“FISH” testing: necessary, but not sufficient
Probably the single most important CLL clinical trial conducted in the last few years is the recent FCR versus FC double arm and large scale study done at multiple European centers. For a change, we have reasonably clear answers on who is likely to benefit from FCR front-line therapy. Almost as important, we have clear guidance on who is not likely to benefit and therefore should not be looking at FCR as their front-line therapy of choice. The results were very clear. Patients with 17p deletion got dismal results whether they used FC or FCR. I thought I would recap the details of this important result.
While the news is gloomy, hardly any of the patients with 17p deletion got a full fledged CR response, it is nevertheless important to recognize the value of this negative result. Why on earth would you want to waste time, effort, money, expose yourself to the undeniable toxicity of either FC or FCR and take it on the chin with respect to potential loss of quality of life, if at the end of 6 months of therapy neither of the two regimens (FC or FCR) is going to give you a half way decent response / remission? If you are in the group of patients with 17p deletion, you are much better off knowing the hard truth ahead of time so that you can explore other and more promising therapy options (Campath, Revlimid, experimental drugs such as flavopiridol and more recent drugs in the pipeline) in order to get a decent remission en-route to a possible mini-allo transplant. Waiting too long dithering or trying unlikely choices may cost you crucial window of opportunity. There is no point in wishful thinking when dealing with high risk CLL – we have to learn to accept reality if we are to play the hand we are dealt to best advantage.
Which brings us to the important issue of FISH testing. It is clear that patients with clinically aggressive CLL (rapidly growing white blood counts, enlarging lymph nodes, nasty B-symptoms) in imminent need of therapy should get tested for their FISH status. If they have clearly identified 17p deletion, FCR is most likely not a good choice. But how about the other side of the equation, does lack of 17p deletion by FISH testing give clear and unambiguous guidance that they do not have to worry about this particular hiccup?
Chromosomal abnormalities in CLL
FISH test is used to see if any important bits of chromosomes are broken off, if there are less or more than the standard two copies of each chromosome. We have discussed FISH test in prior articles, both on this website as well as our flagship website www.clltopics.net . Given its growing importance in how CLL is treated, I think it is important that you understand the value as well as limitations of this important prognostic test.
Each cell (barring egg or sperm cells) in your body has a full set of chromosomes and that is true of the CLL cells as well. We get two copies of each chromosome. In this article we will focus on the 17th chromosome. There are two copies of chromosome 17, just as all the other chromosomes. On the short arm of the 17th chromosome is an important gene that controls how cells that are badly damaged are made to die in an orderly fashion. This gene, called TP53 gene, is particularly important in controlling cancer cells. Cancer cells are dysfunctional cells by definition and it is the job of the TP53 gene to make sure such damaged cells are easily killed. When TP53 gene is not doing its job, cancer cells get a huge advantage. Even in their mangled and cancerous state they can ignore all orders to commit suicide. Even powerful chemotherapy agents such as fludarabine and cyclophosphamide are next to useless in killing these refractory cancer cells. Typically we use the shorthand notation of 17p, but the detailed street address is 17p13.1. The resident living at that street address is the TP53 gene. The main job of the resident (TP53 gene) livingh at this address (17p13.1) is to manufacture a kind of suicide pill (p53 protein), if you will, so that the cell can die a decent death when that becomes necessary.
Remember, each cell has a pair of 17 chromosomes. In other words, each cell has a pair of TP53 genes, two ‘alleles’ or copies. Does it matter if only one of the two TP53 genes is broken off, deleted, but the other one is intact and doing its job exactly as it should? Yes, that makes a difference. Single allele 17p deletions are better than double allele 17p deletions. Having at least one working TP53 gene is better than none. But there is more to this story and it complicates life for patients with aggressive CLL. Very often, with one of the TP53 genes broken off, the second of the pair develops problems down the road. Even without frank deletion, the ability of this second TP53 gene to function may get compromised, as we describe below.
