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.

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

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

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