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The development of BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients with chronic myeloid leukemia (CML). Although there are some common class-wide side effects, differences in safety profiles between TKIs allow physicians and patients to personalize treatment plans. Treatment selection depends on several factors, such as age, disease risk, comorbidities, and concomitant medications. In second- and later-line settings, response to previous TKIs and mutation analyses should also be used to guide TKI selection. Several strategies can be used to manage adverse events (AEs) that emerge during treatment, e.g., dose reductions/interruptions, monitoring, treatment of AEs, lifestyle modifications, prophylactic therapy, and other supportive care strategies. This review summarizes the safety profiles of the currently approved TKIs and how they impact treatment selection in the first- and later-line settings of CML, particularly regarding patient comorbidities and concomitant medications. Additionally, strategies to manage AEs of special interest with TKIs are reviewed.

The recommended starting dose of bosutinib is 500 mg/day for chronic-phase (CP) or accelerated-/blast-phase Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy. However, some patients may require dose reductions to manage the occurrences of adverse events (AEs). Bosutinib efficacy and safety were evaluated following dose reductions in a phase I/II study of Ph + patients with CP CML resistant/intolerant to imatinib or imatinib plus dasatinib and/or nilotinib, and those with accelerated-/blast-phase CML or acute lymphoblastic leukemia after at least imatinib treatment. In all, 570 patients with ≥4 years’ follow-up were included in this analysis. Among 144 patients who dose-reduced to bosutinib 400 mg/day (without reduction to 300 mg/day), 22 (15 %) had complete cytogenetic response (CCyR) before and after reduction, 40 (28 %) initially achieved CCyR after reduction, and 4 (3 %) only had CCyR before reduction. Among 95 patients who dose-reduced to bosutinib 300 mg/day, 23 (24 %) had CCyR before and after reduction, 13 (14 %) initially achieved CCyR after reduction, and 3 (3 %) only had CCyR before reduction. Results were similar to matched controls who remained on 500 mg/day, indicating dose reductions had not substantially affected efficacy. The incidence of treatment-emergent AEs was lower after dose reductions, particularly for gastrointestinal events. The incidence of hematologic toxicities generally was similar before and after dose reduction. The management of AEs with bosutinib through dose reduction can lead to improved/maintained efficacy and better tolerability; still, approximately half of patients on treatment at year 4, maintained a dose of ≥500 mg/day ClinicalTrials.gov: NCT00261846.

Introduction: Long-term follow-up (≥4 years) demonstrated a low incidence of cardiac and vascular treatment-emergent adverse events (TEAEs) with bosutinib treatment. We evaluated cardiac, vascular, hypertension, and effusion TEAEs after ≥ 7 years of follow-up in patients with Philadelphia chromosome–positive (Ph+) leukemia. Methods: This retrospective analysis of a phase I/II study and its ongoing extension study included data from patients with chronic phase chronic myeloid leukemia (CML) treated with bosutinib after resistance/intolerance to imatinib (CP2L) or to imatinib plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after treatment with, at a minimum, imatinib (ADV). Results: In all, 570 patients were treated with bosutinib; median treatment duration was 11.1 months (range: 0.03-133.1). The incidence of cardiac, vascular, hypertension, and effusion-related TEAEs was 10.9%, 8.8%, 9.1%, and 13.3%, respectively. Few patients had maximum grade 3-4 TEAEs (cardiac, 3.9%; vascular, 4.0%; hypertension, 3.0%; effusion, 4.6%). Grade 5 TEAEs occurred in the cardiac (0.7%) and vascular (1.8%) clusters only. In years 5-7, fewer than 5% of patients each year had newly occurring cardiac, vascular, hypertension, or effusion TEAEs. The exposure-adjusted TEAE rates (patients with TEAEs/total patient-year) pooled across CP2L, CP3L, and ADV cohorts were as follows: cardiac, 0.044; vascular, 0.035; hypertension, 0.038; and effusion, 0.056, of which, correspondingly, 0.9%, 1.2%, 0%, and 2.1% required treatment discontinuation. Conclusions: The incidence of cardiac, hypertension, vascular, and effusion events was low in patients with Ph+ CML resistant or intolerant to prior therapy who were treated with bosutinib.

