Abstract Background: Asciminib, an allosteric inhibitor of BCR::ABL1, has the potential to promote deeper molecular response (DMR) with reduced toxicity in patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML). Additionally, asciminib may be combined with low dose ATP-competitive TKIs (lowTKI) to further enhance the depth of molecular response in patients who fail to achieve DMR or do not meet optimal response criteria as defined by the European LeukemiaNet. Methods: This is an ongoing, multicenter phase 2, investigator-initiated, single-arm, open-label study (NCT05143840) within the H Jean Khoury Cure CML Consortium (HJKC3). Patients received either asciminib 40 mg orally twice daily or 80 mg once daily. The primary study endpoint is the rate of MR4 or better at 12 months. Patients who did not achieve MR4.5 after 24 months on asciminib, experienced treatment failure at any time or had a warning response at 12 months were offered the addition of lowTKI (imatinib 300 mg, dasatinib 50 mg or nilotinib 300 mg daily). Patient reported outcomes were collected at multiple timepoints using NIH PROMIS and PRO-CTCAE measures with high rates of completion. With a planned enrollment of 100 subjects, the study is powered at 86% to detect a 13% absolute improvement in the rate of MR4 or better at 12 months from 25% to 38% estimated by the Wald test. Results: Between April 2022 to July 1st 2025, 61 patients were enrolled. The median age was 52 years (range 25-79) and 37.7% were female. Sokal score was low, intermediate, high, and unknown in 20, 18, 5 and 10 patients respectively. With a median follow up of 59 weeks (0-143), 55 (90.2%) patients remained on asciminib treatment. As of this analysis, 12 patients have met the criteria for adding lowTKI: 9 for a warning response, 2 for not achieving a DMR and 1 for failure. Of those 12 patients 7 have started lowTKI. The primary endpoint, MR4 or better at 12 months, was achieved in 41.9%% of patients (3 months 8%, and 29.2% at 6 months). MR3 was achieved in 36%, 60.4% and 74.4% at 3, 6 and 12 months respectively. MR4.5 was achieved in 6%, 12.5% and 25.6% at 3, 6 and 12 months respectively. Grade 1-2 hematologic adverse events (AEs) include anemia (28%), thrombocytopenia (31%), and neutropenia (13%). One patient developed grade 3 neutropenia. Non-hematologic AEs occurring in more than 10% of patients were fatigue (26%), nausea (20%), arthralgia (16%), headache (15%), hypertension (15%), increased CPK (11%), increased lipase (15%), increased ALT (16%), increased AST (13%) and myalgia (15%). Grade 3-4 AEs considered related to asciminib were increased ALT/AST (2%), headache (2%), abdominal pain (2%), flank pain (2%), hyperhidrosis (2%), insomnia (2%), rhabdomyolysis (2%), arthralgia (4%), myalgia (3%), increased CPK (5%), diarrhea (2%), insomnia (2%) pancreatitis (2%) and increased lipase (7%). A total of 6 (10%) patients discontinued treatment. Reasons for treatment discontinuation included grade 3 CPK increase (n=1), grade 3 arthralgia (n=1), grade 3 diarrhea (1), grade 2 nausea (n=1), grade 2 dizziness (n=1), and treatment failure (1). Conclusion: Asciminib monotherapy demonstrated rapid early and deep molecular responses in patients with CP-CML, with a favorable safety profile. Further data will be presented for patients who added lowTKI.
Baim et al. (Mon,) studied this question.