Long-term results of frontline dasatinib in chronic myeloid leukemia.

BACKGROUND: Dasatinib is a second-generation tyrosine kinase inhibitor that, when used as frontline therapy, produces more and faster cytogenetic and molecular responses compared with imatinib. The authors report the long-term follow-up from the first study using dasatinib as initial therapy for chronic-phase chronic myeloid leukemia. METHODS: Between November 2005 and August 2014, patients were randomly assigned to receive 100 mg daily or 50 mg twice daily. After June 2009, all patients started with 100 mg daily. RESULTS: With a median follow-up of 6.5 years, 94 of 149 treated patients (63%) were still receiving dasatinib on study. The median patient age was 48 years (interquartile range, 37-55 years), and 9% of patients had a high risk Sokal risk score. The cumulative complete cytogenetic response rate at 11 years was 92.6%, the major molecular response (MR) rate was 88.2%, and the MR4.5 rate (indicating a ≥4.5-log reduction in BCR-ABL1 transcripts) was 79.5%. The median time to a major MR and MR4.5 was 6 and 23 months, respectively. A sustained MR4.5 (≥2 years) was achieved in 82 patients (55%). The 10-year overall survival, transformation-free survival, event-free survival, and failure-free survival rates were 89%, 95%, 86%, and 65%, respectively. Univariate analysis showed that the achievement of a complete MR was associated with improved overall survival. The most common reasons for treatment discontinuation were toxicity and elective discontinuation. The most common treatment-emergent grade 3 and 4 adverse events were fatigue, thrombocytopenia, and infections. CONCLUSIONS: After this long-term follow-up, dasatinib continues to show an excellent safety profile and produces rapid cytogenetic responses and MRs, durable deep MRs, and excellent long-term survival outcomes in patients with chronic-phase chronic myeloid leukemia.

A quantitative method for the determination of bosutinib in human plasma using high-performance liquid chromatography and ultraviolet detection.

BACKGROUND: We propose a simple, sensitive, and fast high-performance liquid chromatography ultraviolet detection (HPLC-UV) method for the quantitative determination of bosutinib in human plasma. METHODS: Plasma samples were processed using an Oasis hydrophilic-lipophilic balance extraction cartridge (1 mL, 30 mg). Bosutinib and the internal standard imatinib were separated using a mobile phase of 0.5% Na2 PO4 H2 O (pH 3.5)-acetonitrile-methanol (55:25:20, v/v/v) on a CAPCELL PAK C18 MG II reversed-phase column 250 nm×4.6 nm i.d., at a flow rate of 1.0 mL/min, with ultraviolet detection at 250 nm. RESULTS: The calibration curve exhibited linearity over the bosutinib concentration range of 25-1500 ng/mL at 250 nm, with coefficient of variation for intraday precision of 2.42%, 6.04%, and 1.11% for 100, 250, and 1500 ng/mL, respectively, of bosutinib. The lower limit of detection was 20 ng/mL. The extraction recovery rates for bosutinib ranged from 84.36% to 85.82%. The intra- and interday precision was below 8.7%, and the accuracy ranged from -5.95% to 5.85% over the linear range. No notable matrix effects or astaticism were observed. CONCLUSION: The proposed HPLC-UV method was successfully applied as an assay to detect bosutinib in human plasma.

Comparable efficacy and safety of generic and branded imatinib for patients with chronic myeloid leukemia in China.

Background: Generics imatinib became an alternative treatment option for chronic myeloid leukemia (CML) patients in China. However, clinicians and patients alike harbor concerns regarding the long-term safety of generic imatinib. Objectives: Patients with chronic phase CML receiving frontline imatinib treatment. Design: A retrospective study was used to evaluate the blood concentration, effectiveness, and safety of generic in 170 CML patients. Methods: Imatinib plasma concentrations were detected by high-performance liquid chromatography-tandem mass spectrometry. Results: Among the 170 patients, 73 (42.9%) patients treated with branded imatinib as first-line therapy, while 22 (12.9%) switched to generic imatinib during treatment due to economic considerations. No significant differences in trough concentrations between branded and generic imatinib (1549.9 ± 648.8 ng/mL vs 1479.0 ± 507.0 ng/mL; p = 0.95). During the 2-year follow-up, there were no significant differences in molecular response rates (major molecular response (MMR): 33.3% vs 37.0%; deep molecular response: 56.9% vs 42.9%, p = 0.17) between the branded and generic imatinib. Both groups showed similar rates of switching to second-generation tyrosine kinase inhibitor (11.8% vs 15.1%, p = 0.56). Furthermore, there were no significant differences in event-free survival or failure-free survival between branded and generic imatinib. Twenty-two (12.9%) switched to generic imatinib during treatment, 68.2% maintained their level of response, 27.3% improved, and only one patient (4.5%) lost MMR. There were no significant differences in the incidence of various adverse events. Conclusion: Generic imatinib are equally effective and safe compared to branded molecules, both for newly diagnosed patients and those who switch from branded.

