Venetoclax owes its origin to a lady named Eliza Hall, I bet AussieNeil has heard of her. Eliza was a lady from Melbourne Australia who married an Englishman named Walter Hall in 1874. Walter Hall and his two brothers arrived almost penniless in Australia in 1852, coming from England to search for gold. More on that later.
Those of us with cll are fortunate to have many treatment options. The main three categories of therapies available to us are chemotherapies (drugs such as FCR), immunotherapies (drugs like rituximab) and targeted therapies. Venetoclax is a targeted therapy, as are drugs like ibrutinib.
To understand the differences among these therapies requires one to have some basic understanding of cell biology and how cancer works, topics discussed in some previous dummy articles. A short summary would be that cells are the building blocks of life. We have brain cells, skin cells, blood cells, bone cells and so forth and so on. Normal human cells live and die at a constant rate. Some cells live many years, some just a few days. Our bodies replace billions of new cells each day.
All cancers come from cancer cells, cells that have corrupted dna that keep them from dying a normal death. Cancer cells can multiply rapidly, not die a normal death and create tumors that impair the function of healthy cells. Brain cancer comes from cancerous brain cells. Skin cancer is caused by cancerous skin cells. Cll is a blood cancer, specifically a cancer of a type of white blood cell known as a lymphocyte. Cll is both a leukemia (where cancerous cells accumulate in our blood) and a lymphoma (where cancerous cells accumulate in our lymph nodes).
The theory of how to best treat cancer is a simple one. Kill the cancer cells and spare the healthy cells. Figuring out just how to do that is anything but simple.
Chemotherapy, in its simplest form, is a treatment using any chemical to kill cancer cells. Chemotherapy can be compared to a dumb bomb, as opposed to a smart one. Bombs meant for military targets in world war 2 were dumb bombs. Dumb bombs freefall when dropped from planes with no guidance system. In the process of taking out an enemy ammunition dump, a dumb bomb might also hit an apartment building or, god forbid, a hospital or a playground. That's a rough analogy of how FCR works for cll. FCR cant really distinguish good cells from cancer cells. Chemotherapy kills all cells indiscriminately with the hope that the new cells produced by our marrow will only be the healthy ones.
In his never ending quest to find new ways to kill his fellow man, mankind has gotten much more efficient in doing so with the advent of smart bombs. Nowadays a precision missile could be launched from a boat in the Gulf of Mexico and fly through the window I am looking out of as I type this. We are able to kill the bad guys now with less risk to the good guys. (Opinions as to who are the good guys and who are the bad guys, though, can vary greatly).
Immunotherapy drugs, while technically not called targeted therapy drugs, in general try to target cancer cells while sparing healthy cells, just as smart bombs try limit collateral damage. Immunotherapy drugs have a different mechanism of action than targeted drugs to kill cancer cells. The way immunotherapy drugs kill cancer cells is by recruiting our immune system to do the killing.
An example of an immunotherapy drug is rituximab, the "R" drug in FCR (the F drug in the combo is fludarabine, the C drug is cyclophosphamide). Rituximab binds to a protein on the surface of cancerous lymphocytes. This is thought to be a signal to other killer cells in our immune to come find the cancerous cells and kill them. I guess it’s like giving John Travolta and Samuel Jackson from Pulp Fiction the address to your cancer cells. Its a testament to how complex our bodies work that we even have “killer cells” in the first place.
Targeted therapies are also like smart bombs, but they don't so much rely on the immune system to help kill cancer cells, they do it themselves. With cll these targeted therapies are also known as inhibitors. Ibrutinib, acalabrutinib and other btk inhibitors are targeted therapies that target the btk enzyme in cancerous lymphocyte cells. Venetoclax is an inhibitor drug that targets the bcl 2 protein.
Btk and Bcl-2? I know, what the heck? I'm supposed to be dumbing stuff down and now I'm writing about cell proteins. The truth is that its all over my head, so I will take a shot at a very gross over simplification of how these drugs target and kill cancer cells while sparing most of our healthy cells.
Remember that we are made up of cells that live and die. All of our cells have very complex functions that involve chemistry and chemical reactions. The trick to killing cancer cells, and sparing the other cells, is finding out what is different about cancer cells from normal cells, and then targeting that difference in a way that lets the cancer cell die.
It turns out that one way cll cancer cells are different from normal cells is they have too much of a protein called bcl-2. How that protein works, I have no idea (no tengo ni idea). Scientists in Australia (remember Eliza Hall) theorized that if they could find a way to inhibit the bcl protein, which is abnormally expressed in cll cells, that this would kill only the cells with too much bcl, the cancer cells, and spare the other ones. Ibrutinib works kind of the same way, just on another abnormally expressed protein known at btk.
