Optimising initial treatment for peripheral T-cell lymphoma: a tough nut to CHOP
Authors: Ryan A Wilcox
Journal: The Lancet Haematology (2018)

The peripheral T-cell lymphomas remain a therapeutic challenge because these aggressive cancers are both rare and extremely diverse. In fact, the most common peripheral T-cell lymphoma in Europe and North America is unspecified and remains a diagnosis of exclusion. CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) emerged as the standard of care in the treatment of aggressive non-Hodgkin lymphomas in the 1990s when the distinction between peripheral T-cell lymphoma and aggressive B-cell-derived non-Hodgkin lymphoma became apparent. Therefore, CHOP soon became the de facto standard of care for peripheral T-cell lymphoma. Data from the Swedish Lymphoma Registry and a retrospective ad-hoc analysis by the German High-Grade Non-Hodgkin Lymphoma Study Group showed improved event-free survival with the incorporation of etoposide in CHOP (CHOEP) in young patients aged less than 60 years, particularly those with anaplastic large cell lymphoma and normal concentrations of lactate dehydrogenase.1Ellin F Landström J Jerkeman M Relander T Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry.Blood. 2014; 124: 1570-1577Crossref PubMed Scopus (227) Google Scholar, 2Schmitz N Trümper L Ziepert M et al.Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group.Blood. 2010; 116: 3418-3425Crossref PubMed Scopus (436) Google Scholar Therefore, CHOP and CHOEP are widely used for patients with peripheral T-cell lymphoma,3Carson KR Horwitz SM Pinter-Brown LC et al.A prospective cohort study of patients with peripheral T-cell lymphoma in the United States.Cancer. 2017; 123: 1174-1183Crossref PubMed Scopus (44) Google Scholar but are not curative in most of them. Many investigative groups, bolstered by data suggesting improved outcomes in patients treated with anthracycline-based regimens,3Carson KR Horwitz SM Pinter-Brown LC et al.A prospective cohort study of patients with peripheral T-cell lymphoma in the United States.Cancer. 2017; 123: 1174-1183Crossref PubMed Scopus (44) Google Scholar have chosen to build on the CHOP backbone by incorporating novel drugs, including pralatrexate, romidepsin, brentuximab vedotin, and other targeted or immunomodulatory agents. Primary refractory and chemotherapy-resistant disease occurs in around 33% of patients treated with CHOP or CHOEP,4d'Amore F Relander T Lauritzsen GF et al.Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01.J Clin Oncol. 2012; 30: 3093-3099Crossref PubMed Scopus (416) Google Scholar and is associated with dismal outcomes. Therefore, alternative regimens that are not susceptible to potential resistance mechanisms, including multidrug-resistance protein (MDR)-mediated drug efflux, are rational and effective options for specific natural-killer (NK)/T-cell lymphomas, such as extranodal NK/T cell lymphomas. An alternative approach to CHOP-plus-drug is to replace CHOP altogether—as done by Mary Gleeson and colleagues in their CHEMO-T multicentre, phase 2 trial published in The Lancet Haematology.5Gleeson M Peckitt C To YM et al.CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial.Lancet Haematol. 2018; 5: e190-e200Summary Full Text Full Text PDF PubMed Scopus (38) Google Scholar Because gemcitabine is not a substrate for MDR-mediated efflux and has clinical activity as monotherapy and in combination with other agents, Gleeson and colleagues5Gleeson M Peckitt C To YM et al.CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial.Lancet Haematol. 2018; 5: e190-e200Summary Full Text Full Text PDF PubMed Scopus (38) Google Scholar compared standard CHOP (given every 21 days for six cycles) with the GEM-P regimen, a combination of intravenous gemcitabine (1000 mg/m2 on days 1, 8, and 15), intravenous cisplatin (100 mg/m2 on day 15), and oral or intravenous methylprednisolone (1000 mg on days 1–5) given every 28 days for four cycles, in adult patients with previously untreated peripheral T-cell lymphoma. After randomly assigning 87 patients to treatment, 43 to CHOP and 44 to GEM-P (of 186 planned), an interim analysis showed that few patients had achieved the primary outcome of complete response or unconfirmed complete response with GEM-P and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6–38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assessable patients assigned to GEM-P (odds ratio 0·52, 95% CI 0·21–1·31; p=0·164). A challenge for most trials of peripheral T-cell lymphoma, and the CHEMO-T trial might be no exception, is the presence of substantial and unmeasured confounding variables. Most prominent of these is the striking molecular and genetic heterogeneity between the subtypes peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma, which account for most of the histological subtypes enrolled in these trials. Although the cell of origin and the genetic landscape in angioimmunoblastic T-cell lymphoma is increasingly understood, the two molecularly and genetically distinct subtypes of peripheral T-cell lymphoma-not otherwise specified were only recognised more recently (GATA-3 and T-bet PTCL).6Iqbal J Wright G Wang C et al.Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma.Blood. 2014; 123: 2915-2923Crossref PubMed Scopus (333) Google Scholar, 7Wang T Feldman AL Wada DA et al.GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features.Blood. 2014; 123: 3007-3015Crossref PubMed Scopus (125) Google Scholar Importantly, each of these distinct subtypes probably use different mechanisms of chemotherapy resistance and harbour unique therapeutic vulnerabilities,8Wang T Lu Y Polk A et al.T-cell receptor signaling activates an ITK/NF-kappaB/GATA-3 axis in T-cell lymphomas facilitating resistance to chemotherapy.Clin Cancer Res. 2017; 23: 2506-2515Crossref PubMed Scopus (33) Google Scholar as suggested by the poor responses achieved with pralatrexate in angioimmunoblastic T-cell lymphoma9O'Connor O Pro B Pinter-Brown L et al.Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study.J Clin Oncol. 2011; 29: 1182-1189Crossref PubMed Scopus (466) Google Scholar and the rapid and striking remissions achieved with brentuximab vedotin in systemic anaplastic large cell lymphoma.10Pro B Advani R Brice P et al.Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study.J Clin Oncol. 2012; 30: 2190-2196Crossref PubMed Scopus (782) Google Scholar Failure to account for peripheral T-cell lymphoma ontogeny and disease heterogeneity will not only impede the ability to select the optimum regimen, but will also continue to confound trials like CHEMO-T. Hopefully, well designed clinical trials that expedite the selection of the right drug for the right patient, the incorporation of appropriate biomarkers that are based on an improved understanding of peripheral T-cell lymphoma ontogeny, and the development of rational therapeutic strategies combining novel and targeted drugs will improve outcomes for patients. Until then, improving the first-line treatment of peripheral T-cell lymphoma might remain a tough nut to CHOP. I declare no competing interests. CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trialThe number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. Full-Text PDF Open Access