First-in-human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia.

Blood 2017 12 27;130(23):2499-2503. Epub 2017 Sep 27.

Division of Hematology and Hemostaseology, Department of Internal Medicine I.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development, we set out to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Mechanistically, responses to venetoclax correlated with protein expression of BCL-2 but not with expression of the BCL-2 family members myeloid cell leukemia 1 (MCL-1) and BCL-XL in lymphoma cells. BCL-2 expression was inversely correlated with the expression of MCL-1. Based on the ex vivo responses, venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in clinical responses. Our findings demonstrate first evidence of single-agent activity of venetoclax both ex vivo and in humans, offering a novel agent in T-PLL.

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2017-05-785683DOI Listing
December 2017
75 Reads

Publication Analysis

Top Keywords

prolymphocytic leukemia
8
bcl-2 expression
8
expression bcl-2
8
t-pll patients
8
lymphoma cells
8
responses venetoclax
8
inhibitor venetoclax
8
t-cell prolymphocytic
8
bcl-2 inhibitor
8
bcl-2
5
venetoclax
5
treatments t-pll
4
abt-199 demonstrated
4
venetoclax treatment
4
demonstrated strongest
4
vivo responses
4
effective treatments
4
b-cell lymphoma
4
lymphoma bcl-2
4
based vivo
4

Similar Publications