Guideline-based treatment of T-cell non-Hodgkin lymphomas

Peripheral T-cell lymphomas (PTCL) represent a rare and biologically heterogeneous group of mature T- and NK-cell neoplasms accounting for approximately 10–15% of all non-Hodgkin lymphomas worldwide. Despite considerable advances in molecular characterization over the past decade, outcomes remain poor for most subtypes, with 5-year overall survival rates frequently below 30%.¹ A notable exception is ALK-positive anaplastic large cell lymphoma (ALCL), which carries a more favorable long-term prognosis due to its distinct molecular biology and sensitivity to targeted therapy.²

Biological and clinical heterogeneity of PTCL

The WHO 2022³ and ICC⁴ classifications recognize a heterogeneous group of nodal peripheral T-cell lymphoma (PTCL) entities, among which PTCL not otherwise specified (PTCL-NOS), T-follicular helper (TFH) cell lymphomas, most prominently angioimmunoblastic T-cell lymphoma (AITL), and systemic anaplastic large cell lymphoma (ALCL), including ALK-positive and ALK-negative subtypes, are the most common clinically relevant entities. Extranodal entities such as extranodal NK/T-cell lymphoma (ENKTCL), enteropathy-associated T-cell lymphoma (EATL), and hepatosplenic T-cell lymphoma (HSTL) are biologically and clinically distinct and are not discussed further here.

Molecular profiling has considerably improved the understanding of these diseases and increasingly influences therapeutic development.

PTCL-NOS remains a diagnosis of exclusion and is the most frequent nodal subtype. Gene expression profiling has identified at least two major molecular subgroups defined by TBX21 or GATA3 expression patterns. TBX21-driven tumors display a more inflammatory tumor microenvironment and relatively favorable outcomes, whereas GATA3-expressing lymphomas are characterized by genomic instability and inferior prognosis.⁵

TFH lymphomas, particularly the angioimmunoblastic subtype, are characterized by recurrent epigenetic driver mutations in TET2, DNMT3A, IDH2, and RHOA. These alterations often arise in hematopoietic stem cells and support a multi-hit model of lymphomagenesis.⁶ These findings provide a biological rationale for the use of epigenetic therapies such as hypomethylating agents and histone deacetylase inhibitors, both in the relapsed/refractory setting and increasingly in combination strategies in first-line.

Systemic ALCL is defined by universal CD30 expression. ALK-positive disease, resulting from NPM1-ALK or variant translocations,⁷ predominantly affects younger patients and is associated with significantly superior survival. In contrast, ALK-negative ALCL typically occurs in older adults and represents a biologically and clinically heterogeneous group with generally less favorable outcomes. Within ALK-negative ALCL, DUSP22 rearrangements are associated with more favorable outcomes, whereas TP63 rearrangements define a high-risk subgroup.⁸

First-line treatment

Despite increasing biological insights, CHOP or CHOP-like regimens remain the standard induction for most PTCL subtypes (Fig.1). However, outcomes remain inferior compared with aggressive B-cell lymphomas. Several retrospective and prospective studies have evaluated the addition of etoposide (CHOEP). Younger and fit patients, particularly those with higher International Prognostic Index (IPI) scores and ALK-positive ALCL, appear to benefit most from etoposide-containing regimens.⁹ Consequently, current European recommendations support CHOEP in selected patients younger than 60 years with intermediate- or high-risk disease.¹⁰

For limited-stage and non-bulky PTCL, abbreviated chemotherapy with consolidative involved-site radiotherapy has emerged as a potential strategy.¹¹ Although available evidence remains retrospective, recent analyses suggest that selected low-risk patients may achieve outcomes comparable to those receiving six cycles of systemic therapy.¹²

The most important therapeutic advance in frontline PTCL treatment has been the incorporation of brentuximab vedotin into induction therapy for CD30-positive disease. The randomized phase III ECHELON-2 trial compared brentuximab vedotin plus CHP (BV-CHP) with conventional CHOP in previously untreated CD30-positive PTCL.¹³

