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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]

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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


6MP 25mg qd MTX 7.5mg q week

6MP 100mg bid

WBC 1,000/mL

6 5 4 3 2 1 0 0


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.

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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.

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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 ...
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