Incidence of High-Grade Hematologic Toxicities and Hypertension in Patients with Hematological Malignancies Treated with Ibrutinib
Authors: Graf Chandler , Sultan Anita , Quick Donald P. , Grant Bradley J. , Swarup Sriman , Htut Thura Win , Hlaing Pwint Phyu , Han Myat Min , Myat Yin Mon , Hardwicke Fred , Awasthi Sanjay , D'Cunha Nicholas , Tijani Lukman , Thein Kyaw Zin 
Published: November 2019

Introduction:
Ibrutinib, a Bruton's tyrosine kinase inhibitor, has been approved for the treatment of many hematological malignancies including but not limited to, chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma, and marginal zone lymphoma. Despite the efficacy of this drug in the treatment of hematologic diseases, multiple adverse effects have been well reported. This study seeks to present a combined analysis of currently available randomized controlled trials (RCTs) on the incidence of high-grade hematological toxicities and hypertension, in patients being treated with ibrutinib for hematological malignancies.
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 high-grade hematological toxicities and hypertension were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) 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 RR of high-grade hematologic side effects were as follows: anemia, 0.60 (95% CI: 0.36 - 1.02; p = 0.06); neutropenia, 0.76 (95% CI: 0.55 - 1.05; p = 0.10); thrombocytopenia, 0.69 (95% CI: 0.35 - 1.37; p = 0.29); and febrile neutropenia, 0.65 (95% CI: 0.30 - 1.42; p = 0.29). The incidence of high-grade hypertension (HTN) was 187 (8.59%) in study group vs 40 (2.29%) in control group with RR of 2.51 (95% CI: 1.64 -3.85; P < 0.0001). In a subset of patients with CLL/SLL treated with ibrutinib (n= 2658), the RR of high-grade hematologic side effects were as follows: anemia, 0.51 (95% CI: 0.35 - 0.74; p = 0.0005); neutropenia, 0.73 (95% CI: 0.52 - 1.01; p = 0.06); thrombocytopenia, 0.72 (95% CI: 0.38 - 1.39; p = 0.33); and febrile neutropenia, 0.54 (95% CI: 0.22 - 1.37; p = 0.20). High-grade HTN rate was 8.11% higher in ibrutinib group compared to control arm (RR, 2.49; 95% CI: 1.47 - 4.22; P = 0.0007).
Conclusions:
This literature review determined that ibrutinib's efficacy must be carefully balanced against the mentioned side effects on a case by case basis. Of special consideration is the rate of HTN in the Ibrutinib group compared to the control. These findings need to be further explored to determine the efficacy of Ibrutinib in specific patient populations with varying underlying diseases.

Disclosures
No relevant conflicts of interest to declare.