The scientists were right. Indeed clinical trials with venetoclax showed that venectoclax so effectively targeted and destroyed cll cells such that a few brave pioneers died taking the drug in clinical trials when their systems were overwhelmed with clearing out dead cll cells in a process known as tumor lysis syndrome (TLS). Thanks to these brave souls, strategies have since developed where venetoclax is started in very small doses these days to greatly reduce the risk of TLS.
Nowadays venetoclax is offered in many places as first line treatment for cll, often in combination with Gazyva. Gazyva is new and improved immunotherapy drug like rituximab. The theory behind combining drugs with different mechanisms of action to fight cll is simple enough. If the cancer cell escapes one drug, the other one might kill it.
Ibrutinib and the other btk drugs are extremely efficient at controlling cll for most people starting out. Btk inhibitors, however, rarely eliminate cll and are usually taken indefinitely. Venetoclax and and gazyva are typically given for a fixed term and have a relatively high rate of eliminating detectable cll cells.
So why would anyone choose a btk drug over venetoclax, given the choice? It’s because just as smart bombs are no guarantee there will not be collateral damage, so it is with targeted therapies. There are off target toxicities with venetoclax and indeed, with most all cancer drugs. When you add gazyva, you add the risk fo additional toxicities. Even with targeted therapies, we get some side effects or off target effects. We do not get a free ride with any cancer drug, it’s just that some are easier on us than others.
We are all different and our cll is different. I tolerate acalabrutinib just fine. While many, if not most people, tolerate venetioclax very well, when I added it I had stomach problems and neutropenia. And while venetoclax does primarily target cll cells, for some it knocks out too many or another type of white blood cell called neutrophils which we need to fight bacterial infections. Put another way, a cll drug that works for one person might not work as well for another. While cll doctors can make educated guesses as to what drug works best for what person, often it is just a matter or trial and error.
Its hard to complain too much about the side effects of venetoclax and other inhibitor drugs, because treatment for so many other cancers are way more harsh. Venetoclax is an oral pill a day. People with some other cancers may need surgery, radiation and extremely harsh chemo agents just to have a fighting chance. Many people with other challenging illnesses would give anything to be treated with a relatively easy oral drug. I know am grateful that acalabrutinib alone is keeping my cll beast at bay right now as I live a relatively normal life.
So what does all this have to do with Eliza Hall? It turns out that her husband, Walter, did find gold in Australia, and lots of it. His mining company became a predecessor for British Petroleum. After Walter's death in 1911, Eliza used their money to establish the Walter and Eliza Hall Institute for medical research. It was scientists at that institute that discovered the bcl-2 protein in 1988 that led to clinical trials for venetoclax in Melbourne. In 2009, they partnered with Abbvie to develop venetoclax further. Venetoclax is being used now to fight other cancers as well. Eliza probably had no idea how many lives she would save with her philanthropy.
Disclaimer: I have no medical background and found most of this information on the web. Its not intended as medical advice for anyone. The decision to take or not take venetoclax should be discussed with a real doctor, preferably a cll specialist. In a attempt to dumb things down and oversimplify some very complex matters, I do not pretend that all my interpretations are scientifically accurate. This is just an attempt to give a lay person some basic idea of how chemotherapy, immunotherapy and targeted therapies work and how they are different.
It was and is confusing to me as well. One might even argue that venetoclax is a form of chemo and an immunotherapy drug as well as a targeted therapy. Venetoclax is a chemical that treats cancer, so its arguably just another type of chemotherapy. Venetoclax is thought to recruit t-cells to help kill cll cells, so it could be called an immunotherapy drug as well. I think as a general rule, however, venetoclax considered to be a targeted therapy, not chemotherapy. One might argue immunotherapy drugs that recruit the immune system are also targeted therapies in that they target cancer cells and try to spare healthy ones.
I hope in trying to dumb this down I haven't thoroughly confused everyone. I sure confused myself in the process.
PS: Well, I got a request for a garden picture. I have attached picture from one of my front yard gardens with some angelonias, vincas, red coleus, red knockout roses, spirea, crepe myrtles and a border of Joseph’s coat. (Just switched picture to a small bed in my back yard I like).
571-572, June 2022.
Ibrutinib combinations in CLL therapy: scientific rationale and clinical results
Survey for CLL patients having taken Venetoclax or Acalabrutinib
