Dr. Richard Furman of Weill Cornell in Manhattan is a leading researcher in CLL and one of the earliest proponents of a non-chemo approach to managing chronic lymphocytic leukemia.
Always on the cutting edge of new therapies, Dr. Furman was involved in the very earliest development of ibrutinib and idelalisib among other oral agents.
At ASH 2017 in Atlanta, Georgia, we discuss a novel target, MCL-1 that holds much promise in controlling CLL.
Take Away Points:
- Small molecules that can be taken by mouth and are not cytotoxic chemotherapy have revolutionized the treatment of chronic lymphocytic leukemia.
- Some are enzymes that inhibitor the B-cell receptor (BRC) such as ibrutinib (I) and idelalisib.
- Others are proteins that are part of a family (BCL-2) that can lead to programmed cell death (cell suicide or apoptosis) such as venetoclax (V).
- To confuse matters, BCL-2 refers to both a particular protein and also to a family of proteins. For more on this topic see Wayne Well’s helpful explanation of this topic here.
- The protein BCL-2 is “pro-life”. It stops the cell’s apoptosis by blocking the pro-death proteins BAX, BAD, and BIM that tell the cell to die
- In CLL cells, there is excess BCL-2, or in medical terms, BCL-2 is upregulated. This prevents damaged cells from dying.
- Venetoclax is a BCL-2 inhibitor that frees the pro-death protein to do their work and can lead to massive cell death. This is why venetoclax is so effective in treating CLL.
- One possible escape from this leading to resistant disease is upregulation of another pro-life protein in the BCL-2 family, MCL-1.
- There is good reason to believe that a drug that inhibits MCL-1 would be similarly effective in treating CLL and might help those whose leukemia becomes resistance to venetoclax.
- Early clinical trials of MCL-1 blockers are coming including this one using AZD5991.
Summary:
As good as venetoclax is as a single agent, there are now many studies that show even more remarkable responses occur when it is used in combination with ibrutinib or rituximab. See this on the Murano trial from ASH 2017 that combined V+ rituximab. We soon will share the V+I data from ASCO 2018.
An MCL-1 inhibitor combo with V, if safe and tolerable, might seal the deal in CLL. Only time and trials will tell.
Here is my interview with my friend and CLL Society Medical Advisory board member, Dr. Rick Furman from ASH 2017.
There are several abstracts from ASH on MCL-1 looking at the basic science such as this one.
Venetoclax has been an incredible addition to our treatment armamentarium. There is reason to hope drugs that block MCL-1 will also keep us alive even longer.
Brian Koffman, MD 5/4/18
