scholarly journals Risk of Bleeding Associated With Ibrutinib in Patients With B-Cell Malignancies: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

2020 ◽  
Vol 11 ◽  
Author(s):  
Jinjin Wang ◽  
Ailin Zhao ◽  
Hui Zhou ◽  
Jinbing Zhu ◽  
Ting Niu
Keyword(s):  
Systematic Review ◽  
B Cell ◽  
Major Bleeding ◽  
Meta Analysis ◽  
Lymphocytic Leukemia ◽  
Controlled Trials ◽  
B Cell Malignancies ◽  
Risk Of Bleeding ◽  
Randomized Controlled ◽  
Increased Risk

Background: Ibrutinib is an oral covalent Bruton’s tyrosine kinase inhibitor that has been approved for chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia and some other B-cell malignancies. Some studies have found an increased risk of bleeding with ibrutinib. Some studies, however, found no significant differences in the risk of major bleeding between patients treated with ibrutinib and those with other regimens. So, a systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to estimate the risk of bleeding associated with ibrutinib in patients with B-cell malignancies.Methods: A systematic search of PUBMED, EMBASE, Central Register of Controlled Trials, and ClinicalTrials.gov was conducted from January 2000 to February 2020 to identify RCTs by comparing ibrutinib with other agents or placebo in B-cell malignancies. The RevMan software (version 5.3) was used to carry out this analysis, and the analyzed data were represented by risk ratios (RR) and 95% confidence intervals (CI).Results: There were 11 eligible RCTs (4,288 patients). All studies reported major bleeding, and seven studies reported overall bleeding (any-grade bleeding). Ibrutinib was associated with a significantly increased risk of bleeding (overall bleeding and major bleeding) in patients with B-cell malignancies [RR = 2.56, 95% CI 1.68–3.90, p < 0.0001 and RR = 2.08, 95% CI 1.36–3.16, p = 0.0006, respectively]. The bleeding (overall bleeding and major bleeding) risk in patients with CLL was more obvious [RR = 3.08, 95% CI 2.07–4.58, p < 0.00001 and RR = 2.46, 95% CI 1.37–4.41, p = 0.003, respectively]. There were no statistically significant differences for risk of bleeding between the subgroups based on dose and treatment setting.Conclusion: Ibrutinib was associated with a significantly higher risk of bleeding (both overall bleeding and major bleeding) in patients with B-cell malignancies, especially in CLL.

scholarly journals Risk of Bleeding with Ibrutinib in Patients with B-Cell Malignancies: An Updated Meta-Analysis of Phase III Randomized Controlled Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5553-5553
Author(s):  
Somedeb Ball ◽  
Abhishek Maiti ◽  
Meily Arevalo ◽  
Avash Das ◽  
Wasawat Vutthikraivit ◽  
...  
Keyword(s):  
B Cell ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Final Analysis ◽  
Phase Iii ◽  
Controlled Trials ◽  
B Cell Malignancies ◽  
Major Hemorrhage ◽  
Randomized Controlled ◽  
Increased Risk

