In this Blood Cancer for Dummies article the focus is on clonal evolution which is the process by which cancer cells can acquire resistance to treatment. The example taken is CLL, but similar mechanisms may occur in some other blood cancers so the principles are worth understanding for all of us.

Blood Cancer for Dummies

We all know about Darwin’s theory of evolution and natural selection. A common example is the idea behind how giraffes got long necks. As food became scarce on the lower limbs of trees eons ago, long neck giraffes grazed on higher limbs as short necked giraffes starved. Fast forward thousands of years and it is the giraffes with the long neck genes that survived. The giraffes evolved and the long neck versions were “selected” over the short necks for survival.

And so it is with cells. Cells are living organisms and the building blocks of life. Our body has a hundred million million or so cells at any given time. We have about a million cells per second die and a million or so born each second to replace them.

CLL is a cancer of a particular type of white blood cell known as a lymphocyte. For unknown reasons our the chromosomes in our lymphocytes can be damaged. This damage can occur on one of several chromosomes. Our X shaped chromosomes have genes up and down all four arms that tell cells what to do. When we have blood cancer, our lymphocyte cells get bad instructions from damaged genes and do not live and die as normal cells do, they accumulate in our blood and in our lymph nodes.

Just as animals can evolve, so can our cancerous cells. And our blood cancer cells can evolve in a way that makes them harder to kill. It is as if every living thing, cells included, will adapt and change to increase its survival chances.

Clonal evolution of our blood cancer cells is important to us on many levels. It plays a role in why we watch and wait and what treatments we choose. Let me pose this question to you which we will come back to. Which treatment strategy would you choose for blood cancer? Would you choose a drug that controls your blood cancer long term, but does not get a remission? Or would you rather a drug that gets you in a long, MRD negative remission? (MRD means minimal residual disease and being MRD negative or MRD undetectable means modern testing cant find any blood cancer cells).

I am going to use an example I used in an earlier post this year to help illustrate how blood cancer treatment choices can cause clonal evolution. Its an imperfect analogy, but easy to understand.

Imagine your healthy white blood cells as the leaves of grass in a lush, beautiful yard. Imagine any weeds that come along as blood cancer cells. To complete the analogy, we will compare the herbicides we use to kill weeds to our CLL drugs like FCR, venetoclax and ibrutinib.

As most know, we have varieties of CLL that carry a different prognosis based upon the chromosome they are located on. 13q CLL is CLL where there is damage to the long arm (q arm) of the 13th chromosome. Trisomy is CLL with too much material on the 12th chromosome. 11q CLL is where a part of the long arm of the 11th chromosome is missing. 17p CLL is here part of the 17th chromosome is missing. Unfortunately, with 17p what is missing is the TP53 gene, our most important cancer fighting gene.

If CLL cells are weeds, 13q weeds are shallow rooted and easy to kill. Trisomy weeds are bit more stubborn. 11q weeds are big and lumpy. 17p weeds are the worst – prickly, deep rooted and resistant to many herbicides.

A FISH test looks at our chromosomes to see which ones are damaged. If a FISH test looked at 200 cells and found 35% of them had deleted genes at the 13th chromosome, then you have 35% of your pretty yard infested with 13q weeds.

Suppose the FISH test said you were negative for 11q and 17p weeds? That means you have none of the bad weeds, right? Not exactly. If you had only a few 17p cells (or weeds in our analogy), say 5 out of 200, it might still be reported as 17p negative in your FISH report. Depending on the lab, you might need more than 10 or 15% 17p cells of the 200 to be considered 17p positive.

So in our analogy lets assume the 13q weeds are starting to cause problems. You have left them alone for may years but now they are everywhere. You can wipe them out with a six month spraying of FCR. Or you can apply ibrutinib every day and keep them at bay. Which one do you do?

FCR is a great 13q weedkiller, but not so good at killing 17p weeds. If you dont have any 17p weeds, great, FCR might cure your yard of all weeds forever. But what if you just have a few 17p weeds you do not even know about? Sure, FCR will mop up all the easy to kill 13q weeds. But if any 17p weeds are left behind, you have wiped out its competition. You might have had a nice five year weed free remission, but if the weeds come back you could have a yard filled with prickly, deep rooted, stubborn 17p weeds. Or maybe now you have those lumpy 11q weeds everywhere. That’s clonal evolution, your CLL cells have evolved.

Why do we watch and wait? Its because as bad as it was having a yard full of 13q weeds, they were not causing much trouble. We can possibly accelerate clonal evolution with our treatment choice.