Present, but not doing its job
Recently I have had to register my car, get driver’s license etc at the local Motor Vehicle Administration in Maryland. I went in around 10:00am. There were more than a dozen windows open for business. A couple of them had their clerks on indefinite coffee break, no work getting done at their stations. But even among the windows that had a clerk bodily present, several were busy gossiping with their colleagues or doing something other than taking care of business. Net result was that while many windows were open, there were long lines and I had to wait several hours before taking care of my business.
What happens when TP53 genes are physically present but not doing their job? What are they supposed to be doing anyway? Think of genes as “how-to“ manuals, they provide instructions on how to manufacture very complicated and precise proteins. In the final analysis, all of the work of the cell is done by these proteins. TP53 gene has the crucial instructions on how the cell can make protein p53, the ‘suicide pill’ we discussed above. If the cell does not know how to make this very important protein in the right quantities, the cell forgets how to die. It also becomes very hard to kill even when we kick it in the butt with powerful chemotherapy drugs.
FISH test uses probes looking for physical presence of specific genes. The usual CLL FISH panel uses a set of four probes, looking for presence of specific genes at the 13q, 11q and 17p locations as well as verifying there are only two copies of chromosome 12 (Trisomy 12 means there are three copies of this chromosome, instead of the standard 2 copies). These are the four questions asked in a typical FISH test; and like the Oracle of Delphi, the FISH test only answers the questions it is asked. It stays silent on all other issues. For example, it will shed no light on deletions on the long arm of the 6th chromosome – and a small minority of CLL patients do have 6q deletion as their chromosomal abnormality – unless the correct probe looking for this particular abnormality is also used in the test. And most important, the FISH test has nothing to say on the subject of whether the genes in question are doing what they are supposed to do, make the necessary protein correctly and not malingering or asleep at their job.
There are three common reasons why patients may have 17p malfunctioning. The most obvious is 17p deletion, easily detectable by the standard CLL FISH panel. But it is also possible that the TP53 gene is physically present but messed up (mutated TP53) in some fashion so that the protein it makes is not quite right and useless in doing the job of killing the cell that needs to die. The third reason why 17p malfunction can happen is that the TP53 gene is present, there is nothing wrong with it – no mutation etc – but it is so covered up with gunk of various sorts that for all practical purposes it is hog-tied and cannot do its job. This is called“epigenetic silencing” of the gene and a very interesting field of research.
So, to summarize, TP53 function can become compromised for three reasons:
- 17p deletion where the TP53 gene is broken off and p53 protein production comes to a halt. This defect can be detected by FISH testing.
- 17p mutation where the TP53 gene is present but messed up subtly and therefore the p53 protein it makes is also messed up and useless.
- 17p silencing where the TP53 gene is willing and able to make the right p53 protein but it is covered up with gunk and cannot do its job.
Does mutation and / or silencing of TP53 gene function cause as many problems as breaking off and deletion of this important gene? The abstract below is clear in its implications.
J Clin Oncol. 2010 Oct 10;28(29):4473-9. Epub 2010 Aug 9.
TP53 mutation and survival in chronic lymphocytic leukemia.
Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, Bühler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Döhner H, Stilgenbauer S.
University of Ulm, Ulm, Germany.
Abstract
PURPOSE: The precise prognostic impact of TP53 mutation and its incorporation into treatment algorithms in chronic lymphocytic leukemia (CLL) is unclear. We set out to define the impact of TP53 mutations in CLL.
PATIENTS AND METHODS: We assessed TP53 mutations by denaturing high-performance liquid chromatography (exons 2 to 11) in a randomized prospective trial (n = 375) with a follow-up of 52.8 months (German CLL Study Group CLL4 trial; fludarabine [F] v F + cyclophosphamide [FC]).
RESULTS: We found TP53 mutations in 8.5% of patients (28 of 328 patients). None of the patients with TP53 mutation showed a complete response. In patients with TP53 mutation, compared with patients without TP53 mutation, median progression-free survival (PFS; 23.3 v 62.2 months, respectively) and overall survival (OS; 29.2 v 84.6 months, respectively) were significantly decreased (both P < .001). TP53 mutations in the absence of 17p deletions were found in 4.5% of patients. PFS and OS for patients with 17p deletion and patients with TP53 mutation in the absence of 17p deletion were similar. Multivariate analysis identified TP53 mutation as the strongest prognostic marker regarding PFS (hazard ratio [HR] = 3.8; P < .001) and OS (HR = 7.2; P < .001). Other independent predictors of OS were IGHV mutation status (HR = 1.9), 11q deletion (HR = 1.9), 17p deletion (HR = 2.3), and FC treatment arm (HR = 0.6).
