Abstract
In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene's expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses (p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR3.0 (after 6 months; p = 0.003) or an MR4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation.
Highlights
Unlike other solid or hematologic malignancies, Chronic Myeloid Leukemia (CML) is characterized by a single pathogenic alteration: the breakpoint cluster region (BCR)-ABL1 chimeric oncogene [1,2,3,4,5,6]
To establish if BCR-ABL1 DTs could determine the clinical significance of a rise in the transcripts of the chimeric oncogene, we analyzed the evolution of BCR-ABL1 mRNAs in 305 patients with chronic phase CML that had achieved a major molecular response (MR3.0) after receiving standard dose Imatinib Mesllate (IM) as first line treatment
Of the 305 patients, 187 (61.3%) maintained their previously achieved MR3.0 despite an increase in BCR-ABL1 levels, while 118 (38.7%) failed IM according to the 2013 European Leukemia Net (ELN) recommendations (Figure 1A)
Summary
Unlike other solid or hematologic malignancies, Chronic Myeloid Leukemia (CML) is characterized by a single pathogenic alteration: the BCR-ABL1 chimeric oncogene [1,2,3,4,5,6]. While first- and second-generation (2G) tyrosine kinase inhibitors (TKIs) have generated unprecedented results for individuals diagnosed with chronic phase CML, solid evidence indicates that patients who do not achieve early molecular responses often display inferior outcomes, with increased risk of disease relapse, progression and death [13, 14]. They require alternative forms of treatment [15]. Individuals who achieve a deep molecular response (MR4.0 or better) might be candidates for treatment discontinuation [17, 18]
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