Accepted Abstracts: J Cancer Sci Ther
The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of several anti- cancer drugs. We hypothesized that 1199G>A, 1236C>T, 2677G>A/T and 3435C>T variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL), since the treatment includes known P-glycoprotein substrates and 3435C/T may affect methotrexate effects. We studied 522 Danish children with ALL treated according to NOPHO ALL92 and ALL2000 protocols, 93% of all those eligible during 1992-2007. Risk of relapse was increased 2.9-fold for 41 patients with the 1199GA variant compared to 477 with 1199GG (p=0.001), and reduced by 61% and 40%, respectively for 421 patients with the 3435CT or 3435TT variants compared to 96 patients with 3435CC (overall p=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was higher in 71 patients with 3435TT variant (median nadirs: hemoglobin 3% and platelets 34/37% lower in 3435CT/3435CC) compared to 160 patients with 3435CT/3435CC (Hemoglobin p=0.01 and platelets p<0.0001). We observed more liver toxicity after high-dose methotrexate in 109 patients with 3435CC variant versus 3435CT/TT (Median max alanine aminotransferase: 280 versus 142/111 U/L, p=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms and efficacy and toxicity in childhood ALL.