Addition of Etoposide to CHOP Is Associated with Improved Outcome in Adult Anaplastic Large Cell Lymphoma Patients: A Nordic Lymphoma Group Study

Abstract

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.

T-Cell Lymphomas, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology

“…46 The Nordic Lymphoma Group also reported similar findings among 122 patients with ALCL, ALK-positive treated with the CHOEP regimen (5-year OS and PFS rates were 78% and 64%, respectively). 47 CHOEP regimen was associated with an improved OS in patients aged 41 to 65 years, even after adjusting for risk factors (P5.05). Bone marrow involvement was independently associated with poorer PFS in a multivariate analysis.…”

“…44 However, with the exception of ALCL, ALKpositive, outcomes are not optimal in other subtypes. 5,[45][46][47][48][49] In a retrospective analysis of 289 patients with PTCL treated within the DSHNHL trials, CHOEP was associated with an EFS benefit in ALCL, ALK-positive in patients younger than 60 to 65 years and also in patients with The NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.…”

Systemic ALCL Treated in Routine Clinical Practice: Outcomes Following First-Line Chemotherapy from a Multicentre Cohort

“…There are no published randomized trials comparing CHOP with other chemotherapy approaches for newly diagnosed sALCL. Retrospective studies support CHOEP in this context, the Nordic Lymphoma Group study reported improved survival outcomes (HR 0.48, 95% CI 0.32–0.74) when compared to CHOP in sALCL [ 9 , 17 ]. The T cell lymphoma project also reported a trend towards improved outcomes with etoposide regimens with superior 5-year OS (56% vs 69% for etoposide-containing regimens, p = 0.05) and a trend towards improved 5-year PFS (39% vs 50% for etoposide-containing regimens, p = 0.18) [ 8 ].…”

Patient Case Studies and Panel Discussion: Lymphoma

“…Retrospective studies suggest that outcomes may be better than historical data with CHOP. [3][4][5] In a prospective trial, the Nordic group evaluated the role of autologous stem cell transplantation after patients achieved a CR/partial response with CHOEP. 6 At a median follow-up of 5 years, the 5-year progressionfree survival (PFS) and overall survival (OS) rates for AITL were 49% and 52%, respectively, and 38% and 47% for PTCL-NOS, respectively.…”