XML Template (2015) [5.3.2015–4:49pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150014/APPFile/SG-OPPJ150014.3d
(OPP)
[1–5] [INVALID Stage]
Case Report
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
J Oncol Pharm Practice 0(0) 1–4 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215577235 opp.sagepub.com
Yi-Kong Keung, Lap-Woon Keung and Eddie Hong-Lung Hu
Abstract 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.
Keywords Acute promyelocytic leukemia, pancytopenia, methylene tetrahydrofolate reductase, homozygous MTHFR C677T mutation, thiopurine methyltransferase, thiopurine S-methyltransferase
Introduction 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 pharmacogenetic mutations.
Case history This is a 47-year-old Hispanic male who was diagnosed with microgranular variant acute promyelocytic leukemia in 2013 presented with hyperleukocytosis over 100,000/mL and typical cytogenetic abnormalities, 46,XY,t(15;17)(q24;q21)[20]. He achieved complete remission after induction chemotherapy consisting of intravenous daunorubicin, cytarabine and oral alltrans retinoic acid (ATRA) followed by consolidation chemotherapy.1 He was then started on maintenance chemotherapy consisting of oral methotrexate (MTX) 15 mg/m2 with BSA of 2.14 round to total of 30 mg
once a week, oral 6-mercaptopurine (6MP) 90 mg/m2 with total of 100 mg bid, and oral ATRA 45 mg/m2 with total of 50 mg bid for 15 days every 3 months. Sixteen days after the start of maintenance chemotherapy he was admitted to local hospital for right lower quadrant pain and diarrhea, with WBC 1200/mL, hemoglobin 12 gm/dL and platelet was 65,000/mL. Clostridium difficile toxin was negative in the stool. He subsequently developed severe pancytopenia associated with severe mucositis and culture-negative neutropenic fever that was treated with empiric broad spectrum antibiotics. Plasma MTX level was less than 0.05 mmol/L. Repeat bone marrow biopsy showed severely hypocellular marrow with no increased blasts. Quantitative PCR of PML/RARa fusion UCLA, Hematology-Oncology Division Clinic, Alhambra, USA Corresponding author: Yi-Kong Keung, 707, S. Garfield Ave #304, Alhambra, CA 91801, USA. Email: [email protected]
Downloaded from opp.sagepub.com at UNIVERSITE DE MONTREAL on June 12, 2015
XML Template (2015) [5.3.2015–4:49pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150014/APPFile/SG-OPPJ150014.3d
(OPP)
[1–5] [INVALID Stage]
2
Journal of Oncology Pharmacy Practice 0(0)
transcripts (molecular marker for acute promyelocytic leukemia) was not detected. Filgrastim 5 mcg/kg rounded to vial size of 300 mcg was started and the blood counts gradually recovered (Figure 1). ATRA was resumed at 3 months and was tolerated well. He was restarted on the maintenance chemotherapy at a reduced dosage, 6MP 25 mg daily and MTX 7.5 mg weekly. Three weeks later WBC 1900/mL, hemoglobin 8.9 gm/dL and platelet was 31,000/mL. He was admitted again for right upper quadrant abdominal pain associated with aggressive skin rash, fever and mucositis. Wound swab and blood culture were negative. Blood Aspergillus galactomannan antigen was not detected. He was placed on empiric voriconazole and acyclovir, in addition to broad spectrum antibiotics. He was found to be homozygous for methyltetrahydrofolate reductase (MTHFR) C677T mutation. Blood homocystine was normal at 8.1 mmol/L. Quantitative PCR of PML/RARa fusion transcripts were not detected. Filgrastim 5 mcg/kg rounded to vial size of 300 mcg was initiated and the blood counts slowly recovered. With the patient being homozygous for MTHFR C677T mutation possibly causing enhanced methotrexate toxicity, he was then started on 6MP alone at 100 mg bid for 14 days without methotrexate. WBC was 2500/mL, hemoglobin 9.7 gm/dL and platelet 48,000/mL at the completion of 6MP. Two days later he was admitted again for rectal bleeding and worsening pancytopenia with WBC 2100/mL, hemoglobin 8.5 gm/dL and platelet was 5000/mL. He developed neutropenic fever that was treated with broad spectrum antibiotics. 6-Methylmercaptopurine was elevated to
30,986 pmol/8 108RBC (normal < 5700). Thiopurine S-methyltransferase (TPMT) genotype showed one copy of 460 G > A and 719 A > G mutation suggestive of TPMT*3 A genotype. Because of persistent pancytopenia, bone marrow examination was performed and it showed severely hypocellular marrow with no evidence of increased blasts. Quantitative PCR of PML/RARa of the bone marrow was not detected. Filgrastim was started and the blood counts slowly recovered. Maintenance chemotherapy was never restarted.