CONCLUSION: CLL with TP53 mutation carries a poor prognosis regardless of the presence of 17p deletion when treated with F-based chemotherapy. Thus, TP53 mutation analysis should be incorporated into the evaluation of patients with CLL before treatment initiation. Patients with TP53 mutation should be considered for alternative treatment approaches.
PMID: 20697090
Editorial
I try very hard to distinguish between research findings and expert comments that I report in my articles from my own editorial comments. That way you know when you are reading expert testimony and when it is only my two cents. What are the implications of the limitations of FISH testing?
For starters, the clear guidance in the abstract above is that we need better and more comprehensive tests. Since FISH is limited to telling us whether or not a particular gene is present or broken off, we need to move down the chain, we need to be able to test for properly functioning p53 protein. When rubber meets the road, who cares whether the TP53 gene is present, what is important is whether or not it is able to make the right amount of properly functioning p53 protein. Testing for proteins is not quite as easy as testing for genes. But it can be done. It is done even as I write this article, as part of research programs in expert centers. What we do not have is access to this testing technology in commercial testing labs. Heck, IgVH gene mutation status test was not available to CLL patients outside of research centers, just a few years ago. CLL Topics went through significant amount of hassle before we were able to get Quest Diagnostics to put together a CLL prognostics package. Other testing labs soon followed suit when they saw it was profitable business. It was our first and possibly most important patient advocacy effort. What we need is a similar campaign to get p53 protein testing within the reach of CLL patients. We need commercially available testing capability for this very important protein. Since the p53 protein is also important in predicting aggressiveness of many other cancers, we are not the only group of patients interesting in this prognostic testing capability and that should make the job easier. Anyone out there willing to take on this important advocacy job?
In the absence of reliable testing for properly functioning p53 protein, we must understand FISH test results are not the whole story. Lack of 17p deletion does not guarantee lack of malfunctioning p53. Your FISH test may look great, but if your CLL is clinically aggressive and the first couple of cycles of FCR do very little by way of controlling your disease, it may be time to pause, and re-think your treatment strategy. Perhaps you are one of the unlucky group that has 17p dysfunction without FISH detectable 17p deletion.
Interrupting therapy mid-stream is not an easy decision to make and not one that should be taken lightly. But it is important to consider what is at stake here. If nothing much is happening after the third cycle, if the lymph nodes are just as large as ever or even getting bigger, should the patient be put through the trauma and toxicity of another three cycles of FCR? When does the process become wishful thinking? I must confess I have no easy cheat-sheet answers on this one. Each of you who finds yourself in this situation must make the choices based on your own situation after careful consultations with your doctors.
Before we leave the subject of FISH test and its lack of completeness, I would like to address the subject of “normal” FISH result. I have no idea how this term got to be mainstream, the lab-tech who chose this term should be taken out and shot. A “normal” FISH result does not mean there is no chromosomal abnormality. The fact that the patient has CLL means there is one of more chromosomal abnormality – that much is guaranteed.
Since FISH test restricts itself to just 4 probes, the answers it gets are just as restricted. “Normal” in this context just means “none-of-the-above” or “we-don’t-know-what-it-is”. Can patients with “normal” FISH result have some chromosomal abnormality that is less common, such as the 6q deletion, that is not usually tested for? Absolutely. Can it be that in patients who have no deletion of any kind, the driving force behind their CLL is mutation or epigenetic silencing of some important tumor control gene, such as the TP53 gene we have discussed above? ABSOLUTELY!
