Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism.
This study investigated whether a polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) modifies responses to methotrexate (MTX) in patients undergoing bone marrow transplantation. About 10% to 12% of the population carry the MTHFR TT genotype (enzyme activity, 30% of wild type [CC]). Patients (n = 220) with chronic myelogenous leukemia underwent marrow allografts and were given a short course of MTX. MTX toxicity measures included the oral mucositis index (OMI), speed of engraftment (platelet and granulocyte counts), and bilirubin. Patients with lower MTHFR activity (TT genotype) had 36% higher mean OMI during days 1 to 18 (+5.7, P =.046) and 20% higher OMI between days 6 and 12 (+3.8, P =.27). Platelet counts recovered more slowly among patients with the TT genotype compared to wild type (24% slower recovery to 10 000 platelets/microL, P =.23; 34% slower to 20 000/microL, P =.08). Patients with decreased MTHFR activity appear at risk of higher MTX toxicity. Because of the high prevalence of the TT genotype, these results may have implications for MTX dosage.
Ulrich
C M
CM
Public Health Sciences Division and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. nulrich@fhcrc.org
Yasui
Y
Y
Storb
R
R
Schubert
M M
MM
Wagner
J L
JL
Bigler
J
J
Ariail
K S
KS
Keener
C L
CL
Li
S
S
Liu
H
H
Farin
F M
FM
Potter
J D
JD
D000328:Adult; D001663:Bilirubin / Q000097:blood; D001711:Biotransformation; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000150:complications / Q000188:drug therapy; D007958:Leukocyte Count; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000633:toxicity; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D009061:Mouth Mucosa; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D010976:Platelet Count; D017354:Point Mutation; D011110:Polymorphism, Genetic; D013280:Stomatitis / Q000139:chemically induced / Q000209:etiology / Q000235:genetics
D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D001663:Bilirubin; D008727:Methotrexate