Management of TKI-resistant chronic phase CML

Abstract

Chronic phase CML (CP-CML) patients who are resistant to 2 or more tyrosine kinase inhibitors (TKIs) have limited therapeutic options and are at significant risk for progression to the blast phase. Ponatinib has been the drug of choice in this setting for the past decade, but when given at full dose (45 mg/d), the risk of serious vascular occlusive events is substantial. Lower doses mitigate this risk but also reduce the efficacy. Emerging data suggest that a high dose of ponatinib is important to achieve response, but a lower dose is usually sufficient to maintain response, introducing a safer therapeutic pathway for many patients. The recent development and approval of the novel allosteric ABL1 inhibitor, asciminib, for CP-CML patients with resistant disease provides another potentially safe and effective option in this setting. These recent therapeutic advances mean that for most resistant CP-CML patients who have failed 2 or more TKIs, 2 excellent options are available for consideration-dose modified ponatinib and asciminib. Patients harboring the T315I mutation are also candidates for either ponatinib or asciminib, but in this setting, higher doses are critical to success. Lacking randomized comparisons of ponatinib and asciminib, the best choice for each clinical circumstance is often difficult to determine. Here we review emerging evidence from recent trials and make some tentative suggestions about which drug is preferable and at what dose in different clinical settings using case studies to illustrate the key issues to consider.

Graphical abstract

Figure 1.

Overall safety and efficacy of ponatinib based on starting dose. The analysis is a descriptive clinical summary of the data to illustrate the relationship between the efficacy and the AOE rate. TE-AOE, treatment-emergent arterial occlusive events. Reproduced with permission from Cortes et al.

Figure 2.

Subgroup analysis of the ASCEMBL study: risk difference with 95% CIs for MR3 achievement by 24 weeks of either asciminib or bosutinib. CRF, case report form. Reproduced with permission from Rea et al.

Figure 3.

Heat map summary of IC₅₀ values for TKIs against a panel of Ba/F3 cell lines expressing KD mutations. ATP, adenosine triphosphate. Reproduced with permission from Eide et al.