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Role of PI3K-Targeted Therapy in CLL

Insights From:Jennifer R. Brown, MD, PhD, Harvard Medical School;Ian W. Flinn, MD, Sarah Cannon Center for Blood Cancer
Published: Thursday, Jul 07, 2016


Transcript:

Jennifer R. Brown, MD, PhD:
The PI3 kinase pathway is critically important to many of the B-cell malignancies. It signals downstream of a variety of cell surface receptors in CLL and integrates a number of signals that lead to the cells growing and dividing. These include signals from the B-cell receptor, signals from CD40, signals from cytokines in the microenvironment, and the pathways required for the cells to proliferate and survive.

Now, the delta isoform has been most heavily studied within the CLL cells themselves and seems to be the predominant isoform in responding to these various pathways, in that if you inhibit it with a specific inhibitor, you can inhibit most of the signal that’s being transmitted. That being said, there is also an expression of alpha and gamma isoforms within the CLL cells. And so, there’s some possibility that inhibiting those may enhance the effect on the CLL cells themselves directly. We also know that the delta knockout mouse has impairment of B-cell function and development, which justifies delta as a target.

Gamma has additional effects on T-cells and the microenvironment, and we know that the CLL cells derive a lot of survival support, proliferation support, from B cells in the microenvironment. And so, if you inhibit the gamma isoform on top of the delta isoform, it may potentially have some direct effect in the CLL cells, and it will also impact the microenvironment modulation of the CLL cells—and that may also inhibit their ability to grow and proliferate.

The goals of therapy for patients requiring therapy in CLL differ, actually, depending on the patient, and it is also a moving target with our new therapies. Historically, the goals of therapy were just to mitigate symptoms and help patients feel better for some period of time and to be off therapy for a while and then get retreated as needed. To some extent, that can still work, especially for older patients who have comorbidities. For younger patients who have a longer life expectancy, we are often hoping to get them into complete remission or MRD-negative (minimal residual disease–negative) complete remission, which would be a first step for a cure and, at least, a first step toward a very long progression-free survival.

Now, idelalisib is the first-in-class PI3 kinase delta inhibitor to be approved in CLL, and it’s approved in relapse refractory CLL patients with comorbidities—such that rituximab would be considered a standard therapy for those patients. And the approval is actually in combination with rituximab in those patients because the randomized trial compared idelalisib/rituximab to rituximab alone in that patient population.

The efficacy of idelalisib has been established now in three randomized registration trials in the relapse setting. The first was idelalisib/rituximab versus rituximab alone, in which patients with significant comorbidities—who were heavily pretreated with four prior regimens, and about half of whom had the high-risk 17p deletion—had a medium progression-free survival of 19 months, which was markedly better than about 5 months in the rituximab arm. There was also an improvement in overall survival in that trial. Very similar results were seen with ofatumumab with idelalisib compared to ofatumumab alone.

And just recently at the American Society of Hematology meeting in December of 2015, the first results from the bendamustine/rituximab/idelalisib versus bendamustine/rituximab alone trial were reported. That was in relapsed CLL patients. And the bendamustine/rituximab/idelalisib combination had a median progression-free survival of 23 months, which was about 10 months longer than the control arm. And there was also an improvement in overall survival in that trial.

So, the efficacy results are quite impressive, particularly when you consider that the patients are typically much more heavily pretreated, had a higher rate of 17p deletion, and were generally sicker with more comorbidities than any of the patients that have been studied in the ibrutinib trials. That being said, there’s a classic pattern of toxicity with idelalisib, which can be problematic if one is not prepared and knows how to manage it. And, generally, that consists of transaminitis in the second month on therapy. Patients need to be monitored every week or two for that, and if it develops, the drug needs to be held, the labs generally resolve, and those patients can restart at the same or lower dose without necessarily having a recurrence. If it does recur, you can usually hold and restart again; just lower the dose.

The other idiosyncratic toxicities that are problematic is that there’s a delayed, fairly severe diarrhea that can be associated with colitis. And the median time to onset, that is actually 7 months, but some patients will get it quite late after a year, or two, or three on therapy. And that can be quite severe, even progress to life-threatening complications if it’s not identified. So, one has to have a very low threshold to hold the drug, let this resolve, and if it’s not resolving rapidly, to treat either with prednisone or with oral budesonide to control it.

Many of these patients can resume idelalisib. I find that works best if you continue the budesonide or the prednisone on a slow taper when they do so. If you stop them, some patients won’t recur, but those who recur, often need to be maintained on a low dose of budesonide. And there’s also a low rate of drug-related pneumonitis, which responds to steroids and needs to be considered whenever an idelalisib patient has a pneumonia-type pattern.

Several months ago, earlier in 2016, a number of trials were stopped by Gilead when it was observed that there was an excess of deaths in the idelalisib arm on three trials, two of which were in combination with bendamustine/Rituxan and one of which was just with Rituxan. They were all in earlier lines of therapy—some untreated or just one prior therapy—and it turns out that most of these deaths were due to infections, not opportunistic infections most, but more bacterial infections, sometimes in the setting of neutropenia.

This is something that one was aware of, potentially, as a toxicity of idelalisib from the relapse refractory trials. I think perhaps there had been a hope that in less heavily pretreated patients, this would not be as significant, but it seems that it was. There’s also some suggestion that maybe the combination with bendamustine has enhanced the neutropenia and the risk of infections. And so, in the wake of these trials stopping, recommendations are that all patients on idelalisib should receive prophylaxis for pneumocystis, antiviral prophylaxis, be monitored periodically for CMV (cytomegalovirus), and also be monitored regularly for neutropenia. And, generally, I would treat any neutropenia with growth factors in order to mitigate it.

