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PI3K-Targeted Therapy for Follicular Lymphoma

Insights From:Jennifer R. Brown, MD, PhD, Harvard Medical School;Ian W. Flinn, MD, Sarah Cannon Center for Blood Cancer
Published: Friday, Aug 05, 2016


Transcript:

Ian W. Flinn, MD:
The FDA-approved indication for idelalisib is after two prior lines of therapy for patients with follicular lymphoma and small lymphocytic lymphoma. Idelalisib is a PI3 kinase-delta isoform inhibitor. There are four different isoforms of the PI3 kinase—alpha, beta, delta, and gamma. And idelalisib was the first isoform-specific inhibitor. The notion here was that by targeting the delta isoform, we might spare patients from the collateral toxicities that you see with the pan inhibitors, such as problems with glucose metabolism.

However, there are some side effects with idelalisib. We knew very early on in development of idelalisib that we saw liver function abnormalities that occurred in patients. So, early on, perhaps in the first 4 to 12 weeks, we can see an increase in aminotransferases. The good thing here is that this is usually a pretty predictable time frame. We can hold the drug, we can let the aminotransferases decline back to a normal level and restart most patients on this drug. Now, there are also some late toxicities that occur. There’s diarrhea that can occur at any time. But there’s also a late colitis that can occur and this, I’m very sure, is on-target toxicity of idelalisib. We know from animal models that if you inhibit the delta isoform, then patients can develop colitis. It’s really important that physicians and patients alike understand this. And if they see this very severe diarrhea, then they look for colitis, hold the drug, and perhaps use steroids or budesonide—which is an oral steroid that’s not absorbed in these patients.

Now, we also recently have come to understand that there are some infectious toxicities. I think we were aware of this pretty early in the development of the drug and the use of prophylactic strategy against pneumocystis to prevent that infection. But recently, there have been trials that have shown that there is an increase not only in pneumocystis but in CMV (cytomegalovirus). Interestingly, this occurs early in the course of the studies rather than late, which is not what I would have predicted. I would have thought that cumulative immunosuppression would allow CMV to occur later in the course of therapy. And most of these events are occurring in combination with other agents, such as rituximab or bendamustine. It hasn’t been seen so far to nearly the extent in the FDA-approved indication, which is after two prior lines of therapy and as a single agent.

Idelalisib is a tremendous advancement in our patients for follicular lymphoma. We know that in the double refractory patients that there’s a response rate greater than 50%, and these remissions can last more than a year. We were very involved in the frontline trials in the initial phase I, and in my personal experience I’ve seen very similar results, sometimes very durable remissions for patients with idelalisib.

Transcript Edited for Clarity
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Transcript:

Ian W. Flinn, MD:
The FDA-approved indication for idelalisib is after two prior lines of therapy for patients with follicular lymphoma and small lymphocytic lymphoma. Idelalisib is a PI3 kinase-delta isoform inhibitor. There are four different isoforms of the PI3 kinase—alpha, beta, delta, and gamma. And idelalisib was the first isoform-specific inhibitor. The notion here was that by targeting the delta isoform, we might spare patients from the collateral toxicities that you see with the pan inhibitors, such as problems with glucose metabolism.

However, there are some side effects with idelalisib. We knew very early on in development of idelalisib that we saw liver function abnormalities that occurred in patients. So, early on, perhaps in the first 4 to 12 weeks, we can see an increase in aminotransferases. The good thing here is that this is usually a pretty predictable time frame. We can hold the drug, we can let the aminotransferases decline back to a normal level and restart most patients on this drug. Now, there are also some late toxicities that occur. There’s diarrhea that can occur at any time. But there’s also a late colitis that can occur and this, I’m very sure, is on-target toxicity of idelalisib. We know from animal models that if you inhibit the delta isoform, then patients can develop colitis. It’s really important that physicians and patients alike understand this. And if they see this very severe diarrhea, then they look for colitis, hold the drug, and perhaps use steroids or budesonide—which is an oral steroid that’s not absorbed in these patients.

Now, we also recently have come to understand that there are some infectious toxicities. I think we were aware of this pretty early in the development of the drug and the use of prophylactic strategy against pneumocystis to prevent that infection. But recently, there have been trials that have shown that there is an increase not only in pneumocystis but in CMV (cytomegalovirus). Interestingly, this occurs early in the course of the studies rather than late, which is not what I would have predicted. I would have thought that cumulative immunosuppression would allow CMV to occur later in the course of therapy. And most of these events are occurring in combination with other agents, such as rituximab or bendamustine. It hasn’t been seen so far to nearly the extent in the FDA-approved indication, which is after two prior lines of therapy and as a single agent.

Idelalisib is a tremendous advancement in our patients for follicular lymphoma. We know that in the double refractory patients that there’s a response rate greater than 50%, and these remissions can last more than a year. We were very involved in the frontline trials in the initial phase I, and in my personal experience I’ve seen very similar results, sometimes very durable remissions for patients with idelalisib.

Transcript Edited for Clarity
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