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Novel Frontline Combinations With Ibrutinib in CLL

Insights From: Michael Choi, MD, UC San Diego Medical Center; Matthew S. Davids, MD, Dana-Farber Cancer Institute; William Wierda, MD, PhD, MD Anderson Cancer Center
Published: Monday, May 07, 2018



Transcript: 

Michael Choi, MD: The combination of ibrutinib and obinutuzumab was explored as part of a large French study looking at the possibility of frontline options that achieved MRD [minimal residual disease] negativity without the inclusion of chemotherapy drugs, purine analogs, or alkylating agents. This trial had all patients receive obinutuzumab and ibrutinib in combination at first with the thought that patients who have detectable disease would then receive standard chemoimmunotherapy afterwards with the goal of ultimately achieving MRD-negative remissions.

They’ve reported on the patients up until that first endpoint with the combination of ibrutinib and obinutuzumab. They also reported the universally successful outcomes with a 100% response rate. But they did note that not all patients, or not many patients, achieved that MRD negativity: I think it was about 10% or so. So, they did note that most of the patients still needed to receive chemoimmunotherapy afterwards with the goal of achieving MRD negativity. I do think that this study is still successful in showing the feasibility of that combination and the safety of that combination, as well as that the combination did achieve high response rates.

Matthew S. Davids, MD: At the ASH [American Society of Hematology] meeting, we had a number of different combinations of drugs. We had antibodies put together with single-agent BTK [Bruton’s tyrosine kinase] inhibitors and antibodies put together with venetoclax. We had a very exciting study from Kerry Rogers and colleagues from the Ohio State University updating their data on the 3-drug combination combining the CD20 antibody obinutuzumab with ibrutinib and venetoclax. It was a 3-drug study for both frontline and relapsed/refractory treatment of CLL.

This was a phase Ib/II study. They had originally reported the phase Ib results at the ASH meeting the year before, which defined the dose of venetoclax at 400 mg as being safe to use. In this update at the 2017 ASH meeting, Dr Rogers presented data on the upfront cohort of 25 patients treated with this 3-drug regimen as a chemotherapy-free approach to the initial therapy of CLL—a very exciting study.

They generally saw good tolerability. They started each drug 1 at a time to try to help tease out the different toxicities and to help reduce the risk of tumor lysis syndrome from venetoclax. They did see a fair number of infusional-related reactions to obinutuzumab, and that’s the antibody that they started with. We have some data now suggesting that perhaps starting with an ibrutinib-based regimen  then introducing obinutuzumab might mitigate those infusion reactions a bit. But nonetheless, in general, the tolerability of their approach was quite good.

I think the results were also striking: Nearly all of their patients responded. About half of the patients achieved complete remission, and most of those patients actually achieved MRD undetectability. That’s without the need for chemotherapy. So, I think it’s a very exciting development. But really, the key is going to be to know whether these are durable effects. They’ve designed their regimen to last for about 14 months, and it’s certainly nice that it’s a time-limited approach. It does not require ongoing maintenance therapy. But we just don’t know yet whether those patients are going to relapse shortly after they finish the treatments, or whether these may be durable effects as we’ve seen with the older chemotherapy approaches.

Another study that was very exciting at the ASH meeting was from the MD Anderson group and presented by Nitin Jain looking at the combination of ibrutinib and venetoclax. Their study looked at both the frontline setting and the relapsed/refractory setting. I found the results in the frontline cohort to be particularly exciting. All the patients responded. Their study started with ibrutinib monotherapy, and as expected, despite having good responses, they did not see a lot of complete remissions or MRD undetectability with ibrutinib alone.

But when they added in venetoclax, they saw those complete remission rates go up quite dramatically—as well as the rates of MRD undetectability, which went as high as 60% in bone marrow—in patients without the need for chemoimmunotherapy. So, I think that’s a very promising result, particularly as most of our CLL patients are older and frailer patients who may not tolerate chemotherapy-based regimens. I think what’s exciting about Dr Jain’s regimen is that something could be available for most patients with CLL who need treatment.