Discussion Our case underscores the importance of pharmacogenetics in cancer therapy.2 Incidence of MTHFR polymorphism varies among different ethnic groups, with homozygous C677T 1.2% in non-Hispanic blacks, 11.6% non-Hispanic whites to 19.4% in Mexican Americans.3,4 Homozygous C677T mutation is associated with 70% reduction in MTHFR enzyme activity and heterozygous mutation with 35% reduction5; A1298C mutation has a similar reduction in enzyme activity.6 It has been demonstrated that C677T polymorphism may affect the intracellular folate composition for DNA synthesis and so influence the chemosensitivity of the colon and breast cancer cells.7 Severe MTX toxicity associated with MTHFR mutation has been reported in patients with rheumatoid arthritis,8–11 breast cancer,12 ovarian cancer,13 acute leukemia,14–17 lymphoma18 and in bone marrow transplantation,19,20 though not with controversy.21–26 C677T polymorphism has also been associated with
8 ATRA 50mg bidx15days 6MP 100mg bid MTX 30mg q week
7
6MP 25mg qd MTX 7.5mg q week
6MP 100mg bid
WBC 1,000/mL
6 5 4 3 2 1 0 0
20
40 60 80 100 120 140 Number of Days From Initiation of Maintenance Chemotherapy
Figure 1. Trend of WBC with day 0 being the day beginning maintenance chemotherapy.
Downloaded from opp.sagepub.com at UNIVERSITE DE MONTREAL on June 12, 2015
160
180
XML Template (2015) [5.3.2015–4:49pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150014/APPFile/SG-OPPJ150014.3d
(OPP)
[1–5] [INVALID Stage]
Keung et.al.
3
increased risk of relapse in patients with acute lymphoblastic leukemia.21 Thiopurines, such as azathioprine and 6MP, are commonly used to treat leukemia patients as maintenance therapy in acute promyelocytic leukemia and acute lymphoblastic leukemia.1,27 These drugs are converted to active metabolites which are then metabolized and excreted. TPMT deactivates the active metabolites of thiopurines.28 Patients with deficiency of TPMT tend to accumulate the active metabolites leading to enhanced toxicity.29 TPMT deficiency has been extensively studied and characterized.28,30 Common TPMT mutations, TPMT*2 (238 G > C), TPMT*3 A (460 G > A and 719 A > G), TPMT*3B (460 G > A), TPMT*3 C (719 A > G) accounts for 80–95% of cases with reduced TPMT activity.31 Our patient most likely carries two mutations 460 G > A and 719 A > G on one chromosome and normal TPMT*1 in another chromosome, and is thus classified as intermediate metabolizer. There is a rare possibility that 460 G > A and 719 A > G mutations are on two different chromosomes. In that case the patient will be compound heterozygous for TPMT*3B and TPMT*3 C deficiency and thus classified as a poor metabolizer. Decreasing the starting dose of 6MP has been recommended in patients with TPMT deficiency.32 Yet our patient developed severe marrow toxicity even at one-eighth of the standard 6MP dosage probably suggesting that he is a poor metabolizer instead. In order to prevent the ‘‘trial and error’’ dosing, routine pharmacogenetic screening has been recommended for TPMT deficiency and MTHFR polymorphism.33,34 If routine pharmagenetic screening were done in our patient, it may have prevented the repeated admissions on our patient. However, the long-term benefit such as disease control and survival and the cost effectiveness of these testing remains to be determined. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010; 116: 3751–3757. 2. Relling MV and Dervieux T. Pharmacogenetics and cancer therapy. Nat Rev Cancer 2001; 1: 99–108.
