Of 163 patients who received bosutinib, 156 had Ph+ CP CML and were included in this analysis. Of those, 95 patients were <65 years of age, 33 were 65–74 years, and 28 were ≥75 years; and 99, 27, and 30 patients had mCCI scores of 2, 3, and ≥4, respectively. In the <65, 65–74, and ≥75 year age groups, respectively, the proportion of patients resistant to at least one prior TKI was 51.6%, 63.6%, and 42.9%, and the proportion of patients intolerant to all prior TKIs was 48.4%, 36.4%, and 57.1%. In patients with mCCI scores of 2, 3, and ≥4, respectively, the proportion of patients resistant to at least one prior TKI was 51.5%, 59.3%, and 50.0%, and the proportion of patients intolerant to all prior TKIs was 48.5%, 40.7%, and 50.0% (Table 1).

The median duration of treatment was 47.6, 34.7, and 27.1 months in patients <65, 65–74, and ≥75 years of age, respectively; corresponding median dose intensity was 320.9, 319.3, and 264.7 mg/day. Median treatment duration for patients with mCCI 2, 3, and ≥4 was 46.7, 44.9, and 24.8 months, respectively; corresponding median dose intensity was 320.8, 296.1, and 300.3 mg/day (Supplementary Table 1). Dose levels over time are presented in Fig. 1.

Patients grouped by (A) age and (B) comorbidities. CML chronic myeloid leukemia, CP chronic phase, mCCI Charlson Comorbidity Index without age component, Ph Philadelphia chromosome, QD once daily.

Bosutinib was permanently discontinued by 40.0%, 66.7%, and 75.0% of patients <65, 65–74, and ≥75 years of age, and 44.4%, 55.6%, and 73.3% of patients with mCCI 2, 3, and ≥4, respectively (Supplementary Table 1). The majority of discontinuations occurred in year 1 in patients <65 and 65–74 years of age and across CCI scores, and after year 1 in patients aged ≥75 years (Fig. 2 and Supplementary Table 2).

Patients grouped by (A) age and (B) comorbidities. CML chronic myeloid leukemia, CP chronic phase, mCCI Charlson Comorbidity Index without age component, Ph Philadelphia chromosome.

In all patients evaluable for cytogenetic response, cumulative CCyR rates at any time on treatment were, respectively, 85.6%, 66.7%, and 82.6% in patients <65, 65–74, and ≥75 years of age and 87.8%, 72.0%, and 67.9% in patients with mCCI scores 2, 3, and ≥4 (Table 2). Among patients without baseline CCyR, cumulative CCyR rates at any time on treatment were, respectively, 75.0%, 35.7%, and 66.7% in patients <65, 65–74, and ≥75 years of age and 75.0%, 50.0%, and 40.0% in patients with mCCI scores 2, 3, and ≥4.

In all patients evaluable for molecular response, cumulative MMR rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65–74, and ≥75 years of age, respectively (Fig. 3). Corresponding MR4 rates for the three age groups at any time on treatment were 59.3%, 51.6%, and 66.7%, and MR4.5 rates were 47.3%, 48.4%, and 51.9%, respectively (Table 2). In patients with mCCI scores 2, 3, and ≥4, cumulative MMR rates at any time on treatment were 77.9%, 63.0%, and 59.3%, respectively (Fig. 3). Corresponding MR4 rates for the three comorbidity groups at any time on treatment were 62.1%, 55.6%, and 51.9%, and MR4.5 rates were 48.4%, 48.1%, and 48.1%, respectively (Table 2). Among patients without the respective baseline response, respective cumulative MMR, MR4, and MR4.5 rates at any time on treatment were 66.7%, 52.3%, and 41.8% in patients <65 years of age; 47.6%, 42.3%, and 42.9% in patients 65–74 years of age; and 53.8%, 61.9%, and 45.8% in patients ≥75 years of age (Table 2). Cumulative MMR, MR4, and MR4.5 rates at any time on treatment in patients without the baseline response were, respectively, 66.7%, 52.9%, and 42.4% in patients with mCCI 2; 46.2%, 54.5%, and 44.0% in patients with mCCI 3; and 46.7%, 45.0%, and 42.9% in patients with mCCI ≥4.

Patients grouped by (A) age and (B) comorbidities. CML chronic myeloid leukemia, CP chronic phase, mCCI Charlson Comorbidity Index without age component, MMR major molecular response, Ph Philadelphia chromosome.

The majority of patients who had dose reductions to 400 mg, 300 mg, or 200 mg QD achieved MMR for the first time or maintained a previous attained MMR after dose reduction (Table 3). Of the patients who remained on ≥500 mg QD, MMR was achieved or maintained in, respectively, 63.2%, 50.0%, and 33.3% of patients <65, 65–74, and ≥75 years of age; and 60.9%, 50.0%, and 33.3% of patients with mCCI 2, 3, and ≥4, respectively.

