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.

Cortes and colleagues provided further rationale for employing dose-reduction strategies in CML management with bosutinib in a paper published in 

 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.

“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 

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.

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

: 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 [

] 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 

 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.

 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 

 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 

 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 

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.

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. 

. 2024;38(10):2162-2170. doi:10.1038/s41375-024-02372-x

Lipton JH, Brümmendorf TH, Sweet K, Apperley JF, Cortes JE. Practical considerations in the management of patients treated with bosutinib for chronic myeloid leukemia. 

. 2024;103(9):3429-3442. doi:10.1007/s00277-024-05851-4

Articles

Jorge Cortes, MD, discusses findings with bosutinib in CML and the importance of dose adjustment as a strategy for managing bosutinib-related AEs.

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

Dr Cortes on the Phase 4 BYOND Study in Previously Treated Patients With CML

Jorge E. Cortes, MD, director, Georgia Cancer Center, Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer, Augusta University, discusses efficacy and safety findings from 

the phase 4 BYOND study (NCT02228382) investigating bosutinib (Bosulif)

 in previously treated patients with Philadelphia chromosome (Ph)–positive chronic myeloid leukemia (CML) and highlights the adverse effects (AEs) associated with the treatment.

This study highlights the efficacy of the second-generation TKI bosutinib, particularly in the third- and fourth-line settings, Cortes begins. Although bosutinib is mainly used in the second line, it has shown effectiveness even in later treatment stages, he emphasizes. Major molecular response (MMR) rates such as MR4 and MR4.5 with bosutinib remain comparable between subgroups stratified by number of prior lines of therapy. This was true even for patients undergoing fourth-line therapy, who achieved a MR4.5 rate approaching 50%, according to Cortes. This finding underscores the importance of proper dose management, as demonstrated inthe study, Cortes reports. Patients whose doses were adjusted based on their response rarely lost their therapeutic benefit, emphasizing that managing the drug well can optimize outcomes, he says. Beyond the choice of drug, the method of drug administration matters, he adds.

 in 2012 at a daily dose of 500 mg for the treatment of adult patients with Ph-positive CML who are resistant or intolerant to prior TKIs.

One key takeaway from long-term data with bosutinib is the importance of dose adjustments tailored to each patient’s response, Cortes expands. AEs, such as diarrhea, nausea, rash, and liver toxicity, are often manageable with interventions beyond reducing the dose, he explains. For instance, diarrhea can be controlled with anti-diarrheal medications that patients can keep on hand for critical situations, whereas nausea medications and short courses of corticosteroids can address rash or liver toxicity, he highlights, noting that these strategies can help patients avoid immediate treatment changes and maintain their response to the drug. Additionally, dietary interventions and patient education may aid in minimizing AEs, Cortes says.

It is essential to leverage all available tools—dose adjustments, supportive care, and patient education—to manage AEs effectively, he continues. Early intervention often leads to symptom improvement over time, allowing patients to continue treatment and achieve better outcomes, Cortes concludes.

Videos

Jorge E. Cortes, MD, discusses efficacy and safety findings from the phase 4 BYOND study in previously treated patients with Ph+ chronic myeloid leukemia.

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 

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.

 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.

“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.

, 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.

: Over the past year, what were the 3 most important advances in the field of CML?

: 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.

How do final results from the phase 4 BYOND trial reinforce the use of bosutinib in your clinical practice?

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.

In what line of therapy should bosutinib be used in, and when would you consider transitioning to a third-generation TKI?

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.

What should be known about the agent’s safety profile? What differentiates it from that of other available TKIs?

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.

Could treatment-free remission be achieved with bosutinib, as seen with other TKIs in this setting?

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.

What novel agents hold the most promise in CML, and why?

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.

What is your main message for colleagues?

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 

 [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.

U.S. Food and Drug Administration approves Bosulif (bosutinib) for patients with previously treated Philadelphia chromosome-positive chronic myelogenous leukemia (CML). News release. Pfizer Inc. September 4, 2012. Accessed October 8, 2024. 

https://www.pfizer.com/news/press-release/press-release-detail/u_s_food_and_drug_administration_approves_bosulif_bosutinib_for_patients_with_previously_treated_philadelphia_chromosome_positive_chronic_myelogenous_leukemia_cml

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. 

Elias Jabbour, MD, discusses how advancements in the administration and sequencing of TKIs have improved long-term prognosis for patients with CML.

