The role of high‐dose chemotherapy and autologous stem cell transplant for treatment‐naΪve patients with peripheral T‐cell lymphoma: a systematic review of the literature

Peripheral T-cell lymphomas (PTCL) are typically associated with poor prognosis. Anthracycline-containing regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), are commonly used as first-line treatment for PTCL despite a lack of high-level evidence, rational design or biological basis. In the retrospective International T-cell Project (ITcP), in which 85% of patients received CHOP-based chemotherapy, the 5-year failure-free survival (FFS) was 20%, 18% and 36% for PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) respectively (Vose et al, 2008). In a recent phase III study, the 2-year event-free-survival (EFS) was 41% for CHOP-treated PTCL (Simon et al, 2010). Attempts to improve outcomes in CHOP-treated PTCL have included the addition of another agent, such as etoposide (CHOEP), alemtuzumab, romidepsin and brentuximab although, to-date, no survival advantage has been unequivocally demonstrated. Given the disappointing outcome data with CHOP for PTCL, high-dose chemotherapy followed by autologous stem cell transplant (HDC-ASCT) has been widely employed as consolidation therapy for patients with PTCL in first response, notwithstanding an absence of randomized studies to support this treatment approach. We therefore conducted a systematic review of the literature to identify prospective studies of HDC-ASCT as first-line treatment of adult PTCL (including the three most common histological subtypes: PTCL-NOS, AITL and ALCL). Studies incorporating patients with relapsed/refractory disease or those who received allogenic stem cell transplant were excluded. Abstract-only studies were excluded. Outcome measures including response rates, progression-free survival (PFS), overall survival (OS), percentage of patients proceeding to HDC-ASCT, and incidence of treatment-related mortality (TRM) were extracted. Sample size, median age, performance status and stage of disease were also tabulated. Authors were contacted if data was unavailable in the manuscript. The Cochrane assessment of bias tool was used to assess for selection bias, performance bias, attrition bias, detection bias and selective reporting of outcomes. The data were appraised and summarized as a narrative synthesis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used for the preparation of this review (http://prismastatement.org/). The electronic database MEDLINE (1950-present) was searched. Titles, keywords and abstracts of citations were reviewed and full copies of potentially suitable articles were assessed further. The following search strategy was used: ‘Exp Peripheral T-cell Lymphoma’ AND ‘Exp Haemopoietic Stem Cell Transplant’ with limits to English language AND Humans AND Clinical Trials, All. Other sources included reference lists of located trials, British Committee for Standards in Haematology guidelines and personal communication with researchers in the field. The online search retrieved eight publications. Six publications were excluded following abstract review (2 records: relapsed disease; 2 records: unsuitable study design; 1 record: allogeneic transplant; 1 record: paediatric study). Three publications were found by searching the reference lists of retrieved studies. The final selection list included five papers with a total sample size of 333 patients. The selection process was undertaken in March 2015. The results of the prospective studies (Table I) and a risk of bias table (Fig 1) are presented. There are no data available on the role of HDC-ASCT for PTCL from randomized controlled trials. Although HDC-ASCT may improve outcomes in PTCL, the available data comprise non-randomized studies with significant risk of bias, meaning definitive recommendations cannot be made. The achievement of first CR (CR1) before ASCT appears to be a strong predictor of improved survival. However, this observation reflects selection bias: patients who achieve CR1 have inherently more chemo-sensitive disease and are more likely to proceed to HDCASCT. This is supported by a large multicentre US dataset where only 8% of PTCL underwent first-line HDC-ASCT and, although HDC-ASCT associated with a survival benefit, this advantage disappeared in multivariate analyses after adjusting for initial treatment response (Abramson et al, 2014). In the prospective HDC-ASCT studies, as anticipated, ALKpositive ALCL and lower International Prognostic Index scores were associated with favourable outcomes. It is notable that across the HDC-ASCT trials the median age was 47 years compared to the median age of 62 years in the ITcP (Vose et al, 2008). Although direct comparison between studies should not be relied upon, it is notable that younger patients treated within the chemotherapy-only phase III German High-Grade correspondence