3. Yang Q, Bailey L, Clarke R, et al. Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults. Am J Clin Nutr 2012; 95: 1245–1253. 4. Rosenberg N, Murata M, Ikeda Y, et al. The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. Am J Hum Genet 2002; 70: 758–762. 5. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113. 6. Weisberg I, Tran P, Christensen B, et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998; 64: 169–172. 7. Sohn KJ, Croxford R, Yates Z, et al. Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5fluorouracil and methotrexate. J Natl Cancer Inst 2004; 96: 134–144. 8. van Ede AE, Laan RF, Blom HJ, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 2001; 44: 2525–2530. 9. Urano W, Taniguchi A, Yamanaka H, et al. 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. Pharmacogenetics 2002; 12: 183–190. 10. Caliz R, del AJ, Balsa A, et al. The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand J Rheumatol 2012; 41: 10–14. 11. Choe JY, Lee H, Jung HY, et al. Methylenetetrahydrofolate reductase polymorphisms, C677T and A1298C, are associated with methotrexate-related toxicities in Korean patients with rheumatoid arthritis. Rheumatol Int 2012; 32: 1837–1842. 12. Toffoli G, Veronesi A, Boiocchi M, et al. MTHFR gene polymorphism and severe toxicity during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil (CMF). Ann Oncol 2000; 11: 373–374. 13. Toffoli G, Russo A, Innocenti F, et al. Effect of methylenetetrahydrofolate reductase 677C–>T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. Int J Cancer 2003; 103: 294–299. 14. Chiusolo P, Reddiconto G, Casorelli I, et al. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol 2002; 13: 1915–1918. 15. D’Angelo V, Ramaglia M, Iannotta A, et al. Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia
Downloaded from opp.sagepub.com at UNIVERSITE DE MONTREAL on June 12, 2015
XML Template (2015) [5.3.2015–4:49pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150014/APPFile/SG-OPPJ150014.3d
(OPP)
[1–5] [INVALID Stage]
4
16.
17.
18.
19.
20.
21.
22.
23.
24.
Journal of Oncology Pharmacy Practice 0(0) and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol 2011; 68: 1339–1346. Yang L, Hu X and Xu L. Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. Tumour Biol 2012; 33: 1445–1454. Eissa DS and Ahmed TM. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia. Blood Coagul Fibrinolysis 2013; 24: 181–188. Gemmati D, Ongaro A, Tognazzo S, et al. Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin’s lymphoma patients: association with toxicity and survival. Haematologica 2007; 92: 478–485. Ulrich CM, Yasui Y, Storb R, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001; 98: 231–234. Murphy N, Diviney M, Szer J, et al. Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate. Bone Marrow Transplant 2006; 37: 773–779. Aplenc R, Thompson J, Han P, et al. Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res 2005; 65: 2482–2487. Ruiz-Arguelles GJ, Coconi-Linares LN, Garces-Eisele J, et al. Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico. Hematology 2007; 12: 387–391. Fisher MC and Cronstein BN. Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 2009; 36: 539–545. Lasecka L, Dixon PH, Molokhia M, et al. 667C>T and 1298A>C polymorphisms of MTHFR do not predict response to methotrexate in patients with gestational
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
trophoblastic neoplasia. Gynecol Oncol 2011; 123: 605–609. Lopez-Lopez E, Ballesteros J and Garcia-Orad A. MTHFR 677TT genotype and toxicity of methotrexate: controversial results. Cancer Chemother Pharmacol 2011; 68: 1369–1370. Hagleitner MM, Coenen MJ, Aplenc R, et al. The role of the MTHFR 677C>T polymorphism in methotrexateinduced liver toxicity: a meta-analysis in patients with cancer. Pharmacogenomics J 2014; 14: 115–119. Linker C, Damon L, Ries C, et al. Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol 2002 May 15; 20(10): 2464–2471. Sahasranaman S, Howard D and Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008; 64: 753–767. Evans WE, Hon YY, Bomgaars L, et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001; 19: 2293–2301. McLeod HL and Siva C. The thiopurine S-methyltransferase gene locus – implications for clinical pharmacogenomics. Pharmacogenomics 2002; 3: 89–98. Appell ML, Berg J, Duley J, et al. Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics 2013; 23: 242–248. Levinsen M, Rotevatn EO, Rosthoj S, et al. Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer. Pediatr Blood Cancer 2014; 61: 797–802. Sanderson J, Ansari A, Marinaki T, et al. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem 2004; 41: 294–302. Kim SK, Jun JB, El-Sohemy A, et al. Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 2006; 33: 1266–1274.