Long-term outcomes of frontline imatinib therapy for chronic myeloid leukemia in China.

Background: Imatinib is the first-line therapy recommended for chronic myeloid leukemia (CML) patients in China. We reported a long-term follow-up study of patients on imatinib as first-line treatment for chronic phase (CP) CML to provide an important reference for the actual clinical treatment regimen of CML patients in China. Methods: We evaluated the long-term efficacy, safety, low-dose attempt after years of treatment, and treatment-free remission (TFR) of 237 CML-CP patients receiving first-line imatinib therapy. Results: The median age was 46 years (interquartile range: 33-55). After a median follow-up of 6.5 years, the cumulative complete cytogenetic response, major molecular response (MMR), and MR4.5 rates were 82.6%, 80.4%, and 69.3%, respectively. The 10-year transformation-free, event-free, and failure-free survival rates were 97.3%, 87.2% and 53.5%, respectively. Fifty-two (21.9%) patients with sustained deep molecular response (DMR) were treated with low-dose imatinib after years of imatinib treatment. No significant differences in the 1-year and 2-year molecular relapse-free survival in MMR and MR4 were observed between the standard-dose and low-dose groups. Twenty-eight (11.8%) patients discontinued imatinib, and the median time to maintain DMR before discontinuation was 8.43 years. Thirteen patients (5.5%) remained in TFR for a median of 43.33 months. No patients transformed to accelerate or blast phase or died. No new, late toxicity was observed, and the most frequent grade 3/4 adverse events were neutropenia (9.3%), anemia (7.6%), thrombocytopenia (6.3%), and rash (4.2%). Conclusion: This study confirmed the long-term efficacy and safety of imatinib for treating Chinese CML patients. Additionally, it demonstrated the feasibility of imatinib dose reduction and TFR attempts in patients with sustained stable DMR after years of imatinib treatment in real-life settings.

Adherence to tyrosine kinase inhibitor and clinical outcomes in patients with chronic myeloid leukemia.

PURPOSE: To ensure optimal care for patients with chronic myeloid leukemia (CML), adherence to tyrosine kinase inhibitors (TKIs) has emerged as a critical component. The objective of this study was to assess the impact of TKIs adherence on clinical outcomes in a cohort of Chinese CML patients who received treatment with TKIs. METHODS: This retrospective study employed a cross-sectional design utilizing questionnaires to assess adherence to TKIs in a sample of 398 patients diagnosed with CML. Adherence was measured using the Morisky Medication Adherence Scale (MMAS-8), which dichotomizes patients into low, medium, and high adherence groups. RESULTS: Of the patients included in this study, 34.2% were classified as highly adherent, with 43.2% and 22.6% of patients categorized as having medium and low adherence, respectively. Compared to the low-adherence group, patients in the medium- and high-adherence groups exhibited significantly higher rates of achieving major molecular response (MMR) and lower rates of switching TKIs. Moreover, patients who failed to adhere to TKIs treatment demonstrated significantly lower event-free survival and failure-free survival compared to those in the high-adherence group. Notably, regular molecular monitoring and utilization of the "CML Academy" mobile application were positively associated with increased TKI adherence. On the other hand, patients receiving third-generation or above first-line TKIs treatment displayed reduced adherence. CONCLUSION: The findings suggest that high adherence to TKIs treatment confers clinical benefits to patients with CML. Accordingly, the implementation of effective guidance and intervention measures aimed at promoting adherence to TKIs therapy in real-world settings is imperative.