“Normal” FISH result is a pig in a poke. It could be something relatively minor, predictive of a low risk variety of CLL. On the other hand, it could be something as dangerous as damaged (but not deleted) TP53gene. We just don’t know. In this context, it is interesting to note that in the FC versus FCR European study patients with “normal” FISH result did not do very well with FCR. I wonder how many of them were actually TP53 dysfunctional, destined to have poor response to FCR from the get-go.
Moral of the story, get your FISH test done if you have aggressive CLL. You need to know if you have the high risk 17p (TP53 gene) deletion since that will impact therapy decisions. You still won’t know about TP53 gene malfunctioning due to mutation or silencing – that can only be guessed at by how you actually respond to therapy. Stopping FCR therapy mid-stream because of lack of response is a bit like shutting the barn door after the horse has gone over the fence. But it might still be worth considering all the same, to prevent the rest of the horses from bolting as it were, avoid further damage.
Site news
I am happy to report my eye problems are resolved, more or less. I made an emergency flight back from India, went straight from the airport (short detour enroute to get a much needed shower) to consultation at the Wilmer Eye Clinic (Johns Hopkins) and straight into surgery. After 200 or so laser jabs, the surgeon pronounced he has managed to repair / stabilize the tear in the retina of my left eye. I was lucky. It could have become full fledged detachment of the retina and possible loss of vision. As it is, I am typing with a huge number of black spots dancing around in front of my left eye, like a horde of gnats and cobwebs. The good news is that now I have a built-in excuse for poor spelling and punctuation.
38 comments on "When “FISH” Results Can Be Mis-leading"
Chaya,
So happy your surgery was successful! The irritating spots will hopefully clear up soon!
Thank you for continuing to point out things that are nuanced and may not be considered otherwise. Even when you have things going on personally, you are still a wonderful advocate and friend to those with CLL and their families. I really appreciate it!
Sorry to hear about the eye, glad it’s on the mend. Did you get the peripheral flashes of light at night or in a dark room as well?
Hey, my latest bloodwork came back yesterday(only takes an hour now) and I’m still holding at the same level I’ve been for about the past year. Some good news, I hope, for us both.
glad everything worked out for you, but I am sorry you had to go through this ordeal. You explain things so well. I can’t tell you how much I have learned from you. I appreciate all that you do. We are blessed that you take the time to provide such knowledge to us in the CLL world.
Glad your eye problem is on the mend. I am surprised that FISH isn’t up to snuff everywhere. My Kaiser FISH tested for five deletions including 6q…my problem is that I have the 17p at 53p and a poor prognosis. The good (and surprising) news is that my test was in July of ’06! Kaiser was well ahead of the curve. I am at 35k WBC and holding for 3 years. A recent 12 pound weight loss has shown my spleen is enlarged by 6cm…My question is that my 17/53 involvement is 11/100. Does that mean that 89% of my genes are working? I am considered stage II, but if my next physical does not show more spleen enlargement, Doc says I’m still good. He thinks my spleen has been enlarged all along, but could not feel it bcuz of excess weight…Do you recommend a new FISH if we go into treatment?
Hi Chaya,
I’m very happy to hear that your eye surgery went well and that you aren’t going to have any loss of vision. We need your eyes to continue pouring over the medical journal articles and explaining them to us in terms that we can understand. Thank you for all that you do. I hope you have a speedy recovery!!
Regards,
Glenn
Marcy
Thank you, Chaya. I’m pleased your “critical eye” is on the mend.
This 17pdel -p53 patient is still doing just fine, thankfully, after my Dx 4.5 years ago. I want to send this article to my oncologist since he plans to treat me with FR if/when the time comes.
Chaya,
Glad the surgery went well. Thank you for all the updates.
Stay well.
Monique
It must have been frightening – flying in to the hospital from so very far away, not knowing whether your eye could be healed and then being rushed into emergency surgery upon arrival. That was a HUGE deal. Am very glad you’re on the mend, Chaya. Rest now.
Chaya–
You do have an amazing talent for explaining things clearly. I’m glad your eye was rescued.
Cathie
Brilliant news about the eye surgery, Chaya – VERY glad for you! And never forget – your ten cents is worth a million dollars to most of us!
