Translating PI3K-Delta Inhibitors to the Clinic in Chronic Lymphocytic Leukemia: The Story of CAL-101 (GS1101).

Targeted therapy with imatinib has transformed the treatment of chronic myeloid leukemia (CML). Unlike CML, chronic lymphocytic leukemia (CLL) lacks a common genetic aberration but does demonstrate constitutive activation of PI3-kinase (PI3K) as compared to normal B cells. This constitutively active PI3K in CLL likely relates to tonic B-cell receptor signaling that is present across a wide variety of B-cell malignancies. Although PI3K is quite proximal and represents an ideal target to pharmacologically modulate, the complexity of this pathway on which many normal functions are dependent had for many years been problematic. The p110 delta isoform of PI3K is relatively specific to hematopoietic cells, and elegant mouse studies where p110 delta was genetically inactivated demonstrated only a selective B-cell defect. Subsequent development of a potent, selective p110 delta inhibitor prompted translation into the clinic for the treatment of CLL and low-grade non-Hodgkin lymphoma (NHL). From the first patient treated where a dramatic early nodal response was noted, considerable excitement has developed for this class of drugs in CLL and NHL. We will summarize the development process of CAL-101 (now GS1101) in the treatment of chronic lymphoid malignancies such as CLL.