Factors for Sustaining Molecular Remission after Discontinuation of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia: Results of Non-Randomized Prospective Clinical Trial

Abstract

Aim. To study the impact of different clinical and biological factors on sustaining molecular remission after discontinuation of tyrosine kinase inhibitors (TKI) therapy in chronic myeloid leukemia (CML) patients with a stable deep molecular response (MR). Materials & Methods. The prospective multi-center trial on molecular remission sustainability after TKIs withdrawal, held from 2015 to 2019, enrolled 98 CML patients. The trial included patients with chronic phase CML treated with TKIs at least during 3 years and having a stable deep MR (< МО4; BCR-ABL < 0.01 %) during at least 2 years. Molecular monitoring was carried out every month during first 6 months after TKIs withdrawal, every 2 months during 0.5-1 year, and every 3 months after 1-year follow-up. In case of the loss of major MR (BCR-ABL > 0.1 %) therapy was reinitiated. Results. Three-year molecular relapse-free survival was 51 % (95% confidence interval 41-61 %) in all patients, 25 % in patients with the failure of prior treatment discontinuation, and 53 % in patients who discontinued TKI therapy for the first time. According to univariate analysis, the following factors proved to be significant: persistance of deep MR, duration of therapy, and depth of MR. It was shown that TKI therapy duration, but not deep MR persistance, has independent prognostic value for the Russian population of CML patients. No significant differences were identified in 3-year molecular relapse-free survival in the groups of patients treated only with imatinib (55 %) compared with patients who received 2nd generation TKI (TKI2) as first-line (70 %; p = 0.26) and second-line (39 %; p = 0.09) therapy. However, duration of therapy in patients treated with TKI2 as first-line therapy was more than twice as short as in patients treated with imatinib as first-line therapy (median 41.5 vs. 96.4 months, respectively; p < 0.0001). Conclusion. Longer therapy duration and MR depth (< M04.5) before TKI withdrawal raise the probability of sustaining off-treatment remission. The study showed that molecular relapse-free survival does not significantly increase with the use of TKI2 as first-line treatment compared to imatinib. Nevertheless, TKI2 as first-line treatment enables to halve the duration of therapy needed to achieve comparable molecular relapse-free survival, as compared with imatinib.