genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia.

Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical decisions. The conventional MRD method, RQ-PCR for mRNA, reflects a composite of the number of circulating leukemic cells and the transcripts per cell. genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first three months of treatment, mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 was lower than that of e14a2 transcripts at multiple time points during treatment. DNA was quantifiable in 48% of samples with undetectable mRNA, resulting in MRD being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in mRNA over the first three months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond three months, falling levels of mRNA are proportional to the depletion of leukemic cells.