Downloaded from opp.sagepub.com at UNIVERSITE DE MONTREAL on June 12, 2015
(OPP)
[1–5] [INVALID Stage]
Case Report
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
J Oncol Pharm Practice 0(0) 1–4 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215577235 opp.sagepub.com
Yi-Kong Keung, Lap-Woon Keung and Eddie Hong-Lung Hu
Abstract 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.
Keywords Acute promyelocytic leukemia, pancytopenia, methylene tetrahydrofolate reductase, homozygous MTHFR C677T mutation, thiopurine methyltransferase, thiopurine S-methyltransferase
Introduction 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 pharmacogenetic mutations.
Case history This is a 47-year-old Hispanic male who was diagnosed with microgranular variant acute promyelocytic leukemia in 2013 presented with hyperleukocytosis over 100,000/mL and typical cytogenetic abnormalities, 46,XY,t(15;17)(q24;q21)[20]. He achieved complete remission after induction chemotherapy consisting of intravenous daunorubicin, cytarabine and oral alltrans retinoic acid (ATRA) followed by consolidation chemotherapy.1 He was then started on maintenance chemotherapy consisting of oral methotrexate (MTX) 15 mg/m2 with BSA of 2.14 round to total of 30 mg
once a week, oral 6-mercaptopurine (6MP) 90 mg/m2 with total of 100 mg bid, and oral ATRA 45 mg/m2 with total of 50 mg bid for 15 days every 3 months. Sixteen days after the start of maintenance chemotherapy he was admitted to local hospital for right lower quadrant pain and diarrhea, with WBC 1200/mL, hemoglobin 12 gm/dL and platelet was 65,000/mL. Clostridium difficile toxin was negative in the stool. He subsequently developed severe pancytopenia associated with severe mucositis and culture-negative neutropenic fever that was treated with empiric broad spectrum antibiotics. Plasma MTX level was less than 0.05 mmol/L. Repeat bone marrow biopsy showed severely hypocellular marrow with no increased blasts. Quantitative PCR of PML/RARa fusion UCLA, Hematology-Oncology Division Clinic, Alhambra, USA Corresponding author: Yi-Kong Keung, 707, S. Garfield Ave #304, Alhambra, CA 91801, USA. Email: [email protected]
Downloaded from opp.sagepub.com at UNIVERSITE DE MONTREAL on June 12, 2015
XML Template (2015) [5.3.2015–4:49pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150014/APPFile/SG-OPPJ150014.3d
(OPP)
[1–5] [INVALID Stage]
2
Journal of Oncology Pharmacy Practice 0(0)
transcripts (molecular marker for acute promyelocytic leukemia) was not detected. Filgrastim 5 mcg/kg rounded to vial size of 300 mcg was started and the blood counts gradually recovered (Figure 1). ATRA was resumed at 3 months and was tolerated well. He was restarted on the maintenance chemotherapy at a reduced dosage, 6MP 25 mg daily and MTX 7.5 mg weekly. Three weeks later WBC 1900/mL, hemoglobin 8.9 gm/dL and platelet was 31,000/mL. He was admitted again for right upper quadrant abdominal pain associated with aggressive skin rash, fever and mucositis. Wound swab and blood culture were negative. Blood Aspergillus galactomannan antigen was not detected. He was placed on empiric voriconazole and acyclovir, in addition to broad spectrum antibiotics. He was found to be homozygous for methyltetrahydrofolate reductase (MTHFR) C677T mutation. Blood homocystine was normal at 8.1 mmol/L. Quantitative PCR of PML/RARa fusion transcripts were not detected. Filgrastim 5 mcg/kg rounded to vial size of 300 mcg was initiated and the blood counts slowly recovered. With the patient being homozygous for MTHFR C677T mutation possibly causing enhanced methotrexate toxicity, he was then started on 6MP alone at 100 mg bid for 14 days without methotrexate. WBC was 2500/mL, hemoglobin 9.7 gm/dL and platelet 48,000/mL at the completion of 6MP. Two days later he was admitted again for rectal bleeding and worsening pancytopenia with WBC 2100/mL, hemoglobin 8.5 gm/dL and platelet was 5000/mL. He developed neutropenic fever that was treated with broad spectrum antibiotics. 6-Methylmercaptopurine was elevated to
30,986 pmol/8 108RBC (normal < 5700). Thiopurine S-methyltransferase (TPMT) genotype showed one copy of 460 G > A and 719 A > G mutation suggestive of TPMT*3 A genotype. Because of persistent pancytopenia, bone marrow examination was performed and it showed severely hypocellular marrow with no evidence of increased blasts. Quantitative PCR of PML/RARa of the bone marrow was not detected. Filgrastim was started and the blood counts slowly recovered. Maintenance chemotherapy was never restarted.
