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Asciminib monotherapy in Ph+ CML: major molecular responses

Presented by
Prof. Timothy Hughes, University of Adelaide, Australia
EHA 2020
Phase 1
In patients with Philadelphia chromosome-positive (Ph+) chronic phase chronic myeloid leukaemia (CML) refractive to ABL kinase inhibition, asciminib was well-tolerated and showed initial clinical activity.

Prof. Timothy Hughes (University of Adelaide, Australia) explained that asciminib binds a myristoyl site of the BCR-ABL1 fusion protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from all other ABL kinase inhibitors [1]. Asciminib targets both native and mutated BCR-ABL1 fusion proteins, including the T315I-mutant fusion protein. The safety and clinical activity of asciminib in patients with Ph+ leukaemia are unknown.

Patients with Ph+ chronic phase or accelerated phase CML (n=48) were enrolled in an ongoing larger phase 1 study [2]. Patients who were relapsed/refractory or intolerant to ≥2 ABL tyrosine kinase inhibitors were assigned to 9 different oral asciminib dose cohorts (20, 40, 80, 150, 160, and 200 mg twice daily; 80, 120, and 200 mg once daily) evaluating asciminib alone or in combination with other therapies. The analysis presented by Prof. Hughes looked at the asciminib monotherapy cohorts with ≤1% BCR-ABL1 at baseline. Median duration of study treatment exposure was 161 weeks.

At data cut off, 36 patients (75.0%) manifested a major molecular response (MMR) or better, and median time to MMR among responders was 30 days. All 18 patients who achieved MMR maintained this for ≥2 years. Of the 6 patients who did not achieve MMR, 1 had baseline levels of BCR-ABL1 >1%, and 5 were between 0.1-1%.

The most common grade 3-4 adverse events (AEs), occurring in >10% of patients were lipase increases (27.1%) and hypertension (12.5%). Serious AEs were reported in 33.3% patients, and 2 patients experienced myocardial infarction (4.2%).

“In conclusion, asciminib monotherapy was well-tolerated and showed promising clinical activity in patients with baseline BCR-ABL1 levels less than 1%,” concluded Prof. Hughes during his presentation. “These results support further investigation of asciminib in patients who do not achieve optimal response at earlier time points.”

    1. Hughes T, et al. Asciminib in heavily pre-treated patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase sensitive to TKI therapy. EHA25 Virtual, 11-21 June 2020, Abstract S170.
    2. Hughes TP, et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019;381(24):2315-2326.

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