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.

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 Atrial Fibrillation 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. 1869-1869
Author(s):  
Somedeb Ball ◽  
Wasawat Vutthikraivit ◽  
Avash Das ◽  
Peggy J Edwards ◽  
Lukman Tijani ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
B Cell ◽  
Meta Analysis ◽  
Final Analysis ◽  
Phase Iii ◽  
Controlled Trials ◽  
High Grade ◽  
B Cell Malignancies ◽  
Randomized Controlled ◽  
Grade 3

Abstract Introduction: Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase which has become an important part of the therapeutic armamentarium for B-cell malignancies. Ibrutinib has been associated with an increased incidence of atrial and ventricular arrhythmias in studies. We conducted an updated systematic review and meta-analysis of all phase III randomized controlled trials (RCT) to determine the relative risk of atrial fibrillation (AF) associated with ibrutinib use, relative risk of high grade AF (grade 3-5), and to evaluate if the estimation of risk has changed with emergence of new data since prior reports on this adverse event. Methods: We performed a systematic search of PubMed, Embase, Web of Science, Scopus, Clinical Trials.gov, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews 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 AF as a treatment-emergent adverse event. The search strategy, study selection, data extraction, and analysis were conducted 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). The pooled risk ratio (RR) for all grade atrial fibrillation was 4.27 [95% confidence interval (CI): 2.26-8.06, p<0.001, I2=0.0%, figure 1A] in patients on ibrutinib across all B-cell malignancies, as compared to patients in the control arms. The overall incidence of high-grade (grade 3-5) AF was also significantly increased in the ibrutinib arms, as compared to control [pooled RR 4.85, 95% CI: 2.02-11.63, p<0.001, I2=0.0%, figure 1B]. In subgroup analysis of trials (n=4) in pts with CLL only, ibrutinib was again associated with a statistically significant increase in risk of all grade and high-grade AF [pooled RR 4.03, 95% CI: 1.99-8.15, p<0.001, I2=0.0%, figure 2A, and pooled RR 3.83, 95% CI: 1.29-11.42, p=0.016, I2=0.0%, figure 2B, respectively]. No publication bias was observed across all the studies included in final analysis. Conclusion: In agreement with prior reports, this updated meta-analysis confirmed that ibrutinib was associated with a significantly increased risk of all grade AF in pts with B-cell malignancies (RR 4.27). Our analysis shows that the risk of high grade AF (grade3-5) is also significantly increased with ibrutinib (RR 4.85). These pts need to be closely monitored for development of AF to help improve morbidity and mortality. Disclosures Short: Takeda Oncology: Consultancy. Maiti:Celgene Corporation: Other: Research funding to the institution.

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 &lt; 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 &lt; 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.

Differential side effects profile in mCRPC patients treated with abiraterone or enzalutamide: A meta-analysis of randomized controlled trials.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 73-73 ◽  
Author(s):  
Raphael Brandao Moreira ◽  
Marcio Debiasi ◽  
Fernando C. Maluf ◽  
Joaquim Bellmunt ◽  
Andre Poisl Fay ◽  
...  
Keyword(s):  
Side Effects ◽  
Adverse Events ◽  
Randomized Controlled Trials ◽  
Cardiovascular Events ◽  
Meta Analysis ◽  
Phase Iii ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
Increased Risk ◽  
Grade 3

73 Background: Abiraterone and enzalutamide are currently approved for mCRPC patients. Both drugs have distinct mechanisms of action and may have different toxicity profile. There are limited data comparing the side effects of abiraterone and enzalutamide. We performed a meta-analysis of randomized controlled trials (RCT) to better characterize the risk of adverse events associated with both drugs. Methods: We performed a literature search on MEDLINE for studies reported from January 1966 to July 31, 2015. Abstracts presented at ASCO meetings from 2004 to 2015 were selected manually. Phase III RCT were included in analysis. We assessed the risk of adverse events reported in RCT by performing two meta-analysis: abiraterone-prednisone vs. placebo-prednisone (2,283 pts) and enzalutamide vs. placebo (2,914 pts). Summary of incidence, relative-risks (RR), and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: Overall, enzalutamide was not associated with all-grade (RR 1.06 - 95% CI 0.67-1.65) or grade ≥3 (RR 0.81 - 95% CI 0.28-2.33) cardiovascular events, but was associated with increased risk of all-grade fatigue (RR 1.29 - 95% CI 1.15-1.44). On the other hand, abiraterone was associated with increased risk of all-grade (RR 1.28 - 95% CI 1.06-1.55) and grade ≥3 (RR 1.76 - 95% CI 1.12-2.75) cardiovascular events, but was not associated with all-grade (RR 0.85 - 95% CI 0.58-1.23) or grade ≥3 (RR 1.07 - 95% CI 0.97-1.19) fatigue. No evidence of publication bias was observed. Conclusions: In this meta-analysis, abiraterone was associated with an increased risk of cardiovascular events, while enzalutamide was associated with an increased risk of fatigue.

