Emerging Targeted Therapies Under Study in CLL
Posted: Friday, October 1, 2021
Alexey V. Danilov, MD, PhD, of the City of Hope National Medical Center, Duarte, California, shared his perspective on up-and-coming targetable pathways in chronic lymphocytic leukemia (CLL). During the 2021 Society of Hematologic Oncology (SOHO) Annual Meeting, Dr. Danilov explored agents formulated to inhibit the BCL2 family proteins due to possible cell susceptibility and the inevitable resistance of CLL to standard targeted agents (EXABS-196-CLL).
The highly selective BCL2 homology domain 3 (BH3) mimetic AZD5991 has shown an in vitro capability to inhibit MCL1, a regulator of apoptosis, noted Dr. Danilov. Furthermore, it appears that direct inhibition of MCL1 induces mitochondrial dysfunction, disrupts the survival of neoplastic B cells, and cooperates with inhibitors of BCL2/X. A phase I clinical trial is underway to evaluate AZD5991 alone or in combination with venetoclax in various blood cancers (ClinicalTrials.gov identifier NCT03218683).
AMG-176, another MCL1-inhibiting BH3 mimetic, was shown to work well with venetoclax, according to Dr. Danilov. It induced apoptosis of CLL cells and overcame the stromal microenvironment barrier, but it also caused cytopenias. Interestingly, when the small-molecule inhibitor S63845 was used on cord blood–derived CD34-positive cells, investigators observed an almost complete depletion of progenitor and human hematopoietic stem cells, with the survival of mature blood cells.
Indirect inhibition targeting spleen tyrosine kinase (SYK) with entospletinib has been shown to downmodulate the MCL1 protein in CLL, prompting clinical development for use in myeloid malignancies. In addition, Luxeptinib, a dual SYK/Bruton’s tyrosine kinase inhibitor, has also demonstrated downregulation of the MCL1 protein and other BCL2 proteins in CLL.
AZD4320, an agent that co-targets BCL2/X, is currently being developed as an intravenous formulation for CLL, as current preclinical studies show increased sensitivity and antitumor effect in myeloid and lymphoid cell lines compared with venetoclax. ABBV-155 is an antibody-drug conjugate that targets BCLX and has demonstrated success in solid tumors.
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