Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib

Abstract

A reduction in <i>BCR-ABL1/ABL1^IS</i> transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple <i>BCR-ABL1</i> thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant <i>BCR-ABL1/ABL1^IS</i> transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR⁴; 71.5% vs. 16.1%) compared to individuals with <i>BCR-ABL1/ABL1^IS</i> levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with <i>BCR-ABL1/ABL1^IS</i> values >10% at 3 months but <1% at 6 months fared significantly better than individuals with <i>BCR-ABL1/ABL1^IS</i> <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; <i>p</i> < 0.001). Likewise, subjects with <i>BCR-ABL1/ABL1</i>^IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR⁴ compared to patients with <i>BCR-ABL1/ABL1^IS</i> <10% at 3 months but >1% at 6 months (75% vs. 18.2%; <i>p</i> < 0.001). Finally, lower <i>BCR-ABL1/GUS^IS</i> transcripts at diagnosis were associated with <i>BCR-ABL1/ABL1^IS</i> values <1% at 6 months (<i>p</i> < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month <i>BCR-ABL1/ABL1^IS</i> level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.