Authored by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
At six years out, 74% of treatment-naïve (TN) CLL patients on Zanubrutinib had not progressed. For those with the high-risk del17p, 64% had not progressed.
Who Performed the Research and Where Was it Presented:
Dr. Constantine Tam from Monash University in Melbourne, Australia, and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
Zanubrutinib is the newest of the covalent BTK inhibitors. Not surprisingly, it had already proven superior to the chemoimmunotherapy combination, Bendamustine/Rituximab (BR) at 60 months. It is also the only covalently binding BTKi with proven superiority to ibrutinib demonstrated in the ALPINE trial, with improved progression progression-free survival (PFS). This abstract presents the maturing six-year data of zanubrutinib (arm A) versus BR (arm B). Arm C consisted of high-risk chronic lymphocytic leukemia (CLL) patients with del17p. This was the first treatment for all patients.
Methods and Participants:
TN CLL patients without del17p were randomized to receive continuous zanubrutinib (arm A) or 6 cycles of BR (arm B). Crossover from BR to zanubrutinib was allowed. Those with del17p (arm C) received continuous zanubrutinib, as it would have been unethical to treat with chemoimmunotherapy (CIT).
Results:
- In arms A and B, 479 patients received zanubrutinib (n=241) or BR (n=238).
- Zanubrutinib continued to demonstrate markedly superior PFS vs BR. Estimated 72- month PFS rates were 74% versus 32%, the best reported PFS at six years for any BTKi.
- Zanubrutinib treated patients required subsequent therapy less often (n=27) compared to BR-treated patients (n=84), including the 67 who crossed over to zanubrutinib after progressing on BR.
- Arm C included 111 patients (110 with confirmed del17p) who received zanubrutinib. The estimated PFS rate at 72 months was 64%.
- The risk of adverse events was similar to those lower risk patients on zanubrutinib.
Conclusions:
The big news is not that zanubrutinib reduces the risk of disease progression by an impressive 72% over the CIT, BR. Frankly, we have grown to expected that novel agents are superior to CIT. Today, any trial that uses BR as a comparator arm should be suspect. But this trial was initiated back in 2017 when the treatment landscape was still evolving. The other important takeaway is how well it works in frontline high-risk patients with del17p. Not that long ago, those with that poor prognostic marker who needed treatment were lucky to live for more than a year or two. The progress has been amazing. This trial has the largest cohort of TN patients with del17p with the most robust result.
In summary, it is encouraging to see such durable high levels of efficacy across all risk groups.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here for more details, including the risk of adverse events in all groups here: Sustained efficacy of zanubrutinib (zanu) vs bendamustine + rituximab (BR) in treatment (tx)-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN SLL/CLL) and continued favorable survival in non-randomized patients (pts) with del(17p): 6-year.