Another study that was presented at the ASH meeting was my own study of ibrutinib with FCR [fludarabine/cyclophosphamide/rituximab]. This is a regimen that’s geared more toward the young, fit patients, so we have to remember that it’s only something we could use in a relatively small group of CLL patients. But I think one of the reasons we were particularly excited about our data is that we saw rates of MRD undetectability of around 83% in the bone marrow. This was across patients with both mutated and unmutated IGHV CLL. As far as we know, this is the highest rate of MRD undetectability that has ever been described for a regimen for CLL. And so, we think this is a very promising approach for that young, fit population.

Michael Choi, MD: FCR is a very active regimen for patients with CLL, and we’ve seen from the German trials and the MD Anderson trials that some patients have extremely long remissions following this treatment. However, there are some patients who don’t have that quality of remission, particularly those with unmutated immunoglobulin genes. Based on that, Dr Davids and his colleagues conducted a multicenter trial to look at the combination of ibrutinib with FCR, dubbed I-FCR. They enrolled patients who were younger, so the patient population was by definition younger than age 65. They ended up having a fair number of patients with adverse prognostic factors, including a few patients with deletion 17p and more than half of their patients with unmutated immunoglobulin genes.

At this past ASH meeting, Dr Davids presented the results from 35 of his patients. He showed that the response rate was universal. All of his patients responded. Only about a third of them had complete responses, but something that was striking to me was that more than 80% of patients had undetectable residual disease in their bone marrow following treatment. This to me suggests that some of those patients may be able to discontinue treatment and not have an immediate relapse—something that we don’t usually expect with ibrutinib alone—at a higher incidence than we would have expected with FCR alone. I am excited to see the full results of this trial. I do know that they are enrolling more patients, including a cohort that will stop ibrutinib upon achievement of MRD-negative bone marrow with the option to resume ibrutinib in the future if the disease recurs. I think studies like this will be very useful for deciding on optimal therapy for our patients.

Transcript Edited for Clarity 
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Transcript: 

Michael Choi, MD: The combination of ibrutinib and obinutuzumab was explored as part of a large French study looking at the possibility of frontline options that achieved MRD [minimal residual disease] negativity without the inclusion of chemotherapy drugs, purine analogs, or alkylating agents. This trial had all patients receive obinutuzumab and ibrutinib in combination at first with the thought that patients who have detectable disease would then receive standard chemoimmunotherapy afterwards with the goal of ultimately achieving MRD-negative remissions.

They’ve reported on the patients up until that first endpoint with the combination of ibrutinib and obinutuzumab. They also reported the universally successful outcomes with a 100% response rate. But they did note that not all patients, or not many patients, achieved that MRD negativity: I think it was about 10% or so. So, they did note that most of the patients still needed to receive chemoimmunotherapy afterwards with the goal of achieving MRD negativity. I do think that this study is still successful in showing the feasibility of that combination and the safety of that combination, as well as that the combination did achieve high response rates.

Matthew S. Davids, MD: At the ASH [American Society of Hematology] meeting, we had a number of different combinations of drugs. We had antibodies put together with single-agent BTK [Bruton’s tyrosine kinase] inhibitors and antibodies put together with venetoclax. We had a very exciting study from Kerry Rogers and colleagues from the Ohio State University updating their data on the 3-drug combination combining the CD20 antibody obinutuzumab with ibrutinib and venetoclax. It was a 3-drug study for both frontline and relapsed/refractory treatment of CLL.

This was a phase Ib/II study. They had originally reported the phase Ib results at the ASH meeting the year before, which defined the dose of venetoclax at 400 mg as being safe to use. In this update at the 2017 ASH meeting, Dr Rogers presented data on the upfront cohort of 25 patients treated with this 3-drug regimen as a chemotherapy-free approach to the initial therapy of CLL—a very exciting study.

