Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate.
BACKGROUND
Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common mutation of the gene encoding the enzyme that catalyzes reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor in the metabolism of folate, determines a striking reduction in the enzyme activity in carriers of mutation at homozygous status.


METHODS
We retrospectively analyzed the incidence of MTHFR C677T and the influence of genotype on methotrexate (MTX) toxicity in patients with acute leukemia undergoing maintenance chemotherapy. Seventy-eight patients were analyzed and 61 were evaluable for toxicity. MTX toxicity was assessed on bone marrow, liver and mucosae.


RESULTS
The incidence of the C677T mutation was as expected in the general Italian population with 23.08% of patients being TT, 38.46% of patients CT and 38.46% of patients CC. The TT genotype was significantly associated with an increase of toxicity during MTX administration. No specific pattern of toxicity was detected, although in TT patients myelosuppression and liver toxicity were more pronounced.


CONCLUSIONS
TT genotype may indicate a need to reduce the dose of MTX during prolonged administration. Considering the high prevalence of homozygous individuals in the Italian population, pretreatment screening may be worthwhile.
Chiusolo
P
P
Cattedra di Ematologia, Divisione di Ematologia, Università Cattolica Sacro Cuore Roma, Italy. emacat@rm.unicatt.it
Reddiconto
G
G
Casorelli
I
I
Laurenti
L
L
Sorà
F
F
Mele
L
L
Annino
L
L
Leone
G
G
Sica
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D005820:Genetic Testing; D006720:Homozygote; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011336:Probability; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity
D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate