Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors

Abstract

Purpose: We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics.

Patients and methods: We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere.

Results: Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively).

Conclusion: A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Eight-year probability of overall survival (OS) and current complete cytogenetic response survival (c-CCyRS) in the whole population and with patients stratified by risk group defined by BCR-ABL1 transcript level at 3 months. (A) The probability of 8-year survival in the whole population was 84.3%. During follow-up, 34 patients died, 12 of causes unrelated to leukemia. When only the leukemia-related deaths were taken into account, the 8-year probability of OS was 89.2%. The 8-year probability of c-CCyRS was 76.6%, which represents the probability of being alive and in remission (complete cytogenetic response [CCyR]) at a given time point; thus, the curve fluctuates as patients gain or lose CCyR (or die). It is interesting to observe that after the third year, the c-CCyRS curve remains practically unchanged. (B) Eight-year probability of OS and c-CCyRS for patients according to the risk group defined by transcript levels at 3 months (high-risk BCR-ABL1/ABL1 ratio > 9.84% [n = 68]; low-risk BCR-ABL1/ABL1 ≤ 9.84% [n = 211]). The high-risk group (red lines) had a significantly lower OS (56.9% v 93.3%; P < .001) and c-CCyRS (47.0% v 91.1%; P < .001) than the low-risk group (blue). The 6- and 12-month landmark analyses show similar results: OS was 74.7% versus 93.7% (P < .001) and 74.7% versus 95.4% (P < .001) and c-CCyRS was 53.1% versus 91.7% (P < .001) and 53.3% versus 91.3% (P = .001), respectively.

Fig 2.

Eight-year cumulative incidence of complete molecular response (CMR) for patients receiving imatinib therapy according to the BCR-ABL1 transcript level at 3 months. The transcript level at 3 months identifies those patients with higher probability of achieving CMR on imatinib therapy. The 57 patients who had a 3-month transcript ratio ≤ 0.61% (blue line) had an 8-year cumulative incidence (CI) of CMR of 84.7%, and the 222 patients with a ratio of more than 0.61% (gold line) had a CI of CMR of only 1.5% (P < .001). Similar thresholds with high predictive power could be identified for 6 and 12 months (Table 2). Patients in the low-risk group defined at 3, 6, and 12 months also had significantly higher CI of CMR (Table 2).

Fig 3.

Evolution of the transcript level according to the 3-, 6-, and 12-month risk group. Transcript levels are expressed on a log10 scale. (A) Evolution of the transcript level over time. Patients are classified as high risk (gold circles) and low risk (blue circles) according to their transcript level at 3 months (higher or lower than 9.84%). The horizontal black lines represent the transcript level that defines the 3-month (9.84%), 6-month (1.67%), and 12-month (0.53%) risk groups. The majority of patients (all but six) who are classified as high risk at 3 months are also classified as high risk at 6 months, and all are classified as high risk at 12 months. The transcript level declines over time in the low-risk patients, although it remains comparatively high in the high-risk population. Many of the high-risk patients eventually abandon imatinib therapy because of unsatisfactory response, loss of response, or progression. (B) Comparison of transcript levels in the two risk groups defined at 3, 6, and 12 months. Although the optimal cutoffs to define the groups at 3, 6, and 12 months are 9.84%, 1.67%, and 0.53%, the majority of the patients had a transcript level much higher or much lower than the cutoff selected for a given time. The median value (md) of the transcript level is also specified in the figure as a BCR-ABL1/ABL1 ratio (%). The double arrowed lines represent the value of the cutoffs used to define the groups on a logarithmic scale (9.84%, 1.67%, and 0.53%). CMR, complete molecular response.