Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia.

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Objectives: Aim of the study was to assess the therapeutic efficacy and safety of upadacitinib in Rheumatoid arthritis patients with moderate to high disease activity in real-world clinical practice and to identify predictors of therapeutic success. Materials and methods: A retrospective single-center study was performed in RA patients treated with upadacitinib 15 mg daily. Demographic and clinical indicators were analyzed. The effectiveness and safety of the medication were evaluated over a six-month period. Disease activity was assessed with index-based scores. The primary endpoint was defined as low disease activity over a six-month treatment period with upadacitinib 15 mg/day (DAS28CRP ≤ 3.2, CDAI ≤ 10 and SDAI ≤ 11). Results: 41 patients were included, mean age 56.56 years (± 13.4), with long-standing RA (8 years ± 5.8), mostly female (80.5%). 19.5% of them were obese (BMI ≥ 30 kg/m2), 80.5% had osteoarthritis and 58.5% - hypertensive disease. Erosive arthritis was observed in 41.5% of patients  and 61% had functional class III motor deficit. "Bio-naïve" were 58.5%, the rest had previous experience with biologic therapy. Upadacitinib was used as monotherapy in 90% of patients and in combination with Methotrexate in 10%. There was a significant reduction in the painful and swollen joint counts, VAS and CRP six months after starting treatment with upadacitinib. Low disease activity was achieved by a significant proportion of patients (DAS28CRP-70.7%, CDAI-60.5% and SDAI 63.2%).  Therapeutic outcome was not determined by demographics, clinical factors, comorbidities, or prior biologic treatment. Increase in liver enzymes (n=3), decrease in hemoglobin levels (n=2), and urinary tract infection (n=2) were the adverse events recorded over the six-month treatment period. One patient died from COVID-19. Conclusion: A significant proportion of RA patients on treatment with upadacitinib 15 mg was able to achieve the therapeutic target in real clinical settings. No predictors of therapeutic efficacy were found. The registered side effects do not differ from the safety profile of the medication.