Discussion Our case underscores the importance of pharmacogenetics in cancer therapy.2 Incidence of MTHFR polymorphism varies among different ethnic groups, with homozygous C677T 1.2% in non-Hispanic blacks, 11.6% non-Hispanic whites to 19.4% in Mexican Americans.3,4 Homozygous C677T mutation is associated with 70% reduction in MTHFR enzyme activity and heterozygous mutation with 35% reduction5; A1298C mutation has a similar reduction in enzyme activity.6 It has been demonstrated that C677T polymorphism may affect the intracellular folate composition for DNA synthesis and so influence the chemosensitivity of the colon and breast cancer cells.7 Severe MTX toxicity associated with MTHFR mutation has been reported in patients with rheumatoid arthritis,8–11 breast cancer,12 ovarian cancer,13 acute leukemia,14–17 lymphoma18 and in bone marrow transplantation,19,20 though not with controversy.21–26 C677T polymorphism has also been associated with
8 ATRA 50mg bidx15days 6MP 100mg bid MTX 30mg q week
7
6MP 25mg qd MTX 7.5mg q week
6MP 100mg bid
WBC 1,000/mL
6 5 4 3 2 1 0 0
20
40 60 80 100 120 140 Number of Days From Initiation of Maintenance Chemotherapy
Figure 1. Trend of WBC with day 0 being the day beginning maintenance chemotherapy.
Downloaded from opp.sagepub.com at UNIVERSITE DE MONTREAL on June 12, 2015
160
180
XML Template (2015) [5.3.2015–4:49pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150014/APPFile/SG-OPPJ150014.3d
(OPP)
[1–5] [INVALID Stage]
Keung et.al.
3
increased risk of relapse in patients with acute lymphoblastic leukemia.21 Thiopurines, such as azathioprine and 6MP, are commonly used to treat leukemia patients as maintenance therapy in acute promyelocytic leukemia and acute lymphoblastic leukemia.1,27 These drugs are converted to active metabolites which are then metabolized and excreted. TPMT deactivates the active metabolites of thiopurines.28 Patients with deficiency of TPMT tend to accumulate the active metabolites leading to enhanced toxicity.29 TPMT deficiency has been extensively studied and characterized.28,30 Common TPMT mutations, TPMT*2 (238 G > C), TPMT*3 A (460 G > A and 719 A > G), TPMT*3B (460 G > A), TPMT*3 C (719 A > G) accounts for 80–95% of cases with reduced TPMT activity.31 Our patient most likely carries two mutations 460 G > A and 719 A > G on one chromosome and normal TPMT*1 in another chromosome, and is thus classified as intermediate metabolizer. There is a rare possibility that 460 G > A and 719 A > G mutations are on two different chromosomes. In that case the patient will be compound heterozygous for TPMT*3B and TPMT*3 C deficiency and thus classified as a poor metabolizer. Decreasing the starting dose of 6MP has been recommended in patients with TPMT deficiency.32 Yet our patient developed severe marrow toxicity even at one-eighth of the standard 6MP dosage probably suggesting that he is a poor metabolizer instead. In order to prevent the ‘‘trial and error’’ dosing, routine pharmacogenetic screening has been recommended for TPMT deficiency and MTHFR polymorphism.33,34 If routine pharmagenetic screening were done in our patient, it may have prevented the repeated admissions on our patient. However, the long-term benefit such as disease control and survival and the cost effectiveness of these testing remains to be determined. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010; 116: 3751–3757. 2. Relling MV and Dervieux T. Pharmacogenetics and cancer therapy. Nat Rev Cancer 2001; 1: 99–108.
