The advent of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML), transforming its management into a chronic disease model and bringing patient life expectancy close to that of the general population. However, some patients experience treatment failure due to intolerance or insufficient response to at least two existing therapies, or the development of resistance, with consecutive changes in TKIs being associated with an increased risk of treatment failure. Patients with prior treatment intolerance, not achieving major molecular response (MMR) within two years, or with BCR-ABL gene mutations may develop resistance to current TKIs, increasing the risk of disease progression. Moreover, as treatment duration extends, patient demands for treatment tolerability increase. Balancing disease treatment with quality of life is particularly important for long-term survival. During the recent 12th Annual Meeting of the Society for Hematologic Oncology (SOHO 2024), "Hematology Frontier" had the honor of interviewing Dr. Jorge E. Cortes, Director of the Georgia Cancer Center at the Medical College of Georgia, who discussed the profound impact of Asciminib on current CML treatment patterns and future therapeutic landscapes, based on key findings from the ASC4FIRST study.Hematology Frontier：Could you share some preliminary results from the ASC4FIRST study and their potential impact on the field of CML treatment?
Dr. Jorge E. Cortes：The ASC4FIRST study was a randomized trial comparing Asciminib to any available treatment as a frontline therapy for CML. It had two primary endpoints: major molecular response at 48 weeks and a comparison of Asciminib versus Imatinib, as well as Asciminib versus other TKIs. Before randomization, physicians had to decide whether they would use Imatinib or a second-generation TKI if assigned to the control group. The results showed that both primary endpoints were met, with a significantly better rate of major molecular response for Asciminib against all TKIs, with a difference of almost 20%, and against Imatinib specifically, with a difference of almost 30%. This indicates a significant improvement in the primary endpoint. Secondary endpoints, such as early molecular response and deep molecular response (MR4, MR4.5), also demonstrated Asciminib’s efficacy. The safety and tolerability of Asciminib were equal to or better than other TKIs, with fewer patients discontinuing therapy due to adverse events. The safety profile showed fewer adverse events compared to other TKIs. Overall, this suggests that Asciminib could represent an additional improvement in the already effective treatments for CML, potentially advancing the outcomes for patients.
Hematology Frontier：What significance does the ASC4FIRST study hold for the current paradigm of CML treatment?
Dr. Jorge E. Cortes：I think the significance lies in the fact that, although we have very effective treatments for CML, there are still areas where we can make improvements. We’ve almost reached a normal life expectancy, which is already an achievement, but there are still long-term side effects and an impact on quality of life. Additionally, many patients still don’t qualify for treatment discontinuation. We can and should try to improve all of these aspects. I believe that these results, although preliminary, show the potential to overcome some or all of these deficiencies present in our current therapies. Therefore, I consider this study to be important in that regard. It may help us to surpass the limitations we still face in CML treatment.
Hematology Frontier：As a pivotal Phase 3 clinical trial, how will the ASC4FIRST study guide clinical practice?
Dr. Jorge E. Cortes：I think what it can do is become the treatment of choice for patients with newly diagnosed CML. Currently, we have many treatment options, so we will need to decide who the right patient is for these options versus others. It certainly offers an option for patients more interested in treatment discontinuation and for those concerned about adverse events. It may also change the paradigm by starting to use these drugs as our initial therapy. Obviously, in cancer, our aim is to use the best potential treatment available from the start. This study could provide us with the opportunity to begin with the best treatment, using the most effective drug we’ve identified so far, and introduce it as part of the initial therapy.
