Case 3: Therapeutic Approaches for Richter Transformation

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Matthew S. Davids, MD, MMSc:Let’s think about this particular patient, where we’re seeing DLBCL and Richter transformation. Let’s review some of the different therapeutic approaches. There are some more standard approaches, and then there are some novel approaches, in development, that I think are exciting. I’m going to ask Dr. Wierda to review some of the standard therapies. Then Dr. Jain is going to tell us about the novel approaches.

William Wierda, MD, PhD:Standard therapies have been very underwhelming for Richter transformation. We’ve done a lot of work in looking at various chemoimmunotherapy regimens, and the outcomes are very poor. Overall, the response rate is about 50%. It’s very uncommon to get a complete remission. Many times, Richter transformation is associated with 17p deletion and mutatedTP53. Chemoimmunotherapy just does not work well for these patients. It can gain temporary control of the disease. You can debulk the disease with a chemoimmunotherapy regimen, but it’s transient. And so, if I am ever considering chemoimmunotherapy for these patients, it’s with a plan for what is next—like transplant. If I have a donor lined up, and we’re ready to go to transplant, I may consider an intensive chemoimmunotherapy regimen to get that patient in a good debulked state so that they can proceed with transplant.

We’ve done very poorly at treating Richter transformation. We just have not identified good therapies that give good durable disease control and remissions. Transplant has probably performed the best, thus far, of all the treatment options that we have for Richter transformation.

Matthew S. Davids, MD, MMSc:Just to be clear, allotransplantation is what you are referring to?

William Wierda, MD, PhD:Allogeneic stem cell transplant, yes.

Matthew S. Davids, MD, MMSc:Great. Dr. Jain, that sounds fairly grim. What are the new prospects for therapies in Richter transformation?

Nitin Jain, MD:There are several clinical trials, which are ongoing, right now, looking at some novel strategies. One of the strategies, with the most data, right now, is with checkpoint inhibition. The Mayo Clinic has subsequently reported their findings, where they show that in 9 patients with Richter, 4 of them had a response. Most of them were ibrutinib-treated patients. Interestingly, in that particular series, they treated 16 patients with CLL with single-agent pembrolizumab. They did not see any response. But again, 44% were patients with Richter transformation. The median overall survival for the Richter cohort was 10.7 months.

At MD Anderson Cancer Center, we have been conducting an ongoing trial. It’s an ongoing study that looks at the combination of a PD-1 inhibitor, nivolumab (another checkpoint inhibitor), with ibrutinib for both relapsed/refractory CLL and Richter transformation. When we last reported on the data, we had treated several patients with Richter transformation. Some of these patients achieved partial or complete remission. So, I think there is activity with checkpoint inhibition in patients with Richter transformation.

Recently, there was a study reported at the ASH annual meeting. A large study looked at nivolumab and ibrutinib—so PD-1 plus ibrutinib for patients with CLL. The study also included patients with Richter transformation. A total of 141 patients were treated. Among the Richter transformation cohort, they saw a 60% overall response rate. So, again, all 3 of these trials show that there is activity with checkpoint inhibition in patients with Richter. Right now, one ongoing question is, which patients will respond to checkpoint inhibition? That’s something that we don’t know right now. We, and others, are trying to investigate that. So, checkpoint inhibitors are one strategy.

You are leading an effort on treatment with venetoclax plus chemotherapy, which is an ongoing trial. There are preliminary clinical data that suggest that patients with DLBCL and Richter transformation may respond to venetoclax. I think that venetoclax plus chemotherapy may be a valid approach.

More exciting data, which were recently published, looked at CAR T-cell therapy. It was reported that in patients with CLL and Richter transformation, there was a high rate of complete response. There was a PET-negative response, as well as bone marrow—negative response rates.

So, those are the strategies that are in clinical trials. Those are the things that are in the pipeline. There are patients out there, with Richter transformation. You should send them to centers where clinical trials are available. As Dr. Wierda mentioned, with chemoimmunotherapy, their outcomes are quite dismal.

Matthew S. Davids, MD, MMSc:It certainly sounds like there’s a lot of work going on in this space, which is encouraging. But we certainly have a lot more work to do.

Transcript edited for clarity.