ABSTRACT
Introduction: Tyrosine kinase inhibitor (TKI) therapy has greatly improved the prognosis of patients with chronic myeloid leukemia (CML), improving the survival expectancy of patients with chronic phase (CP) CML to that of the general population. However, despite these advances, nearly 50% of patients with CP CML experience failure to respond to frontline therapy, and most fail to respond to the subsequent second-line TKI. Treatment guidelines for patients failing second-line therapy are lacking. This study aimed to determine the efficacy of TKIs as third-line therapy in a "real-world" clinical practice setting and identify factors favorably influencing the long-term outcomes of therapy. Methods: We have retrospectively analyzed the medical records of 100 patients with CP CML. Results: The median age of the patients was 51 (range, 21-88) years, and 36% of the patients were men. The median duration of the third-line TKI therapy was 22 (range, 1- 147) months. Overall, the rate of achieving complete cytogenetic response (CCyR) was 35%. Among the four patient groups with different levels of responses at baseline, the best results were achieved in the groups with any CyR at the baseline of third-line therapy. Thus, СCyR was reached in all 15 and 8/ 16 (50%) patients with partial cytogenetic response (PCyR) or minimal or minor CyR (mmCyR), respectively, whereas CCyR was detected only in 12/69 (17%) patients without any CyR at baseline (p < 0.001). Univariate regression analysis revealed that the factors negatively associated with CCyR achievement in thirdline TKI therapy were the absence of any CyR on first- or second-line TKI therapy (p < 0.001), absence of CHR prior to third-line TKI (p = 0.003), and absence of any CyR prior to third-line TKI (p < 0.001). During the median observation time from treatment initiation to the last visit [56 (4-180) months], 27% of cases progressed into accelerated phase or blast phase CML, and 32% of patients died. Discussion: Progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with CCyR on third-line than in the group without CCyR on third-line therapy. At the last visit, third-line TKI therapy was ongoing in 18% of patients, with a median time of treatment exposure of 58 (range, 6-140) months; 83% of these patients had stable and durable CCyR, suggesting that patients without CHR at baseline and without CCyR at least by 12 months on third-line TKI should be candidates for allogeneic stem cell transplantation, third-generation TKIs, or experimental therapies.
ABSTRACT
BACKGROUND: This study compared the hemodynamic effects and gas exchange under several different ventilator settings-with regard to tidal volume, respiratory rate, and end-expiratory pressure-in patients after coronary artery bypass grafting (CABG). METHODS: Prospective interventional cohort study with a controlled group in a single cardiosurgical ICU involving 119 patients following on-pump CABG surgery. During the 1st postoperative hour, the intervention group patients were ventilated with Vt 10 ml × kg-1, RR 14/min, PEEP 5 cmH2O ("conventional ventilation"). During the 2nd hour, RR was reduced to 8/min ("reduced RR ventilation"). At 3 hrs, Vt was decreased to 6 ml × kg-1, RR returned to 14/min, and PEEP increased to 10 cmH2O ("low Vt-high PEEP ventilation"). RESULTS: Patients in the "low Vt-high PEEP" ventilation period showed significantly lower alveolar ventilation and thoraco-pulmonary compliance than during "reduced RR" ventilation. Mean airway pressure and Vds/Vt peaked during low Vt-high PEEP ventilation; however, driving pressure was lower. Vt decrease and PEEP increase did not lead to oxygenation improvement and worsened CO2 elimination. Hemodynamically, the study revealed significant cardiac output decrease during low Vt-high PEEP ventilation. In 23.2% of patients, catecholamine therapy was initiated. CONCLUSIONS: In postoperative cardiosurgical patients, MV with Vt 6 ml × kg-1 and PEEP 10 cm H2O is characterized by worsened oxygenation and elimination of CO2 and a less favorable hemodynamic profile than ventilation with Vt 10 ml × kg-1 and PEEP 5 cmH2O. New and Noteworthy. (i) Patients after CABG may be especially sensitive to low tidal volume and increased PEEP as it negatively affects hemodynamic profile by means of the right heart preload decrease and afterload increase. (ii) Mechanical ventilation settings aiming to minimize mean airway pressure reduce the negative effects of positive inspiratory pressure and are favorable for hemodynamics.