Tailored Approaches to TKI Dosing Allow for Treatment-Free Remissions and Reduced Toxicity in CML 

Dr Jabbour on the Role of Bosutinb as a Therapeutic Option for TKI-Pretreated CML

Elias Jabbour, MD, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the role of bosutinib (Bosulif) as a therapeutic alternative for patients with chronic myeloid leukemia (CML) who have developed resistance or intolerance to prior TKIs, as supported by confirmatory data from the phase 4 BYOND trial (NCT02228382).

 in 2012 for the treatment of patients with Philadelphia chromosome (Ph)–positive CML who are intolerant to or have become resistant to prior therapy. The recommended dose of bosutinib for this indication is 500 mg once daily. Although the 500 mg dose was found to be effective in an outpatient setting, it was later optimized at 400 mg for frontline therapy, where it demonstrated superior efficacy vs the standard of care, imatinib (Gleevec), Jabbour states.

The single-arm, open-label, non-randomized BYOND trial further assessed the agent in patients with TKI-pretreated CML, Jabbour details. 

 in September 2024, and showed that bosutinib generated high response rates and a manageable safety profile in patients with TKI-pretreated CML. A complete cytogenic response (CCyR) was achieved or maintained with bosutinib by 81.1% (95% CI, 73.7%-87.2%) of evaluable patients at any time. Moreover, major molecular response (MMR), MR4, and MR4.5 was achieved or maintained by 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 patients, respectively, at any time on treatment.

For those who did not achieve CCyR at baseline, a CCyR was achieved with bosutinib at any time during treatment in 63.5% (95% CI, 49.0%-76.4%) of patients. Patients without MMR, MR4, or MR4.5 at baseline achieved respective response rates of 59.5% (95% CI, 47.9%-70.4%), 52.7% (95% CI, 43.0%-62.2%), and 42.7% (95% CI, 34.1%-51.7%) at any time during treatment. Notably, most patients achieved deeper MRs during treatment with bosutinib vs baseline.

Although early use of bosutinib is associated with high rates of diarrhea, which may lead to high treatment dropout rates, the BYOND trial indicated that the agent could be optimized for long-term effectiveness by tailoring and escalating doses as needed, Jabbour explains. The agent’s manageable safety profile further supported its sustained efficacy, reinforcing bosutinib’s role as an important TKI for pretreated patients with CML. Overall, the phase 4 BEYOND trial has shown that bosutinib is clinically active, generates sustained responses, and has a manageable safety profile, reinforcing bosutinib’s role as an important TKI for pretreated patients with CML, Jabbour concludes.

Elias Jabbour, MD, discusses the role of bosutinib as a standard treatment for patients with CML that is resistant or intolerant to prior TKI therapy.

Treatment with bosutinib (Bosulif) led to high response rates with a manageable safety profile in patients with chronic myeloid leukemia (CML) who had previously received a TKI, according to the final results of the phase 4 BYOND trial (NCT02228382), which were published in 

Of evaluable patients, 81.1% (95% CI, 73.7%-87.2%) achieved or maintained complete cytogenic response (CCyR) at any time on bosutinib treatment. Additionally, 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 patients achieved or maintained major molecular response (MMR), MR4, and MR4.5, respectively, at any time on treatment. Among patients who did not achieve CCyR at baseline, 63.5% (95% CI, 49.0%-76.4%) achieved CCyR at any time during treatment. Among patients without MMR, MR4, or MR4.5 at baseline, 59.5% (95% CI, 47.9%-70.4%), 52.7% (95% CI, 43.0%-62.2%), and 42.7% (95% CI, 34.1%-51.7%) achieved these respective responses at any time during treatment. Most of these patients achieved an MR that was deeper than baseline during treatment with bosutinib.

“The results from this long-term study support the use of bosutinib as a standard-of-care alternative in patients with CML that is resistant or intolerant to previous TKI therapy,” lead study author Carlo Gambacorti-Passerini, MD, and coauthors, wrote in the paper.

Gambacorti-Passerini is a full professor in the School of Medicine and Surgery at the Universitá Delgi Studi di Milano in Italy.

 for the treatment of patients with Philadelphia chromosome (Ph)–positive CML who are intolerant to or have become resistant to prior therapy.

 The recommended dose of bosutinib for this indication is 500 mg once daily.

