Pulmonary Adverse Events of Small Molecule Tyrosine Kinase Inhibitors: Meta-Analysis and Systematic Review

2019 ◽  
Author(s):  
Jun Keng Khoo ◽  
Hayley Barnes ◽  
Seraphina Key ◽  
Ian N. Glaspole ◽  
Andrew Ostor
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Meta Analysis

Safety and efficacy of addition of VEGFR and EGFR-family small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: A meta-analysis.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 415-415
Author(s):  
Tomohiro Funakoshi ◽  
Asma Latif ◽  
Matt D. Galsky
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Small Molecule ◽  
Randomized Trials ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Cytotoxic Chemotherapy ◽  
Safety And Efficacy ◽  
Egfr Family

415 Background: The approach of combining cytotoxic chemotherapy with small molecule tyrosine kinase inhibitors (TKIs) has been explored in a large number of randomized trials, in a diverse range of tumor. We performed a systematic review and meta-analysis to evaluate the safety and efficacy of this therapeutic approach. Methods: PubMed and the ASCO databases were searched up to March 2013. Eligible studies included randomized trials in which the FDA approved TKI in combination with chemotherapy was compared with chemotherapy alone in patients with any type of solid cancer. The endpoints included safety [fatal adverse events (FAEs), treatment discontinuation, any severe (grade 3 or 4) adverse events (AEs), and individual severe AEs] and efficacy [progression-free survival (PFS), and overall survival (OS)]. The pooled relative risk (RR) or hazard ratio (HR), with corresponding 95% confidence intervals (CI) were calculated. Results: A total of 16,011 patients from 43 trials were included. Among the 43 trials, ten met their primary efficacy endpoints. Among the 21 phase III trials, two led to Food and Drug Administration approval for the combination. Compared with chemotherapy alone, the addition of a TKI significantly increased the risk of FAEs (RR, 1.63; 95% CI, 1.32-2.01), treatment discontinuation (RR, 1.80; 95% CI, 1.58-2.06), and any severe AE (RR, 1.25; 95% CI, 1.16-1.36). Compared with chemotherapy alone, the addition of a TKI was associated with a significant improvement in PFS (HR, 0.82; 95% CI, 0.76-0.89), but not OS (HR, 0.99; 95% CI, 0.95-1.03). Chemotherapy plus TKI was also associated with a significant higher risk of seven of the 11 evaluated individual AEs: neutropenia (RR, 1.18; P =.004), thrombocytopenia (RR, 1.70; P <.001), febrile neutropenia (RR, 1.48; P <.001), hypertension (RR, 3.01; P <.001), skin toxicities (RR, 6.38; P <.001), diarrhea (RR, 2.57; P =.002) and fatigue (RR, 1.35; P <.001). Conclusions: The addition of a VEGFR or EGFR-family TKI to chemotherapy in solid cancers increases the risk of severe toxicities and treatment discontinuations. These findings might explain the general lack of a survival benefit with these regimens.

scholarly journals Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1643
Author(s):  
Prahathishree Mohanavelu ◽  
Mira Mutnick ◽  
Nidhi Mehra ◽  
Brandon White ◽  
Sparsh Kudrimoti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Gastrointestinal Adverse Events

Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib. Examination of combined TKI average GI AE incidence found diarrhea most prevalent (22.5%), followed by nausea (20.6%), and vomiting (12.9%). Other TKI GI AEs included constipation (9.2%), abdominal pain (7.6%), gastrointestinal hemorrhage (3.5%), and pancreatitis (2.2%). Mean GI AE incidence was significantly different between TKIs (p < 0.001): bosutinib (52.9%), imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). Diarrhea was the most prevalent GI AE with bosutinib (79.2%) and dasatinib (28.1%), whereas nausea was most prevalent with imatinib (33.0%) and nilotinib (13.2%). Incidence of grade 3 or 4 severe GI AEs was ≤3% except severe diarrhea with bosutinib (9.5%). Unsupervised clustering revealed treatment efficacy measured by the complete cytogenetic response, major molecular response, and overall survival is driven most by disease severity, not TKI type. For patients with chronic phase CML without resistance, optimal TKI selection should consider TKI AE profile, comorbidities, and lifestyle.

