Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia

Abstract

High-dose methotrexate (HDMTX) plays an important role in the treatment of acute lymphoblastic leukemia (ALL) although there is great inter-patient variability in the efficacy and toxicity of MTX. The relationship between polymorphisms in genes encoding MTX transporters and MTX response is controversial. In the present study, 322 Chinese children with standard- and intermediate-risk ALL were genotyped for 12 polymorphisms. SLCO1B1 rs10841753 showed a significant association with plasma MTX levels at 48 h (P = 0.017). Patients who had the ABCB1 rs1128503 C allele had longer duration of hospitalization than did those with the TT genotype (P = 0.006). No association was found between oral mucositis and any polymorphism. Long-term outcome was worse in patients with the SLCO1B1 rs4149056 CC genotype than in patients with TT or TC (5-year event-free survival [EFS] 33.3 ± 19.2% vs. 90.5 ± 1.7%, P < 0.001), and was worse in patients with the SCL19A1 rs2838958 AA genotype than in patients with AG or GG (5-year EFS 78.5 ± 4.6% vs. 92.2 ± 1.8%, P = 0.008). Multiple Cox regression analyses revealed associations of minimal residual disease (MRD) at day 33 (hazard ratio 3.458; P = 0.002), MRD at day 78 (hazard ratio 6.330; P = 0.001), SLCO1B1 rs4149056 (hazard ratio 12.242; P < 0.001), and SCL19A1 rs2838958 (hazard ratio 2.324; P = 0.019) with EFS. Our findings show that polymorphisms in genes encoding MTX transporters substantially influence the kinetics and response to HDMTX therapy in childhood ALL.

Factors Contributing to the Duration of Chemotherapy-Induced Severe Oral Mucositis in Oncopediatric Patients

“…MXT is one of most cytotoxic agents used on chemotherapy and is often used on pediatric patients with hematological [ 22 ] and solid neoplasms [ 23 ] including different phases of treatment. In our study, we reported MXT therapeutic is more associated with non-metastatic and older patients despite length of treatment.…”

Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

“…Numerous variants in these pharmacogenes have been found to be associated with different prognosis and probability of toxic events after MTX administration. Several studies found polymorphisms in DHFR, MTHFR, TYMS, SLC19A1 and SLCO1B1 to be significantly associated with event-free survival (EFS) of ALL patients [10][11][12][13][14]. The toxic events can be gastrointestinal, hepatic, neurological, hematologic, etc.…”

“…The toxic events can be gastrointestinal, hepatic, neurological, hematologic, etc. There have been numerous studies in favor of classifying some of variants as biomarkers of MTX induced toxicity [12,13,[15][16][17][18][19].…”

Endogenous Metabolites‐Mediated Communication Between OAT1/OAT3 and OATP1B1 May Explain the Association Between SLCO1B1 SNPs and Methotrexate Toxicity

“…The first description of an association between single nucleotide polymorphisms (SNPs) in SLCO1B1 , the gene coding for organic anion transporting polypeptide 1B1 (OATP1B1), and methotrexate (MTX) disposition and toxicity was published in 2009 . This has since been repeatedly confirmed in children with acute lymphoblastic leukemia (ALL) . Genome‐wide studies showed that numerous variants in SLCO1B1 are involved, although two common SNPs (rs2306283/c.388A>G in exon 4 and rs4149056/c.521T>C in exon 5) may be of particular importance .…”