Rationale for In-Depth Analysis of BTK Inhibitor Tolerability in CLL

John F. Seymour, MBBS, PhD, discusses the rationale for a post-hoc analysis of the phase 3 ELEVATE-RR trial comparing acalabrutinib and ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia.

John F. Seymour, M​BBS, PhD, director of the integrated hematology department, clinical hematologist, and associate director of clinical research at Peter MacCallum Cancer Centre in Victoria, Australia, discusses the rationale for a post-hoc analysis of the phase 3 ELEVATE-RR trial (NCT02477696) comparing acalabrutinib (Calquence) and ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL).

ELEVATE-RR was a randomized noninferiority study comparing the 2 Bruton tyrosine kinase (BTK) inhibitors in patients with R/R CLL with a 17p or 11q deletion. Acalabrutinib demonstrated noninferior progression-free survival (PFS) with a median PFS of 38.4 months in both arms.

According to Seymour, the post-hoc analysis explored the duration and intensity of adverse events (AEs) related to acalabrutinib and ibrutinib to understand the overall toxicity beyond the incidence rates reported from the trial.

In particular, the goal was to examine low-grade muscular, skeletal, and cardiovascular AEs that could impact quality of life (QOL). Both BTK inhibitors are chronic therapies that do not have a fixed duration. The AEs investigated in the study included hypertension, atrial fibrillation, arthralgias, back pain, and muscle spasms; adjusting incidence rate for duration and intensity provided more in-depth data on the QOL impact of these AEs.


0:08 | The rationale for looking in greater depth around toxicity was that we performed the ELEVATE-RR study. So this was a randomized noninferiority study, comparing acalabrutinib to ibrutinib both orally continuously, in patients with R/R CLL and the molecular features of deletion of 17p or 11q. The primary end point of this study was noninferiority by assessing PFS, and that was met, so the treatments were felt to be equivalent in efficacy, with a median PFS of 38.4 months in each arm.

0:59 | So given that equivalence of disease control, an important focus was on patient tolerance and AEs. The original publication reported crude incidence rates. But we know with these long-term chronic therapies that both the duration and intensity of these AEs, and particularly some of the lower-grade, muscular, skeletal, and cardiovascular events, have significant impacts on patient QOL and tolerance. So we wanted to look in some greater detail to try and better describe the overall toxicity burden of these 2 similarly effective treatments in patients with relapsed CLL.