Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199)

Abstract

Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin’s lymphoma (iNHL). In CLL, duvelisib monotherapy is associated with high iwCLL and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene-expression studies (RNA seq, Nanostring, Affymetrix array, and real time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex-vivo cultured CLL cells obtained from patients on duvelisib compared to pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.

Pharmacodynamics and proteomic analysis of acalabrutinib therapy: similarity of on-target effects to ibrutinib and rationale for combination therapy

“…Our prior investigations during therapy of CLL with ibrutinib (33), idelalisib (34), or duvelisib (35) showed similar modulation in the levels of these two pro-survival proteins, further demonstrating that this alteration in protein levels may be a common feature of BCR pathway inhibitors. Our observations are in line with dynamic BH3 profiling data, which suggested Bcl-2 dependence of in vitro and in vivo ibrutinib- and acalabrutinib-treated CLL cells (36).…”

Effectiveness of Venetoсlax in the Treatment of Chronic Lymphocytic Leukemia (Literature Review)

“…идувелисибом [29],ингибиторамиSYKцердулатини-бом [30]иэнтосплетинибом [31],атакжемультики-назным ингибитором сунитинибом [32], однако ре-зультатыиспользованиятакихкомбинацийвклинике покасистематическинеизучены. [28,33].…”

Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia

“…However, this phenomenon also provides a challenge in targeting persistent malignant CLL cells in peripheral blood. The findings of one molecular analysis [62] suggest that these cells have increased BCL2 transcript and proteins. Our clinical ex vivo pharmacological profiling studies suggest that the combination of venetoclax, an exclusive BCL2 antagonist, and duvelisib has potential benefit in CLL [62].…”

“…The findings of one molecular analysis [62] suggest that these cells have increased BCL2 transcript and proteins. Our clinical ex vivo pharmacological profiling studies suggest that the combination of venetoclax, an exclusive BCL2 antagonist, and duvelisib has potential benefit in CLL [62]. This combination is being evaluated in R/R CLL patients who have not received other anti-PI3K or anti-BCL2 therapy (NCT02640833).…”