Prognostic value of etoposide area under the curve (AUC) in lymphoma patients treated with BEAM regimen and ASCT: Multicenter study of Groupe d’Etudes des Lymphomes de l’Adulte (GELA).

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8068 Background: The prospective LYMPK study primary objective was to assess the impact of etoposide pharmacokinetic (PK) parameters on toxicity and efficacy in lymphoma patients receiving the BEAM regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). We previously showed the high inter-individual variability in etoposide PKs, defined by area under the curve (AUC) and trough concentration (Cmin), among study patients treated with the same doses /m2 (You B et al, Proc. ASCO 2008). Methods: Ninety-six patients with malignant lymphoma at 1st line (n=52) or relapse (n=44) were enrolled in 5 centers. All received BEAM regimen, including high-dose etoposide (100 to 200 mg/m2 bid for 4 days), followed by ASCT. Individual etoposide AUC and Cmin were estimated by population PK approach using NONMEM program. The impact of PK parameters on toxicity and survival was assessed using linear regression and univariate/multivariate analyses. Results: Data from 90 patients were assessable after a 4.2-year median follow-up. The bi-compartment model previously reported was used to characterize PK parameters (You B et al, Proc. ASCO 2008). Etoposide AUC and Cmin correlated with mucositis duration, especially for grade 3-4 toxicity (p< 0.05), but not with other toxicities. Cmin had significant prognostic value regarding 5 year progression free survival (p=0.03). Five year overall survival (OS) was longer in patients with higher AUC (76% vs 56%, if AUC > median, p=0.04) as it was in patients with higher Cmin (78% vs 54%, if Cmin > median, p=0.02). When assessed with available IPI prognostic factors (age; performance status; LDH and stage) using Cox analysis, the only independent prognostic factors of OS and disease specific survival were etoposide AUC (HR= 0.39, 95% CI = 0.16-0.94) and Cmin (HR = 0.32, 95% CI = 0.12-0.80). Conclusions: LYMPK study results suggest that individual etoposide systemic exposure has a strong impact on survival in lymphoma patient receiving BEAM regimen and ASCT. Given the high variability in patient AUCs, plasma concentration-based adjustment of etoposide dose may be considered in future studies.