Lawrence, UK
Chaya,
Very pleased to hear that the eye surgery went well
Graham
Chaya-
Extremely happy to know that your vision will be fine once again.
Take care
Chaya,
Wow, this is an excellent tip on tieing in the FISH test with chemo treatment before and even once your receiving it. You come up with such great incite. Keep it up and I’ll nominate you for the Nobel Prize in Medicine….of course we split the millions in prize money 50/50.
William Bates
Chaya, I am so pleased to hear your eye surgery went well and I hope those spots clear out soon!
Thank you once again for a very timely and interesting article! Although I am of the “Trisomy 12” flavor, I still want to learn about all aspects of this monster. Your article is once again superb in explaining in logical, simple terms what I have found to be a confusing and puzzling world of medical jargon.
Chaya,
Thank you for clearing up the confusion I had regarding the 17p and TP53 issues. I now have a much better understanding. Thank you so much.
So glad your eye surgery went well and that it is over.
June Hollen
Chaya,
Thank you for a very interesting article.
Chaya,
I am so glad you have a good report to report to us. You have been in my thoughts and prayers.
Many Blessings,
Rita
Chaya,
Your continued well being is a blessing for all of us who rely so much on your guidance.
After attending CLL support groups at my center, it appears that wanting to know everything about this cancer is not the common outlook. For myself, I can only say that every word you write is like a personal gift for which I give a completely inadequate ‘thank you’.
Chaya,
Great news regarding your eye. However, don’t overdue the use of your eyes until the black “floaties” go away entirely.
Barry
Great article, Chaya!
Do you agree with the cutoff of 20% placed on this deletion?
Also, if you could explain about FISH testing done during remission or directly after treatment and how it is hard to find the deletions at that time? I don’t believe that the deletions have been fixed but that FISH cannot read them.
Glad you were proactive with your own health. Get that eye back in 20/20 shape!
Jenny Lou
jlou:
Let us do a small thought experiment. Say a patient has only 13q deletion to begin with. About 90% of all his B-cells are CLL cells with this 13q deletion. The other 10% are just normal B-cells. His FISH report would show 90% 13q deletion.
Now, as part of clonal evolution, this patient develops a 17p deletion in a few of his CLL cells. Initially only a small subset of his CLL cells have this extra abnormality, perhaps as small as only 5%. His FISH test would report 90% 13q deletion along with 5% of the cells with 17p deletion as well as 13q deletion.
At this point the patient’s clinical response would look pretty much like he had only 13q deletion since they are the vast majority of his CLL cells. The 17p deletion is still there percolating in the background and over time it will grow in numbers. A sequential FISH test done over time will show the % of 17p deleted cells growing, gradually becoming the majority of cells. The 20% cut off is somewhat arbitrary. But you can see that as the percentage of 17p deleted cells becomes larger, the clinical characteristics of the patient become dominated by this specific abnormality.
It is indeed hard to do FISH test or IgVH gene mutation status test when the number of CLL cells floating around in the blood sample are low – which would be the case immediately after successful therapy. It is a simple case of dilution. Since there are so few of the buggers in the blood it is difficult for the instruments to “see” them and the results are inconclusive. None of our present therapy regimens can actually “fix” chromosomal deletions or abnormalities once and for all. That is what makes CLL an incurable cancer. But therapy can beat back the numbers sufficiently that no abnormalities can be seen while the patient is in deep remission. When the remission ends and the counts go back up, the deletions will still be there – perhaps with a few new ones on top of the old ones, a gift of clonal evolution.
God bless you my dear and I hope you are getting better each day…
Your articles are always wonderful. Thank you.
I was going to ask, if upon examination, does the percentage of the total amount of CLL cells carrying this deletion correlate with the aggressiveness of the disease?
It didn’t dawn on me that the percentage of p53 cells will rise with the growth of the disease, I just assumed that it just indicated there was a defect and would indicate the difference between aggressive disease (poor prognosis) and indolent disease.
On my husband’s FSH test from 2006, he had 200 interphase cells analyzed, and 10% of them had the p543 deletion on 17p.13.1. His diseased seems more indolent then aggressive, so far.
