Clinical analysis on outcomes in patients with chronic myeloid leukemia in chronic phase after tyrosine kinase inhibitors discontinuation and their influencing factors

Objective To explore the clinical outcomes and their influencing factors of tyrosine kinase inhibitors (TKI) discontinuation in patients with chronic myeloid leukemia in chronic phase (CML-CP). Methods From January 1999 to April 2018, a total of 16 patients with CML-CP who underwent routine outpatient follow-up in Department of Hematology, West China Hospital of Sichuan University, and discontinued TKI for more than 6 months were selected as subjects. Among them, there were 6 male patients and 10 females; the median age at diagnosis was 39.5 years (24.8-53.8 years). The median age at time of TKI discontinuation was 45.5 years old (30.3-69.0 years old). According to whether molecular recurrence occurred during the follow-up period after TKI discontinuation, the patients were divided into recurrent group (n=5) and non-recurrent group (n=11). The clinical data of patients with TKI before and after discontinuation were collected by retrospective method. The causes of TKI discontinuation, treatment-free remission (TFR) status after TKI discontinuation and its possible influencing factors were analyzed. In this study, composition ratio of gender, stage of CML, and TKI discontinuation causes were compared between the two groups using Fisher′s exact test. The Mann-Whitney U test was used to compare the non-normal distribution measurement data, such as duration of TKI treatment, time from TKI treatment to major molecular response (MMR)/deep molecular response (DMR), time of MMR/DMR maintenance. The TFR rate at 6 and 12 months after TKI discontinuation in patients was calculated by Kaplan-Meier method. The procedure followed in this study was in line with the revised Helsinki Declaration of the World Medical Association in 2013. Results ① Among all the 16 patients with CML-CP, causes of TKI discontinuation included TKI-related adverse reactions (n=5), patients′ expectancy (n=5), pregnancy/planned pregnancy (n=4), financial burden (n=1), and combined solid tumor (n=1). The median time of TKI treatment in 16 patients with CML-CP was 53.0 months (34.0-156.0 months). Among them, 15 patients achieved DMR before TKI discontinuation and 1 patient only obtained MMR. The median time to achieve DMR before TKI discontinuation was 39.0 months (10.0-144.0 months). ② The median follow-up time of 16 patients with CML-CP after TKI discontinuation was 17.0 months (7.0-75.0 months). At the end of follow-up, 11 patients had no molecular recurrence, and the median time of TFR was 12.0 months (2.0-75.0 months). TFR rates at 6 and 12 months after TKI discontinuation were 68.8% and 61.9%, respectively. Molecular recurrence occurred in 5 patients. The median recurrence time was 4.0 months (2.0-5.0 months) after TKI discontinuation, and the BCR-ABLIS level was 0.14%-0.88% at the time of recurrence. Among the 5 patients with molecular recurrence, 4 patients restarted TKI at 3, 4, 6 and 8 months after relapse, obtained MMR after 2, 3, 4, and 5 months of restarting TKI, obtained molecular response (MR)4.5 after 2, 3, 7 and 8 months of restarting TKI, respectively. ③ In this study, 5 patients with molecular recurrence occurred within 6 months after TKI discontinuation. The composition ratio of gender, stage of CML, causes of TKI discontinuation, previous treatment of interferon-α, TKI type, as well as duration of TKI treatment, time of initiation of TKI treatment to MMR/DMR, time of MMR/DMR maintenance, age at TKI discontinuation between two groups were compared. And the differences were not statistically significant (P>0.05). ④ Among 16 patients with CML-CP, 2 patients developed TKI withdrawal syndrome, which was characterized by systemic bone pain or myalgia. Conclusions Patients with CML-CP who receive long-term TKI and maintain continuous DMR, long-term TFR can be obtained in about 50% patients, but long-term MR should be monitored after TKI discontinuation. The above-mentioned influencing factors that may affect the clinical outcomes of TKI discontinuation were not statistically different between the recurrent group and the non-recurrent group, which may be related to small sample size of this study. Key words: Leukemia, myeloid; Leukemia, myeloid, chronic-phase; Leukemia, myelogenous, chronic, BCR-ABL positive; Prognosis; Tyrosine kinase inhibitor; Treatment discontinuation; Treatment free remission