Abstract
Background: In a proportion of patients with chronic phase CML who achieve a sustained deep molecular remission (DMR), treatment discontinuation may be attempted; successful treatment free remission (TFR) is approximately 50%. Remaining patients restart TKI with expectation of indefinite tyrosine kinase inhibitor therapy. Asciminib is a potent BCR::ABL1 inhibitor with a novel, allosteric mode of action. In vitro data demonstrated that the combination of asciminib and TKIs led to synergistic activity, and asciminib monotherapy proved effective in later line therapy and offers response and safety advantages as initial therapy. By using asciminib based therapy in patients with molecular relapse after prior TFR attempt, further and potential synergistic inhibition of residual leukemia causative of relapse after initial treatment discontinuation may induce a different quality of DMR and allow for successful subsequent TFR.
Study Design: This is a single arm phase II study that will enroll a minimum of 47 subjects with a maximum of 51. All patients will have a confirmed diagnosis of CP-CML and must have previously attempted to discontinue TKI. All patients must have restarted the same TKI they were on prior to discontinuation at the time of relapse in order to be eligible for this trial. This trial will use any of the following (based on patient/physician preference) during the consolidation treatment phase: asciminib 40 mg PO daily plus imatinib (maximum dose of 400 mg PO once daily), asciminib 40 mg PO bid plus nilotinib (maximum dose of 300 mg bid), asciminib 80 mg PO daily plus dasatinib (maximum dose of 100 mg daily), asciminib 80 mg PO daily. All eligible patients will begin asciminib ±TKI on cycle 1 day 1 of the consolidation phase. They will continue therapy for a total of 12 cycles (minimum of 12 months). At the end of 12 cycles, asciminib ± TKI will be discontinued in patients who continue to satisfy the requirements for TFR attempt. The primary endpoint of this study is the 12-month ‘second’ TFR rate after completion of 12 cycles of asciminib based therapy. Patients will remain in the TFR phase of the study for up to three years and will have central PCR testing during the first two years. PCR testing will continue locally thereafter.
Results: From Feb 2023 to June 2025, 9 patients were enrolled. The median age was 67 (45-72) and 56% were male. Prior to first TFR the median time on TKI was 5.6 years and 8/1 were on imatinib/dasatinib, respectively. The median time to restarting TKI in first TFR attempt was 100 days (range 59-315 days). After the restart, median duration to start of combination treatment was 4.1 years (range 1.2-6.8 years). Of 9 patients enrolled, 2 are still in combination phase, and 7 have completed the combination phase and attempted TFR. Among patients who reached TFR (N = 7), the median duration of TKI was 5.5 years (range 2.2-7.7 years) prior to second discontinuation and 7 were on Imatinib.
Of the 7 patients who reached second TFR, 5 patients remain in TFR with a median duration of 384 days (range 154-502 days). Two patients restarted TKI at TFR days 63 and 236. The median time from second TFR to restarting TKI has not been reached (95% CI [236, –] days).
The most common AEs were diarrhea (N = 4) and fatigue (N = 4). The only grade 3/4 AE was pain in extremity (N = 1, grade 3) and rectal fissure (N = 1, Grade 3).
Conclusion: This is the first report of asciminib use to attempt 2nd TFR. The combination was well tolerated, and patients were able to complete the combination phase. Preliminary results suggest feasibility and potential to increase cure for CML. The study is ongoing and updated results will be presented at the meeting.