3. Yang Q, Bailey L, Clarke R, et al. Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults. Am J Clin Nutr 2012; 95: 1245–1253. 4. Rosenberg N, Murata M, Ikeda Y, et al. The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans. Am J Hum Genet 2002; 70: 758–762. 5. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113. 6. Weisberg I, Tran P, Christensen B, et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998; 64: 169–172. 7. Sohn KJ, Croxford R, Yates Z, et al. Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5fluorouracil and methotrexate. J Natl Cancer Inst 2004; 96: 134–144. 8. van Ede AE, Laan RF, Blom HJ, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 2001; 44: 2525–2530. 9. Urano W, Taniguchi A, Yamanaka H, et al. 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. Pharmacogenetics 2002; 12: 183–190. 10. Caliz R, del AJ, Balsa A, et al. The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand J Rheumatol 2012; 41: 10–14. 11. Choe JY, Lee H, Jung HY, et al. Methylenetetrahydrofolate reductase polymorphisms, C677T and A1298C, are associated with methotrexate-related toxicities in Korean patients with rheumatoid arthritis. Rheumatol Int 2012; 32: 1837–1842. 12. Toffoli G, Veronesi A, Boiocchi M, et al. MTHFR gene polymorphism and severe toxicity during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil (CMF). Ann Oncol 2000; 11: 373–374. 13. Toffoli G, Russo A, Innocenti F, et al. Effect of methylenetetrahydrofolate reductase 677C–>T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. Int J Cancer 2003; 103: 294–299. 14. Chiusolo P, Reddiconto G, Casorelli I, et al. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol 2002; 13: 1915–1918. 15. D’Angelo V, Ramaglia M, Iannotta A, et al. Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia
Downloaded from opp.sagepub.com at UNIVERSITE DE MONTREAL on June 12, 2015
XML Template (2015) [5.3.2015–4:49pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/150014/APPFile/SG-OPPJ150014.3d
(OPP)
[1–5] [INVALID Stage]
4
16.
17.
18.
19.
20.
21.
22.
23.
24.
Journal of Oncology Pharmacy Practice 0(0) and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol 2011; 68: 1339–1346. Yang L, Hu X and Xu L. Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. Tumour Biol 2012; 33: 1445–1454. Eissa DS and Ahmed TM. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia. Blood Coagul Fibrinolysis 2013; 24: 181–188. Gemmati D, Ongaro A, Tognazzo S, et al. Methylenetetrahydrofolate reductase C677T and A1298C gene variants in adult non-Hodgkin’s lymphoma patients: association with toxicity and survival. Haematologica 2007; 92: 478–485. Ulrich CM, Yasui Y, Storb R, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001; 98: 231–234. Murphy N, Diviney M, Szer J, et al. Donor methylenetetrahydrofolate reductase genotype is associated with graft-versus-host disease in hematopoietic stem cell transplant patients treated with methotrexate. Bone Marrow Transplant 2006; 37: 773–779. Aplenc R, Thompson J, Han P, et al. Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res 2005; 65: 2482–2487. Ruiz-Arguelles GJ, Coconi-Linares LN, Garces-Eisele J, et al. Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico. Hematology 2007; 12: 387–391. Fisher MC and Cronstein BN. Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 2009; 36: 539–545. Lasecka L, Dixon PH, Molokhia M, et al. 667C>T and 1298A>C polymorphisms of MTHFR do not predict response to methotrexate in patients with gestational
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
trophoblastic neoplasia. Gynecol Oncol 2011; 123: 605–609. Lopez-Lopez E, Ballesteros J and Garcia-Orad A. MTHFR 677TT genotype and toxicity of methotrexate: controversial results. Cancer Chemother Pharmacol 2011; 68: 1369–1370. Hagleitner MM, Coenen MJ, Aplenc R, et al. The role of the MTHFR 677C>T polymorphism in methotrexateinduced liver toxicity: a meta-analysis in patients with cancer. Pharmacogenomics J 2014; 14: 115–119. Linker C, Damon L, Ries C, et al. Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol 2002 May 15; 20(10): 2464–2471. Sahasranaman S, Howard D and Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008; 64: 753–767. Evans WE, Hon YY, Bomgaars L, et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001; 19: 2293–2301. McLeod HL and Siva C. The thiopurine S-methyltransferase gene locus – implications for clinical pharmacogenomics. Pharmacogenomics 2002; 3: 89–98. Appell ML, Berg J, Duley J, et al. Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics 2013; 23: 242–248. Levinsen M, Rotevatn EO, Rosthoj S, et al. Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer. Pediatr Blood Cancer 2014; 61: 797–802. Sanderson J, Ansari A, Marinaki T, et al. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem 2004; 41: 294–302. Kim SK, Jun JB, El-Sohemy A, et al. Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 2006; 33: 1266–1274.
Downloaded from opp.sagepub.com at UNIVERSITE DE MONTREAL on June 12, 2015
