Rapid initial decline in BCR-ABL1 is associated with superior responses to second-line nilotinib in patients with chronic-phase chronic myeloid leukemia

Abstract

Background: We evaluated BCR-ABL1 kinetics in patients treated with nilotinib and analyzed whether a dynamic model of changes in BCR-ABL1 levels over time could be used to predict long-term responses.

Methods: Patients from the nilotinib registration trial (CAMN107A2101; registered at http://www.clinicaltrials.gov as NCT00109707) who had imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase with BCR-ABL1 > 10% (on the international scale [IS]) at baseline and, in the first 6 months, had at least three BCR-ABL1 transcript measurements and an average daily dose of at least 720 mg were included in this analysis (N = 123).

Results: More than half of patients (65/123; 53%) had a slow monophasic response and the remainder (58/123; 47%) had a biphasic response, in which patients had a rapid initial decrease in BCR-ABL1 transcripts followed by a more gradual response. The biphasic response type strongly correlated with improved event-free survival (EFS). Data in the first 6 months of follow-up were sufficient to predict EFS at 24 months.

Conclusions: Unlike newly diagnosed patients with Ph+ CML-CP-in whom the majority had a biphasic response-approximately half of patients with imatinib-resistant or -intolerant CML had a slower, monophasic response. Second-line patients who did have a biphasic response had an EFS outlook similar to that of newly diagnosed patients treated with imatinib. Our model was comparable to using BCR-ABL1 (IS) ≤ 10% at 6 months as a threshold for predicting EFS.

Figures

Figure 1

BCR-ABL1 (international scale [IS])% for all 123 patients in this analysis, divided into two groups, with an example patient shown in black within each group: (A) slow monophasic responders (n = 65) with μ = −0.4/year for the example patient and (B) fast biphasic responders (n = 58) with α = −15.1/year and β = −0.9/year for the example patient. The μ*, α*, β* parameters are shown for the example patient, where μ* = μlog10e, α* = αlog10e, and β* = βlog10e. The asterisks (*) indicate when a BCR-ABL1 (IS)% measurement fell below 0.0032% (= 100 × 10-4.5), the approximate limit of quantitation of the assay for all laboratories in the International Randomized Study of Interferon and STI571 trial; (C) histogram of the initial reduction rates μ and α. Note that there is no overlap between the two populations and that the vertical dashed line at −3/year demonstrates where the separation occurs.

Figure 2

Individual fits to 16 patients. Patients 1 to 8 are slow monophasic, and patients 9 to 16 are fast biphasic. The asterisk (*) represents measurements below the limit of quantification of the assay.

Figure 3

Event-free survival (EFS) according to patient group. The Kaplan-Meier plot of the imatinib arm of the International Randomized Study of Interferon and STI571 (IRIS) trial for frontline patients with chronic myeloid leukemia is also shown, to illustrate that biphasic responders do approximately as well as patients receiving frontline imatinib treatment.

Figure 4

(A) Event-free survival (EFS) at 2 years based on patient classification using only the first 6 months of data. The difference between the EFS curves was found to be statistically significant at p = 0.0001 by a log-rank test; (B) the percentage of patients correctly classified as having an event at year 2 as a function of the amount of data used to classify each patient; (C) example patient: the ✩ indicates the transition point, defined as the point of maximum curvature where fast responders transition from the α to the β phase; the * corresponds to measurements below the limit of quantification of the polymerase chain reaction assay, assumed to be 0.0032% for all labs; (D) histogram of transition times between the α and β phases. Abbreviation: IS = international scale.