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M. Bellei et al.
Introduction
The mature or peripheral T-cell lymphomas (PTCL) encompass a biologically and clinically heterogeneous group of rare neoplasia arising from post-thymic lympho- cytes. They represent 10-15% of all lymphomas in the Western hemisphere.1
Peripheral T-cell lymphoma patients, except for anaplas- tic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive, have a poor prognosis.2,3 Current treatment strategies are largely unsatisfactory both in first- line and in the refractory/relapsed settings. First-line ther- apy relies on CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and CHOP-like regimens, with a remission rate of 50-65%.4-6 Phase II studies demonstrated that early consolidation with high-dose chemotherapy and stem cell rescue could improve outcome, but this approach is restricted to good performance status patients and chemotherapy responsive disease. For the majority of patients, risk of relapse remains quite high, and relapsed or refractory patients have been shown to have a dismal outcome.7,8 In recent years, there have been several studies testing novel therapies in this subset of patients.9
Two recent observational, population-based studies focusing on the outcome of relapsed or refractory PTCL patients have been published.7,8 The first, conducted by the British Columbia Cancer Agency, Canada, included 208 refractory or relapsed patients diagnosed between 1976 and 2010. The second study included 53 patients identified from the Modena Cancer Registry, Italy, with diagnosis confirmed between 1997 and 2010. Both showed extremely poor outcome with short remissions (median survival after relapse of 5.5 months and 2.5 months, respectively), and they confirmed that the out- come was superior in patients able to go forward for trans- plant.
The International T-cell Project is an international prospective cohort study that enrolled patients at 74 aca- demic centers on four continents. Data on epidemiology, clinical features, treatments and outcomes were collected. The purpose of the present study was to analyze clinical features and explore factors influencing survival of patients with primary refractory or relapsed PTCL.
Methods
The T-Cell Project (TCP; registered at clinicaltrials.gov identifier: 01142674), sponsored by the International T-Cell Lymphoma Project (ITCLP), was set up in 2006, and builds on the retrospec- tive study carried on by the network.2 Patients with different PTCL subtypes according to World Health Organization (WHO) 2001 or 2008 classifications1,10 were registered in the TCP at initial diagnosis. The T-Cell Project is a prospective cohort study that col- lected clinical and diagnostic information to better define clinical characteristics, therapies and prognosis for the most frequent sub- types of PTCL: PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). Further aims were to better outline clinical characteristics and outcome of the less common PTCL subtypes: extranodal NK/T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic T-cell lym- phoma, peripheral gamma-delta T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma.11 Data were collected on front- line treatment, response evaluation and up-dated follow up for at least five years. Patients who did not receive any kind of treatment
were also to be registered on the study. Data management was performed at the Trial Office in Modena, Italy (Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia). Registration was based on locally established histological diagnosis. A panel of expert hematopathologists reviewed the diagnosis of 70% of all patients. Approximately 4% could not be adequately classified by central reviewers and were retained in the study with the diagnosis made by a local pathologist. Finally, for 26% of cases, samples were not centralized and these cases were evaluated on the basis of the local diagnosis.
The TCP was conducted in compliance with the Declaration of Helsinki and was approved by the appropriate research ethics committees or institutional review boards at each participating institution. Each patient was required to provide written informed consent before registration.
End points
The principal end point of the analysis was survival after relapse (SAR) for patients with primary refractoriness and those who relapsed, measured from the date refractoriness was document- ed/date of relapse until last follow up or death from any cause.
Conventional response assessment after the first treatment has been adapted from the Standardized Response Criteria for Non- Hodgkin’s Lymphoma and from Recommendations for Revised Response Criteria for Malignant Lymphoma.12,13 Assessments were made by computed tomography (CT) scan or positron emission tomography (PET) scan according to physician’s discretion; responses were determined by the treating physician.
For the present analysis, primary refractory disease was defined as no response or progression to initial treatment within one month from the end of initial therapy or unsatisfactory partial remission (PR), i.e. a PR that according to the physician’s judgment was considered to be inadequate for the patient, and thus requir- ing salvage therapy immediately after completion of front-line treatment. Relapsed disease was defined as progression at least one month from completion of front-line therapy in patients who achieved a complete remission (CR) or a satisfactory PR.
Statistical analysis
Standard descriptive analyses were carried out. For a crude asso- ciation analysis, categorical data were analyzed using the χ2 or Fisher’s exact test (two-sided) for data analysis. Survival curves were estimated using the Kaplan-Meier method, and compared using the log-rank test.
Univariate regression analyses were conducted to identify prog- nostic factors associated with SAR. Odds ratios with their 95% confidence intervals (95%CI) were computed. Two-tailed P<0.05 was considered statistically significant. The Stata software, ver- sion 14·0 or greater (StataCorp, LLC, College Station, TX, USA; www.stata.com) was used for data analysis.
Results
From September 2006 to July 2016, 1451 patients have been registered by 74 institutions worldwide. Among them, 1020 had baseline clinical data, information on first- line treatment, response to initial therapy, time to relapse and salvage treatment available for evaluation. At the time of diagnosis, 83 patients (8%) received only best support- ive care and were excluded from this analysis. Out of 937 patients who received an active treatment, 633 (68%) were identified as refractory or relapsed patients, while 304 (32%) patients remained in complete remission.
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