; PRIMO (duvelisib): 62.2% ORR in AITL; dual JAK/PI3K (ruxolitinib + duvelisib): 79% ORR in AITL/TFH.
MB105 CD5 CAR-T: first proof of concept for cellular therapy in T-cell lymphoma; CD5 escape and EBV-related events require mitigation strategies.
Multicenter collaboration and clinical trial enrollment are the most important interventions for relapsed/refractory T-cell lymphoma.

References

Schmitz N, et al. Impact of etoposide in PTCL. Blood, 2010;116:3418–3425.
d’Amore F, et al. Nordic PTCL study (NLG-T-01). Journal of Clinical Oncology, 2012;30:3093–3099.
Horwitz S, et al. ECHELON-2: BV-CHP vs CHOP in CD30+ PTCL. Lancet, 2019.
Herrera A, et al. BV-CHEP with SCT consolidation in PTCL. Presented at ASCO 2022.
Nair R, et al. JACKPOT8 single-center experience with golidocitinib. ASH 2025. Abstract 5422.
Nair R, et al. Linpersilib in R/R PTCL. Presented 2025. Abstract 5432.
Horwitz S, et al. PRIMO: duvelisib in R/R PTCL. ASH 2025.
Ruxolitinib + duvelisib in R/R T-cell lymphoma. ASH 2024.
Nair R. “Treatment of Aggressive T-Cell Lymphomas.” Presented at the 2026 Best of Hematology, Austin, TX, May 2026.