No patient experienced on-treatment transformation to AP or blast phase CML. Median (range) follow-up for OS was 47.9 (3.6–57.1), 47.9 (2.0–55.0), and 46.1 (0.7–50.7) months in patients <65, 65–74, and ≥75 years of age, respectively. Kaplan–Meier estimated OS rates (95% CI) at 4 years were 100.0% (100.0–100.0) in patients <65 years of age, 68.3% (49.0–81.5) with 10 deaths during the study period in patients 65–74 years of age, and 73.3% (52.0–86.3) with seven deaths in patients ≥75 years of age. Median (range) follow-up for OS was 47.9 (0.7–57.1), 47.6 (3.6–51.7), and 47.2 (2.0–53.0) months in patients with mCCI scores 2, 3, and ≥4, respectively. Kaplan–Meier estimated OS rates (95% CI) at 4 years were 94.7% (87.6–97.7) with five deaths in patients with mCCI 2, 75.5% (53.1–88.3) with six deaths in patients with mCCI 3, and 78.9% (58.9–89.9) with six deaths in patients with mCCI ≥4. In the overall population, two deaths were considered to be related to CML (off-treatment progression to AP/blast phase, n = 1; cardiogenic shock, n = 1), and none were considered to be treatment-related by the investigators (Supplementary Table 3).

The incidence of any grade TEAEs was similar between the age groups and between the mCCI risk groups (Supplementary Table 4). Grade 3–4 TEAEs and serious TEAEs, respectively, occurred in 74.7% and 26.3% of patients <65 years of age, 78.8% and 63.6% of patients 65–74 years of age, and 96.4% and 67.9% of patients ≥75 years of age. Respectively, grade 3–4 TEAEs and serious TEAEs occurred in 77.8% and 29.3% of patients with mCCI 2, 77.8% and 48.1% of patients with mCCI 3, and 86.7% and 76.7% of patients with mCCI ≥4. The most frequent grade 3–4 TEAEs by age and mCCI scores are shown in Fig. 4A, B, respectively. Bosutinib was permanently discontinued due to AEs by 22.1%, 39.4%, and 46.4% of patients <65, 65–74, and ≥75 years of age, and 25.3%, 33.3%, and 43.3% of patients with mCCI 2, 3, and ≥4, respectively (Supplementary Table 4). The AEs leading to treatment discontinuation are listed in Supplementary Table 5. Bosutinib dose reductions due to TEAEs occurred in 80.0%, 69.7%, and 89.3% of patients in the three age groups and in 76.8%, 77.8%, and 90.0% of patients with mCCI 2, 3, and ≥4, respectively (Supplementary Table 4).

Patients grouped by (A) age and (B) comorbidities. Includes TEAEs occurring in ≥10% of patients in any subgroup. ALT alanine aminotransferase, CML chronic myeloid leukemia, CP chronic phase, GGT gamma-glutamyl transferase, mCCI Charlson Comorbidity Index without age component, Ph Philadelphia chromosome, TEAE treatment-emergent adverse event.

Medical history and incidences of TEAEs of special interest for the overall population are shown in Supplementary Table 6. Patients with a medical history of liver, myelosuppression, edema, renal, effusion, cardiac, and vascular cluster events were more likely (≥10% increase) to experience the corresponding TEAE event of interest than patients without the relevant medical history.

At baseline, mean (standard deviation) FACT-Leu leukemia-specific subscale scores were, respectively, 128.9 (24.7), 131.1 (20.8), and 125.7 (18.9) in patients <65, 65–74, and ≥75 years; and 129.7 (23.1), 123.9 (24.5), and 130.3 (20.6) in patients with mCCI 2, 3 and ≥4. Over the course of treatment, mean FACT-Leu leukemia-specific scores were maintained in patients aged <65 years and in patients with mCCI 2 (Fig. 5). Scores were generally maintained during the course of treatment in patients aged 65–74 years, although there was a decrease at week 182 based on data from one patient. Decreases met the MID at specific timepoints in patients aged ≥75 years, and in patients with mCCI 3 and 4 (Fig. 5).

Patients grouped by (A) age and (B) comorbidities. The dashed line indicates the MID (i.e., the change identified as being critically meaningful to a patient). CML chronic myeloid leukemia, CP chronic phase, EOT end of treatment, FACT-Leu Functional Assessment of Cancer Therapy-Leukemia, mCCI Charlson Comorbidity Index without age component, MID minimal important difference, Ph Philadelphia chromosome.