scholarly journals First line treatment with newer tyrosine kinase inhibitors in chronic myeloid leukemia associated with deep and durable molecular response – systematic review and meta-analysis

2016 ◽  
Vol 55 (9-10) ◽  
pp. 1077-1083 ◽  
Author(s):  
Ronit Gurion ◽  
Pia Raanani ◽  
Liat Vidal ◽  
Avi Leader ◽  
Anat Gafter-Gvili
Keyword(s):  
Systematic Review ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

scholarly journals The Role of the Newer Tyrosine Kinase Inhibitors As First Line Treatment in Chronic Phase Chronic Myeloid Leukemia – an Updated Meta-Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4563-4563
Author(s):  
Ronit Gurion ◽  
Liat Vidal ◽  
Avi Leader ◽  
Pia Raanani ◽  
Anat Gafter-Gvili
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Meta Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Time Points ◽  
Grade 3 ◽  
First Line Treatment

Abstract Background: Imatinib, nilotinib and dasatinib are all considered first line treatment in chronic phase (CP) chronic myeloid leukemia (CML) patients. The choice of the most suitable tyrosine kinase inhibitor (TKI) for an individual patient is influenced by multiple factors including disease characteristics, patient comorbidities and preferences, as well as each TKI's unique profile of adverse events. A meta-analysis of second generation TKIs as first line treatment for patients with CML was published by our group in 2011. In view of the recently published long term results of three of the trials included in the previous meta-analysis and data from two new trials, we decided to update our data. Objectives: To evaluate the efficacy and toxicity of different TKIs as first line treatment for patients with CML. Methods: Systematic review and meta-analysis of randomized controlled trials comparing first line treatment with the newer TKIs (nilotinib, dasatinib, bosutinib and ponatinib) to imatinib in patients with CP-CML. The MEDLINE, conference proceedings and references were searched until August 2014. Two reviewers appraised the quality of trials and extracted data. The following outcomes were assessed: complete cytogenetic response (CCyR); major molecular response (MMR); complete molecular response (CMR), defined as a 4.5 log reduction in BCR-ABL transcripts; early molecular response, defined as BCR-ABL transcript levels of 10% or less at 3 months; progression to accelerated phase (AP) / blastic crisis (BC); all-cause mortality (ACM) and toxicity. Relative risks (RR) were estimated and pooled. Random-effect model was used in all analysis. Results: Our search yielded six trials including 2,426 patients. These trials compared the effects of nilotinib, dasatinib, bosutinib or ponatinib to imatinib. Data from the six trials were available for analysis of MMR. Treatment with the newer TKIs significantly improved MMR at all-time points (3, 12, 18, 24 and 48 months) compared to imatinib (Table 1). Of note, the newer TKIs significantly increased the rate of CMR compared to imatinib at 12 months (RR 2.68, 95% CI 1.64-4.36, 5 trials, figure 1) and at 24 months (RR 2.04, 95% CI 1.62-2.57, 3 trials). Moreover, there was a statistically significant advantage in favor of the newer TKIs as compared to imatinib in terms of early molecular response at 3 months (RR 1.34, 95% CI 1.27-1.41, 5 trials). Importantly, progression rate to AP/BC at 24 months was significantly lower with the newer TKIs in comparison with imatinib (RR 0.35, 95% CI 0.20-0.61, 4 trials). However there was no difference in ACM (RR 0.73, 95% CI 0.46-1.15, 4 trials). We conducted a meta-analysis for specific adverse events according to the distinct toxicity profile of the different TKIs. Severe peripheral arterial occlusive disease occurs more frequently in the newer TKIs arm (i.e. nilotinib and ponatinib) (RR 8.13, 95% CI 1.51-43.83, 2 trials) than in the imatinib arm. In addition, pleural effusion requiring discontinuation occurs at a higher rate in the newer TKIs arm (RR 4.61, 95% CI 1.31-16.23, 4 trials; dasatinib and bosutinib vs. imatinib). Regarding hematologic toxicity including grade 3-4 anemia and neutropenia, there was no difference between the two arms (all newer TKIs vs. imatinib). However, regarding thrombocytopenia grade 3-4, there were more events with thrombocytopenia in the newer TKIs arm compared to imatinib (RR 1.41, 95% CI 1.01-1.97). Conclusions: With a longer follow-up of 4 years, the newer TKIs remain more potent than imatinib in terms of MMR, CMR and early molecular response. Yet, an effect on overall survival cannot be shown. Since CMR is a prerequisite for treatment discontinuation, the newer TKIs can potentially facilitate cessation of treatment more frequently than imatinib. These data should be taken into consideration in choosing treatment for a newly diagnosed CML patient. Table 1 – MMR at different time points Time point Relative risk 95% Confidence of interval No. of trials 3 months 6.63 2.31-19.01 5 12 months 1.68 1.48-1.89 6 18 months 1.37 1.18-1.59 4 24 months 1.28 1.06-1.54 4 48 months 1.20 1.05-1.38 3 Figure 1 – CMR at 12 months Figure 1 –. CMR at 12 months Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors

