A More Rapid Initial Decline of BCR::ABL1 Transcripts and Longer Treatment Duration with Improvement of Treatment-Free Remission Rate after Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Backgrounds: In recent years, several clinical studies have shown that approximately one-half of patients with chronic phase chronic myeloid leukemia (CP-CML) who receive adequate tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to discontinue therapy successfully. In this context, Treatment free remission (TFR) is a major goal for all CML patients according to the current guidelines and the main factors affecting TFR are the duration of TKIs treatment and the duration of DMR maintenance during TKI treatment.

Aim: To investigate a safer condition of TFR in CML we analyzed the success rate of TFR in CP-CML patients who maintained a DMR for at least 4 years. Additionally, it investigated whether new clinical application criteria could be established by TFR study of longer TKI treatment duration and DMR duration, and factors affecting the maintenance of TFR rate.

Methods: Among patients newly diagnosed with CP-CML and treated at least one of TKIs (Imatinib, Nilotinib, Dasatinib, Bosutinib, and Radotinib) as the first treatment, patients who maintained MR4.5 (BCR::ABL1 ^IS ≤0.0032%) continuously for at least 4 years through reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) tests were enrolled in this study. After discontinuation, molecular responses were monitored using the RT-qPCR method. In the case of relapse, defined as the loss of major molecular response (MMR), the previous TKI treatment with same dose was reintroduced, and molecular responses following the resumption were monitored monthly using RT-qPCR until MMR was re-achievement.

Results: Altogether 116 patients (50 males and 66 females) discontinued TKI treatement. Median age at diagnosis was 43.0 years (range, 40.8-45.3) and the percentages of patients with low, intermediate and high Sokal risk scores ware 58 (50.0%), 35 (30.2%) and 18 (15.5%) patients, respectively with unknown Sokal risk scores in 5 (4.3%) patients. The percentage of patients with low and high EUTOS scores was 69.8% and 6.0%, respectively and 24.1% had an unknown risk. Prior to discontinuation, all patients received TKIs for a median of 118.0 months (range, 63.6-224.7), and the duration of sustained MR4.5 was 67.4 months (range, 48.6-157.9). At the time of discontinuation, 93 patients (80.2%) were using first-line TKI (70 Imatinib, 13 Nilotinib, 6 Radotinib, and 4 Dasatinib) while 13 (11.2 %) and 10 (8.6%) patients were receiving their second and more than three TKIs respectively. All patients who received more than one TKI had changed to adverse events. The patient-specific calculated halving time of BCR::ABL1 after starting TKI treatment to determine early molecular kinetics was median 11.1 days (range, 3.3-722.2).

After a median follow-up from treatment discontinuation of 28.0 months (range, 10.9-150.7), the TFR rates at 12, 24, and 48 months were 81.9%, 76.0%, and 71.0%, respectively. 88 patients were still free of treatment with sustained MR4.5. Despite 45 patients losing UMRD, 17 patients were able to regain their MMR, while 28 (24.1%) patients have lost MMR at a median of 8.4 months (range, 1.8-42.0) after discontinuation; 18 (64.3%) patients had molecular relapse within 6 months of TKI discontinuation. No progression toward advanced-phase CML occurred, and when 28 patients who lost MMR were retreated with same TKI, 26 patients (92.9%) reachieved MMR with a median of 5.6 months (range, 2.3-23.4). Variables demonstrating a significant association on univariate analysis were EUTOS risk score (Low vs. High, HR 5.184, P<.001), total duration of TKI therapy (<118.0 mo vs. ≥118.0 mo, HR 0.384, P=.022) and halving time (<11.1 days vs. ≥11.1 days, HR 4.183, P=.030).

Conclusion: Our result demonstrates that TFR rate can be improved in patients who received TKI treatment for approximately 10 years and maintained DMR for more than 6 years regardless of the type of TKI. Based on results, we can confirm that a more rapid initial BCR::ABL1 decline after commencing TKI and total duration of TKI therapy correlated with an increased probability of achieving TFR eligibility.