Etoposide pharmacokinetics impact the outcomes of lymphoma patients treated with BEAM regimen and ASCT: a multicenter study of the LYmphoma Study Association (LYSA)

Cancer Chemother Pharmacol. 2015 Nov;76(5):939-48. doi: 10.1007/s00280-015-2866-9. Epub 2015 Sep 21.


Background: Relationships between pharmacokinetic (PK) parameters of etoposide and toxicity survivals were reported in cancer patients treated at standard doses. The clinical impact of PK variations of etoposide high doses has never been explored in lymphoma patients.

Patients and methods: The primary objective of LYMPK study was to prospectively assess the impact of etoposide PK parameters on outcomes in lymphoma patients receiving high-dose chemotherapy regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). Individual etoposide PK parameters were estimated with a previously reported bi-compartment model using NONMEM(®) program. The impact of PK parameters on toxicity and survival was assessed using univariate/multivariate analyses.

Results: A total of 91 patients with malignant lymphoma [non-Hodgkin's lymphoma (NHL): 79; Hodgkin's lymphoma: 12] at first line (n = 49) or relapse (n = 42) were enrolled in five centers. Large inter-individual variabilities in individual PK values were found for the same administration doses. In NHL patients, cumulative higher trough concentrations over the eight administrations of the first cycle (TotC min, categorized by the median 58.71 mg/L) had significant prognostic value regarding the 5-year progression-free survival (PFS: 73.6 vs 46.5 %, P = 0.015) and 5-year overall survival (OS: 74.0 vs 52.2 %, P = 0.034). Using a Cox model analysis, integrating disease settings (first line vs recurrent disease), simplified IPI and other prognostic factors, TotC min was the only significant independent prognostic factor influencing PFS, disease-specific survival and OS.

Conclusion: This prospective study suggests survival of NHL patients treated with BEAM regimen and ASCT might be improved by increasing etoposide administration dose, or plasma concentration-based adjustment.

Keywords: Etoposide; Lymphoma; Non-Hodgkin; Pharmacokinetics; Stem cell transplantations; Survival.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bilirubin / blood
  • Carmustine / administration & dosage
  • Creatinine / blood
  • Cytarabine / administration & dosage
  • Disease-Free Survival
  • Etoposide / administration & dosage
  • Etoposide / blood
  • Etoposide / pharmacokinetics*
  • Female
  • Hodgkin Disease / drug therapy
  • Hodgkin Disease / therapy
  • Humans
  • Kaplan-Meier Estimate
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Lymphoma, Non-Hodgkin / therapy
  • Male
  • Melphalan / administration & dosage
  • Middle Aged
  • Peripheral Blood Stem Cell Transplantation*
  • Prognosis
  • Proportional Hazards Models
  • Prospective Studies
  • Risk Assessment
  • Serum Albumin / analysis
  • Transplantation, Autologous
  • Treatment Outcome
  • Young Adult


  • Serum Albumin
  • Cytarabine
  • Etoposide
  • Creatinine
  • Melphalan
  • Bilirubin
  • Carmustine

Supplementary concepts

  • BEAM regimen