Abstract Introduction: Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor which has transformed the management of several B-cell malignancies. Ibrutinib has been associated with an increased incidence of bleeding in retrospective studies. This phenomenon has been explained by potential effects of ibrutinib on different aspects of platelet function, including adhesion and aggregation, mainly through modification of BTK signaling pathways in platelets. A previous meta-analysis (Caron et al.) found a significant increase in overall bleeding in ibrutinib recipients. We conducted an updated systematic review and meta-analysis of all phase III randomized controlled trials (RCT) available till date to determine the relative risk of overall bleeding associated with ibrutinib use, relative risk of major hemorrhage, and to evaluate if the risk estimate has changed with emergence of new data since prior reports. Methods: We performed a systematic search of Embase, PubMed, Web of Science, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov with appropriate keywords through 07/10/18, to find all RCTs comparing ibrutinib with other agents or placebo in patients with B-cell malignancies and also reporting bleeding as a treatment-emergent adverse event. The search strategy, study selection, data extraction, and analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. We pooled the point estimates using random effects model of the generic inverse-variance method described by Der Simonian and Laird. Statistical analyses were performed using the Stata/SE 15.1 (StataCorp LP, College Station, TX, USA). Results: A total of 6 phase III RCTs randomizing 1811 patients (pt; 935 on ibrutinib arms and 876 in the control arms) were included in the final analysis. Four trials were conducted in pts with CLL, one in pts with Waldenstrom macroglobulinemia and the other one in pts with mantle cell lymphoma. Characteristics of these trials are shown in Table 1. In 4 RCTs ibrutinib was compared with an active agent (i.e., ofatumumab, chlorambucil, temsirolimus, and rituximab) and in the other two trials, it was compared with placebo. Ibrutinib was administered as a 1st-line therapy in the RESONATE-2 trial and both as 1st line and in refractory cases in the iNNOVATE trial. The median duration of treatment across studies with ibrutinib was 17.7 months (range 9.4-38.7 months). Major hemorrhage was usually defined as grade 3-5 bleeding or central nervous system bleeding of any grade across trials. The pooled risk ratio (RR) for total number of bleeding events was 2.43 [95%CI: 1.47-4.00, p<0.001, I2=82.5%, figure 1A] in patients on ibrutinib across all B-cell malignancies, as compared to their counterparts in the control arms. The pooled RR for incidence of major hemorrhage in the ibrutinib arm was 1.71 [95%CI: 0.99-2.95, p=0.056, I2=0.0%, figure 1B], showing trend towards statistical significance as compared to control. In subgroup analysis of trials (n=4) in pts with CLL only, ibrutinib was again associated with a significantly increased risk of overall bleeding [pooled RR 3.23, 95%CI: 1.72-6.06, p<0.001, I2=72.7%, figure 2A], although the relative increase in risk was not significant [pooled RR 1.74, 95%CI: 0.83-3.67, p=0.142, I2=0.0%, figure 2B] in the patients on ibrutinib when number of major hemorrhages were compared in both groups. No publication bias was observed across all the studies included in final analysis. Conclusion: In this meta-analysis, ibrutinib was associated with a significantly increased risk of overall bleeding in patients with B-cell malignancies, and incidence of major hemorrhages in ibrutinib arm showed trend towards statistical significance. Knowledge about increased risk of this adverse event should help clinicians to contribute to alleviation of overall morbidity and mortality in patients. Disclosures Maiti: Celgene Corporation: Other: Research funding to the institution.

scholarly journals Risk of Infection with Ibrutinib in Patients with B-Cell Malignancies: A Meta-Analysis of Phase III Randomized Controlled Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2871-2871
Author(s):  
Somedeb Ball ◽  
Wasawat Vutthikraivit ◽  
Avash Das ◽  
Peggy J Edwards ◽  
Fred Hardwicke ◽  
...  
Keyword(s):  
B Cell ◽  
Meta Analysis ◽  
Final Analysis ◽  
Phase Iii ◽  
Controlled Trials ◽  
Risk Of Infection ◽  
B Cell Malignancies ◽  
Randomized Controlled ◽  
Increased Risk ◽  
Grade 3

