Risk of Bleeding with Ibrutinib in Patients with B-Cell Malignancies: An Updated Meta-Analysis of Phase III Randomized Controlled Trials
Authors: Ball Somedeb , Maiti Abhishek , Arevalo Meily , Das Avash , Vutthikraivit Wasawat , Edwards Peggy J , Hardwicke Fred 
Published: October 2019

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.