The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and BCL2 inhibitor venetoclax have been very successful as individual therapies for treating chronic lymphocytic leukemia (CLL), but on their own they rarely lead to the eradication of measurable (a.k.a. minimal) residual disease (MRD). Researchers have been very interested in whether they can combine these therapies to improve outcomes for patients and achieve better remissions. They also want to determine how long would patients need to take the combination for to achieve deep remissions.
At the annual meeting of the American Society of Hematology (ASH) 2020, Dr. John Pagel of the CLL Society Board of Directors interviewed Dr. Peter Hillmen, Professor of Experimental Hematology at the University of Leeds in the United Kingdom. They discussed updates to the phase II CLARITY trial which has been evaluating the efficacy of combination ibrutinib + venetoclax in patients with relapsed/refractory CLL.
Takeaways:
- The CLARITY trial is a phase II study testing the combination of ibrutinib + venetoclax in patients with relapsed/refractory CLL. The primary endpoint the researchers were evaluating was undetectable measurable residual disease (uMRD) after one year, and those results have been published here.
- Almost all patients (89%) responded to treatment.
- Responses continued to improve after the first year of combination treatment with 24/50 (48%) patients achieving uMRD in the bone marrow at month 26 compared to 20/50 (40%) at month 14.
- After 3 years, responses to ibrutinib + venetoclax were sustained even though many patients had discontinued treatment due to achieving uMRD.
- Patients who had not yet achieved uMRD by year 2 were allowed to extend combination treatment duration for and additional year.
- While there was some benefit in year 3, most of the benefit occurs earlier on. This suggests that patients who respond probably only need a limited duration of therapy, and more is not necessarily better.
- The response to treatment in the first 2-3 months seems to predict who will achieve uMRD. Thus, clinicians might want to alter the treatment plan if a patient doesn’t respond to ibrutinib + venetoclax early on.
Conclusions:
These results show that combination therapy with ibrutinib + venetoclax can produce deep remissions with eradication of MRD in many but not all patients with difficult to treat relapsed/refractory CLL. Thus far, these responses seem to be sustained even with planned treatment discontinuation once uMRD is achieved, and researchers continue to follow these patients.
The logical extension of this research is to see if ibrutinib + venetoclax can be used as a first line treatment. We know that the best responses are with first line treatment, and some phase II trials of ibrutinib + venetoclax as a first line treatment for CLL have shown promising results. However, phase II trials usually do not have a comparator group so the results can’t be directly compared to other treatments. To address this gap in knowledge, a large clinical trial is currently underway to test ibrutinib + venetoclax as a first line therapy vs. ibrutinib alone or FCR chemoimmunotherapy.
Please enjoy this brief interview with Dr. Hillmen from the virtual ASH meeting which was held December 2020.
You can read the actual abstract here: Continued Long Term Responses to Ibrutinib + Venetoclax Treatment for Relapsed/Refractory CLL in the Blood Cancer UK TAP Clarity Trial
Take care of yourself first.
Ann Liu, PhD
