abt-199 and Leukemia--Prolymphocytic--T-Cell

Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alemtuzumab, have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and T-cell receptor pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Prolymphocytic, T-Cell; Male; MAP Kinase Signaling System; Middle Aged; Neoplasm Proteins; Nitriles; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Humans; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; Male; Middle Aged; Nitriles; Pyrimidines

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Female; Humans; Leukemia, Prolymphocytic, T-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Sulfonamides

Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where

Topics: Animals; Antineoplastic Agents; Apoptosis; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Synergism; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leukemia, Prolymphocytic, T-Cell; Male; Mice; Molecular Docking Simulation; Molecular Structure; para-Aminobenzoates; Pyrrolidines; Structure-Activity Relationship; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; Pentostatin; Sulfonamides; T-Lymphocytes

Topics: Adult; Alemtuzumab; Bridged Bicyclo Compounds, Heterocyclic; Epigenesis, Genetic; Humans; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; Lymphoma; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sulfonamides; T-Lymphocytes

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.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; High-Throughput Screening Assays; Humans; Leukemia, Prolymphocytic, T-Cell; Male; Middle Aged; Molecular Targeted Therapy; Proto-Oncogene Proteins c-bcl-2; Recurrence; Sulfonamides; Treatment Outcome

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Humans; Leukemia, Prolymphocytic, T-Cell; Sulfonamides