Jennifer A. Woyach, MD
In the treatment of patients with chronic lymphocytic leukemia (CLL), the CD19-directed antibody MOR208 is being explored in combination with lenalidomide (Revlimid) or ibrutinib (Imbruvica) across various patient subgroups.
at ASH, Woyach, an associate professor of Medicine in the Division of Internal Medicine at The Ohio State University Comprehensive Cancer Center, spoke on the preliminary results of this ongoing trial and offered in-depth insight on acquired resistance to ibrutinib in CLL.
OncLive: Could you provide an overview of your study?
: MOR208 is a CD19-targeted antibody that is clinically engineered to improved Fc-gamma receptor binding. In a phase I study at Ohio State University, it was previously established that it was effective in CLL and was also safe.
In the first 2 cohorts—the relapsed/refractory and treatment-naïve patients—there will be 20 patients each. So far, we have enrolled 11 patients in each of the 2 cohorts. The Richter's transformation cohort is going to enroll up to 10 patients. Then, for the patients with ibrutinib-resistance mutations, we may enroll up to 25. However, at the moment, there are only 7 patients.
What are your expectations for this study?
We haven't really reported the efficacy yet, as it is ongoing, but what we've seen so far is that the combination does appear to be safe in this patient population. With the combinations of MOR208 plus lenalidomide and MOR208 plus ibrutinib, we have seen anecdotal preliminary efficacy in the CLL population, as well as the Richter's group.
The thing that is of most interest, though, is the group of patients who have those ibrutinib resistance mutations. Whereof the 7 patients, most them have either stable clonal size—which we tend to not see—or they show a very rapid decrease in the frequency of those mutations.
We are continuing to enroll and are hoping to use this as a proof of concept for lenalidomide to help the antibody be more effective, but we also might be able to take it a step further into a more definitive study in the future.
Could you provide more information on ibrutinib resistance in CLL?
At Ohio State University, we have a very large cohort of patients treated with ibrutinib. We have a group of 308 patients treated in 4 clinical trials. We have been following these trials to study drug discontinuation and to look at mechanisms of resistance in those patients, with a median follow-up of 3.4 years. In that time, we have had 27 patients with Richter's transformation progress and 55 progressed with CLL. Richter's tends to be an earlier phenomenon, usually occurring within the first 18 months and is rare after 2 years. On the other hand, people with CLL progressing on ibrutinib tend to do so after 2 years of treatment.
We found that, of 46 patients, 87% of them had developed mutations in either BTK
at the time of relapse. Therefore, this kind of verifies that these are really the most predominant mechanisms by which people relapse.
The majority of patients did have mutations at the binding site of ibrutinib. Also, since we know the patients who developed these mutations at relapse, we can go back and look at serial samples that we saved. We found that we can actually detect those clones prior to the development of clinical relapse at a median of 9.3 months. Therefore, there is a pretty long time between when we can first develop and detect a clone and when they relapse, suggesting that there might be a potential for targeting that time period.
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