R/R indolent B-cell lymphoma: is idelalisib a new treatment option?

Idelalisib is an orally available, highly selective PI3Kδ small molecule inhibitor identified in kinome-wide screening assays. The PI3K p110δ isoform inhibitor idelalisib was the first agent in a new class of isoform-specific inhibitors to receive regulatory approval. Approved FDA indications for idelalisib include relapsed chronic lymphocytic leukemia (CLL) in combination with rituximab in comorbid patients and relapsed follicular lymphoma (FL) with 2 or more prior therapies.

This article was written by Chan Yoon Cheah and  Nathan Fowler from Sir Charles Gairdner Hospital, Perth and University of Texas MD Anderson Cancer Centre Houston, Texas, respectively; published in the Journal Blood in July 2016 highlighting  the rationale for  targeting pathways, representing safety and efficacy data with idelalisib in patients with lymphoma, describing toxicities of the agent in combination studies and the mechanisms of resistance to idelalisib.¹

The key points of the article are as follows:

• PI3K pathway is deregulated in a subset of cases in a variety of lymphoma subtypes. PI3K inhibition as a therapeutic strategy has been shown to be challenging in various studies because of the ubiquitous expression of the α and β isoforms thereby making inhibition of the δ isoform-specific PI3K signaling as an attractive target in lymphoid malignancies.
• Phase I and II studies by Flinn², Kahl³ and Gopal⁴ in patients with relapsed/refractory indolent B-cell NHL and MCL have demonstrated an overall response rate of 47%, 40% and 57% respectively; and a median duration of response of 18.4 months, 2.7 months and 12.5 months respectively.
• The most frequent grade 3 or above adverse events were diarrhea (defined as >7 stools/day above baseline reported in various clinical trials) and pneumonitis, which was reported to generally occur after several months of treatment (median 7.8 months).
• The triplet combination of lenalidomide, idelalisib and rituximab has shown to cause serious toxicities in clinical studies. This could be due to PI3Kδ inhibition of Treg cells resulting in both qualitative and quantitative aberrations in T-cell subsets with subsequent loss of tolerance.
• A recent study has shown that in an idelalisib–resistant ABC diffuse large B-cell lymphoma cell line, loss of phosphatase and tensin homolog expressions, upregulation of PI3Kγ, activation of PI3K and MAPK pathway, loss of c-Myc downregulation by idelalisib were recognized as potential mechanisms of resistance. 

Conclusions

The article describes an important treatment option for patients with relapsed/refractory indolent B-cell lymphoma. Most of the adverse events were manageable. Use of other PI3K isoform inhibitors are currently under development. Careful design and optimal combinations of idelalisib with other agents need to be established.

Idelalisib in the management of lymphoma

Abstract

Inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway as an anticancer therapeutic strategy was realized with the approval of the orally bioavailable small molecule PI3Kδ inhibitor idelalisib. In this focused review, we highlight the rationale for targeting the pathway in lymphomas, provide a brief summary of the preclinical data, and describe the clinical experience with this agent in patients with lymphoma. We describe some of the idiosyncratic toxicities of this agent, some of the mechanisms of resistance, and some of the ongoing combination strategies.

The complete article can be found here.