Callie Coombs, MD, discusses recent changes you have seen in the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and small lymphocytic lymphoma (SLL) and provides an overview of the Bruton tyrosine kinase inhibitor landscape for CLL, MCL, and SLL.
Ryan Haumschild, PharmD, MS, MBA: Dr Coombs, can you provide an overview of the Bruton tyrosine kinase inhibitor [BTK] landscape for CLL [chronic lymphocytic leukemia], MCL [mantle cell lymphoma], and SLL [small lymphocytic lymphoma]? What agents are available, and what’s their place in therapy? Specifically highlight acalabrutinib, ibrutinib, and zanubrutinib.
Callie Coombs, MD: For mantle cell lymphoma, there are 3 FDA-approved BTK inhibitors that are all covalent inhibitors: ibrutinib, acalabrutinib, and zanubrutinib. These are usually used in the second-line setting or later, though they’re being studied in earlier lines of therapy. As of ASH [American Society of Hematology Annual Meeting], ibrutinib and acalabrutinib were FDA approved in CLL and SLL. Zanubrutinib is anticipated to be approved in early 2023.
The zanubrutinib data are very exciting because there was a head-to-head trial called the ALPINE trial. We got an early look at these data at EHA [the European Hematology Association Congress] in 2021 and then an updated look at ASH, where we had prolonged follow-up. We see that zanubrutinib was superior with respect to progression-free survival compared with ibrutinib in a relapsed/refractory population. We also got a very nice look at the head-to-head toxicity between zanubrutinib and ibrutinib. Zanubrutinib has significantly lower rates of atrial fibrillation compared with ibrutinib. It has similar rates of hypertension, but otherwise it appears to be a well-tolerated drug with lower rates of discontinuation due to intolerance compared with ibrutinib.
Speaking a bit more about acalabrutinib, we have excellent data comparing it with ibrutinib in the ELEVATE-RR trial. This was a head-to-head study comparing acalabrutinib with ibrutinib. A difference I like to point out is that the zanubrutinib ALPINE trial enrolled all comers in the relapsed/refractory setting. The ELEVATE-RR trial focused on patients with high-risk cytogenetics, including 17p deletion and deletion 11q, which isn’t so high-risk in the modern BTKi era. Nonetheless, in that study it was shown to be noninferior with respect to efficacy, compared with ibrutinib, where both drugs had an identical median progression-free survival of 38.4 months and a hazard ratio of 1.0.
We got a great look at head-to-head toxicity. Once again, we saw lower rates of atrial fibrillation and flutter with the acalabrutinib-treated patients compared with the ibrutinib-treated patients—16% vs 9% for ibrutinib and acalabrutinib, respectively. Another advantage of acalabrutinib is that it leads to lower rates of hypertension compared with ibrutinib. Both of these newer-generation drugs are better tolerable with respect to some of the more nagging—although less dangerous—adverse effects, with the most prominent being myalgias and arthralgias.
Transcript edited for clarity.