Phosphatidylinositol 3-Kinase (PI3K) Inhibitors-Related Hematological Toxicities in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma
Authors: Grant Bradley J. , Sultan Anita , D'Cunha Nicholas , Graf Chandler , Swarup Sriman , Win Myint Aung , Phyu Ei Moe , Htut Thura Win , Han Myat Min , Myat Yin Mon , Adhikari Nimesh , Yu Nyein Htway , Quick Donald P. , Thein Kyaw Zin 
Published: November 2019

Introduction:
Chronic lymphocytic leukemia is the most prevalent adult leukemia in western countries. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for the B-cell receptor signaling pathway and has been shown to involve in the pathogenesis of chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/ SLL) by promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), have recently shown to improve survival in patients with relapsed and refractory CLL/ SLL. We undertook a systematic review and meta-analysis of phase 3 randomized controlled trials to determine the risk of hematological toxicities associated with PI3K inhibitors.
Methods:
We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel 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:
Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The RR of all-grade side effects were as follows: anemia, 1.39 (95% CI: 0.89 - 2.17; p = 0.15); neutropenia, 1.33 (95% CI: 1.06 - 1.67; p = 0.02); and thrombocytopenia, 1.23 (95% CI: 0.69 - 2.18; p = 0.48). The RR of high-grade adverse effects were as follows: anemia, 1.29 (95% CI: 0.62 - 2.67, p = 0.50); neutropenia, 1.51 (95% CI: 1.22 - 1.88; p = 0.0001); and thrombocytopenia, 1.21 (95% CI: 0.66 - 2.22; p = 0.53). The incidence of febrile neutropenia was 76 (11.69%) in study group vs 22 (3.92%) in control group with RR of 2.62 (95% CI: 1.27 -5.41, P = 0.009).
Conclusions:
PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), increased the risk of all grades of neutropenia and febrile neutropenia, with RR of 2.62 for febrile neutropenia, in patients with relapsed and refractory CLL/SLL. Vigilant monitoring is warranted, and proper supportive care and dose modifications should be followed.

Disclosures
No relevant conflicts of interest to declare.