Abstract

Abstract 1678

Background.

Imatinib mesylate (IM) is the therapeutic standard for chronic myeloid leukemia (CML), but nilotinib and dasatinib, at least in selected patients, have the potential to replace it. The early prediction of poor outcome is important to optimize the treatment strategy. In IM-treated patients, BCR-ABL transcript levels according to the International Scale (IS) > 10% at 3 and > 1% at 6 months were able to identify high-risk groups (Marin et al, JClinOncol 2011; Hanfstein et al, Leukemia 2012). Similar analysis were performed within the IM arms of the ENESTnd trial (Hochhaus et al, EHA 2012) and the DASISION trial (Jabbour et al, EHA 2012).

Methods.

To investigate the prognostic impact of BCR-ABLIS levels at 3 and 6 months on the future response status and the long-term outcome of CML patients treated frontline with IM, we analyzed 559 patients enrolled within 3 trials of the GIMEMA CML WP (ClinTrialsGov NCT00514488/NCT00510926, observational trial CML023). Patients with evaluable QPCR sample at 3 and 6 months: 487/559 (87%) and 492/559 (88%), respectively. Definitions: major molecular response (MMR): BCR-ABLIS ratio <0.1%; molecular response with 4.0-log reduction (MR4.0): BCR-ABLIS <0.01%; failures: according to 2009 ELN recommendations. The rate of complete cytogenetic response (CCgR) and MMR at 1 year, the rate of MR4.0 at 2 years, the failure-free survival (FFS), the progression-free survival (PFS) and the overall survival (OS) according to the BCR-ABL transcript levels (≤10% vs >10 and ≤1% vs >1%) at 3 and 6 months were analyzed. Patients with events or censored within 3 or 6 months were excluded from the respective analysis. Receiver operating characteristic (ROC) curves were used for descriptive purposes.

Results.

Median age: 52 years (range 18–84). IM dose: 76% 400mg, 24% 800mg. Sokal score: 39% low, 39% intermediate, 22% high; EUTOS score: 93% low, 7% high. Median follow-up: 76 months (range: 7–99); 95% of patients had at least 5-year observation. BCR-ABLIS at 3 months: ≤1% in 336/487 (69%), >1% to ≤10% in 120/487 (25%) and >10% in 31/487 (6%). BCR-ABLIS at 6 months: ≤1% in 425/492 (86%), >1% to ≤10% in 54/492 (11%) and >10% in 13/492 (3%). Responses and outcomes according to transcript levels are presented in table 1. Patients with BCR-ABLIS >10% at 3 months achieved inferior CCgR and MMR rates at 1 year and inferior MR4.0 rate at 2 years, but the long-term outcome was comparable to patients with transcript levels < 10%. On the contrary, a BCR-ABLIS >1% at 3 months was associated, not only to lower subsequent response rates, but also to significantly inferior FFS, PFS and OS. The BCR-ABLIS levels able to predict for FFS, PFS and OS with maximal sensitivity and specificity (ROC curves) were 1.9%, 0.8% and 0.8%, respectively. Results were similar, with small differences, in the 6-month analysis.

Conclusions.

In a multicentric nationwide experience, the proportion of patients with BCR-ABLIS transcript levels >10% at 3 and 6 months was low. The risk distribution and the proportion of patients treated with high-dose IM may explain, at least in part, the differences with other published reports. At 3 and 6 months, a BCR-ABLIS cutoff of 1% was a reliable surrogate marker of response and outcome. A transcript level >10% identified a smaller cohort with inferior responses, but failed to predict the long-term outcome. A BCR-ABLIS level >1% at 3 and 6 months represents a warning, requiring a close monitoring. A switch to 2nd generation tyrosine kinase inhibitors should be considered.

Acknowledgments.

University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo.

BCR-ABL at 3 months (N = 487) < 10% (N = 456) > 10% (N = 31) p* < 1% (N = 336) > 1% (N = 151) p* 
CCgR at 1 year, % 80.9 51.6 <0.001 87.5 60.3 <0.001 
MMR at 1 year, % 62.1 22.6 <0.001 70.5 35.1 <0.001 
MR4.0 at 2 years, % 20.0 3.2 0.017 23.5 8.6 <0.001 
FFS, % 79.2 68.3 0.104 83.7 66.8 <0.001 
PFS, % 85.2 90.0 0.771 87.5 81.9 0.004 
OS, % 86.5 87.1 0.622 88.4 83.6 0.010 
BCR-ABL at 6 months (N = 492) < 10% (N = 479) > 10% (N = 13) p* < 1% (N = 425) > 1% (N = 67) p* 
CCgR at 1 year, % 84.3 30.8 <0.001 88.7 46.3 <0.001 
MMR at 1 year, % 64.7 7.7 <0.001 71.1 13.4 <0.001 
MR4.0 at 2 years, % 19.6 0.143 21.4 4.5 <0.001 
FFS, % 81.0 57.1 0.045 83.6 57.4 <0.001 
PFS, % 86.4 74.1 0.115 87.6 78.4 0.002 
OS, % 87.3 76.9 0.078 88.3 80.8 0.01 
BCR-ABL at 3 months (N = 487) < 10% (N = 456) > 10% (N = 31) p* < 1% (N = 336) > 1% (N = 151) p* 
CCgR at 1 year, % 80.9 51.6 <0.001 87.5 60.3 <0.001 
MMR at 1 year, % 62.1 22.6 <0.001 70.5 35.1 <0.001 
MR4.0 at 2 years, % 20.0 3.2 0.017 23.5 8.6 <0.001 
FFS, % 79.2 68.3 0.104 83.7 66.8 <0.001 
PFS, % 85.2 90.0 0.771 87.5 81.9 0.004 
OS, % 86.5 87.1 0.622 88.4 83.6 0.010 
BCR-ABL at 6 months (N = 492) < 10% (N = 479) > 10% (N = 13) p* < 1% (N = 425) > 1% (N = 67) p* 
CCgR at 1 year, % 84.3 30.8 <0.001 88.7 46.3 <0.001 
MMR at 1 year, % 64.7 7.7 <0.001 71.1 13.4 <0.001 
MR4.0 at 2 years, % 19.6 0.143 21.4 4.5 <0.001 
FFS, % 81.0 57.1 0.045 83.6 57.4 <0.001 
PFS, % 86.4 74.1 0.115 87.6 78.4 0.002 
OS, % 87.3 76.9 0.078 88.3 80.8 0.01 
*

Responses at each timepoint were compared using χ2 test or Fisher exact test, as appropriate. FFS, PFS, OS were estimated using the Kaplan-Meier method and compared by log-rank test.

Disclosures:

Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Speakers Bureau. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Abruzzese:Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzini:Novartis Pharma: Honoraria; Bristol Myers Squibb: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Martinelli:Bristol-Myers-Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.

Author notes

*

Asterisk with author names denotes non-ASH members.