PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Abstract

The efficacy of the prototypical phosphatidylinositol-3-kinase (PI3K) inhibitor idelalisib for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway. Areas Covered: We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor signaling, blockade of microenvironmental pro-survival signals, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We evaluate PI3K inhibitors that have entered trials for the treatment of lymphoma, focusing on agents with selectivity for PI3Kα and PI3Kδ. Expert Opinion: PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, idelalisib has infectious and autoimmune toxicities that limit its use. Outside of trials, idelalisib should be restricted to CLL patients with progression on ibrutinib or iNHL patients with progression on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

Keywords: PI3-kinase inhibitors; chronic lymphocytic leukemia; copanlisib; duvelisib; idelalisib; indolent non-Hodgkin lymphoma; umbralisib.

Figure 1

(a) Upstream signals from the B cell receptor, secreted molecules (e.g. cytokines), and membrane-bound and extracellular matrix proteins stimulate the PI3K pathway. At different stages of B cell development, certain isoforms of the catalytic subunit p110 are responsible for the majority of PI3K pathway output (represented by relative size). p110β and p110γ are not included as knockout mice have no overt B cell phenotype and the role of these isoforms in B cell development is less studied. Downstream effects of PI3K activation include inhibition of IKK, FOXO, and the proapoptotic protein Bad as well as activation of mTOR. (b) A neoplastic B cell co-opts upstream signals from the microenvironment to constitutively activate the PI3K pathway. A more prominent role for p110α in aggressive NHL is hypothesized based on improved efficacy of p110α/δ combinatorial inhibitors for the treatment of these diseases. BCR – B cell receptor, NHL – Nonhodgkin Lymphoma.