The study demonstrated significant improvements in progression-free and overall survival for the BV-CHP arm, particularly in systemic ALCL, which represented the majority of enrolled patients.¹⁴ BV-CHP is now the preferred frontline regimen for systemic ALCL and other clearly CD30-positive PTCL entities. An additional emerging strategy is BV-CHEP, combining brentuximab vedotin with cyclophosphamide, doxorubicin, etoposide, and prednisone. Early phase II data suggest high complete remission rates with manageable toxicity, although randomized confirmation is still lacking.¹⁵

Role of stem cell transplantation

The role of autologous stem cell transplantation (ASCT) in first remission remains one of the central questions in PTCL management. Most available evidence originates from retrospective analyses¹⁶ and single-arm prospective studies.¹⁷ Collectively, these data support consolidative ASCT for transplant-eligible patients with chemosensitive disease, particularly in PTCL-NOS, TFH lymphomas, and ALK-negative ALCL.

The Nordic NLG-T-01 study remains one of the most influential prospective datasets supporting ASCT consolidation in first remission.¹⁸ Similarly, post hoc analyses from ECHELON-2 suggested progression-free survival benefit from transplantation, especially in ALK-negative ALCL.¹⁹ In summary, autologous stem cell transplantation (ASCT) in first remission is recommended for transplant-eligible patients with chemosensitive disease, particularly those with PTCL-NOS, TFH lymphomas, and ALK-negative ALC. In contrast, patients with ALK-positive ALCL and low-risk disease generally achieve excellent outcomes without transplantation and are therefore usually not candidates for ASCT in first complete remission.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not routinely recommended in first remission for most PTCL entities. Prospective comparisons have shown lower relapse rates but substantially higher transplant-related mortality compared with ASCT, resulting in no clear survival advantage.²⁰

Relapsed and refractory PTCL

Relapsed or refractory (r/r) PTCL remains a major therapeutic challenge. Treatment decisions are primarily guided by transplant eligibility, disease biology, prior therapy, and targetable molecular features (Fig.2). Due to poor prognosis, patients should be considered for enrollment in a clinical trial whenever possible.

For fit transplant-eligible patients, salvage chemotherapy followed by ASCT or allogeneic HSCT remains the goal. Common salvage regimens used in relapsed/refractory PTCL are largely extrapolated from approaches used in diffuse large B-cell lymphoma (ICE, DHAP, GDP), although efficacy data in PTCL remain limited.

At relapse, biologically driven therapies become increasingly relevant. ALK inhibitors such as crizotinib²¹ or alectinib²² demonstrate remarkable activity in ALK-positive ALCL, while brentuximab vedotin induces high response rates in CD30-positive disease.²³ Hypomethylating agents such as azacitidine appear especially active in TFH lymphomas with epigenetic alterations.²⁴ Additional agents available in Switzerland, including conventional chemotherapeutics (bendamustine and gemcitabine) as well as lenalidomide and ruxolitinib, demonstrate modest overall response rates, with rare sustained responses.

Conclusion

The treatment landscape of PTCL is shifting from a uniform chemotherapy approach toward more biomarker-informed strategies incorporating molecular profiling and targeted therapies. BV-CHP has become a standard frontline option for CD30-positive disease, while CHOEP remains used in selected younger, high-risk patients.

In parallel, epigenetic agents in TFH lymphomas, antibody-drug conjugates in CD30-positive disease, and kinase inhibitors in ALK-rearranged lymphomas illustrate the growing role of biologically defined treatment selection, particularly in the relapsed/refractory setting.

Despite these advances, the rarity and heterogeneity of PTCL continue to limit the conduct of large randomized trials. Ongoing international collaboration and prospective molecular studies remain important to refine treatment strategies and improve outcomes.

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