Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)

Brentuximab vedotin + CHP ×6 (ECHELON-2, OS benefit) ± consolidative autologous transplant.

CHOP or CHOEP (≤60 years) ×6, autologous transplant consolidation in responders; clinical trial preferred.

Pralatrexate, belinostat, romidepsin (ex-US), brentuximab (CD30+), gemcitabine-based regimens, allogeneic HSCT for fit responders.

Skin-directed therapy (topical steroids, phototherapy, radiotherapy, total-skin electron beam), then mogamulizumab (MAVORIC), brentuximab (ALCANZA, CD30+), bexarotene, interferon, photopheresis; allogeneic HSCT for advanced disease.

Asparaginase-based chemotherapy (P-GemOx, SMILE) with involved-site radiotherapy for localised disease; PD-1 inhibitors at relapse.

Four things to establish before treatment. Which entity: ALK-positive anaplastic large cell lymphoma does much better than every other nodal T-cell lymphoma and is curable with chemotherapy alone in most patients; ALK-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified and the enteropathy-associated forms do considerably worse. CD30 expression by immunohistochemistry, because it decides whether brentuximab vedotin is added to first-line chemotherapy. Whether the disease is nodal, extranodal (nasal NK/T-cell), leukaemic (adult T-cell leukaemia/lymphoma, T-cell prolymphocytic leukaemia) or cutaneous, because those four groups have entirely different treatments. HTLV-1 serology where the patient comes from or has family from Japan, the Caribbean, west Africa, Iran or parts of South America, because adult T-cell leukaemia/lymphoma is treated differently from everything else. A breast implant-associated anaplastic large cell lymphoma presenting as a late seroma around an implant is treated primarily by complete surgical removal of the implant and capsule, and most patients need nothing else. That is a different disease from systemic anaplastic large cell lymphoma despite the shared name.

ECHELON-2 randomised 452 patients with untreated CD30-positive peripheral T-cell lymphoma to brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone (A+CHP) or to CHOP. Median progression-free survival by blinded independent review was 48.2 against 20.8 months (hazard ratio 0.71), with improved overall survival, and toxicity was comparable: febrile neutropenia 18 against 15 per cent and peripheral neuropathy 52 against 55 per cent. It is the only positive randomised first-line trial in this family in twenty years and it changed the standard. Three-quarters of the trial population had systemic anaplastic large cell lymphoma, so the benefit is best established there and is extrapolated to other CD30-positive entities. Six cycles are given, with G-CSF support. Vincristine is omitted because brentuximab vedotin is itself a tubulin-directed agent and giving both causes unacceptable neuropathy.

CHOP for six cycles is the default, and it is a default rather than a demonstrated best. No randomised trial has shown any regimen superior to CHOP in CD30-negative nodal peripheral T-cell lymphoma, and roughly half of patients are not cured by it. Adding etoposide (CHOEP) is standard in much of Europe for patients under 60 with a normal LDH, on the basis of a retrospective analysis of the German High-Grade Non-Hodgkin Lymphoma Study Group trials in which that subgroup had better event-free survival; the analysis was not randomised and not confined to T-cell lymphoma, so the practice rests on an observation rather than a trial. Adding romidepsin to CHOP was tested properly in the Ro-CHOP trial and failed, which is why the United States withdrew romidepsin's peripheral T-cell lymphoma indication. Angioimmunoblastic T-cell lymphoma is the entity in which the epigenetic drugs look most promising, because it is driven by mutations in TET2, DNMT3A, IDH2 and RHOA; azacitidine-containing combinations and histone deacetylase inhibitors are being tested and are not yet standard. Enteropathy-associated T-cell lymphoma is treated with intensive regimens and early nutritional support, because it presents with perforation or obstruction in a malnourished patient with coeliac disease. Entering a trial is a reasonable first choice rather than a last resort in this group.

Consolidating a first complete or partial remission with high-dose therapy and an autologous stem cell transplant is standard practice in Europe and common in the United States for nodal peripheral T-cell lymphomas other than ALK-positive anaplastic large cell lymphoma, which does well enough without it. The evidence is a prospective single-arm Nordic study and a series of registry comparisons; there has never been a randomised trial, and the registry comparisons are subject to the obvious bias that only patients who respond well enough and stay fit enough reach transplant. So the row is written as it is: this is the convention, it is reasonable, and a patient is entitled to be told that its benefit has not been demonstrated against continuing observation. Stem cells are collected after two to four cycles, before the marrow is exhausted. Allogeneic transplant is reserved for relapsed disease and for hepatosplenic T-cell lymphoma, where it is the only treatment that produces long remissions.

Response rates to every available single agent sit between about 25 and 35 per cent, and remissions are usually short, so the question at relapse is whether the patient can be taken to an allogeneic transplant or a trial. Approved single agents in the United States: pralatrexate, an antifolate, approved in 2009 on a response rate of about 29 per cent; belinostat, a histone deacetylase inhibitor, approved in 2014 on about 26 per cent, usable when platelets are low; romidepsin, approved in 2011 and withdrawn from this indication after the confirmatory Ro-CHOP trial failed. Brentuximab vedotin is highly active in relapsed systemic anaplastic large cell lymphoma, where response rates are far higher than in other entities; its first-line United States approval with cyclophosphamide, doxorubicin and prednisone for untreated systemic anaplastic large cell lymphoma and other CD30-expressing peripheral T-cell lymphomas came on 16 November 2018. Availability differs sharply between countries: pralatrexate and belinostat are not routinely commissioned in England. Other options are gemcitabine-based chemotherapy (GemOx, GDP), which is widely used in the United Kingdom and has no randomised support, bendamustine, alemtuzumab in selected cases, and a clinical trial. Allogeneic transplant is the only treatment with curative potential at this point and is offered to fit patients who achieve a response. Valemetostat, an EZH1/EZH2 inhibitor, is approved in Japan for relapsed adult T-cell leukaemia/lymphoma and peripheral T-cell lymphoma and is in trials elsewhere; the corpus does not yet hold a record for it and this page does not quote a figure for it.