Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors

Abstract

Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), i.e., BCR-ABL/ABL of ≤0.1, ≤0.01, ≤0.0032%, and undetectable transcripts, respectively. Four hundred eighty-three patients received imatinib 400 mg/day (IM400, 71, July 2000 to April 2001), imatinib 800 mg/day (IM800, 204, June 2001 to July 2005), nilotinib (106, July 2005 to date), or dasatinib (102, November 2005 to date). UND rates at 36 months were 18.1, 30.6, 29.2, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.

Conflict of interest statement

Disclosure of Conflicts of Interest: H.K.M. has received research funding from Bristol-Myers Squibb, Ariad, Pfizer, and Novartis. E.J.J. has received honoraria from Pfizer, Novartis, and Bristol-Myers Squibb. F.R. has received research funding from Bristol-Myers-Squibb and has received honoraria from Bristol-Myers Squibb, Novartis, and Pfizer. J.E.C.: is consultant for Ariad, Pfizer, and Teva and has received research funding from Ariad, Bristol-Myers Squibb, Novartis, Chemgenex, and Pfizer. L.F., X.W., D.V., S.O., G.B., A.Q., G.G., S.V., and J.A.B. declare no conflicts of interest.

Copyright © 2013 Wiley Periodicals, Inc.

Figures

Figure 1

Cumulative incidence of MMR (A), MR4 (B), MR4.5 (C), and UND (D) according to treatment group. In each plot, for a given treatment group, the cumulative incidence step-function curves increase with each event, with the height of the curve representing the actual proportion of patients who had achieved response by that time point, and the curves continuing until the last response was achieved. IM400, n=71; IM800, n=204; NILO, n=106; DASA, n=102.

Figure 1

Cumulative incidence of MMR (A), MR4 (B), MR4.5 (C), and UND (D) according to treatment group. In each plot, for a given treatment group, the cumulative incidence step-function curves increase with each event, with the height of the curve representing the actual proportion of patients who had achieved response by that time point, and the curves continuing until the last response was achieved. IM400, n=71; IM800, n=204; NILO, n=106; DASA, n=102.

Figure 1

Cumulative incidence of MMR (A), MR4 (B), MR4.5 (C), and UND (D) according to treatment group. In each plot, for a given treatment group, the cumulative incidence step-function curves increase with each event, with the height of the curve representing the actual proportion of patients who had achieved response by that time point, and the curves continuing until the last response was achieved. IM400, n=71; IM800, n=204; NILO, n=106; DASA, n=102.

Figure 1

Cumulative incidence of MMR (A), MR4 (B), MR4.5 (C), and UND (D) according to treatment group. In each plot, for a given treatment group, the cumulative incidence step-function curves increase with each event, with the height of the curve representing the actual proportion of patients who had achieved response by that time point, and the curves continuing until the last response was achieved. IM400, n=71; IM800, n=204; NILO, n=106; DASA, n=102.

Figure 2

TFS (A), and OS (B) according to different levels of molecular response in patients achieving complete cytogenetic remission at any time. P-values for the comparison MR4.5, MR4, MMR, and no-MR versus UND are: 0.49, 0.74, 0.001, and 0.02, respectively (A), and 0.16, 0.28,

Figure 2

TFS (A), and OS (B) according to different levels of molecular response in patients achieving complete cytogenetic remission at any time. P-values for the comparison MR4.5, MR4, MMR, and no-MR versus UND are: 0.49, 0.74, 0.001, and 0.02, respectively (A), and 0.16, 0.28,

Figure 3

Landmark analysis at 18 and 24 months for TFS (A and B) and OS (C and D) according to different levels of molecular response in patients with CCyR. P-values for the comparison MR4.5, MR4, MMR, and no-MR versus UND are: 0.03, 0.25, 0.37 and 0.15, respectively (A), 0.16, 0.30, 0.61 and 0.16 respectively (B), 0.48, 0.86, 0.89 and 0.24, respectively (C), and 0.94, 0.99, 0.38, and 0.44, respectively (D).

Figure 3

Landmark analysis at 18 and 24 months for TFS (A and B) and OS (C and D) according to different levels of molecular response in patients with CCyR. P-values for the comparison MR4.5, MR4, MMR, and no-MR versus UND are: 0.03, 0.25, 0.37 and 0.15, respectively (A), 0.16, 0.30, 0.61 and 0.16 respectively (B), 0.48, 0.86, 0.89 and 0.24, respectively (C), and 0.94, 0.99, 0.38, and 0.44, respectively (D).

Figure 3

Landmark analysis at 18 and 24 months for TFS (A and B) and OS (C and D) according to different levels of molecular response in patients with CCyR. P-values for the comparison MR4.5, MR4, MMR, and no-MR versus UND are: 0.03, 0.25, 0.37 and 0.15, respectively (A), 0.16, 0.30, 0.61 and 0.16 respectively (B), 0.48, 0.86, 0.89 and 0.24, respectively (C), and 0.94, 0.99, 0.38, and 0.44, respectively (D).

Figure 3

Landmark analysis at 18 and 24 months for TFS (A and B) and OS (C and D) according to different levels of molecular response in patients with CCyR. P-values for the comparison MR4.5, MR4, MMR, and no-MR versus UND are: 0.03, 0.25, 0.37 and 0.15, respectively (A), 0.16, 0.30, 0.61 and 0.16 respectively (B), 0.48, 0.86, 0.89 and 0.24, respectively (C), and 0.94, 0.99, 0.38, and 0.44, respectively (D).

Figure 4

TFS (A) and OS (B) of patients with susMR4.5 compared to those with MR4.5 not sustained for at least 2 years after a minimum follow-up of 48 months. P-values for the comparison are: 0.58 (A) and 0.30 (B).

Figure 4

TFS (A) and OS (B) of patients with susMR4.5 compared to those with MR4.5 not sustained for at least 2 years after a minimum follow-up of 48 months. P-values for the comparison are: 0.58 (A) and 0.30 (B).