At present, he is still W&W (though platelets are dropping).
There must be other intricate, unknown factors that make his case an exception to the rule. For the sake of genetics, I hope his disease was a fluke so as his children are not affected by this mutation.
(I am assuming that my whole food “blending” for keeping his immunity up made a difference …wishful thinking).
Keep up the great work and again,my prayers go out to you & your eyes!
Great news Chaya.We are also extremely happy that your surgery went well, and that you aren´t going to have any loss of vision.
YOU DESERVE LUCKY.
We appreciate all that you do. Thank you for another excellent article.
You explain very well difficult and important things with a language that all of us can understand.
Jorge/Ana
What about a much less toxic triple therapy for CLL including ECGC, echinacea, and melatonin? Has anyone else thought about this?
Thank you for the update on your eye and vision. I was wondering about you. Thanks again for a clear take on the above article.
Linda Lee
howard5777:
If you honestly think aggresive cancers driven by 17p deletion / dysfunction can be treated or controlled by “EGCG echinacea and melatonin”, you are wasting your time reading my reviews. That position is far removed from reality in my honest opinion – even though I spent big chuncks of time raising more than $70,000 for funding and sponsoring the EGCG trial at Mayo Clinic and proud of it.
Chaya,
I’m glad to hear your retinal repair went well, and I hope the floating spots fade quickly for you.
Thanks for your explanation of the meaning of the percentage measure of deletions, I had a FISH test result of 20% for 17p, and hadn’t quite figured out whether that was 20% of the CLL cancer cells (and if so what were the others?). Now of course, it is clear that it is 20% of my total B cells, but that I can expect that to change.
One point I would like to raise however, and that is concerning 17p people with mutated IgVH genes. I have heard informed speculation that this subgroup of a subgroup may have a better prognosis. If you look at the results of the FCR vs FC trial described above, Figure 3, graph C shows a leveling off of the overall survival line for 17p just below the 40% mark, between 30 and 36 months…. I have reason to believe these continuing survivors are IgVH mutated patients. Do you have any information or research statistics to support the concept of a better prognosis for this group?
Thanks,
Chris
Chris:
Good to see you are reading the original article and bothering to get your arms around the details. My reviews are no more than cheat sheets that I hope will tempt more people to read the full version.
With respect to graph 3C in the lancet article, here are my comments. The study had 22 patients with 17p deletion in the FCR arm. By the time you see the leveling of the survival curve for the 17p patients (a tad longer than 36 months), there are only 40% of them still alive – in other words between 8 – 9 patients.
Now we want to further divide this small group: how many of this small group were mutated, how many were unmutated IgVH? Drawing conclusions regarding differences between survival of such small (low single digit groups of patients) is statistically meaningless – no more than anecdotal information.
Someday we may have more robust information based on larger groups of 17p deleted patients with and without IgVH gene mutation who undergo FCR to make such distinctions. But the data we have at this point is not sufficient to hang our hats on this assumption.
Annette
Just read it and I think it is interesting for all CCLers :2 shots are better than one.
A publication in Haematologica 2010.
Repeated vaccination is required to optimise seroprotection against H1N1 in the immunocompromised host.
Conclusions. These data demonstrate the efficacy of H1N1 vaccine in most patients with haematological malignancies and support the recommendation for the administration of 2 vaccine doses in immunocompromised patients. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in such patients in the future.
http://www.haematologica.org/cgi/reprint/haematol.2010.032664v1.pdf
Chaya, take care and stay healthy, we need you.
Annette
I am sorry. I was probably referring to the 13q deletion which I have. I did review the study of leukemic mice which seemed to respond well to echinacea. Lymphocytosis was actually decreased in the mice while macrophages were activated so that both adaptive and general immunity were improved. The conclusion was that a combination of echinacea and melatonin would be even better. I did not intend to minimize the seriousness of the 17p deletion/dysfunction.
Hello Chaya and fellow CLLers,
I am brand new to your site and find it extremely helpful. I have spent hours learning from the vast amount of information here. I appreciate it very much. My 54 yr. old husband has been recently diagnosed with CLL. He is of the 13q- crowd at 80% 13q-.
