Original Article

Leukemia advance online publication 3 February 2017; doi: 10.1038/leu.2016.382

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

V M Patel1, K Balakrishnan1, M Douglas2, T Tibbitts2, E Y Xu2,4, J L Kutok2, M Ayers1, A Sarkar1, R Guerrieri1, W G Wierda3, S O'Brien3, N Jain3, H M Stern2 and V Gandhi1,3

  1. 1Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2Infinity Pharmaceuticals Inc., Cambridge, MA, USA
  3. 3Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence: Professor V Gandhi, Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Unit 1950, 1901 East Road, P.O. Box 301429, Houston, TX 77230-1429, USA. E-mail: vgandhi@mdanderson.org

4Current address: Sanofi Genzyme, Framingham, MA 01701, USA.

Received 29 May 2016; Revised 21 November 2016; Accepted 24 November 2016
Accepted article preview online 26 December 2016; Advance online publication 3 February 2017

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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. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) 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 (RNAseq, 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 with 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.