Lessons learned from experience of phosphatidylinositol 3-kinase inhibitors in chronic lymphocytic leukemia and lymphoma.

The development of phosphoinositide 3-kinase (PI3K) pathway inhibitors for the treatment of lymphoma and chronic lymphocytic leukemia (CLL) has been a journey characterized by significant promise and important challenges.1,2 Starting as a very rational targeted approach for B- and T-cell lymphoproliferative disorders, the development of PI3K inhibitors faced regulatory setbacks due to class-specific adverse events and complex interpretation of the survival outcomes.3 The recently published CHRONOS-4 clinical trial,4 a randomized placebo-controlled study comparing copanlisib in combination with bendamustine plus rituximab and placebo with bendamustine plus rituximab demonstrated that adding copanlisib to the standard-of-care bendamustine plus rituximab did not improve survival and increased toxicity. In this article, we examine the scientific rationale, clinical experience, regulatory hurdles, and future developments of PI3K inhibitors. We analyze the complexity of balancing PI3K therapeutic potential and safety.