Analysis Of Efficacy And Related Factors Of Acquired Deep Molecular Response In Chronic Myeloid Leukemia Patients Treated With TKI

Background and Objective: The introduction of tyrosine kinase inhibitors (TKI) has significantly altered the survival and prognosis of patients with chronic myeloid leukemia (CML). During TKI therapy, cytogenetic and molecular monitoring is used to guide and predict the effect of TKI treatment. Achievement of a stable undetectable BCR-ABL transcripts not only means an improved long-term prognosis and is the requirement for patients entering trials, making it possible to reach treatment-free remission(TFR).Methods: A retrospective analysis of 237 adult patients newly diagnosed with CML between July 2008 and July 2017 was carried out. The patients were enrolled from the General Hospital of the People's Liberation Army. Patients were excluded if they were diagnosed in accelerated phase (AP) or blast phase (BP),had previously initial treatment with rIFN-a, chemotherapy, or hematopoietic stem cell transplantation(HSCT) or had been followed up for <6 months. The optimal response, MR4.5, stable MR4.5, total survival (OS) and progression-free survival (PFS) were defined.Frequencies were compared using the x2 test. The cumulative incidence of MR4.5,stable MR4.5,OS and PFS was statistically analyzed using the Kaplan-Meier method.SPSS Version 20 was used for all statistical analyses.Results: (1) All 125 patients were treated with imatinib in the first line, of which 39 were converted to second-generation TKI because of resistance or intolerance. The results of the time-course analysis showed that 60.9%, 57.1% and 56.6% of the patients received the best response at 3, 6, and 12 months after conversion therapy.Besides, there was no significant difference between the treatment of nilotinib and dasatinib(P> 0.05).(2)The median follow-up time was 4.26 years (range 0.5- 9.1 years). The 6-year cumulative incidence of MR4.5 and stable MR4.5 for TKI treatment was 50.4% and 29.6%. In the patients switch to second-generation TKI,38.5% and 23.1% patients achieved MR4.5 and stable MR4.5.(3) Multivariate analysis showed that WBC count at the time of diagnosis and BCR-ABLIS level at 3 months were independent factors for obtaining MR4.5 (P=0.023,P=0.037) and stable MR4.5(P<0.001), and the 3-month BCR-ABLIS level was an independent factor to obtain MR4.5 and stable MR4.5(P<0.001). In addition, the time to obtain MMR was associated with stable MR4.5, and the cumulative incidence of stable MR4.5 was higher for obtain MMR at 3 months compared with those obtained at 6 or 12 month(83.3%vs 57.1% vs 40.7%,P < 0.001). (4) Patients who didn't reduced or interrupted imatinib dose had a significantly higher cumulative incidence of MR4.5 and more stable MR4.5 after 6 years (20.6% vs 61.5%, P<0.001; 11.8% vs 36.3%,P<0.001) . For patients with leucopenia and thrombocytopenia during TKI treatment,the results were consistent for 6 years' cumulative incidence of MR4.5 (7.1% vs 47.1%, P=0.005;7.1%vs 33.3%,P=0.008).Conclusion:TKI for the treatment of CML can obtain excellent hematologic,cytogenetic and molecular response. WBC count at the time of diagnosis and BCR-ABLIS level at 3 months was influencing factors of deep molecular response.Long-term TKI dose modification significantly associated with MR4.5 and stable MR4.5, especially in patients with hematological AEs. Avoidance of unnecessary dose adjustments and the strengthening of rational therapeutic strategies may lead to an increase in the proportion of patients eligible for discontinuation trials.