INTRODUCTION Anaplastic Large Cell Lymphomas (ALCL) are rare T-cell neoplasms grouped according to whether they express the fusion protein anaplastic lymphoma kinase (ALK+) or not (ALK-). ALK+ ALCL has consistently been found to have a favorable outcome compared to ALK- ALCL, but ALK+ ALCL is also associated with young age and other low risk features and not all studies have found ALK-expression to be an independent prognostic factor. In this population-based study, we aimed at analyzing the outcome and risk factors for survival in a bi-national cohort of patients with systemic ALCL. METHODS All adult (>18 years) patients with systemic ALCL in the Swedish and Danish Lymphoma Registries diagnosed between 2000 and 2010 were included in the study. Primary cutaneous ALCL cases were excluded. The diagnosis of ALCL was established in routine care and no study-specific pathology review was performed. RESULTS A total of 371 patients (ALK+ ALCL n=122) were identified, representing 1.3% of all lymphomas, through both national registries. ALK-status was missing in 33 patients (ALK u ALCL). The median follow-up was 7.2 years. ALK+ patients were younger than ALK- patients (median age 40 versus 66 years, p<0.001). In all, 209 patients died (ALK+ n=32, ALK- n=151, ALK u n=26) and among the 328 patients with available relapse data, 118 patients experienced relapse or progression (ALK+ n=20, ALK- n= 83, ALK u n=15). The 5-year overall and progression-free survival (OS and PFS, respectively) were 78% and 64% in ALK+ ALCL, 37% and 32% in ALK- ALCL and 27% and 25% in ALK u ALCL. Data on primary treatment was available in 341 out of 371 patients (92%). The majority of patients (n=278, 82%) was treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP plus etoposide (CHOEP). Up-front autologous stem cell transplantation (ASCT) was performed in 38 patients with ALK- ALCL and in 6 patients with ALK+ ALCL. Most ALK- ALCL patients undergoing up-front ASCT consolidation received CHOEP as induction treatment. Age had a profound impact on survival and based on the Kaplan-Meier estimates the age cut-offs described for the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) were used. All features, including treatment with CHOP compared to CHOEP, that were associated with survival at the level of p<0.1 in univariable analysis were tested in a multivariable model. The only independent risk factors in the multivariable analysis were treatment with CHOEP, which was associated with better OS (HR 0.48 95% CI 0.32-0.74, p=0.001), and increasing NCCN-IPI score (HR [for each increment] 1.6 95% CI 1.5-1.8, p<0.001), which was associated with inferior OS. A separate multivariable risk factor analysis for OS was performed in patients treated with CHOEP (N=108). In this analysis, age (HR 2.9 95% CI 1.5-5.3, p=0.001), ALK-negativity (HR 2.6 95% CI 1.2-6.0, p=0.020) and elevated LDH (HR 2.1 95% CI 1.0-4.3, p=0.047) were independently associated to worse OS. Assigning 0,1 and 2 points for age <40, 40-60 and 60-75 respectively, ALK negativity 1 point and elevated LDH 1 point, we created a score that identified 4 groups with significantly different OS. Patients with a score of 3 or 4 had a similar OS, and were thus combined. DISCUSSION This population-based study based on two national registries reports the outcome of the largest cohort of adult ALCL patients published so far. Our study confirms the favourable outcome of ALK+ ALCL patients and the association with low-risk features. The addition of etoposide to CHOP was independently associated with a superior OS, and when adjusting for this treatment modification, the impact of ALK-expression on OS was mitigated. We also performed a separate risk factor analysis in the group of patients receiving CHOEP treatment. Age, ALK-negativity and elevated LDH were independent risk factors for OS in this group and were assembled in a proposed novel score, which could represent a useful tool in future management strategies in ALCL. Our data supports that the addition of etoposide to CHOP, if tolerated, is an important component in the treatment of ALCL and that the impact of ALK-expression on outcome is affected by treatment. Based on multivariable risk factor analysis in CHOEP treated patients, we propose a novel ALCL-specific score for future validation in independent cohorts. Disclosures Relander: Respiratorius: Patents & Royalties: valproate for DLBCL.
Background PET/CT has proven to be highly accurate for staging of Hodgkin lymphoma. A recent study also reported that PET/CT detected additional disease sites in 50% of patients with peripheral T-cell lymphoma (PTCL) as compared to conventional CT-based staging and had higher sensitivity for extranodal disease. This may challenge the validity of pre-therapeutic prognostic tools such as the widely used international prognostic index (IPI), which contains imaging-depended clinical features such as Ann Arbor stage and extranodal disease. Aim To examine the validity of IPI in PET/CT staged PTCL patients treated with CHOP or CHOP-like first line therapies. Patients and Methods The present retrospective study included PTCL patients from five Danish referral hematology centers. Potential candidates for the study were identified from a search in the Danish Lymphoma Registry (LYFO). Patients with PTCL not otherwise specified (PTCL NOS), anaplastic large cell lymphoma (ALCL), or angioimmunoblastic T-cell lymphoma (AITL) were included if they underwent PET/CT staging and were treated with CHOP or CHOP-like first-line therapy +/- consolidating high-dose therapy. Medical records were retrieved and reviewed for all included patients. Results During the time period 2006-2013 a total of 137 out of 259 PTCL patients were staged with PET/CT. Of these 119 (87%) received CHOP or CHOP-lile first-line therapy and were included in this analysis. The patients were diagnosed with PTCL NOS (n=49), AITL (n=18), and ALCL (n=52). The median age was 58 yrs. and the male:female ratio was 1.3. Advanced stage disease (III-IV) was diagnosed in 71% (n=85) and 27% (n=32) of the patients had more than one extranodal site involved. In univariate Cox regression analyses elevated LDH (HR 2.77, 95%CI 1.44-5.34), > 1 extranodal disease site (HR 3.09, 95%CI 1.67-5.72), age > 60 yrs. (HR 2.49, 95%CI 1.35-4.59), ECOG performance > 1 (HR 2.03, 95% CI 1.08-3.83), and Ann Arbor stage III-IV (HR 2.43 95%CI 1.08-5.73) were all significantly associated with inferior overall survival (OS). The presence of more than one extranodal disease site was an adverse prognostic factor for both age groups. In a multivariate Cox regression analysis including these variables, age > 60 yrs., > 1 extranodal site, and elevated LDH retained independent association with short OS. Using IPI score 0-1 (low-risk) as reference group score the HRs for death were 2.49 (95%CI 0.87-7.19) for low-intermediate, 4.31 (95%CI 1.53-12.09) for high-intermediate, and 12.74 (95%CI 4.43-36.61) for high risk patients. IPI-specific OS fractions are show in the figure. Conclusions Despite the potential stage migration associated with the introduction of new and more accurate imaging modalities such as PET/CT, the original IPI developed two decades ago continues to be a highly valid tool for predicting overall survival in PTCL patients treated with CHOP or CHOP-like first-line therapies. TCEG, MBP, and LCG contributed equally to the present work. Disclosures: No relevant conflicts of interest to declare.
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