Transcript Edited for Clarity
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Transcript:

Jennifer R. Brown, MD, PhD:
The PI3 kinase pathway is critically important to many of the B-cell malignancies. It signals downstream of a variety of cell surface receptors in CLL and integrates a number of signals that lead to the cells growing and dividing. These include signals from the B-cell receptor, signals from CD40, signals from cytokines in the microenvironment, and the pathways required for the cells to proliferate and survive.

Now, the delta isoform has been most heavily studied within the CLL cells themselves and seems to be the predominant isoform in responding to these various pathways, in that if you inhibit it with a specific inhibitor, you can inhibit most of the signal that’s being transmitted. That being said, there is also an expression of alpha and gamma isoforms within the CLL cells. And so, there’s some possibility that inhibiting those may enhance the effect on the CLL cells themselves directly. We also know that the delta knockout mouse has impairment of B-cell function and development, which justifies delta as a target.

Gamma has additional effects on T-cells and the microenvironment, and we know that the CLL cells derive a lot of survival support, proliferation support, from B cells in the microenvironment. And so, if you inhibit the gamma isoform on top of the delta isoform, it may potentially have some direct effect in the CLL cells, and it will also impact the microenvironment modulation of the CLL cells—and that may also inhibit their ability to grow and proliferate.

The goals of therapy for patients requiring therapy in CLL differ, actually, depending on the patient, and it is also a moving target with our new therapies. Historically, the goals of therapy were just to mitigate symptoms and help patients feel better for some period of time and to be off therapy for a while and then get retreated as needed. To some extent, that can still work, especially for older patients who have comorbidities. For younger patients who have a longer life expectancy, we are often hoping to get them into complete remission or MRD-negative (minimal residual disease–negative) complete remission, which would be a first step for a cure and, at least, a first step toward a very long progression-free survival.

Now, idelalisib is the first-in-class PI3 kinase delta inhibitor to be approved in CLL, and it’s approved in relapse refractory CLL patients with comorbidities—such that rituximab would be considered a standard therapy for those patients. And the approval is actually in combination with rituximab in those patients because the randomized trial compared idelalisib/rituximab to rituximab alone in that patient population.

The efficacy of idelalisib has been established now in three randomized registration trials in the relapse setting. The first was idelalisib/rituximab versus rituximab alone, in which patients with significant comorbidities—who were heavily pretreated with four prior regimens, and about half of whom had the high-risk 17p deletion—had a medium progression-free survival of 19 months, which was markedly better than about 5 months in the rituximab arm. There was also an improvement in overall survival in that trial. Very similar results were seen with ofatumumab with idelalisib compared to ofatumumab alone.

And just recently at the American Society of Hematology meeting in December of 2015, the first results from the bendamustine/rituximab/idelalisib versus bendamustine/rituximab alone trial were reported. That was in relapsed CLL patients. And the bendamustine/rituximab/idelalisib combination had a median progression-free survival of 23 months, which was about 10 months longer than the control arm. And there was also an improvement in overall survival in that trial.

So, the efficacy results are quite impressive, particularly when you consider that the patients are typically much more heavily pretreated, had a higher rate of 17p deletion, and were generally sicker with more comorbidities than any of the patients that have been studied in the ibrutinib trials. That being said, there’s a classic pattern of toxicity with idelalisib, which can be problematic if one is not prepared and knows how to manage it. And, generally, that consists of transaminitis in the second month on therapy. Patients need to be monitored every week or two for that, and if it develops, the drug needs to be held, the labs generally resolve, and those patients can restart at the same or lower dose without necessarily having a recurrence. If it does recur, you can usually hold and restart again; just lower the dose.

The other idiosyncratic toxicities that are problematic is that there’s a delayed, fairly severe diarrhea that can be associated with colitis. And the median time to onset, that is actually 7 months, but some patients will get it quite late after a year, or two, or three on therapy. And that can be quite severe, even progress to life-threatening complications if it’s not identified. So, one has to have a very low threshold to hold the drug, let this resolve, and if it’s not resolving rapidly, to treat either with prednisone or with oral budesonide to control it.

Many of these patients can resume idelalisib. I find that works best if you continue the budesonide or the prednisone on a slow taper when they do so. If you stop them, some patients won’t recur, but those who recur, often need to be maintained on a low dose of budesonide. And there’s also a low rate of drug-related pneumonitis, which responds to steroids and needs to be considered whenever an idelalisib patient has a pneumonia-type pattern.

Several months ago, earlier in 2016, a number of trials were stopped by Gilead when it was observed that there was an excess of deaths in the idelalisib arm on three trials, two of which were in combination with bendamustine/Rituxan and one of which was just with Rituxan. They were all in earlier lines of therapy—some untreated or just one prior therapy—and it turns out that most of these deaths were due to infections, not opportunistic infections most, but more bacterial infections, sometimes in the setting of neutropenia.

This is something that one was aware of, potentially, as a toxicity of idelalisib from the relapse refractory trials. I think perhaps there had been a hope that in less heavily pretreated patients, this would not be as significant, but it seems that it was. There’s also some suggestion that maybe the combination with bendamustine has enhanced the neutropenia and the risk of infections. And so, in the wake of these trials stopping, recommendations are that all patients on idelalisib should receive prophylaxis for pneumocystis, antiviral prophylaxis, be monitored periodically for CMV (cytomegalovirus), and also be monitored regularly for neutropenia. And, generally, I would treat any neutropenia with growth factors in order to mitigate it.

Transcript Edited for Clarity
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