Abstract Introduction: Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor which has transformed the management of several B-cell malignancies, particularly chronic lymphocytic leukemia (CLL). B-cell malignancies inherently confer increased risk of infections due to defects in innate and adaptive immunity. Recent studies have provided conflicting data regarding the risk of infection with ibrutinib therapy, with some reports suggesting an increased risk of infection owing to BTK inhibition while others suggesting decreased risk due to B-cell recovery and humoral reconstitution. We conducted a systematic review and meta-analysis of all phase III randomized controlled trials (RCT) to determine the relative risk of infection associated with the ibrutinib. Methods: We performed a systematic search of Embase, PubMed, Web of Science, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov with appropriate keywords through 07/10/18, to find all RCTs comparing ibrutinib with other agents or placebo in patients with B-cell malignancies and also reporting infection as a treatment-emergent adverse event. The search strategy, study selection, data extraction, and analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. We pooled the point estimates using random effects model of the generic inverse-variance method described by Der Simonian and Laird. Statistical analyses were performed using the Stata/SE 15.1 (StataCorp LP, College Station, TX, USA). Results: A total of 6 phase III RCTs randomizing 1811 patients (pt; 935 on ibrutinib arms and 876 in the control arms) were included in the final analysis. Four trials were conducted in pts with CLL, one in pts with Waldenstrom macroglobulinemia and the other one in pts with mantle cell lymphoma. Characteristics of these trials are shown in Table 1. In 4 RCTs ibrutinib was compared with an active agent (i.e., ofatumumab, chlorambucil, temsirolimus, and rituximab) and in the other two trials, it was compared with placebo. Ibrutinib was administered as a 1st-line therapy in the RESONATE-2 trial and both as 1st line and in refractory disease in the iNNOVATE trial. The median duration of treatment across studies with ibrutinib was 17.7 months (range 9.4-38.7 months). Ibrutinib was associated with a statistically significant increased incidence of total infections (any grade) in pts with B-cell malignancies [pooled risk ratio (RR) = 1.34, 95% confidence interval (CI): 1.06-1.69, p=0.015, I2=73.2%, fig. 1A]. Pneumonia and upper respiratory tract infection (URTI) were two most commonly reported infection in pts across trials. The incidence of pneumonia (grade 3-5) and URTI (any grade) with ibrutinib was not significantly different from the same in the control arm (pooled RR = 1.30, 95% CI: 0.84-2.02, p=0.237, I2=0.0%, fig. 1B, and pooled RR =1.26, 95%CI: 0.94-1.70, p=0.122, I2=34.5%, fig. 1C respectively). In subgroup analysis of trials (n=4) in pts with CLL only, ibrutinib was associated with a trend towards increased incidence of total infection (any grade) in pts with CLL, but the result was not statistically significant (pooled RR =1.24, 95% CI: 0.99-1.54, p=0.061, I2=75.7%, fig. 2A). No statistically significant difference was noted in the incidence of pneumonia (grade 3-5) and URTI (any grade) in pts with CLL on ibrutinib, as compared to their counterparts in the control arms (pooled RR =1.19, 95%CI: 0.76-1.88, p=0.448, I2=0.0% fig. 2B, and pooled RR =1.16, 95%CI: 0.86-1.56, p=0.341, I2=25.4%, fig. 2C, respectively). No publication bias was observed across all the studies included in final analysis. Conclusion: In this meta-analysis, ibrutinib was associated with significantly increased risk of infection in pts with B-cell malignancies, whereas this risk was not significantly increased when the analysis was limited to patients with CLL. Future well-designed prospective trials with longer duration of follow up are needed to truly evaluate the association of ibrutinib and infections in pts with B-cell malignancies. Disclosures Short: Takeda Oncology: Consultancy. Maiti:Celgene Corporation: Other: Research funding to the institution.

The role of anticoagulants for the primary prophylaxis of venous thromboembolism in patients with malignancy: A systematic review and meta-analysis of randomized controlled trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14691-e14691
Author(s):  
Mahmoud Barbarawi ◽  
Yazan Zayed ◽  
Babikir Kheiri ◽  
Inderdeep Gakhal ◽  
Owais Barbarawi ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Major Bleeding ◽  
Meta Analysis ◽  
Primary Prophylaxis ◽  
Controlled Trials ◽  
Risk Of Bleeding ◽  
Randomized Controlled ◽  
Increased Risk ◽  
All Cause Mortality

