In recent years, there has been great interest in using combinations of drugs to treat chronic lymphocytic leukemia (CLL) because of CLL’s ability to mutate and develop resistance to single therapies.
At the annual meeting of the American Society of Hematology (ASH) 2019, our own Dr. Brian Koffman interviewed Dr. Paul Barr, an Associate Professor of Medicine at the Wilmot Cancer Institute in Rochester, NY. They discussed the preliminary results of a phase 1/2 clinical trial testing a novel combination of 3 different drugs for treatment of relapsed or refractory CLL.
The goal of this research is to create a treatment regimen that is well-tolerated and can be administered over a limited period of time, but still produce deep remission for patients with CLL. The combination being tested is umbralisib, ublituximab, and venetoclax.
- Umbralisib is an experimental PI3K inhibitor. Even though it has not been approved by the FDA yet, current data suggests that it might be better tolerated than other drugs in this class, such as idelaslisib.
- Ublituximab is an anti-CD20 antibody. These types of antibodies (ie, rituximab, obinutuzimab) have been used with chemotherapy and targeted agents for enhanced efficacy.
- Venetoclax is a Bcl2 inhibitor that is very effective for treating CLL.
- This early-stage clinical trial is ongoing, and it is studying the safety and efficacy of the combination of umbralisib, ublituximab, and venetoclax in patients with relapsed or refractory CLL.
- Treatment starts with umbralisib and ublituximab for 3 months, after which venetoclax is introduced. Staggering the treatments this way avoids tumor lysis syndrome (when cancer cells are killed too quickly, the internal contents of the cells spill out and damage other organs)
- Thus far, the combination has been very well tolerated. Very few patients have had to reduce their dose or discontinue.
- The first 9 patients experienced deep remission: 4/9 had complete remission, all had undetectable minimal residual disease (uMRD) in the blood, 7/9 had uMRD in the bone marrow.
- Because the study is still in its early stages, it is unknown how long the remissions will last. This will take years to study.
- Researchers continue to study this combination in patients with CLL, Richter’s transformation, and mantle cell lymphoma.
These preliminary results are promising for the treatment of relapsed or refractory CLL. Longer-term follow up with larger numbers of patients is still needed, and it is currently a work in progress. More information on the ongoing clinical trials with this combination can be found here and here.
A Brief Explanation of Different Ways of Evaluating Treatment Response
You may have noticed that almost all of the first 9 patients in this trial had uMRD, but only about half of them were considered to be in complete remission. Put another way, you can have uMRD but still only be in partial remission. What is the difference between complete/partial remission and uMRD? This is a concept that is a bit confusing for patients and doctors alike, so let’s try to clarify what this means.
On a basic level, remission means that the signs and symptoms of your cancer are reduced. In clinical practice remission/response (complete or partial) is based on a number of different factors. One of these criteria is the size of the lymph nodes and spleen, which is measured in clinical trials by clinical exam (palpation) and CT scan. If there is some significant improvement, but there is remaining enlargement of the lymph nodes and/or spleen after treatment, it is considered a partial response. The problem with this classification is that it doesn’t matter whether there has been a 50% reduction or 95% reduction in nodal disease. If only one node remains >1.5 cm in its largest diameter, the remission is considered partial. It all gets bucketed under partial remission, which doesn’t really give you an idea of the size of the treatment effect.
uMRD is based on the number of CLL cells, and it is determined by flow cytometry or next-generation sequencing. A patient is considered to have uMRD if they have less than 1 CLL cell per 10,000 lymphocytes. This can be measured in the blood or bone marrow. When we treat CLL, we are looking for long remissions, and uMRD seems to correlate well with the length of remission. Though MRD quantification is not routinely used in clinical practice, it allows for improved prediction of progression-free survival.
Please enjoy this brief interview with Dr. Barr from December 2019 at ASH in Orlando, FL.
You can read the actual abstract here: A Phase 1/2 Study of Umbralisib Ublituximab and
Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
Take care of yourself first.
Ann Liu, PhD