Tailored TKI Dosing Strategies Improve Outcomes in Chronic Myeloid Leukemia
核心洞察
Tailored dosing of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (搜索) (CML (搜索)) improves safety without compromising efficacy, according to Elias Jabbour, MD.
The phase 4 BYOND trial demonstrated that bosutinib is effective with sustained responses and manageable adverse effects in TKI-pretreated CML (搜索) patients.
Treatment-free remission is achievable with bosutinib, similar to other TKIs, when patients achieve a sustained deep molecular response.
With timely initiation, appropriate dosing, and potential treatment discontinuation in the event of a sustained response, patients with chronic myeloid leukemia (搜索) (CML (搜索)) can expect to experience greater benefit and longer survival outcomes from standard TKIs than ever before. Elias Jabbour, MD, emphasized the importance of tailored approaches to TKI dosing to optimize efficacy and minimize toxicity. Ongoing investigations into novel agents aim to identify those that can offer deeper, longer-lasting responses without compromising long-term safety or increasing financial burden.
Bosutinib: A Potent Second-Generation TKI
Bosutinib (Bosulif) is a potent, second-generation TKI that can be optimized for long-term efficacy through lower initial dosing. The agent was FDA approved at a dose of 500 mg daily in 2012 for adult patients with Philadelphia chromosome (搜索)–positive CML (搜索) who are resistant or intolerant to prior TKIs.
Data from the phase 4 BYOND trial (NCT02228382), published in Leukemia in September 2024, showed that 81.1% (95% CI, 73.7%-87.2%) of evaluable patients achieved or sustained a complete cytogenic response (CCyR) at any time with bosutinib. Furthermore, major molecular responses (MMR) were achieved or maintained by 71.8% (95% CI, 63.9%-78.9%) of patients at any time on treatment. Deeper molecular responses were reported during treatment with bosutinib compared with baseline.
Optimizing TKI Dosing for Improved Outcomes
According to Jabbour, clinicians can tailor and escalate the dose of bosutinib to deliver an effective drug that is maintained in the long run. Dose adjustments based on response and adverse effects (AEs) are crucial for improving safety without compromising efficacy. The BYOND trial has reiterated that bosutinib is effective, provides sustained responses, and has manageable AEs.
Bosutinib in the Treatment Landscape
Bosutinib is as effective as any other secondary TKI. If imatinib is used in the frontline, bosutinib should be considered in the second line. For patients with resistance to a second-generation TKI, a third-generation TKI such as ponatinib (Iclusig) or asciminib (Scemblix) may be necessary.
Safety Profile and Cardiovascular Considerations
The median age for patients with CML (搜索) is approximately 65 years or older, making them susceptible to cardiovascular AEs. Bosutinib has the least cardiovascular AEs compared to other TKIs, which is a major advantage. Diarrhea can occur but is highly manageable and typically resolves within the first episode.
Treatment-Free Remission
Data from more than 300 patients showed no difference between one drug over another when it comes to treatment-free remission. As soon as the patient can have a deep response sustained for a couple of years, TKI treatment can be stopped. There is no advantage of nilotinib or dasatinib over bosutinib; all are equivalent in that sense.
Novel Agents in CML
Several drugs are being tested in CML (搜索). Ponatinib is a potent TKI but has cardiovascular toxicities. Asciminib is approved but may not be earth-shaking. Olverembatinib and other drugs are being explored in the relapsed setting and may move to the frontline soon. For a drug to become the frontline standard of care, it should induce a higher rate of sustained deep molecular response, be safe in the long run (7 to 8 years), and be affordable (no more than $40,000 per year).
Key Takeaways for Clinicians
Patients with CML (搜索) can expect to have a normal life span. It is important to start TKI treatment immediately, but patients are often overdosed. Intolerance is common but can be fixed by adjusting the dose. TKI switching should be reserved for patients with true resistance, defined as BCR::ABL1 transcript levels of 1% or more after more than 12 months of therapy. When considering survival equivalence, the cheapest drug should be considered. For young patients aiming to stop therapy, a second-generation TKI should be considered.