Updated Meta-Analysis to Evaluate the Incidence of Atrial Fibrillation and Major Bleeding in Patients with Hematologic Malignancies Treated with Ibrutinib
Authors: Swarup Sriman , Sultan Anita , Tijani Lukman , Htut Thura Win , D'Cunha Nicholas , Wongsaengsak Sariya , Quick Donald P. , Htwe Khaing Khaing , Hlaing Pwint Phyu , Han Myat Min , Myat Yin Mon , Dash Akshar , Hardwicke Fred , Thein Kyaw Zin 
Published: November 2019

Introduction:
Bruton's tyrosine kinase (BTK) is a kinase involved in cellular signaling downstream of the B cell receptor and is involved in B-cell survival and proliferation. Hence, BTK inhibitors have become an attractive therapeutic target for a multitude of B cell malignancies, mainly chronic lymphocytic leukemia. Ibrutinib is an oral potent covalent inhibitor of BTK and hence employed in many hematologic malignancies for BTK inhibition. Yet, the risk of atrial fibrillation and major bleeding remains considerable. We undertook an updated analysis of phase III trials to assess the incidence of atrial fibrillation and major bleeding associated with ibrutinib in this susceptible population.
Methods:
We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with hematologic malignancies that mention atrial fibrillation and major bleeding were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied.
Results:
A total of 3,920 patients with CLL/SLL, mantle-cell lymphoma, Waldenstrom's macroglobulinemia and diffuse large b-cell lymphoma, from 10 phase III RCTs were eligible. Studies compared ibrutinib+ obinutuzumab vs chlorambucil+ obinutuzumab, ibrutinib vs chlorambucil, bendamustine+ rituximab vs ibrutinib vs ibrutinib+ rituximab, ibrutinib+ rituximab vs fludarabine+ cyclophosphamide+ rituximab, ibrutinib vs rituximab, ibrutinib vs ofatumumab, ibrutinib+ bendamustine+ rituximab vs bendamustine+ rituximab, ibrutinib vs temsirolimus, ibrutinib+ rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone vs rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone were included in the analysis. The randomization ratio was 2:1 in E1912 study and Huang et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 32, suggesting some heterogeneity among RCT. The atrial fibrillation incidence was 142 (6.52%) in study group vs 17 (0.97%) in control group. The RR for atrial fibrillation was 5.37 (95% CI: 2.74 - 10.54; P < 0.0001) and RD was 0.06 (95% CI: 0.04 to 0.08; P = < 0.0001). Major bleeding was reported in 50 (2.29%) in ibrutinib arm vs 21 (1.20%) in control arm with the RR of 1.73 (95% CI: 1.03 -2.91; P = 0.04). In a subset of patients with CLL/SLL treated with ibrutinib (n= 2658), atrial fibrillation rate was 6.29% higher in study group compared to control arm (RR, 6.14; 95% CI: 2.49 - 15.14; P < 0.0001) and major bleeding rate was 1.32% higher in ibrutinib arm (RR, 2.16; 95% CI: 1.02 - 4.55; P = 0.04).
Conclusions:
Our study again demonstrated that ibrutinib increases the risk of atrial fibrillation in patients with hematologic malignancies, significantly with a RR of 5.37. Ibrutinib also contributed to higher risk of major bleeding by 1.73. These results are concordant with our previous findings on ibrutinib and remain persistent. Hence, caution is advised with the use of ibrutinib amongst patients who are predisposed to these conditions.

Disclosures
No relevant conflicts of interest to declare.