학술논문
Pharmacogenetic study of the impact of ABCB1 single-nucleotide polymorphisms on lenalidomide treatment outcomes in patients with multiple myeloma: results from a phase IV observational study and subsequent phase II clinical trial.
Document Type
Academic Journal
Author
Jakobsen Falk I; Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. Ingrid.jakobsen.falk@liu.se.; Lund J; Unit for Hematology, Department of Medicine, Karolinska Institute, Huddinge, Sweden.; Gréen H; Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.; Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.; Gruber A; Unit for Hematology, Department of Medicine, Karolinska Institute, Huddinge, Sweden.; Alici E; Unit for Hematology, Department of Medicine, Karolinska Institute, Huddinge, Sweden.; Lauri B; Department of Internal Medicine, Sunderby Hospital, Luleå, Sweden.; Blimark C; Hematology Department, Sahlgrenska University Hospital, Gothenburg, Sweden.; Mellqvist UH; Division for Haematology, Oncology and Lung, Department of Medicine, South Elvsborg Hospital, Borås, Sweden.; Swedin A; Hematology Department, Skåne University Hospital, Lund, Sweden.; Forsberg K; Department of Hematology, Norrland University Hospital, Umeå, Sweden.; Carlsson C; Department of Internal Medicine, Hallands Hospital, Halmstad, Sweden.; Hardling M; Department of Hematology, Uddevalla Hospital, Uddevalla, Sweden.; Ahlberg L; Department of Hematology, Linköping University Hospital, Linköping, Sweden.; Lotfi K; Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.; Department of Hematology, Linköping University Hospital, Linköping, Sweden.; Nahi H; Unit for Hematology, Department of Medicine, Karolinska Institute, Huddinge, Sweden.
Source
Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7806519 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0843 (Electronic) Linking ISSN: 03445704 NLM ISO Abbreviation: Cancer Chemother Pharmacol Subsets: MEDLINE
Subject
Language
English
Abstract
Purpose: Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment. We, therefore, investigated the influence of ABCB1 genetic variants on Len treatment outcomes and adverse events (AEs).
Methods: Ninety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G>A (Ser400Asn, rs2229109), 1236C>T (silent, rs1128503), 2677G>T/A (Ala893Ser, rs2032582), and 3435C>T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, outcomes, and AEs were investigated.
Results: No significant associations were found between genotype and either best response rates or hematological AEs, and 1236C>T, 2677G>T or 3435C>T genotypes had no impact on survival. There was a trend towards increased time to progression (TTP) in patients carrying the 1199A variant, and a significant difference in TTP between genotypes in patients with standard-risk cytogenetics.
Conclusions: Our findings show a limited influence of ABCB1 genotype on lenalidomide treatment efficacy and safety. The results suggest that 1199G>A may be a marker of TTP following Len treatment in standard-risk patients; however, larger studies are needed to validate and clarify the relationship.
Methods: Ninety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G>A (Ser400Asn, rs2229109), 1236C>T (silent, rs1128503), 2677G>T/A (Ala893Ser, rs2032582), and 3435C>T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, outcomes, and AEs were investigated.
Results: No significant associations were found between genotype and either best response rates or hematological AEs, and 1236C>T, 2677G>T or 3435C>T genotypes had no impact on survival. There was a trend towards increased time to progression (TTP) in patients carrying the 1199A variant, and a significant difference in TTP between genotypes in patients with standard-risk cytogenetics.
Conclusions: Our findings show a limited influence of ABCB1 genotype on lenalidomide treatment efficacy and safety. The results suggest that 1199G>A may be a marker of TTP following Len treatment in standard-risk patients; however, larger studies are needed to validate and clarify the relationship.