In my interview with Dr. Peter Hillmen of Leeds, UK at EHA, the European Hematology Association Annual Congress, held in 2019 in Amsterdam, the professor discusses the results of the CLL14 trial using frontline venetoclax (V), a potent BCL-2 blocker that induces CLL cell to “commit suicide”, and obinutuzumab (O), a potent monoclonal antibody that targets CD20, a surface marker on CLL cells and normal B cells, similar to rituximab and ofatumumab.
The CLL14 study was designed by the German CLL study group for “unfit” patients who had one or more complicating illnesses or decreased kidney function.
- The combination of V+O offers an attractive non-chemo fixed duration new approach compared to:
- Fixed duration chemo-immunotherapy such as FCR or BR.
- Ibrutinib taken indefinitely until intolerant or disease progression.
- V+O as a 1 year of therapy, then stopping, offers several advantages:
- Patients are less likely to develop resistance as the drug exposure is limited.
- The cost will be less.
- Patients keep open the option to be re-challenged with the same combination if the CLL comes back.
- Responses with V+O were impressive with some 50% of patients reaching undetectable minimal residual disease (U-MRD) with a strong match between U-MRD in the blood and the marrow, perhaps meaning less need for bone marrow biopsies in both clinic and in trials.
- Those who reached U-MRD tended to have much more durable remissions.
- There were no new side effects using the combination, but there were the expected infusions reactions and low neutrophil counts (neutropenia).
This is clearly the new direction for both chronic lymphocytic leukemia research and for treatment outside of trials, namely fixed duration therapies that include novel agents. In fact, in the USA now, V+O is approved as a 12-month frontline treatment.
But there are many unanswered questions:
- What should we do for those who are not in U-MRD at the end of a year? Do we keep treating? There is evidence from other trials that may not help as the CLL may have developed resistance to the venetoclax. So, do we add a third drug? Do we just stop therapy, hope for a decent remission and then retreat when needed?
- These data are very early, and we don’t know how durable the responses will be.
That said, we are learning from some ASH 2019 abstracts that there may be life for CLL patients after progressing on venetoclax. Patients are responding to ibrutinib and other therapies post venetoclax.
Expect more research comparing all sorts of fixed duration of combinations. Expect more on the proper sequencing of therapies.
All very exciting. All looking at either curing CLL or turning it into a manageable chronic illness.
Here is my interview with Professor Hillmen:
Here is the actual abstract and a video of the oral presentation from EHA 2019:
We are all in this together