BYOND further investigated the efficacy and safety of the agent in patients with pretreated CML. Initial findings from the trial showed that by 1 year, the major cytogenetic response (MCyR) rate was 75.8% among patients who had received 1 or 2 prior TKIs and 62.2% among those who had received 3 prior TKIs.

The single-arm, open-label, non-randomized BYOND trial enrolled patients at least 18 years of age with CML who had previously progressed on commercially available TKIs due to resistance or intolerance or who were otherwise not eligible for treatment with commercially available TKIs.

 Patients received bosutinib at 500 mg daily per protocol. Dose escalation to a maximum dose of 600 mg daily was allowed in cases of disease progression or an unsatisfactory response, provided patients did not have grade 3/4 or persistent grade 2 adverse effects (AEs). Dose reductions to 400 mg, 300 mg, or 200 mg daily because of toxicity or tolerability were also permitted.

Patients continued bosutinib treatment for a maximum of 4 years from the time of the first dose, or until progressive disease, unacceptable toxicity, withdrawal of consent, death, or study discontinuation. Patients who completed 4 years of bosutinib and experienced continued benefit could be switched to commercially available therapy after 4 years. Patients who discontinued bosutinib before completing 4 years of therapy were followed for survival until they completed 4 years on study. The final analysis of BYOND was based on the final database lock, which occurred after at least 3 years of follow-up.

The primary end points were MCyR by 1 year in patients with Ph-positive chronic-phase (CP) CML who had received 1 or 2 prior TKIs, MCyR by 1 year in patients with Ph-positive CP-CML who had received 3 prior TKIs, and cumulative confirmed overall hematologic response by 1 year in patients with accelerated-phase (AP) or blast-phase (BP) disease. Secondary and exploratory end points included cumulative response rates, duration of response, on-treatment transformation to AP or BP disease, progression-free survival, overall survival (OS), newly observed 

mutations, and safety. Per study protocol, CCyR was imputed on any date where MMR was achieved and no valid cytogenic assessment was available.

Among 163 patients who were treated with bosutinib, 156 had Ph-positive CP-CML. Of those patients, the median age at study entry was 61.0 years (range, 20.0-89.0), 51.9% were male, 52.6% were resistant to at least 1 prior TKI, and 47.4% were intolerant to all prior TKIs.

In the patients with Ph-positive CP-CML, the median duration of bosutinib treatment was 40.9 months (range, 0.2-50.1). At study completion, with a median follow-up of 47.8 months, 48.1% of patients were still on study treatment, and 68.6% of patients had completed the study. The most common primary reason for permanent bosutinib discontinuation was AEs (26.9%), and most AE-related discontinuations happened in year 1 (17.9%). One patient underwent a dose escalation to 600 mg daily because of insufficient clinical response. In total, 76.3% and 79.5% of patients underwent dose interruptions and reductions, respectively, because of AEs. Dose reductions to 400 mg, 300 mg, or 200 mg daily without further reductions occurred in 22.4%, 29.5%, and 24.4% of patients, respectively.

Among patients who remained on the dose of 500 mg or higher (n = 32) for the duration of their on-study treatment, 56.3% achieved MMR. Of patients who underwent a dose reduction to 400 mg, 71.4% had an MMR for over 6 months after their dose reduction; among those patients 40.0% maintained their MMR, and 31.4% achieved MMR after dose reduction. Additionally, 8.6% of patients achieved MMR before their dose reduction and discontinued treatment before the next longer-than 6-month assessment. None of these patients lost a previously achieved MMR following dose reduction.

Of patients who underwent a dose reduction to 300 mg, 43.5% of patients experienced an MMR for longer than 6 months; 39.1% maintained their MMR, and 4.3% achieved MMR after dose reduction. Furthermore, 39.1% of patients achieved MMR before dose reduction and discontinued treatment before the next longer-than 6-month assessment. None of these patients lost a previously achieved MMR following dose reduction.

Of patients who underwent a dose reduction to 200 mg, 71.1% of patients experienced an MMR for longer than 6 months; 65.8% maintained their MMR, and 5.3% achieved MMR after dose reduction. Furthermore, 10.5% of patients achieved MMR before dose reduction and discontinued treatment before the next longer-than 6-month assessment. One of these patients lost their previously attained MMR after this dose reduction.

