Bruton’s tyrosine kinase (BTK) inhibitors have been very effective for treating chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). However, first-generation BTK inhibitors such as ibrutinib can potentially have undesirable cardiovascular side effects. Zanubrutinib is a next-generation BTK inhibitor currently approved for treating mantle cell lymphoma and is seeking approval for CLL / SLL. It is much more specific for BTK than ibrutinib, so researchers hope it will have fewer side effects.
At the annual meeting of the American Society of Hematology (ASH) 2020, our own Steven Bloom interviewed Dr. Jennifer Brown, Director of the CLL Center at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. They discussed the SEQUOIA trial, which is a phase 3 trial testing the efficacy of zanubrutinib in patients with CLL / SLL.
Takeaways:
- The SEQUOIA trial is a global phase 3, open-label, randomized study of zanubrutinib versus bendamustine plus rituximab in patients with previously untreated CLL / SLL with or without del(17p).
- The main goal of the SEQUOIA trial is to compare the efficacy of zanubrutinib versus bendamustine plus rituximab (Arms A and B).
- The SEQUOIA trial also has a nonrandomized Arm C, which assesses the efficacy of zanubrutinib in previously untreated patients with a deletion of the short arm of chromosome 17 [del(17p)].
- Patients with del(17p) are considered high-risk because they tend to be resistant to chemoimmunotherapies and experience worse outcomes.
- Arm C of the trial is currently at about two years of follow-up with a response rate of 95% and a progression-free survival rate of 90%.
- Thus far, there have not been any cases of cardiac toxicity, and the most common adverse events have been neutropenia (low white blood cell count) which is usually manageable, and infections which are common in CLL / SLL studies
- Researchers are trying to answer one of the remaining questions whether it’s best for patients (especially high-risk patients) to receive continuous therapy with a single agent or if combination therapy should be used to get them into a deep remission with undetectable measurable residual disease (uMRD).
- Arm D of the SEQUOIA study tests zanubrutinib plus venetoclax in patients with del(17p) or TP53 mutation to get them to uMRD. This arm is still open to enrollment, and more information can be found here.
- There might be different risks to using limited-duration treatments in patients with del(17p). Some data indicate that higher-risk patients may also have a higher risk of relapse if they stop therapy, so researchers are trying to explore whether continuous or time-limited treatments are better for high-risk patients.
Conclusions:
There is a lot of research going on right now on the use of next-generation targeted therapies and limited-duration combination therapies for the treatment of CLL / SLL. Thus far, the data from the SEQUOIA trial looks promising for zanubrutinib, but it is still early on. We look forward to continuing to learn more about what individual therapies are effective, what combination therapies are effective, how long they should be used, and how they might help high-risk patients.
Please enjoy this interview with Dr. Brown from the virtual ASH meeting held in December 2020.
You can read the actual ASH abstract here: Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Follow-up Results from Arm C of the SEQUOIA (BGB-3111-304) Trial
Take care of yourself first.
Ann Liu, PhD
