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 . 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 . 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.”
- 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.
- 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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