Efficacy of Phosphatidylinositol 3-Kinase (PI3K) Inhibitors in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

Introduction:

Chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL) is the most common adult lymphoproliferative disorder in western countries and the B-cell receptor signaling pathway has been shown to be involved in the pathogenesis of CLL/ SLL. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein in downstream signaling for multiple pathways in B cells, promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), are currently being studied in the treatment of relapsed and refractory CLL/ SLL. The purpose of our study is to explore and consolidate the efficacy of PI3K inhibitors in patients with relapsed and refractory CLL/SLL.

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 were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) 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 eligible for analysis. 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 the study by Jones et al. and 1:1 in other studies. The I2 statistic for heterogeneity was 82%, suggesting moderate heterogeneity among RCTs. The overall pooled HR for PFS was statistically significant at 0.30 (95% CI: 0.20- 0.47; P < 0.0001). The PFS benefit was observed across all ages and regardless of del 17p or TP53 status; age <65 (HR, 0.35; 95% CI: 0.27- 0.46; P < 0.0001), age ≥65 (HR, 0.32; 95% CI: 0.19- 0.54; P < 0.0001), either del 17p or TP53 cohort (HR, 0.33; 95% CI: 0.21- 0.52; P < 0.0001), and neither del 17p nor TP53 cohort (HR, 0.32; 95% CI: 0.19- 0.54; P < 0.0001). In the subset of patients with CLL treated with idelalisib, the pooled HR for PFS was statistically significant at 0.26 (95% CI: 0.18-0.37; P < 0.0001) and the PFS benefit was observed across all ages, and regardless of del17p or TP53 status and IGHV mutation status; age <65 (HR, 0.32; 95% CI: 0.24- 0.43; P < 0.0001), age ≥65 (HR, 0.26; 95% CI: 0.14- 0.47; P < 0.0001), either del17p or TP53 cohort (HR, 0.29; 95% CI: 0.15- 0.57; P = 0.0003), neither del17p nor TP53 cohort (HR, 0.26; 95% CI: 0.20- 0.35; P < 0.0001), IGHV mutated cohort (HR, 0.29; 95% CI: 0.17- 0.51; P < 0.0001), and IGHV unmutated cohort (HR, 0.25; 95% CI: 0.15- 0.40; P < 0.0001).

Conclusions:

Our study showed that PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), significantly improved PFS in patients with relapsed and refractory CLL/ SLL regardless of age and poor prognostic features such as del17p or TP53 and IGHV unmutated status, compared to control arm. The efficacy of these drugs must be balanced against the possible side effects.