2020 ◽  
Vol 9 (5) ◽  
pp. 1542
Author(s):  
Jee Hyun Kong ◽  
Elliott F. Winton ◽  
Leonard T. Heffner ◽  
Manila Gaddh ◽  
Brittany Hill ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Blastic Phase

We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4–190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1–53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.

Systematic Review and Meta-Analysis of ­New-Generation Tyrosine Kinase Inhibitors versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia

2019 ◽  
Vol 143 (3) ◽  
pp. 204-216 ◽  
Author(s):  
Pan Pan ◽  
Lijuan Wang ◽  
Yanjun Wang ◽  
Li Shen ◽  
Pingping Zheng ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Molecular Response ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
Time Points ◽  
New Generation ◽  
First Line Treatment

Backgrounds: We performed this systematic review and meta-analysis to compare the efficacy of new-generation tyrosine kinase inhibitors (NG-TKIs; including dasatinib, nilotinib, bosutinib, radotinib, and ponatinib) versus imatinib for patients with newly diagnosed chronic myeloid leukemia (CML). Summary: We identified randomized controlled trials comparing the efficacy of NG-TKIs versus imatinib as the first-line treatment for CML patients by searching the PubMed, Cochrane library, and EMBASE databases. Two reviewers independently extracted data and assessed study quality. A meta-analysis was performed to calculate risk ratios and 95% CIs using a fixed-effects model.Our study included 10 trials. Overall, treatment with NG-TKIs significantly improved the major molecular response and MR4.5 at all time points, and early molecular response at 3 months. Importantly, overall survival (OS) was significantly higher with the NG-TKIs at 12 months. Besides, NG-TKI-treated patients showed a significantly lower CML-related death and progression to the accelerated phase/blast crisis. Key Messages: In first-line treatment, NG-TKIs are superior to imatinib regarding OS at 12 months, and because molecular response rates were higher with the NG-TKIs at all time points, the NG-TKIs favor treatment-free remission.

scholarly journals Cardiovascular Toxicities of Tyrosine Kinase Inhibitor in CML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Samip R Master ◽  
Richard Preston Mansour
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Line Treatment ◽  
Front Line ◽  
First Line ◽  
First Line Treatment

Background: Cardiovascular (CV) toxicity is a known toxicity of tyrosine kinase inhibitors (TKI) used for chronic myeloid leukemia (CML). Imatinib, dasatinib, nilotinib and bosutinib are all approved for first line treatment for CML. We did a retrospective analysis on adverse effects (AE) of TKIs that has been made available to public by the FDA. Methods: The FDA has made the data on AEs of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the CV AEs of various TKIs for the years 2017-2019. Results: The percentage of CV AE compared to total AEs reported for Imatinib, Dasatinib, Bosutinib , Nilotinib and Ponatinib were 7.2%, 10.5%, 15.8%, 23.4% and 23.5% respectively. The percentage of CV AE leading to death for Imatinib, Dasatinib, Bosutinib , Nilotinib and Ponatinib were 8.3%, 9.1%, 9.1%, 13.7 % and 18.6% respectively. Conclusions: Out of the reported cases of AEs to TKIs approved for front line CML, nilotinib appears to have more CV AE compared to imatinib, dasatinib and bolutinib. Imatinib appears to have least CV AE out of the total AEs reported Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document