Continuing saga of CLL
I have a couple of friends who have watched the same soap opera on TV for more than 25 years. The plot line twists and turns in bizarre ways, some characters get killed off, new ones added – but the show goes on year after year. In some ways, the CLL saga is a bit like that. New drugs making their debut are hyped to the skies, some old drugs fall out of favor. Some of our CLL experts gain rock star status – for a while, until things change and someone else claims the mantle. Food fights among patient internet forums are always fun to watch from the safety of sidelines. Once in a while a truly new drug discovery or new concept in our understanding comes along that changes the landscape. More often than not, we trundle on with not much happening on any given day. I have been a devoted fan of this soap opera for the past 10 years!
Very often, I come across interesting little nuggets of CLL information that are not quite big enough for a full review article on this website. In an attempt to capture these tidbits, I thought I would start this on-going thread. New items will be reported under this heading as they come to my attention. I will get Radha (our webmaster) to find a way of making the “Tidbits” title heading stand out from the other regular articles so that you can easily find it on the homepage. In an attempt not to bombard you too many emails, I do not plan to send out any heads-up emails whenever I add a new item to this heading. You will just have to visit the website and click on the “Tidbits” icon to see if there is anything new under this heading. I will have a full listing of all the items under “Tidbits Archives“. As always, your comments are welcome but you have to be a registered member and log on before you can participate in the member discussions.
Here is the first tidbit, attached below to get you going. Remember, there will be no more emails alerting you to future tidbits! (Not to worry, we will continue sending out email alerts to our registered members whenever we publish new full length articles on this website).
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Is a higher percentage of cells with 13q deletion more dangerous?
This question has come up in our prior discussions. The standard CLL FISH panel looks for four types of chromosomal abnormalities: 13q deletion, 12 Trisomy, 11q deletion and the most dangerous 17p deletion. Of the lot, 13 q deletion is considered the most favorable prognostic indicator. Does it make a difference if both alleles have 13q deletion? (Remember, you have a pair of 13 chromosomes, so it is possible to have one or both of these chromosomes with the relevant bit broken off. Please browse our recent article on Prognostic Indicators to understand this better).
Does it matter if majority of your CLL cells have 13q deletion, as opposed to just a small percentage? And here is a new wrinkle on the subject, does it matter if the bit broken off is a big piece as opposed to a teensy little piece? The abstract below suggests that the answer to both questions is YES. Higher percentage of CLL cells with 13q deletion is worse prognosis than lower percentage. Larger chunks of DNA broken off of the 13th chromosomes means more trouble than if the piece broken off is just a small little piece. Who knew.
All the same, I will keep an eye out to see if any other research group backs-up these findings or refutes them. It helps to be patient until the dust settles, sometimes the first word out is not always the correct finding.
Genes Chromosomes Cancer. 2011 May 11. doi: 10.1002/gcc.20885. [Epub ahead of print]
13q14 Deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia.
Dal Bo M, Rossi FM, Rossi D, Deambrogi C, Bertoni F, Del Giudice I, Palumbo G, Nanni M, Rinaldi A, Kwee I, Tissino E, Corradini G, Gozzetti A, Cencini E, Ladetto M, Coletta AM, Luciano F, Bulian P, Pozzato G, Laurenti L, Forconi F, Di Raimondo F, Marasca R, Del Poeta G, Gaidano G, Foà R, Guarini A, Gattei V.
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
Deletion at 13q14 is detected by fluorescence in situ hybridization (FISH) in about 50% of chronic lymphocytic leukemia (CLL). Although CLL with 13q deletion as the sole cytogenetic abnormality (del13q-only) usually have good prognosis, more aggressive clinical courses are documented for del13q-only CLL carrying higher percentages of 13q deleted nuclei. Moreover, deletion at 13q of different sizes have been described, whose prognostic significance is still unknown. In a multi-institutional cohort of 342 del13q-only cases and in a consecutive unselected cohort of 265 CLL, we investigated the prognostic significance of 13q deletion, using the 13q FISH probes locus-specific identifier (LSI)-D13S319 and LSI-RB1 that detect the DLEU2/MIR15A/MIR16-1 and RB1 loci, respectively. Results indicated that both percentage of deleted nuclei and presence of larger deletions involving the RB1 locus cooperated to refine the prognosis of del13q-only cases. In particular, CLL carrying <70% of 13q deleted nuclei with deletions not comprising the RB1 locus were characterized by particularly long time-to-treatment. Conversely, CLL with 13q deletion in <70% of nuclei but involving the RB1 locus, or CLL carrying 13q deletion in ≥70% of nuclei, with or without RB1 deletions, collectively experienced shorter time-to-treatment. A revised flowchart for the prognostic FISH assessment of del13q-only CLL, implying the usage of both 13q probes, is proposed. © 2011 Wiley-Liss, Inc.
