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

Abstract

A reduction in BCR-ABL1/ABL1^IS 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 BCR-ABL1 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 BCR-ABL1/ABL1^IS 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 BCR-ABL1/ABL1^IS 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 BCR-ABL1/ABL1^IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1^IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1^IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR⁴ compared to patients with BCR-ABL1/ABL1^IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUS^IS transcripts at diagnosis were associated with BCR-ABL1/ABL1^IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1^IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.

Keywords: BCR-ABL1; European Leukemia Net; chronic myeloid leukemia; early molecular response; imatinib mesylate.

Figure 1

Event-free survival (EFS) estimates (A) and cumulative incidence of major molecular response (MR³) (B) and deep molecular response (MR⁴) (C) according to BCR-ABL1/ABL1^IS transcripts at 3 and 6 months. Patients were divided into four groups according to their BCR-ABL1 expression at the 3 and 6 months. EFS probability (A) and cumulative incidence of MR³ (B) and MR⁴ (C) were calculated for each group. Vertical lines indicate censored patients. p-values refer to statistical significance among all four groups included in the analyses.

Figure 2

Comparison between BCR-ABL1/GUS^IS levels at diagnosis and BCR-ABL1/ABL1^IS transcripts at 3 and 6 months. BCR-ABL1/GUS^IS levels were determined for each group and depicted as boxplots delimited by the 25th (lower) and 75th (upper) percentile. Horizontal lines above and below each boxplot indicate the 5th and 95th percentile, respectively. Thick lines in each boxplot represent median BCR-ABL1/GUS^IS in each patients group. The p-value above the figure refers to statistical significance among all four groups included in the analysis while p-values displayed inside the figure refer to statistical significance among the population groups indicated by the bracket (comparison between groups A and D: p < 0.001; comparison between groups C and D: p = 0.025).