ELEVATE-RR is a randomized trial comparing ibrutinib vs acalabrutinib in high-risk patients with relapsed CLL and a 17p deletion or an 11q deletion. The interim results were presented at the European Hematology Association (EHA) 2021 Virtual Congress. There was no difference between agents for progression-free survival (PFS); the curves were completely overlapping. In contrast, and probably not unexpectedly given the phase 2 data, the incidences of hypertension, atrial fibrillation, arthralgia, bleeding, and diarrhea were reduced with acalabrutinib compared with those seen with ibrutinib. Acalabrutinib was associated with more headache, which is a typical side effect that is specific to the treatment and is generally mild and transient, and often responds to caffeine; there was also a slightly higher incidence of cough with acalabrutinib. 

Regarding the findings of the ELEVATE-RR trial, I think that they could suggest that acalabrutinib might be the preferred drug. Now, would there be any caveats or reasons why this might not be the case? There could be, and 2 factors that come to mind are the twice-daily dosing schedule of acalabrutinib and the inability to administer it with proton pump inhibitors. The twice-daily schedule can potentially affect adherence, especially in older patients who may forget to take the second dose. Additionally, proton pump inhibitors are quite commonly used. Finally, ibrutinib has a longer track record as a single agent. 

The other head-to-head comparison presented at the recent EHA Congress was the ALPINE study, which compared zanubrutinib with ibrutinib. Currently, zanubrutinib has an indication for mantle cell lymphoma only. The ALPINE trial included all relapsing patients with CLL, not just those with high-risk CLL. Other caveats for this study include that it was an interim analysis and that response assessment was conducted by investigators rather than by independent review. The results showed a significantly higher objective response rate, longer PFS, similar overall survival, and significantly less atrial fibrillation with zanubrutinib vs that seen with ibrutinib; however, there was no difference in hypertension, interestingly. Rates of major bleeding and adverse events leading to discontinuation or death were also lower with zanubrutinib. Rates of neutropenia were higher with zanubrutinib, while grade 3 or higher infections were lower with zanubrutinib. 

Overall, I am more cautious with interpreting the efficacy data in the interim analysis of ALPINE than I am for ELEVATE-RR, a completed study that had PFS as the primary end point and used an independent review committee to assess responses.