I have question about a publication I read in Haematologica. (www.haematologica.org/cgi/content/abstract/94/3/364)
The publication states “Conclusions: Patients with B-cell chronic lymphoid leukemia with a high number of losses in 13q14 as the sole cytogenetic aberration at diagnosis display different clinical and biological features: short overall survival and time to first therapy as well as more proliferation and less apoptosis. A quantification of the number of cells showing a genetic abnormality should, therefore, be included in the study of the prognostic factors of B-cell chronic lymphoid leukemia.
Note**Time to first treatment at 36 months and OS as 57 months
Does anyone know anything more about this?
I am new to this and haven’t been around the block yet.
Any feedback would be greatly appreciated. Thanks so much
Mary
Just read the above post and freaked out, I confess. My 13q14 percentage is 85% according to NIH. That puts me in the poor prognosis. Sure hope I’m the exception as I’m just about to retire and going through crunching the numbers hoping to live more than 57 month. (And, please help me .. when they say OS of 57 months, what is their “starting point”?) So, suddenly, the “better” deletion turns into what looks to me like one of the worst deletions. Hopefully new therapies can deal with this. I’m like Mary above .. any feedback would be greatly appreciated.
Lynn
Here is the abstract that Mary is talking about:
Haematologica. 2009 Mar;94(3):364-71.
A high number of losses in 13q14 chromosome band is associated with a worse outcome and biological differences in patients with B-cell chronic lymphoid leukemia.
Hernández JA, Rodríguez AE, González M, Benito R, Fontanillo C, Sandoval V, Romero M, Martín-Núñez G, de Coca AG, Fisac R, Galende J, Recio I, Ortuño F, García JL, de las Rivas J, Gutiérrez NC, San Miguel JF, Hernández JM.
BACKGROUND: Among patients with B-cell chronic lymphoid leukemia, those with 13q14 deletion have a favorable outcome. However, whether the percentage of cells with 13q- influences the prognosis or the biological characteristics of this disease is unknown. We analyzed the clinico-biological characteristics and outcome of patients with B-cell chronic lymphoid leukemia with loss of 13q as the sole cytogenetic aberration.
DESIGN AND METHODS: Three hundred and fifty patients with B-cell chronic lymphoid leukemia were studied. Clinical data were collected and fluorescence in situ hybridization and molecular studies were carried out. In addition, a gene expression profile was obtained by microarray-based analysis.
RESULTS: In 109 out of the 350 cases (31.1%) loss of 13q was the sole cytogenetic aberration at diagnosis. In the subgroup of patients with 80% or more of cells with loss of 13q (18 cases), the overall survival was 56 months compared with not reached in the 91 cases in whom less than 80% of cells had loss of 13q (p< 0.0001). The variables included in the multivariate analysis for overall survival were the percentage of losses of 13q14 (p=0.001) and B symptoms (p=0.007). The time to first therapy in the group with 80% or more vs. less than 80% of losses was 38 months vs. 87 months, respectively (p=0.05). In the multivariate analysis the variables selected were unmutated status of IgV(H) (p=0.001) and a high level of beta(2)microglobulin (p=0.003). Interestingly, these differences regarding overall survival and time to first therapy were also present when other cut-offs were considered. The gene expression profile of patients with a high number of losses in 13q14 showed a high proliferation rate, downregulation of apoptosis-related genes, and dysregulation of genes related to mitochondrial functions.
CONCLUSIONS: Patients with B-cell chronic lymphoid leukemia with a high number of losses in 13q14 as the sole cytogenetic aberration at diagnosis display different clinical and biological features: short overall survival and time to first therapy as well as more proliferation and less apoptosis. A quantification of the number of cells showing a genetic abnormality should, therefore, be included in the study of the prognostic factors of B-cell chronic lymphoid leukemia.
