BCL2 Inhibition in Leukemia - Episode 7

Chronic Lymphocytic Leukemia: Future Directions in Care

June 25, 2019

Harry Erba, MD, PhD:Let’s turn to some future directions. And 1 area that I know we’re all concerned about are those patients with CLL [chronic lymphocytic leukemia who] progress into Richter syndrome. Anything going on in that area?

Matthew Davids, MD, MMSc:Fortunately there’s been more attention paid to Richter in recent times over the last few years because we’re seeing more of it in these patients treated with novel agents. These are patients probably who would have died from their CLL. We’re able to keep them alive now for a few more years, but unfortunately some of them do then go on to get Richter, which remains very challenging. At the ASCO [American Society of Clinical Oncology Annual] Meeting in the past I presented data from a cohort of patients on novel agents who developed Richter. We had about 80 patients in our series, and the median survival was only about 3 months.

The prognosis is particularly poor for those patients who develop Richter on novel agents. Fortunately, there are a number of studies underway looking at these novel approaches to therapy here. One of them is a study that we’re doing actually building on the chemoimmunotherapy experience. We’re using R-EPOCH [rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride] as our backbone. We’re actually adding venetoclax to that. That, I think, is the chemotherapy-sensitive approach that actually was recently published in diffuse large B-cell lymphoma in a study and looked promising there. We’re hoping that type of approach for Richter patients may be beneficial.

Another really exciting approach at The University of Texas MD Anderson Cancer Center is using the PD-1 [programmed cell death protein 1]—blocking antibody nivolumab with ibrutinib to try to harness the immune effects against Richter. Nitin Jain and his colleagues have seen some really dramatic responders there. But it’s still the minority of patients who are responding to either of these regimens. Unfortunately, in the few cases of Richter syndrome that have gone for CAR T-cells [chimeric antigen receptor T-cells], we haven’t seen the same types of responses that we see with de novo DLBCL [diffuse large B-cell lymphoma]. That’s going to be a particularly challenging group even for CAR-T.

Harry Erba, MD, PhD:Anything else at this year’s ASCO congress that pertains to our patients with CLL?

Matthew Davids, MD, MMSc:We’ve been talking a fair bit about CAR-T-cell therapy, and they’re going to update the data on the JCAR017 study, which is a very promising CAR-T product where in the data set that they’re presenting, close to half of patients are achieving complete remission, though in a relatively small numbers of patients. That’s a bit higher than we’ve seen with other studies of CAR-T therapy. And about three-quarters of the patients in that study are getting into a bone marrow undetectable MRD [minimal residual disease]. I think that this highlights the excitement of CAR-T in CLL right now.

The other study that’s very promising is another combination with a newer BTK inhibitor called acalabrutinib, which is a more selective BTK inhibitor, and it’s being combined now with obinutuzumab for frontline and relapsed-refractory patients, and the Ohio State University group is updating the 3-year data for their study. Before they’d seen only about 15% of patients in an early data cut achieving complete remission, and now it’s a little over 30%. So the responses do seem to be deepening over time, and so I think that’s going to be another promising regimen, although that is 1 that is a continuous therapy as well. They continued the acalabrutinib after the combination portion is complete.

Harry Erba, MD, PhD:Now acalabrutinib is available for mantle cell, right?

Matthew Davids, MD, MMSc:That’s right.

Harry Erba, MD, PhD:Are there patients with CLL for whom you would consider using acalabrutinib now?

Matthew Davids, MD, MMSc:I would. I think we don’t have the head-to-head data yet of acalabrutinib versus ibrutinib. This is the elevated study that we hope will read out soon. But really extrapolating across the different studies, it does seem that there’s a bit lower risk of cardiovascular toxicity with acalabrutinib: atrial fibrillation, also ventricular dysrhythmias. And the major bleeding risk does seem to be a bit less, at least as we compare across studies. If I have a patient who’s got significant cardiac issues, if they need to go on a BTK inhibitor and I have access to acalabrutinib, that’s often 1 that I’ll choose.

Harry Erba, MD, PhD:And if you didn’t want to use venetoclax.

Matthew Davids, MD, MMSc:Right.

Harry Erba, MD, PhD:Right.

Transcript edited for clarity.