Background

For patients diagnosed with chronic myeloid leukemia (CML), the prospect of eventual treatment-free remission (TFR) is highly attractive. However outside of clinical trials, it is unclear what the real-world feasibility is of becoming eligible for a TFR attempt and the actual success rate. Consequently, we sought to investigate the factors associated with TFR eligibility and sustained TFR in CML treatment referral sites in Australia.

Aim

To determine factors associated with TFR eligibility and sustained TFR for CML patients treated at two CML academic centres in South Australia according to the selected frontline TKI therapy.

Methods

Adult patients receiving their primary CML management at the Royal Adelaide Hospital and Flinders Medical Centre were included. Registry data of patients reviewed between January 2008 and May 2025 were analysed. Patients enrolled in clinical trials were also included. Minimum criteria for qualifying for a TFR attempt were ≥3 years of tyrosine kinase inhibitor (TKI) therapy and ≥2 years of sustained molecular response 4.5 (MR4.5, BCR::ABL1 <0.0032% IS). In the event of molecular relapse, TKI was recommenced promptly. Sustained TFR was defined as remaining off TKI with no molecular relapse ≥12 months after TKI cessation.

Results

A total of 530 patients were included in our analysis with a median follow up of 8.1 years (0.1-35.2 years) from diagnosis. Males accounted for 57% of the diagnosed cohort and the median age at diagnosis was 55.8 years (7.1-92.6 years). The frontline TKI, defined as the initial TKI used in the first 3 months of TKI therapy, was imatinib (n= 283), nilotinib (n=69), dasatinib standard dose (n=39) or modified dose (n=80) and asciminib (n=44). The median dose of dose-modified dasatinib was 50mg daily. The 3, 6 and 12-year cumulative incidence (CI) of MR4.5 was 43.3%, 60.9% and 75.4%, respectively while the 3, 6 and 12-year CI of TFR eligibility was 4.1%, 34.4% and 56.6%, respectively. Overall, the 3, 6 and 12-year CI of attempting TFR was <1%, 23.0% and 46.6%, respectively. Of the 530 patients, 203 (38%) ceased TKI in a TFR attempt. The 12-month sustained TFR rate was 53.2%.

Factors previously demonstrated to predict TFR were examined. The 3-month halving time, sex, ELTS and frontline TKI predicted for MR4.5 achievement, whereas age and transcript type did not. Females were more likely to achieve MR4.5 compared with males (3-year CI 53.6% vs. 35.9%) although the difference was less pronounced by 12-years (80.1% vs. 73.1%, P=.004). There was no significant difference between the CI of MR4.5 by 6 years between patients who were treated with nilotinib compared with 100mg dasatinib and dose-modified dasatinib (75.9% vs. 75.9% vs 73.8% respectively, P=0.1). However, patients treated with dasatinib (at any dose) took longer to achieve MR4.5 compared with those treated with frontline nilotinib (3-year CI of MR4.5 50.7% vs. 42.2% vs 64.7% respectively, P<.001).

With regards to TFR eligibility, more females achieved this target compared to males (12-year CI 64.2% vs. 52.0%, P=.005). Halving time and ELTS also predicted for TFR eligibility as did the frontline TKI. The 12-year CI was 65.3% for patients treated with frontline second-generation TKIs (2G-TKIs) compared with 52.2% for frontline imatinib (P<.001). Interestingly, there were differences observed based upon the frontline 2G-TKI utilised. The 6-year CI of TFR eligibility was 30.0%, 50.8%, 35.2% and 61.3% for imatinib, 100mg dasatinib, modified dose dasatinib and nilotinib respectively, P<.001. The differences observed between the frontline 2G-TKIs are likely due to delayed achievement of stable MR4.5 as modified-dose dasatinib took longer to reach this.

Of the 203 patients that ceased TKI in a TFR attempt, 64% were treated with frontline imatinib while the remainder were commenced on 2G-TKI. The 12-month sustained TFR rate was 74% in patients treated with frontline 2G-TKI compared with 50% if patients were initiated on imatinib (P<.001).

Conclusion

The frontline TKI and the dose influences TFR eligibility and sustained TFR, highlighting the need for frontline optimal TKI selection, especially for patients that have high priority for TFR. Frontline 2G-TKIs enable more patients to achieve TFR eligibility at 6 and 12 years of TKI exposure compared to imatinib. Preliminary data demonstrates that nilotinib has the highest rates of TFR eligibility compared with dasatinib, especially dose-modified dasatinib.

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2025
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