PMID: 21563234
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30 comments on "Interesting Tidbits"
hmmmm I don’t think I understand — if 13 q deletion is a good thing and a good marker…..why would higher percentage of 13 q deletion in the cll cells mean bad news? I think I must be missing something…
love the tidbit idea Chaya – as always you are on the top of keeping us informed:-)
Dee Dee:
13q deletion is “good” only in the context of other worse deletions (such as 11q, 17p and 12 Trsisomy). Having any kind of chromosomal abnormality is not a “good” thing in a real sense of the word “good”.
I think it is safe to say 13q deletion is “good” in the same sense that CLL is “a good cancer” – by contrast to all the other much nastier cancers that kill people a whole lot faster.
Why is 13q a good prognostic factor compared to other chromosome abnormalities or none at all is a long mystery. My guess is that it is still a cancer, but not as bad as the other ones. So a worse form of the best type is still worse. As Chiorazzi has shown, if you look deep enough you can find chromosome lesions in practically every CLL case. So a case labeled as having no chromosome abnormalities is probably a case where it means none were detected not none exist. Fish is limited to having to know what you are looking for. It is a probe to one specific chromosome site, not a screen.
Thanks Chaya for all you do. I also love the Tidbits idea.
Wow, this tidbit brings about another layer to the CLL puzzle. So presumably, my Cll, a combo of Trisomy 12 plus 13q, could very well be tempered either way, good or bad, by the amount of deletion on 13. I never thought of it that way. Typically, the dominate marker tells the most about your prognosis but now, are the bets off the table for mixed diseases?
Jeff
Chaya – I am confused about your comment above (at 1:23 p.m.). You state that “13q deletion is ‘good’ only in the context of other worse deletions.”
It has always been my understanding that, for a CLL patient, having a 13q deltion is better than having no deletions at all. Is this incorrect?
My deletion is 13q14 and I don’t think I understand what that means as opposed to just 13q.
I appreciate all tidbits and any other information as there is soooo much to learn.
OK guys. Let’s get this right.
The present day standard CLL FISH panel tests for just four chromosomal abnormalities: 13q, 11q and 17p deletions, and 12 Trisomy. It is a matter of economy, dollars and cents. Of this lot, 13q deletion is the least dangerous and therefore often considered a “good” chromosomal defect to have.
Labs test for just these four defects because they are the most common. But there are many, many more less common chromosomal defects that exist in CLL patients, over and beyond the 4 defects listed above. When your lab FISH report returns the verdict “normal”, they are not saying you have pristine and completely normal chromosomes. If you did, you would not be a CLL patient in the first place. “Normal” in this context only means it is not one of the 4 specific defects they looked for. A more accurate descriptive phrase would be “none of the above” or “we don’t know that chromosomal defect you have because we did not look for it”.
Since “normal” FISH report typically means a less well understood and often times somewhat more dangerous chromosomal abnormality, “Normal FISH” carries with it a middle risk category. If you are a fan of our “Bucket” grading system, 13q deletion is low risk Bucket A. “Normal” and 12 Trisomy fall into middle risk Bucket B. 11q deletion and 17p deletion rate high risk Bucket C.
I hope that makes things clear. Once again, please review prognostic information presented in our earlier Workshop-III write up!
Love this idea! Thank you! Question: Is there anything other than chemotherapy that causes cll to mutate / change? Does it happen randomly after the onset of the disease, or are subsequent changes caused primarily by treatment?
