Advances of next-generation STAMP inhibitors in chronic myeloid leukemia

Introduction: Specifically Targeting the ABL1 Myristoyl Pocket inhibitors (STAMPi) have reshaped the management of chronic myeloid leukemia (CML). Yet, major challenges remain, including resistance and compound mutations, cross-intolerance, and long-term toxicities. Asciminib has shown efficacy in heavily pretreated patients and in the first-line setting, but resistance and limited benefit after ponatinib highlight the need for new therapeutic options. Covered areas: This review summarizes preclinical and early clinical evidence on next-generation STAMPi. TGRX-678 exhibits potent activity against wild-type and mutant ABL1, including T315I, synergism with orthosteric tyrosine kinase inhibitors (TKIs), central nervous system (CNS) penetration, and encouraging phase Ia/Ib clinical activity in heavily pretreated CML. Early but promising data are also emerging for TERN-701 from the CARDINAL trial. Expert opinion: Next-generation STAMPi may extend therapeutic options beyond asciminib by addressing resistant mutations and enabling rational dual-site inhibition. TGRX-678 ability to achieve CNS exposure raises potential in blast phase CML and Ph+ acute lymphoblastic leukemia. Key questions regarding durability, long-term safety, and optimal integration with ATP-competitive TKIs remain open. Ongoing trials will define the clinical role of these STAMPi and their potential to advance cure-directed strategies, including treatment-free remission.