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Duvelisib in Relapsed/Refractory CLL

Insights From:Jennifer R. Brown, MD, PhD, Harvard Medical School;Ian W. Flinn, MD, Sarah Cannon Center for Blood Cancer
Published: Tuesday, Jul 12, 2016


  Transcript:

Jennifer R. Brown, MD, PhD:
Duvelisib inhibits both the delta and gamma isoforms of PI3 kinase. This is distinct from idelalisib, which inhibits only delta. And inhibiting gamma could have multiple benefits, or toxicities, actually. Benefits include that it will inhibit the microenvironment stimuli to the CLL cells. It might also directly affect the CLL cells because gamma is expressed in the CLL cells. The potential negatives are that it could also cause some immunodeficiency from effects on T cells or neutrophils. And from the early studies with duvelisib, prophylaxis has been included as part of the studies. So, infections haven’t been seen as a particularly greater problem, and that’s probably been helpful.

The mechanisms of resistance to PI3 kinase inhibitors are currently under investigation by me and others, and it’s not clear that they necessarily involve upregulation of other isoforms. We really don’t know that yet. So, it’s theoretically possible that inhibiting a second isoform may be beneficial in avoiding resistance—but that remains theoretical.

Transcript Edited for Clarity
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  Transcript:

Jennifer R. Brown, MD, PhD:
Duvelisib inhibits both the delta and gamma isoforms of PI3 kinase. This is distinct from idelalisib, which inhibits only delta. And inhibiting gamma could have multiple benefits, or toxicities, actually. Benefits include that it will inhibit the microenvironment stimuli to the CLL cells. It might also directly affect the CLL cells because gamma is expressed in the CLL cells. The potential negatives are that it could also cause some immunodeficiency from effects on T cells or neutrophils. And from the early studies with duvelisib, prophylaxis has been included as part of the studies. So, infections haven’t been seen as a particularly greater problem, and that’s probably been helpful.

The mechanisms of resistance to PI3 kinase inhibitors are currently under investigation by me and others, and it’s not clear that they necessarily involve upregulation of other isoforms. We really don’t know that yet. So, it’s theoretically possible that inhibiting a second isoform may be beneficial in avoiding resistance—but that remains theoretical.

Transcript Edited for Clarity
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