Authored by Brian Koffman, MDCM (retired), MSEd
Bottom Line:
In frontline CLL patients, taking sonrotoclax 320 mg plus zanubrutinib led to undetectable measurable disease (uMRD) in 92% at 48 weeks and 98% at 96 weeks.
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:
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL / SLL) treatment has been shifting toward limited-duration therapies with medications that work orthogonally. What that refers to is the use of two medicines that control the cancer in different, independent ways that don’t overlap and instead complement each other. Instead of attacking the cancer from the “same angle” twice, it’s hit from two “separate directions” at once. This approach has revolutionized care for many types of cancer. And now for CLL, we have all oral novel therapies that work orthogonally. The combination of ibrutinib and venetoclax, while commonly used in Europe and other countries around the world, is not approved in the USA due to its side effects. The recently FDA-approved combination of acalabrutinib and venetoclax, based on the AMPLIFY trial, showed improved tolerance, but the rates of undetectable measurable disease (uMRD) were < 50%. Achieving uMRD has proven to be predictive of a prolonged remission after stopping treatment.
This trial uses sonrotoclax, a more potent BCL2i compared to venetoclax, in combination with zanubrutinib to see if this doublet can achieve deeper remission with lower toxicities in treatment naïve (TN) CLL / SLL.
Methods and Participants:
137 patients with TN CLL / SLL were enrolled in the sonrotoclax 160 mg (n=51) and 320 mg (n=86) cohorts. 14% had del17p.
Zanubrutinib was first dosed for 8-12 weeks to lower the tumor burden and reduce the risk of tumor lysis syndrome (TLS). Then sonrotoclax (160 or 320 mg QD) was added with a slow ramp-up to the target dose. Patients were treated until progression, toxicity, or 96 weeks of combination study treatment at the target dose (24 cycles).
Results:
- The average age was 62 years, 72% were male, and 91% were White.
- 29% of tested patients, 61% (80/132) had unmutated IGHV, and 14% (18/128) had T P 5 3 mutation or del(17p).
- 100% of the patients responded.
- In those on 320 mg of sonrotoclax, the median time to uMRD was less than three months of combination treatment.
- uMRD-4 (undetectable measurable residual disease at one in 10,000 or 1 x 10-4 cells) rates by week were 48 and 96, which were 92% and 98%, respectively.
- One patient progressed with Richter transformation, not CLL.
- The most common adverse events (AEs)were:
- Low neutrophil count or neutropenia (42%),
- COVID-19 (39%),
- contusion (39%),
- diarrhea (30%).
- Perhaps because of the slow ramp-up, despite the increased potency of sonrrotoclax, there were no tumor lysis syndrome (TLS) and no fatal AEs.
Conclusion:
The experimental BCL2 inhibitor sonrotoclax, and the approved BTKi Zanubrutinib, made for a well-tolerated all oral combination with a quick response in 19 out of 20 patients uMRD-4 by two years on the higher dose of sonrotoclax. The progress in CLL / SLL therapy with new drugs and new combinations is becoming available. One can hope that a time is coming soon when nearly all patients can look forward to a normal life expectancy.
Links and Resources:
Watch the interview on the abstract here:
If you are interested in more details, you can read the actual ASH abstract here: Frontline treatment of sonrotoclax (BGB-11417) and zanubrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL / SLL) demonstrates high undetectable minimal residual disease (uMRD) rates with favorable tolerability: Updated data from BGB-1
