Efficacy of Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Combined Analysis of Three Phase III Randomized Controlled Trials

Introduction:

The B-cell receptor signaling pathway involves in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL), the most common adult lymphoproliferative disorder in western countries. Ibrutinib, a novel Bruton's tyrosine kinase (BTK) inhibitor, has shown great efficacy in the treatment of hematological malignancies via inhibition of BTK, a kinase involved in cellular signaling downstream of the B-cell receptor. However, treatment becomes more challenging upon progression after initial treatment. We performed a combined analysis of currently available randomized controlled trials (RCTs) to evaluate the efficacy of ibrutinib in relapsed or refractory CLL/SLL.

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 previously treated, relapsed or 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:

Three phase III RCTs (HELIOS, RESONATE and Huang et al. studies) with a total of 1,129 patients with relapsed or refractory CLL/SLL were eligible. Studies compared ibrutinib vs ofatumumab, ibrutinib vs rituximab, and ibrutinib+ bendamustine+ rituximab vs bendamustine+ rituximab were included in the analysis. The randomization ratio was 2:1 in Huang et al. study and 1:1 in other studies. The I² statistic for heterogeneity was 49, suggesting some heterogeneity among RCT. The pooled HR for PFS was statistically significant at 0.17 (95% CI: 0.12-0.22; P < 0.0001). The PFS benefit was observed in all Rai stages, either del11q or del17p status and bulky disease (≥ 5cm); Rai stage ≤ 2 cohort (HR, 0.14; 95% CI: 0.09- 0.22; P < 0.0001), Rai stage >2 cohort (HR, 0.26; 95% CI: 0.19- 0.36; P < 0.0001), del11q group (HR, 0.10; 95% CI: 0.06- 0.17; P < 0.0001), del17p group (HR, 0.24; 95% CI: 0.14- 0.39; P < 0.0001), and bulky disease cohort (HR, 0.19; 95% CI: 0.15- 0.25; P < 0.0001).

Conclusions:

Our study depicted that ibrutinib maintains activity in previously treated, relapsed or refractory CLL/SLL, across all Rai stages, in bulky disease and in del11q or del17p. Thus, the use of ibrutinib is likely beneficial to patients with relapsed or refractory CLL/SLL, regardless of disease stage, bulkiness or del11q/del 17p status.