Effect of genetic alterations of cytarabine- metabolizing enzymes in childhood acute lymphoblastic leukemia.
BACKGROUND
Single nucleotide polymorphisms (SNPs) of deoxycytidine kinase (dCK) and cytidine deaminase (CDA) are known to alter their enzymatic activities, which affect the metabolism of cytarabine. Currently, treatment of childhood acute lymphoblastic leukemia (ALL) includes cytarabine, especially in high-risk patients. Therefore, we hypothesized that a genetic variation of dCK and CDA genes may influence the risk of cytarabine-related toxicities and early response to treatment.


METHODS
We included children diagnosed with ALL and lymphoblastic lymphoma (LL) stage III and IV. The patients received a modified St Jude Total Therapy Study XV protocol. Cytarabine was used during induction remission (low-dose cytarabine) and reinduction II (high-dose cytarabine) phases. Genotyping of dCK-360C>G and -201C>t and CDA 79A>C and 208G>A was performed. Minimal residual disease (MRD) at the end of the induction phase was measured using flow cytometry.


RESULTS
Ninety-four children with ALL (n=90) and LL (n=4) were analyzed. The median age at diagnosis was 5.8 years (range, 0.4-15 years). All four SNPs showed predominant wild type alleles. There was no CDA-208A allele in our population. Children with dCK-360G allele were at risk of mucositis after receiving low-dose cytarabine (OR=3.7; 95%CI, 1.2--11.3). neither dCK nor CDA polymorphisms affected the MRD status at the end of the induction phase.


CONCLUSIONS
The dCK-360G allele was found to increase the risk of mucositis after exposure to low-dose cytarabine in childhood ALL therapy.
Banklau
Chumphorn
C
Department of Pathology and Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. rasam@mahidol.ac.th
Jindadamrongwech
Sumalee
S
Sawangpanich
Ruchchadol
R
Apibal
Suntaree
S
Hongeng
Suradej
S
Paisooksantivatana
Karan
K
Pakakasama
Samart
S
D000293:Adolescent; D000483:Alleles; D018941:Antigens, CD19 / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007223:Infant; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D052016:Mucositis / Q000139:chemically induced; D009367:Neoplasm Staging; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
D018941:Antigens, CD19; D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003842:Deoxycytidine Kinase; D017493:Leukocyte Common Antigens; D003564:Cytidine Deaminase