Clinical experience with phosphatidylinositol 3-kinase inhibitors in hematologic malignancies

The phosphatidyl-inositol 3-kinase (PI3K)-Akt pathway is a pivotal signaling cascade regulating several crucial cellular functions, including proliferation, protein synthesis, apoptosis, and metabolism. It plays a particularly relevant role in lymphomagenesis. For this reason, there is great interest in designing and developing agents specifically designed to inhibit PI3K. Idelalisib, copanlisib, duvelisib, and umbralisib now have approved indications in the treatment of multiply relapsed or refractory follicular lymphoma. Idelalisib and duvelisib also have an approval in patients with chronic lymphocytic leukemia (CLL), and umbralisib is also indicated in for patients with relapsed or refractory marginal zone lymphoma. This chapter reviews the commercially available PI3K inhibitors in terms of their mechanism of action and application in lymphoproliferative malignancies, in light of the trials that have led to their regulatory approval. Published clinical experiences in combination with other lymphoma-directed drugs are also discussed. A glimpse into next-generation PI3K inhibitors now in development within clinical trials will also be provided.