Individualized Bosutinib Dose Adjustments Lend a Manageable AE Profile in Pretreated CML

Jorge Cortes, MD

Cultivating increased awareness of bosutinib (Bosulif)-related adverse effects (AEs) and creating dose-reduction plans are crucial for delivering effective, yet tolerable doses of this agent to patients with chronic myeloid leukemia (CML), according to Jorge Cortes, MD.

Findings from the phase 4 BYOND trial (NCT02228382) showed that at a median follow-up of 47.8 months, 71.8% (95% CI, 63.9%-78.9%), 59.7% (95% CI, 51.4%-67.7%), and 48.3% (95% CI, 40.1%-56.6%) of evaluable patients with Philadelphia chromosome (Ph)–positive chronic-phase CML (CP-CML) who received bosutinib attained or maintained major molecular response, molecular response (MR4), and MR4.5, respectively, at any point during treatment. AE-related dose interruptions and reductions occurred in 76.3% and 79.5% of patients, respectively.¹

Cortes and colleagues provided further rationale for employing dose-reduction strategies in CML management with bosutinib in a paper published in Annals of Hematology in September 2024. Other practical considerations for the use of this agent and other TKIs in CML noted in this paper included adjusting starting doses and administering supportive care.²

“We need to consider dose reductions as part of how we manage CML,” Cortes, the director of the Georgia Cancer Center in Augusta, said in an interview with OncLive^®.

In the interview, Cortes discussed the evolution of the later-line CML treatment paradigm, expanded on key findings from the BYOND trial, and explained the importance of dose adjustment as a strategy for managing bosutinib-related AEs in this patient population.

OncLive: What research has shifted clinical practice for patients with pretreated CML?

Cortes: There’s been a lot of development of new drugs. In addition to the new drugs themselves, [there is a] new schedule of administration for some of the drugs we already [had, such as] ponatinib [Iclusig]. We’ve learned how to use ponatinib better by using dose adjustments for patients who respond, and that decreases the risk [of developing AEs]. We knew the efficacy was good.

Then comes asciminib [Scemblix], a new drug with a new mechanism of action that creates more opportunities. We had only 1 drug that worked against [BCR-ABL1] T359 mutations, and now we also have asciminib. Its novel mechanism of action opens more [treatment] options for patients.

It’s also exciting to see research coming out with new drugs that are emerging that are also attractive. Olverembatinib [HQP1351] has good data. [This agent is] already approved in China and has data already coming from multicenter, multinational studies. Others are a bit earlier [in development, such as] vodobatinib [K0706] and TERN-701. It’s exciting to see that we continue [developing] new drugs. In general, having a larger portfolio and a better understanding of the mechanisms of action, sequencing, and so on, has been exciting.

What research in this realm has been the most hypothesis generating?

These mechanisms of resistance [have been hypothesis-generating] because of our increasing use of asciminib. [We have had an increased focus] on the roles that myristoyl-binding pocket mutations play, [as well as on the roles of] some mutations that appear to be sensitive to a drug, but then we don’t see responses. We’re starting to understand the mechanisms of how these [mutations] may affect the action of asciminib, even when they are distant. Some of them, because of dosing, may not be sensitive to asciminib at all.

The other area that’s been hypothesis-generating—and we need to do a lot more research on this—is mutations in other cancer-related genes. Patients with ASXL1 mutations don’t do well; [these mutations] affect the response to asciminib, which makes sense, because it’s a TKI. We are trying to understand the best way to manage these mutations. How and when do we investigate them? [Do we target them] in the frontline or at [another] point during therapy? All that has reinvigorated our interest in better understanding what drugs work, when, and how we overcome [resistance] when they stop working.

How might the pending FDA approval of asciminib in the frontline setting for patients with newly diagnosed, Ph-positive CP-CML affect your current treatment sequencing with these TKIs?

We’re going to use asciminib as frontline therapy in many patients. I don’t see asciminib replacing the other drugs. It is good to have the variety of options we have.

Asciminib, based on the early data from the phase 3 ASC4FIRST trial [NCT04971226], seems to be superior to imatinib [Gleevec] and second-generation TKIs. It is valuable for patients [in whom I want to generate] deep molecular responses and probably have a better chance of treatment-free remission. We need longer follow-up, but that seems to be where the data are going. We may still be using the other drugs in other settings because of familiarity, cost, or other reasons.

[Regarding] sequencing, if we use asciminib initially, what do we use next? Generally, in cancer, we want to use our best approach first; that’s when we have the best chance for a patient to have a good outcome. The patients who don’t do well with the best [treatment] have the worst prognosis. However, I want to have the fewest patients possible in that bucket of patients who have a poor prognosis.

