At the virtual American Society of Hematology Annual Meeting and Exposition or ASH 2020, Dr. Alexey Danilov of City of Hope was interviewed by CLL Society’s Steve Bloom on his important preclinical research to address one of the significant unmet needs in CLL/SLL/ patients: resistant to venetoclax and/or ibrutinib.
In understanding the background biology, CLL cells have learned how to increase or upregulate protein that keeps them alive. These include BCL2, MCL1, and BCLX that are anti-apoptotic or anti- suicidal “guardians” proteins. The high levels of these proteins prevent the cells from dying when they should.
That is why venetoclax is such a great CLL drug. It blocks BCL-2 and allows a mass suicide of the CLL/SLL cells while sparing normal cells that have not distorted the apoptosis or cell death pathway.
But resistance can develop to venetoclax. So one possible option to keep the chronic lymphocytic leukemia/small lymphocytic lymphoma under control is to block another of the anti-death proteins, in this case, MCL1, with the preclinical, experimental molecule AZD5991. MCL1 inhibition causes damage to the mitochondrial structure leading to rapid cell death.
How well AZD5991 will be tolerated, how well it will work with other CLL drugs, and if it should be used in combination or on its own will only be answered by clinical trials
There are no active clinical trials now, and the only one listed on ClinicalTrials.gov was suspended, so it is unclear how AZD5991 research is advancing.
Whether it is AZD5991 or a different medication, it’s a strategy that deserves serious study.
Dr. Danilov does a great job of explaining these critical concepts in the interview and the relevant ASH abstract.
Here is Steve Bloom’s interview from ASH 2020 with Alexey Danilov, MD, Ph.D.:
Here is the ASH 2020 abstract: Pharmacologic Targeting MCL1 with AZD5991 Induces Apoptosis and Mitochondrial Dysfunction in Non-Hodgkin Lymphoma (NHL) CellsThis is a complex and potentially significant topic, but Dr. Danilov makes it understandable.
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.