scholarly journals Poly(ADP-Ribose) Polymerase Inhibitors (PARPi) for Patients With Advanced Breast Cancer: a Meta-analysis of Randomized Controlled Trials

2020 ◽  
Author(s):  
YongCheng Su ◽  
XiaoGang Zheng
Keyword(s):  
Breast Cancer ◽  
Randomized Controlled Trials ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Parp Inhibitors ◽  
Cochrane Library ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
Increased Risk ◽  
Grade 3

Abstract BACKGROUND: Poly(ADP–ribose) polymerase (PARP) inhibitors are new class of drugs that are currently being studied in several malignancies. However, datas about the efficacy and safety of the PARP inhibitors are limited. Therefore, we conducted a meta-analysis of randomized controlled trials (RCT) in patients with breast cancer.METHODS: Pubmed/Medline, Embase, Cochrane Library, and abstracts presented at the annual meeting of the American Society of Clinical Oncology (ASCO) were searched for articles published from 2000 to June 2018.Summary incidences and the RR, HR with 95% confidence intervals, were calculated by using a random-effects or fixed-effects model.RESULTS: The summary HR indicated PARPi was not associated with OS (HR=0.83, 95%CI 0.66–1.06, Z=1.49, P=0.14), while it could significantly improve PFS ande time to deterioration (TTD) of global health status/quality of life(GHS/QoL) as compared with traditional standard therapy, the HR was 0.60(95%CI 0.50-0.72; Z=5.52, P＜0.00001) and 0.4 (95%CI 0.29–0.54,z=5.80 ,p=0.000),respectively.The RR of grade 3 or more anemia ,fatigue and headache was 3.02 (95% CI, 0.69–13.17;p = 0.14,,I2=90%),0.77 (95%CI, 0.34–1.73;p=0.52,I2=7%) and 1.13 (95% CI,0.30–4.18;p=0.86,I2=0%),respectively.CONCLUSION: The findings of this meta-analysis showed that PARPi has no significant effect on OS, while it could significantly improve in PFS and TTD of GHS/QoL for patients with advanced or metastatic breast cancer.Furthermore,our findings also demonstrated that the PARPi treatment is connected with an increased risk of grade 3 or more anemia adverse events.

scholarly journals Treatment of Advanced Gastro-Entero-Pancreatic Neuro-Endocrine Tumors: A Systematic Review and Network Meta-Analysis of Phase III Randomized Controlled Trials

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 358
Author(s):  
Claudio Ricci ◽  
Giuseppe Lamberti ◽  
Carlo Ingaldi ◽  
Cristina Mosconi ◽  
Nico Pagano ◽  
...  
Keyword(s):  
Systematic Review ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Neuroendocrine Neoplasms ◽  
Controlled Trials ◽  
Endocrine Tumors ◽  
Randomized Controlled ◽  
Grade 3

Several new therapies have been approved to treat advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP–NENs) in the last twenty years. In this systematic review and meta-analysis, we searched MEDLINE, ISI Web of Science, and Scopus phase III randomized controlled trials (RCTs) comparing two or more therapies for unresectable GEP–NENs. Network metanalysis was used to overcome the multiarm problem. For each arm, we described the surface under the cumulative ranking (SUCRA) curves. The primary endpoints were progression-free survival and grade 3–4 of toxicity. We included nine studies involving a total of 2362 patients and 5 intervention arms: SSA alone, two IFN-α plus SSA, two Everolimus alone, one Everolimus plus SSA, one Sunitinib alone, one 177Lu-Dotatate plus SSA, and one Bevacizumab plus SSA. 177Lu-Dotatate plus SSA had the highest probability (99.6%) of being associated with the longest PFS. This approach was followed by Sunitinib use (64.5%), IFN-α plus SSA one (53.0%), SSA alone (46.6%), Bevacizumab plus SSA one (45.0%), and Everolimus ± SSA one (33.6%). The placebo administration had the lowest probability of being associated with the longest PFS (7.6%). Placebo or Bevacizumab use had the highest probability of being the safest (73.7% and 76.7%), followed by SSA alone (65.0%), IFN-α plus SSA (52.4%), 177Lu-Dotatate plus SSA (49.4%), and Sunitinib alone (28.8%). The Everolimus-based approach had the lowest probability of being the safest (3.9%). The best approaches were SSA alone or combined with 177Lu-Dotatate.

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