They generally saw good tolerability. They started each drug 1 at a time to try to help tease out the different toxicities and to help reduce the risk of tumor lysis syndrome from venetoclax. They did see a fair number of infusional-related reactions to obinutuzumab, and that’s the antibody that they started with. We have some data now suggesting that perhaps starting with an ibrutinib-based regimen  then introducing obinutuzumab might mitigate those infusion reactions a bit. But nonetheless, in general, the tolerability of their approach was quite good.

I think the results were also striking: Nearly all of their patients responded. About half of the patients achieved complete remission, and most of those patients actually achieved MRD undetectability. That’s without the need for chemotherapy. So, I think it’s a very exciting development. But really, the key is going to be to know whether these are durable effects. They’ve designed their regimen to last for about 14 months, and it’s certainly nice that it’s a time-limited approach. It does not require ongoing maintenance therapy. But we just don’t know yet whether those patients are going to relapse shortly after they finish the treatments, or whether these may be durable effects as we’ve seen with the older chemotherapy approaches.

Another study that was very exciting at the ASH meeting was from the MD Anderson group and presented by Nitin Jain looking at the combination of ibrutinib and venetoclax. Their study looked at both the frontline setting and the relapsed/refractory setting. I found the results in the frontline cohort to be particularly exciting. All the patients responded. Their study started with ibrutinib monotherapy, and as expected, despite having good responses, they did not see a lot of complete remissions or MRD undetectability with ibrutinib alone.

But when they added in venetoclax, they saw those complete remission rates go up quite dramatically—as well as the rates of MRD undetectability, which went as high as 60% in bone marrow—in patients without the need for chemoimmunotherapy. So, I think that’s a very promising result, particularly as most of our CLL patients are older and frailer patients who may not tolerate chemotherapy-based regimens. I think what’s exciting about Dr Jain’s regimen is that something could be available for most patients with CLL who need treatment.

Another study that was presented at the ASH meeting was my own study of ibrutinib with FCR [fludarabine/cyclophosphamide/rituximab]. This is a regimen that’s geared more toward the young, fit patients, so we have to remember that it’s only something we could use in a relatively small group of CLL patients. But I think one of the reasons we were particularly excited about our data is that we saw rates of MRD undetectability of around 83% in the bone marrow. This was across patients with both mutated and unmutated IGHV CLL. As far as we know, this is the highest rate of MRD undetectability that has ever been described for a regimen for CLL. And so, we think this is a very promising approach for that young, fit population.

Michael Choi, MD: FCR is a very active regimen for patients with CLL, and we’ve seen from the German trials and the MD Anderson trials that some patients have extremely long remissions following this treatment. However, there are some patients who don’t have that quality of remission, particularly those with unmutated immunoglobulin genes. Based on that, Dr Davids and his colleagues conducted a multicenter trial to look at the combination of ibrutinib with FCR, dubbed I-FCR. They enrolled patients who were younger, so the patient population was by definition younger than age 65. They ended up having a fair number of patients with adverse prognostic factors, including a few patients with deletion 17p and more than half of their patients with unmutated immunoglobulin genes.

At this past ASH meeting, Dr Davids presented the results from 35 of his patients. He showed that the response rate was universal. All of his patients responded. Only about a third of them had complete responses, but something that was striking to me was that more than 80% of patients had undetectable residual disease in their bone marrow following treatment. This to me suggests that some of those patients may be able to discontinue treatment and not have an immediate relapse—something that we don’t usually expect with ibrutinib alone—at a higher incidence than we would have expected with FCR alone. I am excited to see the full results of this trial. I do know that they are enrolling more patients, including a cohort that will stop ibrutinib upon achievement of MRD-negative bone marrow with the option to resume ibrutinib in the future if the disease recurs. I think studies like this will be very useful for deciding on optimal therapy for our patients.

Transcript Edited for Clarity 
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