Maryann:
Yes, clonal evolution in CLL can happen all by itself, without any help from exposure to chemotherapy drugs. CLL cells are “unstable genome” to varying degrees. Over time, it is possible for other little bits to get broken off, pieces from one chromosome getting stuck where they don’t belong on other chromosomes (the word for it is “translocation”). In general, people with 11q and 17p deletions have more unstable situation than those with 13q deletion or 12 trisomy. Such additional chromosomal abnormalities become more likely as the years go by.
There is no doubt however, that the most common cause of clonal evolution is exposure to mutagenic (i.e., mutation causing) chemotherapy drugs.
Talk about timely! I was reading this article when my NIH report became available changing me from “normal” to 13q. I suppose this could be considered an improvement in the context of ‘the devil you know’ but who really knows what will be determined about these markers as research goes forward?
Obviously, tidbits has already been proved a great idea from my perspective.
I’m one of those with a large percentage of cells with 13q14 deletion .. 85%. I believe this article gives us a new name, 13q type 2. I don’t know how much is deleted in each cell. Which test would show that? One of the “wide array” tests?
Thanks
Lynn
I like the Tidbits idea. Thank you for this and for all you do.
LynnS:
I do not believe we presently have any commercial labs offering the test that can determine how big a piece has broken off. This is still in the realm of research institutions only.
Chaya
I was initially diagnosed 13q14 deletion, but after chemo when I had the test at another facility, the clonal evolution occurred and it became a double allele at that location. Based on reading the article, I assume that it is now a bigger chunk than initially.
This is a great idea! thank you for your tidbits.
Thank you, Chaya as well as Radha, for the new “Tidbits” articles on the homepage. It’s an excellent idea.
Monique
Tidbits seems another good idea. Would it be possible to have a little flag up on the main articles when there’s been a new tidbit added on the website?
aamster:
The fact that you were subsequently diagnosed with double allele 13q deletion means both of your 13th chromosomes now carry this defect. (Remember, each cell contains a pair of each kind of chromosome).
Double allele deletion does NOT mean a bigger chunk is broken off. Just that both chromosomes carry the defect, not just one of them.
Molly:
I have no idea what can or cannot be done by way of HTML coding – our webmaster is away on a business trip (her day job). When she gets back, we will figure out what can be done. As you most of you know, we run a pretty tight shoe-string operation here, especially when it comes to manpower.
WillB
Chaya, thanks for the 13q deletion – piece broken off – perspective. This was new info on my end, and most appreciated.
William Bates
Question…
single deletion vs double deletion.
ie. does the D13S319 deletion have to be double or will a high percentage of single deletion change the statistical prognosis?
thanks again
My husband has the 13q deletion, but how do I find out the percentage?
Finally, things appear to be coming together so far as my understanding just how to look at this awful condition I have. Thanks for the “tidbit”. This unlocked a few mysteries for me and finally I begin to understand. Since this condition is a fluid, changing one, the deletions obviously must change over time. Should the fish test be repeated from time to time? I had to “fuss” with the doctor to have one done in the first place. When I was first diagnosed, I had a test showing 13q deletion…and was told it was a “good” result…one chromosome only. At that time, my white cell count was 17,000 and during the 2+ years since diagnosis, wbc has risen to around 88,000. I have been told this is a slow doubling time although the checkups are getting closer together and there are murmurings about chemo coming up. I certainly would like, for my personal curiosity, to see the results of a second FISH. But should I “fuss” some more to have a repeat of the test? I know they are expensive and we all know what is happening about insurance.
So there it is…to “fuss” or “not to fuss”? that is the question.
Hi Chaya,
This could be a blockbuster of a “tidbit” in the understanding of why CLL is such a heterogeneous disease.
When I consulted with Dr. Kanti Rai in June of 2009 just prior to TX, he commented on the striking features of my CLL being that for a Mutated IgVH 13q deleted patient I had a very aggressive disease but a remarkable level of health.
