Early Predictors of Treatment-Free Remission in Chronic Myeloid Leukemia
Authors: Farhat Aziz , Kantarjian Hagop M. , Haddad Fadi G. , Short Nicholas J. , Montalban-Bravo Guillermo , Hammond Danielle , Jabbour Elias , Garcia-Manero Guillermo , Sasaki Koji , Issa Ghayas C. 
Published: December 2024

Background: The advent of tyrosine kinase inhibitors (TKI) drastically improved outcomes of chronic myeloid leukemia (CML), leading to a near normal life expectancy in most cases. With that, new treatment goals have emerged such as attaining a treatment-free remission (TFR) where the TKI can be stopped, an important goal for younger patients. However, current criteria to successfully select patients for a TFR attempt rely on evidence of a sustained deep molecular remission following years of treatment, with early predictors lacking. Therefore, we sought to characterize factors that may predict for TFR eligibility.
Methods: We screened patients treated at The University of Texas MD Anderson Cancer Center between January 2012 and December 2023 and found 780 patients with newly diagnosed chronic phase CML. We identified those who met the NCCN Criteria for TFR attempt which is defined as attaining a sustained molecular remission 4.5 (MR4.5) for 2 years following 3 years of therapy (TFR cohort: N = 333, 43%). We compared the characteristics of this TFR cohort to those who did not attain these criteria (control cohort: N = 447, 57%) and evaluated predictive factors of attaining TFR criteria using univariate and multivariate logistic regressions. Predictive factors with significance levels &lt;0.1 on univariate analysis were included in the multivariate model.
Results: There was no difference in age or sokal score between the TFR and control cohorts (median age 50 vs 47 years; P=0.15 and median sokal score 0.73 for both). The distribution of TKIs in each cohort was similar except for ponatinib (P=0.005) [comparing the TFR and control respectively, imatinib: 121 pts (36%) vs 160 pts (36%); dasatinib: 136 pts (41%) vs 164 pts (37%); nilotinib: 64 pts (19%) vs 84 pts (19%); ponatinib: 12 pts (4%) vs 39 pts (9%)]. The incidence of the BCR::ABL e13a2 transcript was higher in the control group (48% vs 32%; P&lt;0.001) whereas the e14a2 transcript was more common in the TFR group (35% vs 47%; P=0.001). Co-occurrence of both transcripts had a similar incidence in both groups (16% vs 21%; P=0.07). Resistance mutations in the ABL gene were only detected in the control cohort in 51 patients (11%). A univariate logistic regression identified the following factors associated with higher odds of meeting TFR criteria: older age [odds ratio (OR): 1.01, P=0.018], BCR::ABL transcript halving-time &lt;20 days (OR: 1.95, P&lt;0.001), and BCR::ABL transcript levels &lt;10% IS at 3 months (OR: 4.45, P&lt;0.001), 1% IS at 6 months (OR: 3.78, P&lt;0.001) and 0.1% (or major molecular remission, MMR) at 1 year (OR: 3.59, P&lt;0.001). The e13a2 transcript was associated with lower odds of attaining TFR criteria with an OR of 0.51 (P&lt;0.001) while the e14a2 transcript had higher odds of success with an OR of 1.67 (P&lt;0.001). Treatment with imatinib vs other TKIs did not show any impact on chances of reaching TFR criteria. In a multivariate analysis, the only independent predictors of meeting TFR criteria were halving-time &lt;20 days (OR: 1.66; P=0.017), BCR::ABL transcript levels &lt;0.1% at 1 year (OR: 1.78; P=0.045), and transcript e13a2 (OR: 0.48, P=0.006).
Conclusion: In summary, early predictors of attaining TFR criteria include halving-time &lt; 20 days and MMR at 12 months of therapy. The BCR::ABL transcript e13a2 was associated with a lower chance of attaining TFR criteria. Following validation, these factors could be used in the design of prospective trials as early surrogates of TFR.