Single-agent ibrutinib in RESONATE-2™ and RESONATE™ versus treatments in the real-world PHEDRA databases for patients with chronic lymphocytic leukemia

Abstract

After analyzing treatment patterns in chronic lymphocytic leukemia (CLL) (objective 1), we investigated the relative effectiveness of ibrutinib versus other commonly used treatments (objective 2) in patients with treatment-naïve and relapsed/refractory CLL, comparing patient-level data from two randomized registration trials with two real-world databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using a multivariate Cox proportional hazards model, adjusted for differences in baseline characteristics. Rituximab-containing regimens were often prescribed in clinical practice. The most frequently prescribed regimens were fludarabine + cyclophosphamide + rituximab (FCR, 29.3%), bendamustine + rituximab (BR, 17.7%), and other rituximab-containing regimens (22.0%) in the treatment-naïve setting (n = 604), other non-FCR/BR rituximab-containing regimens (38.7%) and non-rituximab–containing regimens (28.5%) in the relapsed/refractory setting (n = 945). Adjusted HRs (95% CI) for progression-free survival (PFS) and overall survival (OS), respectively, with ibrutinib versus real-world regimens were 0.23 (0.14–0.37; p < 0.0001) and 0.40 (0.22–0.76; p = 0.0048) in the treatment-naïve setting, and 0.21 (0.16–0.27; p < 0.0001) and 0.29 (0.21–0.41; p < 0.0001) in the relapsed/refractory setting. When comparing real-world use of ibrutinib (n = 53) versus other real-world regimens in relapsed/refractory CLL (objective 3), adjusted HRs (95% CI) were 0.37 (0.22–0.63; p = 0.0003) for PFS and 0.53 (0.27–1.03; p < 0.0624) for OS. This adjusted analysis, based on nonrandomized patient data, suggests ibrutinib to be more effective than other commonly used regimens for CLL.

Real-World Characteristics and Outcome of Patients Treated With Single-Agent Ibrutinib for Chronic Lymphocytic Leukemia in Spain (IBRORS-LLC Study)

“…The benefit demonstrated with ibrutinib in clinical trials has also been observed in the real-world setting [20][21][22][23][24][25][26][27][28][29][30][31] . However, most real-world evidence came from studies in R/R CLL 20, 25-27, 30, 31 , including reports where ibrutinib was used in compassionate use programs 24,27,30,31 and from single-site experience 22,26 .…”

Screening and monitoring of the BTKC481S mutation in a real‐world cohort of patients with relapsed/refractory chronic lymphocytic leukaemia during ibrutinib therapy

“…[2][3][4] Clinical management of patients with R/R CLL or with treatment-naive CLL harbouring high-risk genetic features has been revolutionized by the irreversible Bruton's tyrosine kinase (BTK) inhibitor ibrutinib which confers remarkable response rates both in first-line and in previously treated patient cohorts. [5][6][7][8][9] Although clinical trials and the analyses of real-world patient cohorts have shown a survival advantage with ibrutinib over standard therapies, 6,7,[10][11][12][13] durable remission is eventually followed by either Richter's transformation or progressive CLL in a subset of the patients. While Richter's transformation tends to occur during the first or second year of ibrutinib treatment and its cumulative incidence shows a plateau after the third year, CLL progression emerges later, typically after a 12-15-month period of BTK inhibition with events regularly occurring during the third, fourth and fifth years after therapy initiation.…”

Approaches to Selecting “Time Zero” in External Control Arms with Multiple Potential Entry Points: A Simulation Study of 8 Approaches

“…This approach was discussed at length by Backenroth 22 with published examples also available. 23,24 Rebalancing the external control arm to minimize the mean absolute error in the number of prior lines of therapy between data sets. This is a modification of the random line approach, whereby 1 line is selected per patient but with the objective of minimizing the difference in the number of prior lines between the external control and intervention data sets.…”

“…This approach was discussed at length by Backenroth 22 with published examples also available. 23,24…”