Cytidine Deaminase Genotype Modifies the Toxicity of Therapy for Childhood AML.
Authors: Bhatla Deepika , Gerbing Robert B. , Conner Heather D. , Alonzo Todd A. , Zhai Xiaowen , Mehta Parinda , Ross Julie A. , Geiger Hartmut , Lange Beverly J. , Perentesis John P. , Davies Stella M. 
Published: October 2019

Cytosine arabinoside (Ara-C), given at standard or high dose, is an important component of AML therapy. A major catabolic pathway of Ara-C is deamination by cytidine deaminase (CDD) to the non-toxic metabolite uridine arabinoside. A non-synonymous single nucleotide polymorphism, A79C, in CDD changes a lysine residue to glutamine. In-vitro studies indicate reduced activity of the variant glutamine allele compared with the lysine allele. We hypothesized that children with the low activity CC CDD genotype would have increased toxicity of Ara-C based therapy for AML. CDD A79C genotype frequencies were determined for 457 children with de novo AML treated on Children’s Cancer Group protocols 2941 and 2961. Outcomes were examined stratified by genotype. All patients received intensively timed induction therapy with IDA-DCTER (idarubicin, dexamethasone, Ara-C (800 mg/m2 total dose), thioguanine, etoposide and daunomycin) given on days 0 to 3 followed by DCTER given on days 10 to 13. On recovery of ANC and platelet counts, patients were randomized to consolidation therapy with a further course of IDA-DCTER/DCTER or IDA-FLAG (idarubicin, fludarabine, Ara-C (7590 mg/m2 total dose Ara-C) and G-CSF). Patients received intensification with a single course of high dose Ara-C (24,000 mg/m2 total dose) and L-asparaginase unless a family donor was available when allogeneic transplant was performed.

Genotype frequencies did not differ according to WBC at diagnosis, FAB group, cytogenetics or gender. The CDD variant C allele was more frequent in white children (36%) compared with black (9%), Hispanic (26%) and Asian children (11%), p= 0.00002. No significant differences in overall survival (OS) or event-free survival (EFS) were observed according to CDD genotype (5 yr OS 52 ± 7% for AA, 46 ± 8% for AC, 55 ± 15% for CC; p=0.56), (5 year EFS 40 ± 7% AA, 37 ± 7% AC, 41 ± 15% CC; p=0.90). However cumulative incidence of treatment related mortality (TRM) after two courses of chemotherapy was significantly elevated in children with the low activity CC genotype compared with AA and AC genotypes (5 year TRM 17 ± 13% CC (n=36) vs 7 ± 4% AA, 5 ± 4% AC (n=257), p= 0.019), reflecting events during intensification when the large majority of Ara-C therapy was given (24,000 mg/m2). TRM after 2 courses of chemotherapy, analyzed according to prior randomized therapy, was significantly increased in those children randomized to IDA-FLAG consolidation (5 year TRM 24 ± 20% CC vs 6 ± 6% AA, 6 ± 6% AC, p=0.017) but the increase was not statistically significant in those randomized to IDA-DCTER/DCTER prior to intensification (5 year TRM 15 ± 20% CC vs 8 ± 6% AA, 4 ± 6% AC; p=0.261). Relapse-free survival was increased in children with the CC genotype treated with IDA-FLAG but this was not statistically significant (76 ± 20% CC vs 59 ± 12% AA and 55 ± 14% AC; p= 0.104). These data suggest that children with a low activity CDD genotype are at increased risk of treatment-related mortality when treated with Ara-C based therapy for AML.