Similar trends were seen for CCyR across patients who underwent dose reductions. The CCyR rate was 62.5% among patients who remained on a dose of 500 mg or higher and 74.3%, 45.7%, and 76.3% after dose reductions to 400 mg, 300 mg, and 200 mg, respectively.

Across all responders, the Kaplan-Meier probabilities of maintaining CCyR, MMR, and MR4 at 36 months were 96.5% (95% CI, 89.5%-98.9%), 87.2% (95% CI, 78.0%-92.7%), and 80.7% (95% CI, 69.4%-88.1%), respectively. No patients progressed to AP or BP disease during treatment.

At 48 months of follow-up, the cumulative rate of on-treatment progression or death was 5.1% (95% CI, 2.4%-9.4%), and the OS rate was 88.3% (95% CI, 81.8%-92.6%).

Seventeen patients died during the study. Two deaths were considered related to CML (cardiogenic shock, n = 1; off-treatment progression to AP or BP disease, n = 1). No deaths were deemed treatment related.

A total of 112 patients with CP-CML were assessed for mutations at baseline, 106 of whom had a post-baseline sample. Most patients (51.9%) were not assessed for mutations because they were in response and their 

transcript levels were too low. Additionally, 18.9% of patients had a non-evaluable sample. Among the 31 patients who were evaluated for new 

point mutations upon disease progression, treatment failure, or the end of treatment, 1 with a baseline 

 mutation had both that mutation and a newly detected 

Overall, 99.4% of patients had any-grade treatment-emergent AEs (TEAEs), and 79.5% of patients had grade 3/4 TEAEs. The authors noted that the safety findings in this final analysis were similar to those previously reported in the 12-month analysis in the total patient population. In total, 30.1% of patients had AEs leading to permanent bosutinib discontinuation. The most common AE that led to permanent discontinuation was hepatic enzyme increase, which the authors said occurred early in the treatment course.

The only AE that led to treatment discontinuation in more than 1 patient since the initial data report was cardiac failure, which led to treatment discontinuation in 2 of the 3 patients who had this AE during the trial. New AEs of special interest that led to treatment discontinuation since the prior study report included diarrhea (n = 1; total, n = 3), abdominal pain (n = 1; n = 1), and pleural effusion (n = 1; n = 3). During the trial, 1 patient discontinued treatment because of a vascular AE (peripheral ischemia); however, no patients discontinued treatment because of cardiovascular AEs. Furthermore, the authors reported no COVID-19–related TEAEs or discontinuations.

The most common TEAEs leading to dose reduction were diarrhea (28.2%) and increased alanine aminotransferase (ALT; 12.8%). The most common TEAEs leading to dose interruptions were diarrhea (32.1%), increased ALT (15.4%), vomiting (14.1%), increased aspartate aminotransferase (11.5%), and nausea (10.9%).

All patients who underwent dose reductions had at least 1 any-grade TEAE before dose reduction. Of the patients who underwent a dose reduction to 400 mg daily, 88.6% had at least 1 any-grade AE after the reduction; maximum grade 3/4 TEAEs occurred in 68.6% of these patients before reduction vs 62.9% of patients after reduction. These respective rates were 91.3%, 80.4%, and 54.3% among patients who underwent a dose reduction to 300 mg daily, and 94.7%, 76.3%, and 68.4% among those who underwent a dose reduction to 200 mg daily. When the bosutinib dose was reduced, investigators saw a consistent decrease of more than 10% in the incidence of nausea, diarrhea, abdominal pain, vomiting, and headache, regardless of the dose to which the agent was reduced.

“Dose reduction and temporary treatment interruption can be used to manage the AEs associated with bosutinib treatment while achieving and maintaining cytogenetic and molecular responses,” the authors concluded.

U.S. Food and Drug Administration approves Bosulif (bosutinib) for patients with previously treated Philadelphia chromosome-positive chronic myelogenous leukemia (CML). News release. Pfizer Inc. September 4, 2012. Accessed September 30, 2024. https://www.pfizer.com/news/press-release/press-release-detail/u_s_food_and_drug_administration_approves_bosulif_bosutinib_for_patients_with_previously_treated_philadelphia_chromosome_positive_chronic_myelogenous_leukemia_cml

Hochhaus A, Gambacorti-Passerini C, Abboud C, et al. Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study. 

. 2020;34(8):2125-2137. doi:10.1038/s41375-020-0915-9

Treatment with bosutinib led to high response rates with a manageable safety profile in patients with CML who had previously received a TKI.

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