The treatment landscape for chronic myeloid leukemia (CML) is evolving, with recent updates to the National Comprehensive Cancer Network (NCCN) guidelines reflecting significant advancements in therapeutic strategies. Asciminib, an allosteric tyrosine kinase inhibitor (TKI), has gained increased prominence, while treatment monitoring and cost considerations are also shaping clinical decision-making.
Asciminib's Expanded Role in CML Therapy
Asciminib (Scemblix) has been added as a preferred first-line treatment option for patients with chronic phase CML, regardless of risk score. This recommendation follows the FDA's approval of asciminib as a frontline option in late October 2024. According to Neil P. Shah, MD, PhD, chair of the CML NCCN guidelines, this change is immediately influencing clinical practice, offering another option alongside the four other approved TKIs. Asciminib has also been included as an option for advanced phase CML, further solidifying its role in treating this disease.
Michael Mauro, MD, director of the CML program at Memorial Sloan Kettering Cancer Center, highlighted asciminib's superior efficacy in frontline treatment compared to imatinib (Gleevec) and some second-generation TKIs. The accelerated approval was based on phase 1 and 3 data, with compelling frontline data presented at the 2024 ASCO meeting. Mauro noted that asciminib may be the best first choice, showing statistical superiority to imatinib and numerical improvements over second-generation inhibitors, with comparable or improved safety profiles.
Refinements in Treatment Monitoring
The NCCN guidelines have also been updated regarding treatment milestone guidelines. The "yellow category," which previously indicated possible TKI resistance at both 3 and 12 months, has been revised. Now, the yellow category applies only at 3 months for patients not meeting the treatment milestone. The recommendation to consider a bone marrow biopsy to determine major cytogenetic response (MCyR) at 3 months has been removed, as it is considered reasonable to continue until 6 months if patients are approaching the milestone. A new "orange category" has been added, suggesting a bone marrow biopsy at 12 months if the complete cytogenetic response (CCyR) level is approaching the 1% milestone but not yet achieved.
Furthermore, a footnote has been added to the "green category," acknowledging that patients with a transcript level of ≤10% at 12 months have very good outcomes. According to Shah, these patients' outcomes are likely to be very close to those achieved in patients at or below the 1% level at 12 months, potentially deferring bone marrow transplant evaluation unless the transcript level exceeds 10%.
Considerations for Resistance and Mutation Profiles
The guidelines now include M244V as a contraindicated mutation for asciminib. This mutation, known to be resistant to imatinib, unexpectedly confers resistance to asciminib. Patients with this pre-existing mutation following prior imatinib therapy should not be treated with asciminib. Additionally, research indicates that patients with CML who have atypical transcripts, such as b3a3 variants, may be highly resistant to asciminib, though they respond well to the prior five approved TKIs.
Addressing Cost Disparities
With the availability of generic imatinib and, more recently, generic dasatinib, the guidelines are beginning to address the cost disparities between CML therapies. Shah noted that if several therapies are considered equivalent, it may be reasonable to recommend alternatives based on cost differences alone, considering the societal cost rather than just the patient's out-of-pocket expenses.
Balancing Clinical Data and Real-World Insights
Mauro emphasized the importance of integrating real-world data with clinical trial evidence to optimize patient outcomes. Managing CML is a long-term endeavor, requiring adherence, adverse effect management, and open communication between patients and healthcare providers. The challenges lie in considering all factors and making appropriate decisions based on individual patient circumstances. For patients with issues in response, resistance, or tolerance, the focus shifts towards disease biology, therapy choice, mutational analysis, and exploring factors like non-BCR-ABL myeloid mutations to improve outcomes.