Now it might be that you had no 17p weeds when you sprayed FCR. A lot of people with mutated IGHV cll do not have any 17p weeds in the background and their yard is cured with one spraying of FCR.

Suppose someone used ibrutinib on their yard instead of FCR? Would it “select” for the 17p weed too? That is what they are trying to figure out. Unlike FCR, ibrutinib does work on 17p weeds, it works on all CLL weeds. But it controls the weeds as opposed to killing them all. There is thinking that for many who start with ibrutinib as their first treatment, so long as they take that pill a day for their yard every day, it will not “select” for 17p weeds in the same way FCR does. Your yard might not ever be free of weeds, but all weeds will stay under control as long as you apply ibrutinib.

So now lets go back to the question we posed. Should our treatment goal be remission and MRD negativity? Or should it be long term disease control? That answer might be different for different people. If FCR gives someone a permanent remission, that was a great choice. But if someone has a five year remission that leaves them with tougher weeds, long term control with ibrutinib might have been better.

In my view, remission is not the holy grail. Overall survival time should be the goal, which treatment plan keeps me alive the longest? If controlling CLL keeps me alive longer than periodic remissions, that’s what I choose.

But that does not really answer the question for everyone deciding what herbicide to use and when. Rather it should inform people in a way where they can ask their doctors the right questions. Will remissions with combinations like venetoclax and ibrutinib be durable and even cure CLL? Or will also they select for harder to treat CLL weeds down the road?

And it might not be a one size fits all answer. Overall survival for one group might be better with FCR and for another group, better with novel drugs.

What to do with this information? Use it to ask the right questions. If I am choosing FCR, can they look deeper at my FISH results to see if there are any tiny clones unreported? If 2 of my 200 tested cells were 17p, a negligible amount, am I at risk of FCR selecting that tiny clone? Or does the potential for cure outweigh that risk?

Do drugs like ibrutinib and venetoclax also carry a risk of accelerating clonal evolution? If not, does that change the watch and wait paradigm? If ibrutinib is not going to select for a bad clone, why not start it early rather than wait until a bad weed grows on its own ?

These are the questions experts are trying to answer with ongoing trials. And these super qualified experts are not all of the same mind. Some favor going for MRD negativity and drug free remissions. Doctors like Dr Furman do not see a role for chemo and think progression free survival length is the most important metric. Put another way, Furman thinks if you can control CLL indefinitely with drugs like ibrutinib, that is better than even a ten year remission if at the end of the remission you have hard to treat CLL.

I hope I have not thoroughly confused everyone. My hope is we get combination therapies that are the best of both worlds, that is, drug combination that give us long drug free remissions without selecting for harder to treat CLL.

I think CLL cells are like animals and bacteria evolving to stay alive. We either need to make it extinct or we need to have evolving herbicides that stay ahead of it.

Editor’s note: The general principle in this excelent illustration is that sometimes cancer cells can become resistant to the weed killers that we use. What we simply do not know is if you blast them with weed killer to attempt to destory them all then do not apply anything for a while, when the weeds grow back will they be hard to treat or still easy to treat.

And of course the weed killers ibrutinib and venetoclax can also give rise to mutations making the weeds become resistent to them though many people are able to take these newer treatments for years successfully as outlined. Would using at least two of the new wonder drugs together in a super blast make it much less likely that the weeds can survice at all, or if they do grow back they would stil be resistant to the combination since a mutation would only protect against one of the two or three treatments.

Right now if you do not want FCR (or have had it for one series already) depending on your health system you may be able to choose to try Venetoclax plus rituxumab (or newer more selective obinituzimab), or monotherapy ibrutinib (or maybe newer more selective acalabrutinib). In the UK the FLAIR trial is comparing Venetoclax plus ibrutinib vs ibrutinib alone vs FCR.

Another study is throwing all three main differnet types of modern selective weed killer into the mix looking at acalabrutinib plus venetoclax plus obinituzimab. Sounds a potent mix and the hope is that it might just be the new gold standard. Obviously the clinical trial needs to be completed to be find out for sure how well it works, and there will then be a nice new crop of people who’s weed garden is wiped out (sadly often the healthy lymphocytes get wiped out whichever weed killer we use….) and we will all hopefully watch as man of them get really long remissions.

Two strategies that are outlined nicely by Jeff and ultimately only you can decide which one fits more comfortably for you if treatment emerges. But a true CLL expert will guide you through the maze and try and match the treatments to your specific situation and philosophical make up. Some of us just want to smash things up a bit, whilst others want to aim for a more peaceful long term co-habitation with our weakened weeds!