How will we treat these patients? It depends. If they have a myristoyl-binding pocket mutation, they would likely respond to 1 of the other drugs, or a second-generation TKI, maybe even imatinib. Asciminib is well tolerated.

However, if [patients were to have AEs with asciminib, such as] elevated lipase levels or pancreatitis, imatinib [is less associated with] that, so that could be an option [for subsequent therapy]. If [patients do not respond to asciminib] because of an ASXL1 mutation, we should probably consider a transplant earlier on and not leave it as a last resort, which is [a strategy we’ve been using] up until now. Sequencing the next treatment for an individual patient depends on the circumstances.

The final results from the phase 4 BYOND trial were published in Leukemia in August. What is the significance of these data?

[These data show] us that a second-generation TKI used well can have good efficacy, even in the third and fourth lines. This was a study of patients who had received prior therapy. Some were in the second line, which is where we mostly use bosutinib. However, even in the third and fourth lines, it works well. The MR4 and MR4.5 [outcomes were similar between patients who received the agent in earlier vs later lines of therapy]. Even in patients who receiving their fourth line of therapy, the MR4.5 almost reached 50%, which is good.

The difference between those data and the data we’ve seen in other studies, [such as] the initial study with bosutinib and the control arm of the phase 3 ASCEMBL study [NCT03106779], is how we manage the drug, [such as] by adjusting doses. Another lesson we learned from the BYOND long-term data is that some patients need to adjust by going toward the standard dose and then dose reducing when they have a good response. Patients who underwent dose reductions rarely lost their responses. That tells us that the dynamics of dose adjustments and using the drug well are how we can get the best out of the drug. [Efficacy and safety of CML management come down to] not just what drug we use, but how we manage the drug.

How do you typically manage the AEs that occur with bosutinib, even after dose reductions?

Some AEs are manageable with other interventions. However, for example, with bosutinib, a common AE is diarrhea. Give anti-diarrhea medication. Patients usually don’t have to take it all the time, but they can have it available when circumstances are more critical, [such as] when they’re not at home or in an office where they may not feel comfortable with [diarrhea]. Diarrhea often strikes when [patients are] on the road. You can give nausea medication. Some AEs, such as rash and even some liver toxicities, may respond to short courses of corticosteroids.

The issue here is: What AEs can we manage? What AEs can we overcome with dose adjustments and other interventions that can help? Even dietary interventions and education of patients sometimes help.

We need to put all our armamentarium together. The first time the patient has an AE, a dose adjustment could take care of it. Some of these AEs, particularly when they happen early, often get better over time.

How does the tolerability profile of bosutinib compare with the safety profiles of other second-generation TKIs?

Bosutinib is well tolerated. The issue with the diarrhea is that it’s common; however, it’s not severe. Most patients can work around their diarrhea. It happens more at the beginning than later, and the severity tends to be only grade 1 or 2. If we educate patients and help them manage these AEs, they tend [to occur] closely after the administration of the drug.

In contrast, we don’t see as many of the arterial occlusive events, pleural effusions, or pulmonary hypertension [with bosutinib] that we see with other second-generation TKIs. [After] overcoming the diarrhea, bosutinib tends to be a well-tolerated, safe drug. I use it a lot in patients with comorbidities and risk factors for arterial occlusive events because of this good tolerance. When we educate patients and help them go through these issues, most patients do well.

Overall, what practical considerations for CML management did you highlight in the paper you coauthored that was published in Annals of Hematology?

One of the aspects we emphasized was the issue of easing the patient into the full dose [of bosutinib]. The standard dose is 500 mg in the salvage setting and 400 mg in the frontline setting. Many times, we start with a lower dose at 200 mg. Some of the gastrointestinal toxicity, such as diarrhea, [occurs] earlier on. If we start with a lower dose, patients can adjust to it a bit better, and they have fewer problems. After a couple of weeks, we escalate the dose, and depending on the response, we [determine whether to] escalate more. That allows us to help the patients go through the treatment with fewer problems.

References

1. Gambacorti-Passerini C, Brümmendorf TH, Abruzzese E, et al. Efficacy and safety of bosutinib in previously treated patients with chronic myeloid leukemia: final results from the BYOND trial. Leukemia. 2024;38(10):2162-2170. doi:10.1038/s41375-024-02372-x
2. Lipton JH, Brümmendorf TH, Sweet K, Apperley JF, Cortes JE. Practical considerations in the management of patients treated with bosutinib for chronic myeloid leukemia. Ann Hematol. 2024;103(9):3429-3442. doi:10.1007/s00277-024-05851-4