P1/2, N=34, Recruiting, Novartis Pharmaceuticals | Trial primary completion date: Jun 2026 --> Sep 2027

After the first TFR attempt, major molecular response (MMR) was lost, and ponatinib was initiated but discontinued because of cerebral infarction. Imatinib was reintroduced, leading to the reachievement of a deep molecular response. This case underscores the importance of careful patient selection and long-term molecular monitoring following TFR attempts, including those involving novel TKIs such as asciminib.

We report an octogenarian man with chronic-phase CML who was intolerant to multiple tyrosine kinase inhibitors and underwent temporary discontinuation of asciminib. All-trans retinoic acid plus arsenic trioxide achieved molecular remission of PML::RARA and was followed by an initial marked reduction in BCR::ABL1 transcript levels, which subsequently remained detectable at low levels during continued follow-up. This case highlights the importance of integrated cytogenetic and molecular evaluation to distinguish blast phase from independent leukemogenesis in patients with CML who develop cytopenias.

The landscape of asciminib resistance is broader and more complex than previously appreciated, involving mutations across multiple domains that disrupt ABL1 autoinhibition. Epistasis between mutations acquired during sequential therapies can create unexpected and potent resistance. However, these diverse genetic resistance mechanisms converge on a single biophysical measurement of the openness of the active ABL1 conformation. This provides a unified framework for understanding asciminib resistance and underscores the need for routine clinical resistance monitoring to include the SH3 and SH2 domains in first line and later line therapy.

The introduction of imatinib established proof of principle for oncogene-targeted therapy, leading to sustained survival improvements...More recently, the development of the allosteric inhibitor asciminib introduced a novel mechanism of action and expanded therapeutic options for pretreated patients...Thus, CML represents a unique model of translational oncology, demonstrating how mechanistic insight can drive therapeutic innovation. Future strategies will focus on increasing TFR rates, overcoming resistance, targeting leukemic stem cells, and improving global access to therapy and monitoring, with the ultimate aim of achieving functional cure in the majority of patients.

P=N/A, N=1000, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P1/2, N=50, Not yet recruiting, Friedrich-Schiller-Universitaet Jena

P1/2, N=14, Recruiting, Novartis Pharma AG | Not yet recruiting --> Recruiting

P1, N=30, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

P=N/A, N=37, Completed, Novartis Pharmaceuticals

P=N/A, N=98, Not yet recruiting, Gruppo Italiano Malattie EMatologiche dell'Adulto

P1, N=12, Not yet recruiting, Washington University School of Medicine | Trial completion date: Nov 2027 --> Mar 2028 | Initiation date: Apr 2026 --> Aug 2026 | Trial primary completion date: Oct 2027 --> Feb 2028