Since that time I have pursued testing to further define the cytogenetic characteristics of my CLL and lo-an-behold It turns out that my last FISH revealed that I have 93% of clone with 13q deletion. Through a CGH (Comparative Genomic Hybridization) scan I learned that I am mono-allelic deleted (better than bi-allelic) deleted but that I had other genetic damage which included a tumor suppressor gene called the PRAME gene (significance unknown) on Chromosome 22q. Early in this year I had a repeat at a higher resolution of the CGH scan and an Oligo HD scan looking at the minimally deleted region on chromosome 13 which showed extensive damage to include the RB1 tumor suppressor. Dr. Hamblin thought the loss of the RB1 in 13q patients may be analogous to the loss of ATM for 11q patients, in some 13q deleted patients.
Given this extended knowledge from scanning, it may provide the main cause for my progression but also confirm that the response to Rituxan/Fludarabine and Rituxan monotherapy, as far as killing the cancer goes, reflects the “better” or more favorable position I am in being a 13q deleted patient than a 17p or 11q profiled patient.
Chaya, there is a commercial company that can provide the more comprehensive scanning referred to above. The company I used is called CMDX (Combimatrix Molecular Diagnostics) located in Irvine California ( http://www.cmdiagnostics.com ). They have reps for the US and Canada that I know of.
The first scan was CGH CA-1500 whole genome array which picked up the deletion on chromosome 22q done in 2008. This year they brought out a more powerful CGH array and an Oligonucleotide High Definition array that can, to some degree, measure the extent of the genetic damage.
Before anyone rushes to get these tests, it is to be pointed out that this has not influenced my choices of treatment in any major way and these tests are not cheap. (Hey, everyone needs a hobby) The tests do not show everything such as balanced translocations and copy number neutral genomic changes but having said that, the goal of individual treatments will be based on these and other scans that are coming out of labs like CMDX. We have a lot of information in the form of “dots” and we need “connections” to get better less toxic treatments. You can’t treat less toxically or with efficacy when you don’t know what is going on.
My personal hope is that the more I can know about the nature of my CLL the more opportunity I might have to pick a more efficacious Treatment.
WWW
Wayne, could you please share the cost of your scans and let us know if your insurance covered any portion of them? (I’m on Medicare with am F supplement). I should have asked the NIH docs if they do any of this High Definition Array Testing, but I didn’t. Perhaps I’ll email them about it. Or perhaps someone else in the Natural History Study there has the answer.
One thought about the high percentage of 13q that we share. After treatment, would that percentage have any role? The cited study talked about time to treatment. But the question would be, after treatment is that initial percentage relevant?
Lynn
For LynnS and others interested for more detail in the HDscan through CMDX.
First a disclosure: Because of my discordant disease (good markers but aggressive disease) I was able to present my case as interesting enough to get a free scan in the Spring of 2008 as CMDX was in the process of developing their scans. Part of how this came about was the pain in the rear end to get this scan done in the state of NY which is apparently unique among states in “hoop jumping”, This, even when I did not pay for it.
This year when they had upgraded their scans and already had me in their data base, I was a good subject to compare with the scan I had done in 2008. From my point of view CMDX has been good to me but I do want anyone who might consider getting a scan from CMDX to know that I have no financial interest in the company and no promise of any further free scans or services from CMDX for promoting their scans.
Anyone interested in knowing more about their disease should be aware of what any scan will reveal and what it cannot see. It is interesting that my scan showed a deletion of chromosome 22q to include the PRAME gene that has as yet no clinical interpretation. Through my own research these findings may explain a double neurilemoma removed from my neck in 1969. Though I remain remarkably healthy regarding infections of any kind (one cold in 2008 with no others since 2005) I have contracted my first secondary cancer being a squamous cell carcinoma on my shoulder. I question if some of the secondary cancers observed in CLLers are related to some of the damage revealed in the CMDX scan? Having speculated on this, there is no proof of connection and depressingly no clinical remedy as a result of having gotten the scan even if a connection to damage were to be revealed.
Because I firmly believe that knowing the state of DNA damage is an important part of unraveling the mysteries of our disease I have no reservations about sharing information about CMDX scanning that may shed light on what ails us. As in all things, be aware of what you are buying and why it may be important to you.
