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4192 Preclinical Evaluation of T-Cell Prolymphocytic Leukemia Demonstrates Heterogeneous BCL2-Family Dependency That May be Effectively Targeted with Small Molecule Inhibitors

Program: Oral and Poster Abstracts
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster III
Hematology Disease Topics & Pathways:
Biological therapies, Research, Lymphoid Leukemias, Translational Research, Lymphomas, Combination therapy, T Cell lymphoma, Diseases, Therapies, Lymphoid Malignancies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Vishakha Anand Pawar, PhD1, Akanksha Aradhya2*, Daniel Galvan2*, Gautam Borthakur, MD3, Swami P. Iyer, MD4, Mark Kirschbaum5*, David Blake, PhD6*, Tapan M. Kadia, MD3, Deepa Sampath, PhD1 and Francisco Vega, MD, PhD7

1Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX
2Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
5Cyclacel Pharmaceuticals, Berkeley Heights
6Cyclacel Limited, Dundee, GBR
7Department of Hematopathology, MD Anderson Cancer Center , Houston, TX

T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive, mature T-cell leukemia with very few treatment options and adverse prognosis. There are currently no approved therapies for patients with relapsed T-PLL, where the median OS is less than 6 months. There are limited reports suggesting clinical activity of the BCL2 inhibitor venetoclax in patients with T-PLL.

We aimed to characterize the dependencies of T-PLL on members of the BCL2-family of antiapoptotic proteins 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. We then sought to experimentally exploit these dependencies with targeted therapies alone, and in combination, designed to inhibit the antiapoptotic proteins towards a therapeutic goal. Cell lines of mature T cell lymphomas/leukemias (TCL/L) including SUPT11 (T-cell leukemia with rearranged TCL1) (n=10) and bone marrow and peripheral blood samples from untreated patients with T-PLL (n=7) were analyzed by BH3 profiling. We also used a relapsed/refractory T-PLL patient sample that were able to engraft and expand in a PDX model. Finally, scRNA/ATAC seq has also been performed in a set of naïve-treated T-PLL patients.

In contrast to TCL/L that demonstrated heterogeneity on BCL2 family member dependency, T-PLL samples were primed and consistently exhibited dependency on BCL2/BCL-xL and MCL1. Integration of scRNA/ATAC seq confirmed high expression of BCL2 and MCL1 in T-PLL cells from four patients supporting the premise that BCL2 and MCL1 could potentially be targeted for therapeutic benefit. Therefore, SUPT11 cells (used as a model of T-PLL) were exposed to venetoclax (25 and 50nM; BCL-2inh), fadraciclib (25 and 50nM; CDK2/9inh – indirect inhibitor of MCL-1 as it decreases mRNAs with high decay rates including MCL1 and MYC) or a combination of venetoclax and fadraciclib. We demonstrate that exposure to fadraciclib caused a rapid decline in the levels of phosphorylation on Serine 2 of RNA polymerase II C-terminal domain, as well as decline in the levels of MCL1 within 4 hours and completely depleted these proteins by 8-12 h of exposure. We also show that there was a synergistic increase both in mitochondrial dysfunction as measured by cytochrome C release by 18h and in cell death in cells exposed to the combination at 24h. These results suggest that combining venetoclax and fadraciclib might represent a potential therapeutic approach for T-PLL.

In conclusion, preclinical evaluation of a T-PLL cell line and primary patient samples demonstrate BCL2-family dependency that can be effectively targeted with small molecule inhibitors of BCL2 and CDK2/9. In vivo studies in PDX models of T-PLL are underway to form the basis for clinical trials to study these combinations.

Disclosures: Borthakur: Pacylex, Novartis, Cytomx, Bio Ascend:: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Iyer: Yingli: Consultancy, Research Funding; CRISPR: Consultancy, Research Funding; Innate: Research Funding; Acrotech: Consultancy, Research Funding; Legend: Research Funding; Astra Zeneca: Research Funding; Ono: Research Funding; Pfizer: Research Funding; Salarius: Consultancy; Drenbio: Research Funding; Merck: Research Funding; American Society of Transplant and Cellular Therapy: Speakers Bureau; CuraBio: Speakers Bureau; American Society of Hematology: Speakers Bureau; Seagen: Consultancy, Research Funding. Kirschbaum: Cyclacel: Current Employment. Blake: Cyclacel Limited: Current Employment; Cyclacel Pharmaceuticals: Divested equity in a private or publicly-traded company in the past 24 months. Kadia: Genzyme: Honoraria; Astex: Honoraria; Agios: Consultancy; Liberum: Consultancy; Cure: Speakers Bureau; Cellenkos Inc.: Research Funding; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Delta-Fly Pharma, Inc.: Research Funding; Iterion: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Novartis: Consultancy; GenFleet Therapeutics: Research Funding; Cyclacel: Research Funding; Genentech: Consultancy, Research Funding; Hikma Pharmaceuticals: Speakers Bureau; Amgen, Inc.: Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Pinotb-Bio: Consultancy; Servier: Consultancy; BMS: Consultancy, Research Funding; Janssen Research and Development: Research Funding; Glycomimetics: Research Funding; Ascentage Pharma Group: Research Funding; Astellas Pharma Global Development: Research Funding; Pfizer: Consultancy, Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Regeneron Pharmaceuticals: Research Funding; Sanofi-Aventis: Consultancy; SELLAS Life Sciences Group: Research Funding. Vega: Allogene: Research Funding; Geron: Research Funding.

*signifies non-member of ASH