Background: In the phase 3 BFORE trial (NCT02130557), treatment with bosutinib resulted in a significantly higher major molecular response rate at 12 months versus imatinib in the modified intent-to-treat (mITT) population of patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). Assessment of patient-reported outcomes (PROs) was an exploratory objective. Methods: Patients with newly diagnosed CP CML were randomized 1:1 to receive once-daily bosutinib 400 mg or imatinib 400 mg as first-line therapy. Patients completed the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQoL-5 Dimensions (EQ-5D) questionnaires at baseline, every 3 months for the first 24 months of treatment, every 6 months thereafter, and at treatment completion. We report PRO results at month 12 in the mITT population (bosutinib: n = 246; imatinib: n = 241). Results: Mean FACT-Leu combined and subscale scores were similar at baseline in the bosutinib and imatinib arms; at month 12, all scores demonstrated improvement or maintenance of health-related quality of life (HRQoL) in both treatment arms. Repeated-measures mixed-effects models showed no significant difference between bosutinib and imatinib for any FACT-Leu score. Functional health status, as measured by EQ-5D, also demonstrated improvement or maintenance with bosutinib and imatinib at month 12. Conclusions: Similar improvements in PROs compared with baseline were seen after 12 months of treatment with first-line bosutinib or imatinib in the BFORE trial. Newly diagnosed patients with CP CML receiving bosutinib or imatinib can preserve or improve HRQoL during treatment, although clinical efficacy was superior with bosutinib

Objective: In clinical trials of second-line therapies for chronic phase chronic myeloid leukemia (CP-CML), to date, only single-arm trials have been conducted for the available tyrosine kinase inhibitor treatments (bosutinib, dasatinib and nilotinib). These trials included heterogeneous patient populations in terms of disease and baseline characteristics. These hamper the use of standard network meta-analyses for indirect treatment comparison of relative efficacy. In this situation, a matching-adjusted indirect comparison (MAIC) in second-line CP-CML was performed. The aim was to compare the relative efficacies of bosutinib, dasatinib and nilotinib in second-line CP-CML patients. Methods: The MAIC was preceded by a systematic literature review that ensured inclusion of the underlying data for the analyses. The outcomes were measured in terms of overall survival (OS), progression-free survival (PFS) and major cytogenetic response (MCyR). The treatments were quantitatively compared based on Cox proportional hazard ratio (HR) regressions, on restricted mean survival (RMST, when the proportionality assumption showed evidence of violation) and on odds ratios (for response measures). Results: Comparing with dasatinib, bosutinib resulted in HRs for PFS and OS of 0.63 (0.44–0.90, p <.05) and 0.82 (0.54–1.26, p =.37) respectively, and resulted in an OR for MCyR of 0.78 (0.53–1.16). Although the proportionality of hazards assumption was violated for PFS, the RMST analyses confirmed the findings of the Cox regression. When compared with nilotinib, bosutinib showed a significant HR of 0.54 (0.38–0.76, p <.01) in favor of bosutinib for PFS, a non-significant HR of 0.72 (0.46–1.13, p =.16) for OS and a non-significant OR of 0.98 (0.71–1.35) for MCyR. Conclusions: Bosutinib had a significantly greater PFS than both dasatinib and nilotinib. For OS, the findings were numerically in favor of bosutinib, but not statistically significant. For MCyR, the findings were numerically

Poster presented at American Society of Clinical Oncology in Chicago Illinois. Background: Tyrosine kinase inhibitors (TKI) are the current standard therapy for patients with chronic myeloid leukemia (CML). Fluid retention and pleural effusions have been reported in patients treated with TKIs, particularly with dasatinib. Although TKIs have been shown to reverse pulmonary hypertension (PH) in animal models, there have been some reports of development of reversible PH with dasatinib. Methods: We conducted a retrospective analysis on 401 patients diagnosed with CML in chronic phase (CP) who were treated with TKIs (imatinib, dasatinib, or nilotinib) as initial therapy for CML and had a transthoracic echocardiogram (TTE) done at some point during the course of therapy. PH was diagnosed if the patient had an estimated right ventricular systolic pressure (RVSP) of 35 mm Hg or greater. Secondary causes of PH (systolic or diastolic dysfunction on TTE, chronic obstructive pulmonary diseases [COPD], obstructive sleep apnea [OSA] and pulmonary embolism) were investigated during chart review. Results: Twenty (23%) out of 87 patients had evidence of PH by TTE; median age 57 years, with 46% being males. Six pts (30%) received nilotinib 400mg twice daily, 4 (20%) patients had imatinib (400mg; n=1, 600mg; n=1 and 800mg daily; n=2), and 10 (50%) patients received dasatinib (dose varied 40-140mg daily). Five (25%) patients had coronary artery disease, 9 (45%) had systemic hypertension, 2 (10%) had COPD and 3 (15%) had OSA. Thirteen pts had serial TTE to compare the progression of PH including 6 (7%) who had a TTE prior to starting TKI. Among these 13 pts with serial TTE, 7 had rising RVSP with one patient having mild global hypokinesia, another with diastolic dysfunction and another with OSA. Four of those 7 patients had normal RVSP on their TTE prior to starting therapy. Six other pts had improvement in the RVSP on serial TTE, 4 of them with systemic hypertension. Two of those 6 pat