e14691 Background: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Despite this, pharmacologic prophylaxis for the primary prevention of VTE is not offered for most medical oncology patients, likely due to the competing risk of bleeding. Recent trials may offer new insight into the role of anticoagulants for the prevention of cancer associated thrombosis (CAT). Accordingly, we conducted a meta-analysis of randomized controlled trials (RCTs) that evaluated anticoagulants for the primary prophylaxis of VTE in cancer patients. Methods: A literature search of Pubmed/MEDLINE, Embase, and Cochrane library was done by two investigators. All RCTs that used anticoagulant in cancer patients for primary prevention of VTE were included. The primary outcomes were VTE events and all-cause mortality; VTE related mortality and major bleeding were secondary outcomes. A random effects model was used to report the risk ratios (RR) with 95% confidence intervals (CIs), and odds ratios (ORs) with Bayesian 95% credible intervals for both direct and network meta-analysis, respectively. Results: Twenty-four RCTs were included with a total of 13,338 patients (7,197 received anticoagulants and 6,141 received placebo). Of these trials, 19 used low-molecular weight heparin (LMWH), 3 used direct oral anticoagulants (DOACs), 2 used warfarin, and 1 used heparin. Mean age ranged between 54.6 to 68.1 years, with 50.5% male. Compared with placebo, LMWH or DOACs were associated with reduced VTE events (RR 0.58; 95% CI 0.48-0.69, p < 0.001) and (RR 0.39; 95% CI 0.24-0.63, p < 0.001), respectively. LMWH compared with placebo was associated with decreased VTE, and all-cause mortality (P < 0.05). While DOACs was associated with decreased PE events only compared with placebo (RR 0.28; 95% CI 0.11-0.71, P = 0.008). Regarding the safety outcome, LMWH and DOACs were associated with an increased risk of major bleeding compared with placebo, but this did not reach statistical significance in this study (RR 1.26; 95% CI 0.92-1.74, p = 0.16 and RR 1.76; 95% CI 0.83-3.73, p = 0.14). Results regarding VTE events and major bleeding were consistent in both lung and pancreatic cancers. Conclusions: Both LMWH and DOACs were associated with a lower number of VTE events compared with placebo. However, this potentially protective effect must be balanced against a possible increased risk of bleeding for some patients.

A systematic review and meta-analysis of randomized controlled trials to evaluate the risk of fatigue and pain among patients treated with ibrutinib.

2017 ◽  
Vol 35 (31_suppl) ◽  
pp. 213-213
Author(s):  
Myo Zaw ◽  
Kyaw Zin Thein ◽  
Myat M. Han ◽  
Ruth D’Cunha ◽  
Hassan Kaleem ◽  
...  
Keyword(s):  
Systematic Review ◽  
Back Pain ◽  
Side Effects ◽  
Randomized Controlled Trials ◽  
B Cell ◽  
Meta Analysis ◽  
Cell Receptor ◽  
Muscle Spasm ◽  
Controlled Trials ◽  
Randomized Controlled

213 Background: Bruton’s tyrosine kinase (BTK), a kinase downstream of the B-cell receptor, involves in the B cell survival and proliferation and has become an attractive therapeutic target. Ibrutinib is an oral potent, covalent inhibitor of BTK and hence employed in many hematologic malignancies. We performed a systematic review and pooled analysis of randomized controlled trials (RCTs) to determine the risk of fatigue and pain among patients treated with ibrutinib. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through December 31, 2016. RCTs that mention fatigue, arthralgia, muscle spasm, back pain, pain in extremity and myalgia as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% confidence interval (CI). Results: Four phase 3 RCTs with a total of 1505 patients were eligible for the analysis. Studies compared Ibrutinib (I) vs ofatumumab, I vs chlorambucil, I+ bendamustine (B)+ rituximab (R) vs placebo + B+ R and I vs temsirolimus were included in the analysis. The relative risks (RR) of all-grade side effects were as follows: fatigue, 0.87 (95% CI: 0.74- 1.03, p = 0.11); arthralgia, 1.97 (95% CI: 1.11- 3.50, p = 0.02); muscle spasm, 1.92 (95% CI: 1.22- 3.02, p = 0.005); back pain, 1.56 (95% CI: 1.02- 2.37, p = 0.03); pain in extremity, 2.47 (95% CI: 1.14- 5.36, p = 0.02); and myalgia, 2.68 (95% CI: 1.18- 6.05, p = 0.01). The RR of high-grade side effects were as follows: fatigue, 0.70 (95% CI: 0.37- 1.33, p = 0.28); arthralgia, 3.62 (95% CI: 0.74- 17.66, p = 0.11); back pain, 2.80 (95% CI: 0.42- 18.35, p = 0.28); pain in extremity, 2.96 (95% CI: 0.31- 28.4, p = 0.34); and myalgia, 2.96 (95% CI: 0.31- 28.44, p = 0.34). Conclusions: Our meta-analysis demonstrated that the risk of all-grade arthralgia, muscle spasm, back pain, pain in extremity and myalgia with ibrutinib was high. Pain is a major determinant of quality of life in cancer patients undergoing chemotherapy and recognizing these may help clinicians in delivering proper supportive care.

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