Authored by Brian Koffman, MDCM )retired), MSEd
Bottom Line:
Zanubrutinib, a newer BTK inhibitor (BTKi), showed 60-month progression-free survival (PFS) in frontline high-risk CLL / SLL patients with del(17p) of >72%. This was only slightly less than the 76% PFS seen in lower-risk chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) without del(17p), proving that in the modern era of targeted therapies, what used to be poor prognostic markers are much less significant.
Who Performed the Research and Where Was it Presented:
Dr. Constantine Tam from Alfred Hospital and Monash University, Melbourne, VIC, Australia, and his international colleagues presented the results of one cohort of the SEQUIOA trial at the American Society of Clinical Oncology (ASCO) Annual Meeting 2025.
Background:
Zanubrutinib is a next-generation BTKi that is approved for CLL / SLL and several other blood cancer indications. Not surprisingly, initial results in the SEQUOIA trial demonstrated superior PFS at 26.2 months in treatment-naive (TN) CLL / SLL patients without del(17p) compared to those who received bendamustine + rituximab (BR). Later, we also learned that after five years of follow-up, a clear PFS benefit persisted with estimated 60-month PFS rates of 76%. This ASCO abstract updates the results of the CLL / SLL cohort of patients with del(17p) after approximately five years of follow-up.
Methods
This arm of the trial was non-randomized as it would have been unethical to treat patients with del(17p) with BR. It would not be effective. All the TN SEQUOIA patients with del(17p) received zanubrutinib as monotherapy. The study assessed:
- PFS
- Overall Survival (OS)
- Overall Response Rate (ORR)
- Safety and tolerability
- Adverse events (AEs)
Results:
- Patient Characteristics:
- Between February 2018 and March 2019, 111 TN patients with del(17p) were enrolled.
- The average age was 71 years old.
- 79 (71%) were male, 67 (60%) were IGHV unmutated, and 47 (42%) had both del(17p) and TP53 mutation.
- Responses:
- At a median follow-up of 5.5 years, the median PFS was not reached. The estimated 60-month PFS rate was 72.2%.
- Median OS was also not reached.
- The estimated 60-month OS rate was 85.1% or 87.0% (79.0%-92.1%) when adjusted for COVID-19.
- The ORR was 97.3%.
- The complete response (CR) was low at 18.2%, as expected with any BTKi.
- More than six of ten patients were still on treatment at five years
- The most common causes for treatment discontinuation were AEs and progressive disease in 17.1% and 15.3%, respectively
- Key AEs of interest (AEI) included:
- any-grade infection (82%)
- bleeding (60%)
- neutropenia or a low count of neutrophils, a type of white blood cell (19%)
- hypertension (18%)
- anemia (9%)
- thrombocytopenia or low platelet count (8%)
- atrial fibrillation/flutter, which are types of irregular heart rhythms (7%)
- Grade ≥3 or more serious AEI included
- infection (33%),
- neutropenia (16%)
- hypertension (8%)
- bleeding (6%)
- atrial fibrillation/flutter (5%)
- thrombocytopenia (2%)
Conclusions:
It is reassuring that no new safety signals appeared after more than five years of zanubrutinib. Over 62% of “high-risk” patients with del(17p) remained on zanubrutinib monotherapy. With 72.2% showing no signs of progression after five years, the definition of who is “high risk” or has a poor prognosis needs to be reassessed in the era of potent targeted therapies. A well-tolerated, effective BTKi such as zanubrutinib has rewritten the expectations for all CLL / SLL, but especially for those with del(17p) who were left behind in the era of chemoimmunotherapy (CIT). Sadly, too many patients are still receiving inferior CIT. We have better treatments. We must work to ensure all patients are offered their best options.
Links and Resources:
You can read the actual ASCO 2025 abstract here: SEQUOIA 5-year follow-up in arm C: Frontline zanubrutinib monotherapy in patients with del(17p) and treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL / SLL).
