Predictive Factors of Stable Deep Molecular Response in Chronic Myeloid Leukemia Patients Treated with Imatinib Standard Dose: A Study from the Gruppo Triveneto LMC

Background. A sustained deep molecular response (MR⁴ or better) is a validated criterion for discontinuation of Tyrosine Kinase Inhibitors (TKI) in patients with Chronic Myeloid Leukemia (CML), but only a minority of patients attain this response. Predictive factors of stable MR⁴ have been reported in patients treated with different dosages of imatinib (i.e from 400 to 800 mg daily) but data about long-term treatment with standard dose imatinib are lacking. Moreover, various definitions of sustained MR⁴ have been used in these studies.

Aims and methods. To assess the probability and the predictors of a stable MR⁴ we restrospectively analyzed our cohort of chronic phase CML patients treated with imatinib 400 mg daily, as first-line therapy or after interferon (IFN) failure. IFN-treated patients already in complete cytogenetic response at the time of imatinib start were excluded from the analysis. Major molecular response (MMR) was defined as BCR-ABL^IS ratio <0.1%. Deep molecular response (MR⁴) was defined as BCR-ABL^IS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Patients with MR⁴ lasting ≥ 2 years and at least a Q-PCR test every 6 months were defined as stable MR⁴. Patients with any sample >0.01% BCR-ABL^IS after the achievement of MR⁴ were defined as unstable MR⁴. Baseline factors (age, sex, Sokal, Hasford and EUTOS risk score, type of BCR-ABL transcript, pre-treatment with IFN) and response to imatinib at 3, 6, and 12 months according to the European LeukemiaNet (ELN) 2013 recommendations have been examined for the association with stable MR⁴. Frequencies were compared by Fisher's exact test. Univariate and multivariate regression analysis were performed using the competing risk model of Fine and Gray, where the achievement of the response was the event of interest, and cessation of imatinib 400 mg daily for any reason (including dose increase for resistance, and death) were the competing risks. The significance of individual parameters comprising more than 2 variables was determined by the Wald test.

Results. A total of 320 patients (260 treated with imatinib front-line and 60 after IFN) was evaluated. Median age at diagnosis was 57 years (range 20-88). Sokal distribution was 42%, 40% and 15% for low, intermediate and high risk, respectively (3% were not evaluable). After a median follow-up from imatinib start of 74 months, 146 patients (46%) never reached MR⁴, 84 patients (26%) obtained an unstable MR⁴ and 90 patients (28%) achieved a stable MR⁴. The cumulative incidence of stable MR⁴ was 26.8% (95% CI: 20.8-32.3%) at 5 years and 39.3% (95% CI: 32.1-45.7%) at 10 years. Median time to first MR⁴ for patients subsequently obtaining a stable MR⁴ was 25.3 months and all but 5 stable responders achieved the MR⁴ within 5.5 years of imatinib. As compared to patients with unstable MR⁴, those with stable MR⁴ tended to have a higher frequency of e14a2 transcript (63% vs 53%; p=0.07) and had a marginally significant lower frequency of IFN pre-treament (16.7% vs 29.8%; p=0.048) while no differences were observed concerning the other baseline factors, including sex. Predictors of stable MR⁴ were: type of transcript (e14a2 vs e13a2 HR 2.07; p=0.003), pre-treatment with IFN (no IFN vs IFN HR 2.45; p=0.002), BCR-ABL level at 3- (≤10%^IS vs >10%^IS HR 3.48; p=0.004), 6- (<1%^IS vs 1-10%^IS HR 9.95; p=0.001) and 12-months (MMR vs no MMR HR 12.5; p<0.001). Considering only patients with optimal response to imatinib, rates of stable MR⁴ were significantly higher for e14a2 than e13a2 or e13a2/e14a2 patients both at 3 (47.8% vs 23.2% and 21%; p=0.003), 6 (48.6% vs 28.8% and 33.3%; p=0.027) and 12 months (53.7% vs 25.9% and 40%; p=0.037).

Conclusions. Biological variables such as the type of BCR-ABL transcript could influence the achievement and the stability of MR⁴, also in patients with optimal kinetics of response to imatinib. Moreover, our results suggest that a rapid attainment of MR⁴ during the first years of imatinib treatment is a predictor of a subsequent sustained response, a prerequisite for TKI discontinuation.