Commentary
Article
Elias Jabbour, MD, discusses how advancements in the administration and sequencing of TKIs have improved long-term prognosis for patients with CML.
With timely initiation, appropriate dosing, and potential treatment discontinuation in the event of a sustained response, patients with chronic myeloid leukemia (CML) can expect to experience greater benefit and longer survival outcomes from standard TKIs than ever before, according to Elias Jabbour, MD, who added that 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 (Bosulif) is one such example of a potent, second-generation TKI that could be optimized for long-term efficacy through lower initial dosing, Jabbour noted. The agent was FDA approved at a dose of 500 mg daily in 2012 for the treatment of adult patients with Philadelphia chromosome–positive CML who are resistant or intolerant to prior TKIs.1
Data from the phase 4 BYOND trial (NCT02228382), which were 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.2
“What you see in the BYOND trial is that the drug can be optimized,” said Jabbour, who is a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “We can tailor and escalate the dose. By doing so, we can deliver a drug that is effective and maintained in the long run.
In an interview with OncLive®, Jabbour outlined key advancements in CML management in recent years; discussed efficacy and safety data in support of bosutinib as a standard second-line treatment option; and emphasized the need for treatment discontinuation to improve toxicities without negatively affecting patient outcomes.
Jabbour: In CML, the [development of] TKIs that are normalizing overall survival has been amazing. The second [major advancement] is the possibility for [a given] treatment to not be administered for [the patient’s entire] lifetime, which is very important. The third advancement is [efforts that enable patients] to afford medicine [because] TKIs are expensive.
When it comes to how we can improve outcomes, we’ve learned that we do not need to use a drug at the full dose, or maximum-tolerated dose, but can [administer the drug] at a lower dose, what we call the optimal dose. That is important, because without compromising efficacy, we improve on safety. Second, we’ve learned how to address adverse effects [AEs] by adjusting the dose. Once a patient is responding, we can reduce or tailor the dose based on response and deliver a lower dose that is safer. Finally, when it comes to salvage treatment, we have several options today. Some of them are approved and some of them are under investigation, but all seem to be promising.
Bosutinib is a very potent TKI that has [a reputation of] being extremely safe, mainly when it comes to the cardiovascular adverse effects. The drug was shown to be effective in an outpatient [setting] at 500 mg per day and was taken thereafter to the frontline setting at 400 mg per day. It was shown to be superior to imatinib [Gleevec], and therefore it gained approval. The problem with the drug was that it came as the first drug in a line of [subsequent] TKIs, and the drug can cause diarrhea early on that may lead to high dropout [rates]. The phase 4 BYOND trial has reiterated that bosutinib is effective, [provides] sustained responses, and [has] manageable AEs.
Bosutinib is as effective as any other secondary TKI. If we’re using imatinib in the frontline, bosutinib should be one of the drugs used in the second line and not be left for a third or fourth line. In fact, if a patient had resistance to a second-generation TKI, then we have to move to a third-generation TKI, among them ponatinib [Iclusig] or asciminib [Scemblix]. But we must use dasatinib [Sprycel] or bosutinib or nilotinib [Tasigna]. I do not rotate them; I just use one of them. If the patient [develops] resistance, I will move to a third-generation TKI.
The [median age for patients] with CML is [approximately] 65 years or older; therefore, they have risk factors for cardiovascular AEs. Nilotinib, for example, can cause a lot of problems. Bosutinib is the drug with the least cardiovascular AEs, which are common for these patients, which is why I favor bosutinib over other drugs. Diarrhea can be [reported], but this AE is highly manageable, and it’s [typically] resolvable within the first episode. When it comes to safety profile, bosutinib has a major advantage compared with the other drugs.
We looked at our own data from more than 300 patients, and we saw 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, you can stop the TKI. I see no advantage of nilotinib or dasatinib over bosutinib; all are equivalent in that sense.
Right now, we’re testing several drugs in CML. One of the most potent TKIs is ponatinib, but it has cardiovascular toxicities, and that was a problem with the drug. Asciminib was [also] approved [by the FDA]. It’s good, but I don’t think its earth shaking. There’s olverembatinib coming, and so many other drugs being explored right now in the relapsed setting that may move to the frontline soon.
However, for a drug to become the frontline standard of care, it should induce a higher rate of sustained deep molecular response. That eventually will lead to more treatment-free remissions. Second, it should be safe in the long run, [which is] 7 to 8 years. We have to wait for [more follow-up data with] asciminib to prove that it’s safe in the long run. Finally, it should be affordable, [costing] no more than $40,000 per year.
Patients with CML can expect to have a normal life span. It’s good to start somebody on a TKI immediately, but they are [often] overdosed. Intolerance is common, but [this can be fixed] by adjusting the dose. We should not switch TKIs right away unless a patient has true resistance, defined as BCR::ABL1 [transcript levels] of 1% [or more after more than 12 months of therapy]. We have several drugs [available for these patients], but we should be cognizant that when it comes to survival or the equivalent, [we should consider] the cheapest drug. If a patient is young and you aim to stop therapy, [you should] consider a second-generation TKI.