Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a 2-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox proportional hazards model. 154 genetically European patients were used for the primary analysis. An intronic SNP in ABCC3 (rs4148405) was associated with a significantly shorter DFS (HR=3.2, p=5.6 x 10(-6)) in our primary cohort. In addition a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, p=0.001 for 154 European ancestry; HR=1.7, p=0.028 for 125 non-European patients). Thus for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.

Identification and Utilization of Donor and Recipient Genetic Variants to Predict Survival After HCT: Are We Ready for Primetime?

“…A high Bu steady-state plasma concentration can be toxic, whereas low concentrations are associated with poor engraftment and higher relapse risk [ 72 ]. Consequently, clinical outcomes are improved by targeting plasma concentrations and thus variants in the predominant metabolizing enzymes involved in Bu conjugation, glutathione S -transferase ( GST ) isoenzymes A1 ( GSTA1 ) and M1 ( GSTM1 ), have been tested for association with survival after transplant [ 10 , 17 , 54 , 66 – 68 , 72 – 75 ]. Yee et al found a SNP in the GSTM1-GSTM5 locus, rs3754446, associated with an almost twofold shorter disease-free survival in two cohorts of acute myeloid leukemia (AML) patients treated with chemotherapy-based autologous HCT.…”

“…Yee et al found a SNP in the GSTM1-GSTM5 locus, rs3754446, associated with an almost twofold shorter disease-free survival in two cohorts of acute myeloid leukemia (AML) patients treated with chemotherapy-based autologous HCT. Despite replicating in both cohorts ( p = .001 and p = .028), the finding was not significant after correction for multiple testing [ 10 ]. The authors found similar relationships with rs4148405 in ABCC3 , although while passing multiple testing correction in cohort 1 ( p < 10e−06), it did not replicate in cohort 2.…”

“…Another approach has focused on selecting and evaluating SNPs in genes within drug metabolism/detoxification pathways. By demonstrating genetic associations with transplant outcomes after exposure to various chemotherapeutic agents or combinations, the potential to assign a conditioning regimen based on genotype becomes a possibility [ 10 , 11 ]. To date, these candidate gene approaches have not been conclusive, in part due to sample size limitations and marked heterogeneity in population, disease, HLA matching, donor, and graft source.…”

Surmounting Cytarabine-resistance in acute myeloblastic leukemia cells and specimens with a synergistic combination of hydroxyurea and azidothymidine

“…Cytarabine uptake via equilibrative nucleoside transporters (ENTs) 5 and concentrative nucleoside transporter 3 (CNT3) 6 , is followed by three consecutive phosphorylation steps resulting in the cytotoxic metabolite Ara-CTP 1 . The rate-limiting enzyme in Cytarabine phosphorylation is deoxycytidine kinase (dCK), a central enzyme in the nucleoside salvage pathway (NSP) 7–9 , which also phosphorylates the naturally occurring deoxycytidine, deoxyadenosine and deoxyguanosine to their monophosphate form 8 .…”

Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia

“…Although several prognostic factors in childhood AML have been identified, current predictive survival analysis remains inadequate. A number of studies have evaluated mechanisms of drug resistance in AML; however, rather than taking a broad approach, these studies have focused on genes involved in the cellular metabolism of cytarabine (Ara‐C), the backbone of nearly all AML treatment strategies, or have used a candidate gene approach of drug metabolizing enzymes or drug transporters with inconclusive results …”