Page 86 - Haematologica Vol. 110 - January 2025

ARTICLE - Chronic Lymphocytic Leukemia
LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax- resistant chronic lymphocytic leukemia
Janani Ravikrishnan,1* Daisy Y. Diaz-Rohena,2* Elizabeth Muhowski,1 Xiaokui Mo,3 Tzung-Huei Lai,1 Shrilekha Misra,1 Charmelle D. Williams,2 John R. Sanchez II,2 Andrew Mitchell,1 Suresh Satpati,4 Elizabeth Perry,1 Tierney Kaufman,1 Chaomei Liu,2 Arletta Lozanski,1 Gerard Lozanski,1 Kerry A. Rogers,1 Adam S. Kittai,1 Seema A. Bhat,1 Mary C. Collins,5 Matthew S. Davids,5 Nitin Jain,6 William G. Wierda,6 Rosa Lapalombella,1 John C. Byrd,7 Fenlai Tan,8 Yi Chen,8 Yu Chen,8 Yue Shen,8 Stephen P. Anthony,8 Jennifer A. Woyach1# and Deepa Sampath2#
1Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH; 2Division of Hematopoietic Biology and Malignancy, MD Anderson Cancer Center, Houston, TX; 3Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH; 4Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX; 5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 6Department of Leukemia, MD Anderson Cancer Center, Houston, TX; 7Department of Internal Medicine, University of Cincinnati, Cincinnati, OH and 8Newave Pharmaceutical Inc., Pleasanton, CA, USA
*JR and DYD-R contributed equally as first authors. #JAW and DS contributed equally as senior authors.
Abstract
Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the B-cell lymphoma 2 (BCL2) in- hibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demon- strated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax-naïve and -resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells express- ing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eμ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax-responsive and -relapsed CLL.
Correspondence: D. Sampath DSampath@mdanderson.org
J.A. Woyach
JenniferWoyach@osumc.edu
Received: Accepted: Early view:
October 11, 2023. July 30, 2024. August 8, 2024.
https://doi.org/10.3324/haematol.2023.284353
©2025 Ferrata Storti Foundation Published under a CC BY-NC license
Introduction
In chronic lymphocytic leukemia (CLL), upregulation of the anti-apoptotic protein B-cell lymphoma 2 (BCL2) allows cells to evade apoptosis by sequestering pro-apoptotic proteins containing BCL2 homology 3 (BH3) domains. Venetoclax is a first-in-class BCL2 inhibitor approved for the treatment of CLL in front-line and relapsed settings. In combination with anti-CD20 monoclonal antibodies, venetoclax produces re- sponse rates of over 80% and durable remissions.1,2 However, patients progressing on venetoclax often do so due to one
or more resistance mechanisms.3-9
One recurring mechanism of venetoclax resistance in CLL is the acquisition of a G101V point mutation in BCL2 result- ing in a conformational change in the binding pocket which reduces its binding affinity for venetoclax.5 Our group and others have identified other novel point mutations in BCL2 in patients who relapsed with venetoclax therapy, including D103Y/E/V, F104L, L119V and duplication in R107_R110.3,4,6 Aberrations in the tumor suppressor gene TP53 are another marker of progression on venetoclax.9 Lastly, resistance to venetoclax can arise from upregulation of other members
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