John F. Seymour, MBBS, PhD

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 and the Royal Melbourne Hospital in Victoria, Australia, discusses the results of a post-hoc analysis of adverse events (AEs) in the phase 3 ELEVATE-RR trial (NCT02477696) comparing acalabrutinib (Calquence) and ibrutinib (Imbruvica) in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL).

Seymour explains that the analysis accounted for the overall toxicity burden of each Bruton tyrosine kinase (BTK) inhibitor by examining exposure-adjusted incidence rates. The median treatment exposures were 38.3 months for patients who received acalabrutinib and 35.5 months for those who received ibrutinib.

For cardiovascular toxicities, the rate of AEs in the trial was 24% with acalabrutinib and 30% with ibrutinib, but the exposure-adjusted time of patients experiencing these events was 7.1 months per 100 patient-months with acalabrutinib versus 13.0 months with ibrutinib. Those with ibrutinib had an even higher exposure-adjusted time with atrial fibrillation and hypertension of 3.8 months and 15.0 months, respectively, versus 1.3 months and 4.1 months with acalabrutinib.

Several other AEs such as diarrhea, arthralgias, back pain, muscle spasm, and dyspepsia showed greater exposure-adjusted time with ibrutinib. While muscle spasms occurred about twice as frequently (13% with ibrutinib versus 6% with acalabrutinib), exposure-adjusted time was over 10 times as much: 10 months with ibrutinib versus only 0.8 months with acalabrutinib.

The only AEs where ibrutinib was better tolerated in the analysis were headache and cough; these were higher with acalabrutinib in both the initial incidence rate and the exposure-adjusted time.

 In general, the exposure-adjusted time with events for these cardiovascular toxicities were, on average, 2- to 4-fold higher with the ibrutinib than with acalabrutinib, particularly for hypertension and atrial fibrillation. And this was regardless of the age of the patient or the number of prior therapies, as well as in patients without a prior history of these events.

 Some of the other generally lower-grade AEs such as diarrhea, arthralgias, back pain, muscle spasm, dyspepsia, for example, were 1.4- to 13-fold higher in their exposure-adjusted incidence in exposure-adjusted time with these events with ibrutinib compared [with] acalabrutinib, and I think the muscle [spasm] is probably the one that best illustrates the utility of this method of analysis. The overall incidence was 6% versus 13%, the higher rate with ibrutinib. That is moderately different. Yet, if we factor in the time with these events, that was actually 0.8 with ibrutinib per 100 patient months of treatment. An average of an expectation of less than 1 per 100 months of treatment versus 10.0 with ibrutinib, we have roughly 10% of the time that typical patient would be expected to have some of that toxicity. So that illustrates the greater precision that we get by factoring in this exposure adjustment.

 There were 2 toxicities with this adjustment that were more frequent, and with a greater time with acalabrutinib. They were headache and cough that had a 1.1- to 1.6-fold higher exposure-adjusted incidence then with ibrutinib.

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

Acalabrutinib Shows Better Exposure-Adjusted Tolerability in R/R CLL

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.

 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.

 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.

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.

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

John F. Seymour, MBBS, PhD, clinical hematologist, associate director of Clinical Research, Peter MacCallum Cancer Centre, director of the integrated Haematology Department of the Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, discusses some emerging themes in research for targeted therapies as a treatment for patients with chronic lymphocytic leukemia (CLL).

Targeted agents are here to stay, says Seymour. These agents are more effective, safer, and are less genotoxic than treatment with chemoimmunotherapy.

John F. Seymour, MBBS, PhD, discusses some emerging themes from recent research for targeted therapies as treatment of patients with chronic lymphocytic leukemia.

John F. Seymour, MBBS, PhD | Authors

Articles

Acalabrutinib Shows Better Exposure-Adjusted Tolerability in R/R CLL

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

Emerging Themes in Targeted Therapy Research for CLL