<i>BCR-ABL1</i> genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia

Abstract

Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical decisions. The conventional MRD method, RQ-PCR for <i>BCR-ABL1</i> mRNA, reflects a composite of the number of circulating leukemic cells and the <i>BCR-ABL1</i> transcripts per cell. <i>BCR-ABL1</i> 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. <i>BCR-ABL1</i> 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, <i>BCR-ABL1</i> mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of <i>BCR-ABL1</i> mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 <i>BCR-ABL1</i> was lower than that of e14a2 transcripts at multiple time points during treatment. <i>BCR-ABL1</i> DNA was quantifiable in 48% of samples with undetectable <i>BCR-ABL1</i> 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 <i>BCR-ABL1</i> 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 <i>BCR-ABL1</i> mRNA are proportional to the depletion of leukemic cells.