Restricted accessCase reportFirst published online 2016-6
A case of recurrent pancytopenia in a patient with acute promyelocytic leukemia on maintenance chemotherapy and concomitant methyltetrahydrofolate reductase and thiopurine S-methyltransferase mutation - review of literature
Pharmacogenetics is a study of how genetic variation of an individual affects the drug response. We report a case of recurrent pancytopenia resulting from maintenance chemotherapy in a patient with acute promyelocytic leukemia and two pharmacogenetic mutations, namely, methylene tetrahydrofolate reductase C677T homozygous mutation and thiopurine methyltransferase mutation.
PowellBLMoserBStockW. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood2010; 116: 3751–3757.
2.
RellingMVDervieuxT. Pharmacogenetics and cancer therapy. Nat Rev Cancer2001; 1: 99–108.
3.
YangQBaileyLClarkeR. Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults. Am J Clin Nutr2012; 95: 1245–1253.
4.
RosenbergNMurataMIkedaY. The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. Am J Hum Genet2002; 70: 758–762.
5.
FrosstPBlomHJMilosR. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet1995; 10: 111–113.
6.
WeisbergITranPChristensenB. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab1998; 64: 169–172.
7.
SohnKJCroxfordRYatesZ. Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst2004; 96: 134–144.
8.
van EdeAELaanRFBlomHJ. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum2001; 44: 2525–2530.
9.
UranoWTaniguchiAYamanakaH. Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics2002; 12: 183–190.
10.
CalizRdelAJBalsaA. The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand J Rheumatol2012; 41: 10–14.
11.
ChoeJYLeeHJungHY. Methylenetetrahydrofolate reductase polymorphisms, C677T and A1298C, are associated with methotrexate-related toxicities in Korean patients with rheumatoid arthritis. Rheumatol Int2012; 32: 1837–1842.
12.
ToffoliGVeronesiABoiocchiM. MTHFR gene polymorphism and severe toxicity during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil (CMF). Ann Oncol2000; 11: 373–374.
13.
ToffoliGRussoAInnocentiF. Effect of methylenetetrahydrofolate reductase 677C–>T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. Int J Cancer2003; 103: 294–299.
14.
ChiusoloPReddicontoGCasorelliI. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol2002; 13: 1915–1918.
15.
D'AngeloVRamagliaMIannottaA. Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol2011; 68: 1339–1346.
16.
YangLHuXXuL. Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. Tumour Biol2012; 33: 1445–1454.
17.
EissaDSAhmedTM. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia. Blood Coagul Fibrinolysis2013; 24: 181–188.
18.
GemmatiDOngaroATognazzoS. Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin's lymphoma patients: association with toxicity and survival. Haematologica2007; 92: 478–485.
19.
UlrichCMYasuiYStorbR. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood2001; 98: 231–234.
20.
MurphyNDivineyMSzerJ. Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate. Bone Marrow Transplant2006; 37: 773–779.
21.
AplencRThompsonJHanP. Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res2005; 65: 2482–2487.
22.
Ruiz-ArguellesGJCoconi-LinaresLNGarces-EiseleJ. Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico. Hematology2007; 12: 387–391.
LaseckaLDixonPHMolokhiaM. 667C>T and 1298A>C polymorphisms of MTHFR do not predict response to methotrexate in patients with gestational trophoblastic neoplasia. Gynecol Oncol2011; 123: 605–609.
25.
Lopez-LopezEBallesterosJGarcia-OradA. MTHFR 677TT genotype and toxicity of methotrexate: controversial results. Cancer Chemother Pharmacol2011; 68: 1369–1370.
26.
HagleitnerMMCoenenMJAplencR. The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer. Pharmacogenomics J2014; 14: 115–119.
27.
LinkerCDamonLRiesC. Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol2002 May 15; 20(10): 2464–2471.
28.
SahasranamanSHowardDRoyS. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol2008; 64: 753–767.
29.
EvansWEHonYYBomgaarsL. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol2001; 19: 2293–2301.
30.
McLeodHLSivaC. The thiopurine S-methyltransferase gene locus – implications for clinical pharmacogenomics. Pharmacogenomics2002; 3: 89–98.
31.
AppellMLBergJDuleyJ. Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics2013; 23: 242–248.
32.
LevinsenMRotevatnEORosthojS. Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer. Pediatr Blood Cancer2014; 61: 797–802.
33.
SandersonJAnsariAMarinakiT. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy?Ann Clin Biochem2004; 41: 294–302.
34.
KimSKJunJBEl-SohemyA. Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol2006; 33: 1266–1274.
