In the second article of a 2-part series, William G. Wierda, MD, PhD, looks at the efficacy and safety outcomes with the second generation BTK inhibitor zanubrutinib for patients with relapsed/refractory chronic lymphocytic leukemia.
History and Presentation:
A 70-year-old White man with asymptomatic lymphocytosis identified 4 years previously
6 Months Later
Due to progression of disease after BCL2 inhibitor, the decision was made to initiate therapy with a Bruton tyrosine kinase (BTK) inhibitor.
Targeted Oncology: What was the efficacy outcomes with zanubrutinib (Brukinsa) on the ALPINE trial (NCT03734016)?
WILLIAM G. WIERDA, MD, PhD: There was a significant difference in progression-free survival (PFS) with the follow-up that they had on this trial favoring patients with chronic lymphocytic leukemia [CLL] who had had treatment with zanubrutinib.1 [In the zanubrutinib arm], 78.4% had a PFS at 2 years vs 66.0% [in the ibrutinib (Imbruvica) arm], with the end result of treatment at 2 years. Now….this trial’s follow-up, on a scale of things, for BTK inhibitor maintenance-type treatment is a relatively short follow-up [at 29.6 months].1
Comparatively, you'll see that the follow up [for the ELEVATE-RR (NCT02477696) trial] as a longer follow-up at 40.9 months.2 If you look at the patients with 17p deletion [del(17p)], TP53 mutation, or both, you'll see a similar pattern of improved PFS for patients who have received the zanubrutinib, [at 72.6% vs 54.6% on ibrutinib (HR, 0.53; 95% CI, 0.31-0.88)].1 Most of these patients get partial response [with treatment] at 76%...and 7% had a complete remission with zanubrutinib vs 4.9%.1
What was notable about the safety profile of this therapy for patients with CLL?
I think the one feature to highlight is the safety profile and the difference in events that we've seen between zanubrutinib and ibrutinib…. [Compared with zanubrutinib], ibrutinib was associated with higher incidences of some of the more serious and concerning adverse events [AEs] that we see, particularly, atrial fibrillation [at 1.9% vs 3.7%, respectively]. Serious AEs were seen in 42% with zanubrutinib over 50% with ibrutinib.1
What are some of the AEs to watch out for on this therapy?
In these patients [with relapsed CLL], we see a reasonable frequency of cytopenias, anemia, neutropenia, etc, which is somewhat expected. There has been some discussion about the neutropenia associated with zanubrutinib groups, and [in this trial] it's a little bit higher than it was for ibrutinib at grade 3 or greater, [with 16.0% vs 13.9%, respectively].1 The cumulative incidence [of cardiac disorders and atrial fibrillation or flutter] were greater for both cardiac disorders and atrial fibrillation for the patients who received ibrutinib vs zanubrutinib. [Further], the cumulative risk long-term [of these cardiac disorders] runs around 10% to 15%.1
1. Brown JR, Eichhorst B, Hilmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388:319-332. doi:10.1056/NEJMoa2211582
2. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210