Risk of arterial thromboembolic events (ATEs) with tyrosine kinase inhibitors (TKIs) used in renal cell carcinoma: A systematic review and meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13119-e13119
Author(s):  
Muhammad Zain Farooq ◽  
Jessey Mathew ◽  
Saad Malik ◽  
V V Pavan Kedar Mukthinuthalapati ◽  
Noureen Asghar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Thromboembolic Events ◽  
Phase 2 ◽  
Open Label ◽  
Increased Risk ◽  
Arterial Thromboembolic Events

e13119 Background: Tyrosine kinase inhibitors (TKIs) are routinely used in the treatment of metastatic RCC and Sunitinib is approved for the use in adjuvant setting. Arterial thromboembolic events (ATEs) have been described with these agents, although the overall risk remains unclear. We did a systematic review and meta-analysis to determine the incidence associated with the use of FDA approved TKIs used in treatment of RCC. Methods: PubMed, EMBASE, Cochrane Central and Scopus databases were searched to identify phase 2 and 3 RCTs of TKI therapy in RCC. Trials were included if they reported ATEs defined as arterial thrombosis, cerebral ischemia or infarction, myocardial ischemia and myocardial infarction. The DerSimonian-Laird random effects meta-analysis was performed using CMAv3 software to derive pooled estimates of incidence rates of ATEs with its 95% confidence interval (CI). I2 statistic was computed to express the percentage of the total observed variability due to study heterogeneity. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: 1755 studies retrieved in the initial search, and 13 phase 2 and 3 clinical trials (n = 4983) were included in the quantitative analysis. The trials had open label design which can potentially result in bias. Risk of bias was low in all other domains. TKIs used for the treatment of RCC included sunitinib (n = 2632), sorafenib (n = 981), cabozantinib (n = 78), pazopanib (n = 844), axitinib (n = 189) and tivozanib (n = 259). The incidence of ATEs with the use of TKIs was 2.9% (95% CI: 2-3%). Cabozantinib was associated with the highest rate of ATEs (11.5%, 95% CI: 6-21%), followed by sunitinib (2.6%, 95% CI:2-3%) pazopanib (2.6%, 95% CI:2-4%) and axitinib (2.1%, 95% CI: 1-6%). The TKI with lowest event rate of ATE was tivozanib (0.8%, 95% CI:0.2-3%). Conclusions: The use of TKIs is associated with increased risk of developing ATEs. Clinicians should be aware of the possibility of increased ATEs and counsel the patients about this increased risk to enhance the process of informed decision making.

scholarly journals Arterial Hypertension and Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Olga Mulas ◽  
Giovanni Caocci ◽  
Brunella Mola ◽  
Giorgio La Nasa
Keyword(s):  
Systematic Review ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Cardiovascular Complication ◽  
Third Generation ◽  
Pubmed Database

Background: Off-target effects in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) are associated with cardiovascular toxicity. Hypertension represents an important cardiovascular complication and, if not appropriately managed, can contribute to developing thrombotic events. Third-generation TKI ponatinib is associated with hypertension development, and its use is more restricted than in the past. Few data are reported for second-generation TKI, nilotinib, dasatinib, and bosutinib. The aim of this article was to evaluate with a systematic review and meta-analysis the real incidence of hypertension in CML patients treated with second- or third-generation TKI.Methods: The PubMed database, Web of Science, Scopus, and ClinicalTrials.gov were systematically searched for studies published between January 1, 2000, and January 30, 2021; the following terms were entered in the database queries: Cardiovascular, Chronic Myeloid Leukemia, CML, Tyrosine kinases inhibitor, TKI, and Hypertension. The study was carried out according to the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) statement.Results: A pooled analysis of hypertension incidence was 10% for all new-generation TKI, with an even higher prevalence with ponatinib (17%). The comparison with the first-generation imatinib confirmed that nilotinib was associated with a significantly increased risk of hypertension (RR 2; 95% CI; 1.39-2.88, I2=0%, z=3.73, p=0.0002). The greatest risk was found with ponatinib (RR 9.21; 95% CI; 2.86-29.66, z=3.72, p=0.0002).Conclusion: Hypertension is a common cardiovascular complication in CML patients treated with second- or third-generation TKI.

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