Data from the EHA2023 Hybrid Congress on late-line CML treatment reflect important ongoing work to address resistance and intolerance to second-generation TKIs, but several key unmet needs remain. Overall, we have more and more momentum gathering with asciminib, but we also have confirmation that patients who develop resistance to ponatinib do not seem to do very well on asciminib.

Previously, we have seen that, although asciminib constitutes a valid treatment option for patients failing second-generation TKIs, responses in those with ponatinib failure seem to be poor (abstract EP670, 2021). This year, we continue to see that responses to asciminib appear to be better in ponatinib-naive patients in studies such as the one by Kuzmina et al from EHA2023 (abstract P673). This group of patients with ponatinib resistance remains high risk, and alternative treatments are needed. There is a possibility that olverembatinib may represent another possible strategy in this setting, but this remains to be demonstrated, as the data thus far are quite limited.

Several studies at EHA2023 dealt with the T315I mutation, which has been considered a bad mutation to have, in part from the perspective of imatinib resistance and second-generation TKI resistance. However, it is important to emphasize that, while the presence of the T315I mutation does, in fact, dictate treatment, patients with T315I-positive chronic-phase CML can still have good outcomes if they receive appropriate treatment.

In keeping with this observation, Bidikian and colleagues reported data suggesting that patients with CML who remain in chronic phase at the time of developing the T315I mutation may have a more indolent disease course than those who developed the T315I mutation during the accelerated or blastic phase (abstract P672). A total of 107 patients with CML who developed the T315I mutation were identified, having received a median of 3 therapies prior to T315I mutation. A total of 83 patients underwent T315I repeat testing after therapy, of which 45% cleared their mutation with ponatinib, autologous stem cell transplantation, omacetaxine, chemotherapy plus TKI therapy, asciminib, and other investigational agents. The authors noted that those with CML who remained in chronic phase at the time of T315I diagnosis had better overall survival (median, 132 months) compared with those in the accelerated or blastic phase (median, 31 months and 6 months, respectively). Patients who cleared their T315I mutation after therapy had a 5-year overall survival of 70% compared with 25% in those who did not clear their mutation.

Internationally, although ponatinib may be more accessible than asciminib, a number of patients with CML have received asciminib through managed access programs. Many patients with highly treated CML and T315I mutation are able to achieve a favorable response to treatment with asciminib. For example, Kuzmina and colleagues reported data from a study of 82 patients with Ph-positive, chronic-phase CML in Russia who were treated with asciminib, and the T315I mutation was detected in 23 patients. Patients with highly pretreated CML with T315I mutation achieved a response with asciminib 200 mg twice daily, particularly those in the ponatinib-naive group. However, as noted initially, ponatinib resistance continues to be an unmet need, and newer-generation TKIs and novel agents are needed for patients with advanced-phase T315I-positive CML. Furthermore, the high cost of asciminib at 200 mg twice daily remains prohibitive, severely limiting its use, and longer follow-up is still needed to decipher the safety of asciminib at 200 mg twice daily.