PMID: 19252174———————————-
A similar comment was made in an earlier paper out of Mayo clinic:
"a higher percentage of 13q- nuclei was associated with significantly shorter TFT (P < 0.001). The 5-year untreated rate was 79% for patients with isolated 13q- in 65.5% of nuclei (P < 0.001)." PMID: 19895615
Judging by these two abstracts, it does seem a higher percentage of 13q deleted cells points to shorter time to when therapy is needed and perhaps shorter overall survival.
However, I want Mary and Lynn to take a deep breath first and look carefully at the details. Time to first therapy was 38 months versus 87 months. First, 38 months to treatment is not bad. That is a tad more than three years since diagnosis, still one of the better prognosis and one that a lot of patients would kill for. Second, there were only 18 cases where patients had 80% or more of their cells with 13q deletion. Not a huge sample size. Third, I have not seen any other researchers jumping on this research finding.
My gut sense is that anytime one sees the percentage of cells with a certain chromosomal abnormality increasing, it is an indication of a progressive disease. 80% 13q deleted cells is not as good as 20% 13q deleted cells. But that is not the same as 80% 17p deleted cells versus less than 20% 17p deleted cells. Things could be a whole lot worse than high percentage of 13q deleted cells.
13q deletion is still a good prognostic indicator, given all the other chromosomal abnormalities one could have. But CLL is a a cancer – as of now, it is still an incurable cancer. One more reason why I refuse to buy the argument that it is a "good" cancer.
Thanks Chaya .. as always, you have put this into a more intelligent context. And while my disease hasn’t romped along at a rapid rate, my ALC has gone over 200k, with a doubling rate of between 1.5 and 2 years. I wonder if, then, this “percentage of deletion” becomes a surrogate for, or is a function of, the increasing malignancy,i.e increasing ALC. Put another way, I wonder if we can assume that ALC trending upward automatically mean the % of b-cells with the deletion would increase? I guess it comes down to .. do I have malignant b-cells that don’t have the deletion? Would be interested to know if there are CLL-ers here with high ALC, 13q14 deletions AND low percentage of that deletion.
My personal hope is that the treatments now available will help me / us beat that 57 month OS .. that was the biggest shock from the abstract. I haven’t seen the entire article to know how these patients with higher % were actually treated.
Each of us with CLL has such a different path to travel. I still feel great .. wouldn’t know I had the disease if I were on a desert island with no doc. Yet I continue to get “wake up” calls, such as this new information, that I am doing the right thing in searching out the best care for when my treatment time comes. I am so glad to be a part of the CLL Natural History Study, which I would not have known about if it weren’t for Chaya.
Again, thank you so much Chaya for helping me digest this latest view of the state of my CLL.
Lynn
Chaya,
Thank you so much for your prompt response. You also put my mind at ease and gave me better perspective. I didn’t mean to scare anybody, just trying to process and sort the information out there. I thought when my husband was first diagnosed that this would be easy because of the talk of how great it was to have CLL compared to other cancers. Ha!
Your site has made me better prepared with what to expect than anything out there. Again, thanks so much
Mary
Mary
Chaya,
You have answered a couple emails I had with comments/questions about your outstanding articles. I admire and appreciate your dedication, especially considering all you have going on and your recent health issue.
I do hope you recover quickly with no black spots or futher issues.
Thanks for all you do,
Bree
Wishing you a speedy recovery from your op.
Thank you for your excellent articles.
J
I made this observation elsewhere here, but it bears repeating here when the inadequacies of FISH testing are being discussed:
I’m surprised there is still this heavy emphasis on FISH test results for CLL yet no mention at all of array-based karyotyping, which not only has been found to be more cost-effective than FISH testing but also catches some things that FISH tests miss. For those of us who are uninsured (and possibly out of work as well), a more cost-effective test is welcome news. Here’s two citations to look up and pass along to your hematologist:
SNP Array-Based Karyotyping May Offer Better Detection of CLL Lesions
http://www.medscape.com/viewarticle/713398
The Vanguard Has Arrived in the Clinical Laboratory: Array-Based Karyotyping for Prognostic Markers in CLL
http://www.journals.elsevierhealth.com/periodicals/jmdi/article/PIIS1525157810600414/fulltext
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