Key Points• A preclinical cell-based model identifies SNPs associated with cytarabine sensitivity that also associate with outcome in leukemia patients.• SNPs within the MCC gene were associated with cytarabine sensitivity in lymphoblastoid cell lines and leukemic blasts from patients.A whole-genome approach was used to investigate the genetic determinants of cytarabineinduced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from 1.7-to 26.6-fold in LCLs. A total of 33 SNPs ranked at the top of the meta-analysis (P < 10
25) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-related mortality). This count (n 5 18) was significantly greater than expected by chance (P 5 .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P 5 1.31 3 10
26) and AA (vs GA or GG) genotype was associated with poorer OS (P 5 .015), likely as a result of greater treatment-related mortality (P 5 .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084. (Blood. 2013;121(21):4366-4376)
IntroductionAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults and also occurs in children. Despite the genetic heterogeneity of the disease, patients have been treated for decades with similar combinations of cytarabine and anthracyclines with little improvement in overall survival (OS).1 Although the majority of patients (50%-60%) under 60 years achieve complete remission with traditional anthracycline-and cytarabine-based induction regimens, the long-term survival rates continue to be around 30% to 40% for adults and 60% for children. [2][3][4][5][6] Outcomes are worse for patients >60 years, with complete response rates in the range of 40% to 55% and poor long-term survival rates. 7 The main reason for treatment failure among patients with AML is resistance to therapy. [8][9][10] In addition, treatment with cytarabine is associated with a number of adverse side effects including myelosuppression, infections, mucositis, neurotoxicity, and acute pulmonary syndrome.
11Cytarabine requires activation through intracellular phosphorylation to araC-triphosphate (ara-CTP). The mechanism of action of cytarabine involves the incorporation of ara-CTP in place of deoxycytidine triphosphate, resulting in chain termination, blocking DNA and RNA synthesis and causing leukemic cell de...