Chromosome changes?

[Pokerguy]

Had a FISH done last May which presented 13q deletion. Then after 6 rounds of Chemo and a year later another FISH presents as 13q and 17p deleted. I was under the impression that my chromosomes were my chromosomes and are the same since birth. Can someone explain how changes can occur? Is it the progression of CLL or can the chemo impact it? And does anyone know where I can get efficacy information on treating 17p with Calquence and Venteclax?

[seelel]

Sorry to hear about the 17p. There are a few questions to be answered:

1. The deletions at chromosome 13 and 17 are on your CLL B-cells only. The rest of your cells don't contain these deletions.

2. In CLL there is something termed, 'clonal evolution'. This can be triggered by therapy or happen as part of natural disease progression.

3. In your case, the deletion on chromosome 17p may have happened either way. The 17p deletion may have been present at the time of your 1st FISH test, but not circulating in the peripheral blood. The bone marrow, the spleen, and hundreds of lymph nodes around the body are places where these cells could have been concealed.

4. If therapy didn't cause the deletion (it may or may not have), then once the CLL cells with the 13q deletion have been cleared, the cells with the 17p deletion may emerge in an opportunistic manner.

5. There is no absolute certainty in all this............

[Pokerguy in reply to seelel]

Thanks for the information, it does provide clarity.

[AussieNeil Administrator]

Your CLL arose because of chromosomal changes in just one originating B-lymphocyte. Every time a CLL cell divides, as the chromosomes are copied more errors can creep in, This is called clonal evolution and it's how sub-clones with additional chromosomal deletions occur. The FISH test checks for common chromosomal causes of CLL.

Cancer arises because of chromosomal errors reducing the effectiveness of the error checking and repair process after cell division. Normally, when an error is found, processes are implemented to repair the DNA damage in the relevant chromosome(s) and if that process fails, then other processes are triggered so the cell undergoes programmed cell death (apoptosis).

Sub-clones arise over time, which is why it is important to have a FISH test before starting treatment to determine which treatment will work best. During treatment, any sub-clones that are more resistant to the treatment are more likely to survive, so eventually they become dominant through this selective pressure. Chromosomes have two arms, the small (petite, hence p) arm with the larger arm labelled the q arm. The 17p chromosome arm contains the TP 53 gene, know as "the guardian of the genome". Chemoimmunotherapy is reliant on having a functional TP53 gene to identify that CLL cells which cloned in the presence of the chemo have irreparable DNA errors induced by the chemo, triggering apoptosis. It's common to develop 17p del after chemo - it's a significant reason why it works less well a second time. How well subsequent chemo will work depends on what percentage of the CLL has the 17 p del sub-clone, where the deletion has occured (i.e. is the TP 53 gene intact) and whether one or both halves of the chromosome from each of your parents are impacted.

The targeted therapies calquence and venetoclax cause CLL cells to undergo apoptosis by blocking 'keep alive' signals, so there isn't the reliance on a functional TP53 gene. There are regular updates to our community on how patients with 17p del or mutated TP53 perform on these and other newer drugs. Keep an eye out for the results from longer term study updates. The results are quite promising.

Neil

[Pokerguy in reply to AussieNeil]

Thanks Neil, I thought the chemo may have impacted. I’m having a tough time finding any efficacy information. Most everything I found was for “previously untreated” CLL, not after a course of chemo treatments. Obviously from my name you can tell that I need statistics, what are my odds? What is statistical longevity?

[AussieNeil Administrator in reply to Pokerguy]

Are you particularly interested in the monotherapy results or in combination? The reason I suggested keeping an eye out for updates is that both calquence and venetoclax are new drugs, so the long term results are still on the way, particularly when used in combination (which should be a very effective combination). I'm surprised you can't find stats for those previously treated with chemo, because most of the trial participants for the targeted drugs like calquence and venetoclax are for relapsed/refractory patients, particularly with 17p del or TP53 mutated CLL - simply because chemo no longer works that well for those patients!

Look through my maintained post on all the approved and CLL clinical trial BTKi drugs here: healthunlocked.com/cllsuppo...

Also look at my later lengthy reply to that post on alternatives to BTKis and combination treatments (also updated regularly). Search within the post for 17p.

Neil

[larrymarion in reply to Pokerguy]

Allow me to offer some supplemental advice to what AussieNeil offered. As you've figured out, he's an expert. I've dealt with cll for 16 years, including 7 years using ibrutnib and venetoclax. Together they put me into uMRD, otherwise known as no disease found in my blood ( i had 11q and several other bad markers, so i was considered high risk patient). so i'm a veteran rider at this rodeo.

combining Venetoclax with either a BTK inhibitor, other novel agent or something else , is definitely the way to go. Aussieneil hinted at the combo approach and he's right on. While the long term combo approach data re not yet in, the experts and us patients are betting that the novel agent combo approach is the most effective way to knock out CLL/17p, at least temporarily. BTW, you don't waNt to wait for long term data, by definition.

YOu should keep in mind that the novel agents like ibrutinib, calquence and venetoclax are extremely expensive. Finding a clinical trial of a combination of these drugs, or their close cousins (i'm talking about you, Zanabrutnib) would be a smart strategy.

getting a second opinion on treatment and clinical trial options from a cll expert would also be a good idea. the cllsociety offers FREE second opinion help and your situation begs for more views.

For example, there is another super anti CLL drug called Loxo 305 in clinical trials. it has defeated CLL that has prevailed in patients who have tried everything else. While you may not need that stuff, it's great to have a conversation with someone who can discuss all of the alternatives.

While you should be annoyed and disappointed that your 13p morphed into 17p, you should be relieved that the new stuff will really do a number on 17p. And the best news is that Venetoclax isn't nasty--very minor side effect profile for most people.

[Pokerguy in reply to larrymarion]

Thanks Larry, good news, thanks for the advice.

[studebaker in reply to AussieNeil]

Neil, I am wowed at the depth of your knowledge 👍🏻 and Thank you for educating the rest of us.Dana

[cajunjeff]

Here is an article I wrote as an amateur Cll non expert patient describing how treatments can accelerate our Cll to morph into a harder to treat Cll. It’s my admittedly amateurish take on clonal evolution:

healthunlocked.com/cllsuppo...

[Pokerguy in reply to cajunjeff]

Thanks Jeff, a wealth of knowledge there. It’s much appreciated

[neurodervish]

Pokerguy, I'm curious if you've had the IGVH mutation test. Patients who are unmutated can have their chromosomes mutate into a worse chromosome, whereas mutated patients remain stable. It sounds counter-intuitive, but that's how it works. Think of 13q FISH designation as the breaks on this disease, but unmuated IGVH designation as the gas pedal.

"It is important to test IgVH (also called IgHV, both are correct) mutation status. IgVH mutation status almost never changes over time, so it is generally not recommended that it be retested. It is important because we know that patients with a “mutated” IgVH immunoglobulin do much better with FCR based therapies than those who are unmutated. Generally only patients who have mutated IgVH should consider FCR based therapies." from cllsociety.org/docs/CLL%20T...