First-Line Treatment and Survival of Stage I(E) Peripheral T-Cell Lymphoma in the Netherlands; A Nationwide Population-Based Cohort Study
Authors: Meeuwes Frederik O. , Brink Mirian , Van Der Poel Marjolein W.M. , Kersten Marie José , Wondergem Mariëlle , Mutsaers Pim G.N.J. , Böhmer Lara H. , Woei-a-Jin F.J. Sherida H. , Visser Otto J. , Oostvogels Rimke , Jansen Patty M. , Neelis Karen J. , Crijns Anne P.G. , Daniëls Laurien A. , Vermaat Joost S.P. , Huls Gerwin A. , Nijland Marcel 
Published: November 2021

Abstract
Introduction: Peripheral T-cell lymphomas (PTCL) comprise a heterogenous group of mature T-cell neoplasms with generally an unfavorable prognosis. Presentation of PTCL with stage I(E) disease, according to the Ann Arbor classification, is uncommon. Clinical trials in diffuse large B-cell lymphoma (DLBCL) support the use of an abbreviated treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone combined with radiotherapy (combined modality therapy (CMT)) in case of stage I(E) disease. CMT in stage I(E) PTCL has been adapted in daily practice, but clinical trials are lacking. A recent population-based study conducted in Scandinavia indicated that the outcome in patients with limited stage PTCL is as poor as in patients with extensive disease. However, the outcomes of different treatment modalities were not analyzed.
Aim: The aim of this nationwide population-based cohort study is to describe first-line treatment and outcome of patients with stage I(E) PTCL in comparison to advanced stage PTCL.
Methods: All newly diagnosed patients ≥ 18 years with stage I(E) PTCL who were diagnosed in 1989-2018 were identified in the Netherlands Cancer Registry (NCR). Survival follow-up was available through February 1, 2021. The PTCL subgroups analyzed included anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma (EATL) and peripheral T-cell lymphoma NOS (PTCL NOS). Patients were categorized according to treatment regimen, i.e. chemotherapy, chemotherapy followed by autologous stem cell transplantation (ASCT), radiotherapy, CMT, and no/other therapy. Calendar period analyses (1989-1999 and 2000-2018) were conducted to assess trends in primary therapy and overall survival (OS) over time. The calendar periods were defined according to the implementation of CMT in patients with limited stage DLBCL from approximately 2000 onward in the Netherlands. The primary endpoint was OS, defined as all-cause-death post-diagnosis.
Results: From 1989 to 2018, 854 patients with a median age of 62 years were diagnosed with stage I(E) PTCL, accounting for 19% of all PTCL diagnoses. In stage I(E), the predominant PTCL subtype was PTCL NOS (40%, n=343). Furthermore, 26% (n=222) of patients were diagnosed with ALCL, 3% (n=28) with AITL, 11% (n=93) with EATL and 20% (n=168) with other histological subtypes. In contrast, for patients with advanced stage disease, 42% was diagnosed with PTCL NOS, 23% with ALCL, 24% with AITL, 6% with EATL and 5% with other histological subtypes .
To evaluate treatment and survival outcome in patients with stage I(E) PTCL, patients with ALCL, AITL, PTCL NOS and EATL were included for further analyses (n=686). Patients with ALCL, AITL and PTCL NOS were most commonly treated with CMT (n=164; 28%) or chemotherapy only (n=154; 26%). Only 10 patients (1%) received chemotherapy followed by ASCT. The remaining patients were treated with either radiotherapy only (n=116; 20%) or received other/no therapy (n=149; 25%). More patients were treated with CMT in 2000-2018 as compared to 1989-1999 (36% versus 17%, p&lt;0.01). Patients with EATL were most commonly treated with either chemotherapy only or other/no treatment (both n=45; 48%), while 3 patients (4%) received chemotherapy in combination with ASCT (n=2) or CMT (n=1). In EATL, no differences in treatment strategy were observed over time.
Overall, 5-year OS for all stage I(E) PTCL was 52%. There was no significant difference in outcome between the two time periods (53% vs. 52%, p=0.92). EATL had a worse prognosis when compared to ALCL, AITL and PTCL NOS (5-year OS 15% vs. 58%, respectively; p&lt;0.01). Five-year OS was significantly higher for patients with ALCL, AITL and PTCL NOS treated with CMT (71%) as compared to patients treated with either chemotherapy alone or with radiotherapy alone (52%, and 53%, respectively; p&lt;0.01). Independent predictors for poor prognosis were higher age, male gender and EATL subtype whereas CMT was associated with a lower risk of mortality when evaluated for in multivariable analysis.
Conclusions: For stage I(E) ALCL, AITL and PTCL NOS, 5-year OS is 58%. This compares favorably to the reported outcomes in advanced stage disease. EATL, even when presenting with limited stage disease, is associated with a very poor prognosis. CMT is associated with superior OS when compared to either chemotherapy or radiotherapy alone.

Disclosures
Van Der Poel: Roche, Janssen, Abbvie: Honoraria. Kersten: Kite/Gilead: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy; Miltenyi Biotech: Consultancy; Novartis: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy. Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Woei-a-Jin: University Hospitals Leuven, Belgium: Current Employment; Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Kyowa Kirin: Research Funding.