The BCR-ABL Transcript Levels At 3 and 6 Months Predict the Long-Term Outcome of Chronic Myeloid Leukemia Patients Treated Frontline with Imatinib Mesylate: A Gimema CML WP Analysis

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).

To investigate the prognostic impact of BCR-ABL^IS 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-ABL^IS ratio <0.1%; molecular response with 4.0-log reduction (MR^4.0): BCR-ABL^IS <0.01%; failures: according to 2009 ELN recommendations. The rate of complete cytogenetic response (CCgR) and MMR at 1 year, the rate of MR^4.0 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.

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-ABL^IS at 3 months: ≤1% in 336/487 (69%), >1% to ≤10% in 120/487 (25%) and >10% in 31/487 (6%). BCR-ABL^IS 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-ABL^IS >10% at 3 months achieved inferior CCgR and MMR rates at 1 year and inferior MR^4.0 rate at 2 years, but the long-term outcome was comparable to patients with transcript levels < 10%. On the contrary, a BCR-ABL^IS >1% at 3 months was associated, not only to lower subsequent response rates, but also to significantly inferior FFS, PFS and OS. The BCR-ABL^IS 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.

In a multicentric nationwide experience, the proportion of patients with BCR-ABL^IS 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-ABL^IS 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-ABL^IS level >1% at 3 and 6 months represents a warning, requiring a close monitoring. A switch to 2^nd generation tyrosine kinase inhibitors should be considered.

University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo.

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.