Intracellular vincristine levels in lymphoblasts affect treatment outcome in childhood B-lymphoblastic leukaemia: Ma-Spore ALL 2010 Study.

AIMS Vincristine (VCR) is a key drug in the successful multi-drug chemotherapy for childhood ALL. But it remains unclear how VCR pharmacokinetics affects its anti-leukaemic efficacy. The objective of this study is to explore the VCR PK parameters and intracellular VCR levels in an up-front window of Ma-Spore ALL 2010 (MS2010) study. METHODS We randomised 429 children with newly diagnosed ALL to 15 min versus 3-h infusion for the first dose of VCR to study if prolonging the first dose of VCR infusion improved response. In a subgroup of 115 B-ALL and 20 T-ALL patients, we performed VCR plasma (n=135 patients) and intracellular (n=66 patients) pharmacokinetic studies. The correlations between PK parameters and intracellular VCR levels with early treatment response, final outcome and ABCB1 genotypes were analysed. RESULTS Between 15 min versus 3-h infusion schedules, there was no significant difference in median Day 8 peripheral or bone marrow blast response. Plasma VCR pharmacokinetic parameters did not predict outcome. However, in B-ALL, Day 33 MRD negative patients and patients in continuous complete remission had significantly higher median intracellular VCR24h levels (P=0.03 and P=0.04 respectively). The median VCR24h intracellular levels were similar among the common genetic subtypes of ALL (P=0.4). Patients homozygous for wild type ABCB1 2677GG had significantly higher median intracellular VCR24h (P= 0.04) than 2677TT. CONCLUSIONS We showed that in childhood B-ALL, the intracellular VCR24h levels in lymphoblasts affected treatment outcomes. The intracellular VCR24h level was independent of leukaemia subtype but dependent on host ABCB1 G2677T genotype.