Duvelisib + Venetoclax: A Time-Limited, All Oral Option for CLL | Jennifer Crombie, MD | #ASH24

Hi, my name is Jennifer Crombie and I'm one of the lymphoma and CLL investigators at Dana-Farber Cancer Institute in Boston. And I'm excited, at this ASH to be presenting updated results from our, investigator sponsored phase two trial of Duvelisib and Venetoclax in patients with relapsed or refractory CLL or Richter syndrome. So we know that, venetoclax plus rituximab is a very active regimen for patients with relapsed or refractory CLL.

However, that treatment requires two years of treatment and requires an IV therapy. So we wanted to ask whether we could combine two oral therapies that have known activity in CLL and design a time limited strategy. So in this study, we combined both duvelisib, which is a PI3 kinase inhibitor, which is already FDA approved, as well as venetoclax, a BCL two inhibitor.

And so patients were treated with both drugs, starting with one week of duvelisib, and then adding in the venetoclax for a total of one year. And then at the end of that one year, if patients had a complete remission with undetectable MRD, which stands for minimal residual disease, patients had the option of discontinuing both drugs.

If patients had a partial response or could still detect some, minimal residual disease, then they would transition to venetoclax alone. And that was to try to avoid some of the side effects that we know can occur with ongoing duvelisib use. And so what we saw, was that a total of 29 patients, enrolled in the phase two portion of the CLL study and nine patients enrolled in the Richter's cohort.

This was a high risk patient population. We had about 60% of patients who had been treated already with a prior BTK inhibitor, and 45% of patients in the study had a Tp53 mutation. And just over 30% of patients had a deletion 17p, which are higher risk markers. And so, what we saw was that this was a, highly active combination.

The best overall response rate of the combination was, 97%, with a complete response rate of 62%. And, we also looked at that minimal residual disease rate, and that was, 60% in the undetectable rate, 60% in the blood, and 49% in the bone marrow. After the total combination period of 12 cycles, 11 patients in the CLL cohort were able to stop both drugs, and three patients did have recurrent detectable MRD and were able to safely restart the Venetoclax alone.

And those among those three patients, they stayed off treatment for an average of, 1.2 years. We now have longer follow up of this study and we saw that the three year progression free survival was, 68%. And, the averaged, progression free survival of the median progression free survival was just, under four years. And even among those high risk patients, they we saw that, the average, the median progression free survival was just over two years, which, is favorable for, for those high risk markers.

In terms of the tolerability, we saw that this combination was well tolerated with the expected side effects that we would see with drugs like duvelisib and Venetoclax. We saw that patients had diarrhea and rash so we could manage that with lowering the dose or, with steroids. Patients also had neutropenia or low blood counts. And many patients did require, growth factor support to help improve their blood counts.

Among the patient with the Richter's cohorts, we did have of the nine patients, three who had a complete remission, one patient was able to go on to transplant. But we do need more patients to understand the activity of this combination in that cohort. So overall, we think this is, a, active regimen that was well tolerated and hopefully can be further studied in patients with CLL.

Thankfully, we have a growing number of, treatment options for patients with CLL. What's attractive about this combination is the fact that it's, an all oral combination and that it can be time limited for, with a minimum of one year of treatment, which is, shorter than some of the other, treatment options. And we're also using MRD to guide the treatment duration, which, is a strategy that is, appealing for patients with CLL.