I would urge anyone to go to CMDX website and particularly for those with 11q deletion as Dr. Shelly Gunn has an article specific to 11q del. I would love to see Chaya’s input concerning this tool.
Dr. Byrd (CLL expert at OSU) was interested in seeing my scans so I sent him a pdf but in typical fashion he has not replied to my email so I can’t tell if he values the additional info in the scan. I will be going to OSU most likely in June and will report his reaction when we consult again.
The test is conducted on a peripheral blood sample drawn at a lab after you have received a kit from CMDX.
I emailed a CMDX Rep. (Chris Emery) regarding current scan prices and this is his reply:
“We are willing to offer a Heme Profile
High Definition microarray for $900 to a patient that wants to pay cash.
The test is also covered by private insurance and Medicare. We bill insurance $1950 and accept the payment we receive from insurance plus a co-pay as dictated by insurance. We DO NOT balance bill the difference between $1950 and what the insurance pays – we only bill the small co-pay to the patient.
Regards and all the best to you.
Anyone can contact me directly.”
Chris
Cemery@cmdiagnostics.com
310.497.7478
Dancing with a Bear,
WWW
Thank you Chaya for the elucidating articles, and thank you Radha for making the web page possible. You always manage to explain obtuse ideas in an understandable way. We really depend on you for information. The tidbits idea is great.
Bless you both.
Blair and Barb
“Normal FISH” carries with it a middle risk category. If you are a fan of our “Bucket” grading system, 13q deletion is low risk Bucket A
If “normal” means we do not know what abnormally you have because we did not test for it, why is 13q deletion better? It may by itself be in the low risk bucket, but having this deletion still seems to mean that there are a whole stable of other things you could have that we did not test for. Does having a known devil make additional unknown devils less likely?
Hi tsvieps,
The bio-chemical complexities that determines CLL behaviors are indeed complex and when we are profiled by tests such as FISH, immunophenotyping, IgVH mutation status, Ig levels, ZAP-70 positivity and more recently the epigenetic markers like miR-15a/miR-16-1, we are not seeing the dynamics of the signaling nor the unique interactions represented by the varying degree of DNA damage that is certainly unique to each CLL patient if one looks deep enough.
I would suggest looking up the 4 Part postings of Al Janski on Jan. 15, 2011 (ACOR CLL LISTSERV) in which he provides a synopsis of a JAMA paper co-authored by the likes of (Drs. Calin, Rai, Kipps, Keating, Croce etc.) Al is a sharp CLLer with technical knowledge and an intellectual curiosity to provide us with conceptual insights regarding your questions. If the experts do not yet understand all the connections, do not be discouraged if these concepts are confusing. The expanding knowledge and basic understanding by we consumers with a growing choice in therapies, may give those who make the effort to learn an edge. This is doubly true when seeing the ignorance of so many general oncologists regarding CLL/SLL. These facts make this forum, with the quality that Chaya brings to the discussion, a real gift.
Al quotes from the paper: ” The recurring deletion hot spots at 13q, 11q, and 17p actually represent nodes of a complex regulatory network in CLL that integrates the miR-15a/miR-16-1 and miR-34b/miR-34c clusters with TP53,” Allendorf and Davis concluded in JAMA.
This paper does try to address your central question of why in most cases a 13q del may be better than a patient who has a “normal” cytogenetic FISH profile. Keep in mind that if FISH does not include a probe for 6q and you happen to have this deletion you would be classified as FISH “Normal”.
Hope this helps,
WWW
Thanks Waynewells,
I will try to review the Al Janski posting in detail…but as you suggest, as I try to drill down to details that are outside my field, I am…well a FISH out of water.
But as you say, there is good reason to try and it is surprising what an amateur can learn that can help in the discussion with an overworked oncologist. I am fortunate enough to have a good one who is also humble and welcomes research gathered by patients. This kind of digging is actually fun…if our lives were not at stake, it would be even more fun.
I’m new to your website. Still finding my way around! It looks like there is a lot of information to learn… There is also a Tidbits email newsletter I started receiving from CLL Global Research Foundation. Are you affiliated with them?
linz_lou210
No, we are not associated with the CLL Global Research Foundation or any other organization.
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