Specifically targeting the ABL myristoyl pocket: STAMP inhibitors for chronic myeloid leukemia

Chronic myeloid leukemia (CML) has been transformed by ATP-competitive BCR:ABL1 tyrosine kinase inhibitors (TKIs); however, resistance, intolerance, and long-term toxicity remain clinically relevant challenges, particularly in patients requiring prolonged therapy or multiple treatment lines. Asciminib, the first-in-class Specifically Targeting the ABL Myristoyl Pocket (STAMP) inhibitor, represents a paradigm shift by restoring physiologic ABL1 autoinhibition through allosteric binding.

This Special Report reviews the mechanistic basis, preclinical development, and clinical evidence supporting asciminib in CML. We summarize key data from pivotal trials, including ASCEMBL and ASC4FIRST, as well as emerging real-world studies, focusing on molecular response depth, safety, resistance mechanisms, and patient selection. Particular attention is paid to how STAMP inhibition differs from ATP-competitive TKIs in terms of selectivity, toxicity profile, and resistance patterns, and how asciminib can be positioned relative to ponatinib in later-line settings.

Asciminib has established itself as an effective and generally well-tolerated option for patients with TKI-resistant or -intolerant CML and is poised to expand into earlier lines of therapy. Its ability to induce rapid and deep molecular responses with reduced off-target toxicity may have important implications for long-term disease control and future treatment-free remission (TFR) strategies. Ongoing studies will clarify its optimal sequencing, combination potential, and role in facilitating durable TFR.