“Prognosis at Diagnosis”
Perhaps it had to do with the flip and wrong-headed way my husband’s initial diagnosis was handled. Perhaps it had to do with both of our desire to have a better handle on what the future held in store for us. Whatever the reason – soon after my husband’s CLL diagnosis – when I came across the Mayo Clinic article titled “Prognosis at Diagnosis“, it was like a door opened. We felt less trapped and the future was less murky. You can read the review I did of that seminal article back then, as well as the “Bucket” classification that developed as I read more articles on the subject. Since then I have written many other articles on the subject of modern prognostic indicators and their value in making informed therapy decisions for CLL patients. But I will never forget the rush of excitement I felt reading about it all for the first time.
That was back in 2003. Has that initial judgement regarding the potential value of modern prognostic indicators stood the test of time? What do the experts say, today? Have we added any new prognostic indicators to the list of IgVH gene mutation status, B2M, CD38, ZAP70 and FISH status that I discussed in my review seven years ago? Many new markers have been proposed over this time. There has been heated discussions among doctors and patients about the need to know. Are patients better served knowing about their prognosis, or are they better off by letting the doctor read the tea-leaves and make the necessary decisions for them? I suppose it depends on the psychology and personality of the patient involved. I think most patients would agree with me that if a given patient wants to know, he or she has a right to the information. It is our bodies, our lives, we have a right to know; if we want to know.
Below is an article on the subject of CLL prognostic indicators, where we stand today, and what patients can reasonably expect to understand from these indicators – by the man who was responsible for a big chunk of the developments that have been made in the area. Dr. Terry Hamblin needs no introduction in this patient community. Without further ado, this is what the MAN himself had to say. And who knows, he might even answer questions posed to him in the discussion section, if you ask nicely.
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Where are we with prognostic markers today?
By Dr. Terry Hamblin
Who should have their prognostic markers done?
When I first started working in this area, I was motivated by the fact that many people were labelled as having leukemia who would never need any treatment for it. I spent a good deal of my career trying to figure out a means of distinguishing between those who would be in this bucket and those who definitely would need treatment. Many of these problems have been cleared up by the change in definition of CLL to require a minimum of 5000/cu mm B lymphocytes for the diagnosis. Many of those who had fewer than this would have been diagnosed as stage 0 CLL under the old definition. Now they are called monoclonal B cell lymphocytosis (MBL) and no-one thinks such people should be called leukemia patients or even followed up. They comprise about 4% of the population over-40 and no-one is going to contemplate making 4% of the mature population into invalids.
There is no reason to think that such people need their prognostic markers done.
What about people who really do have CLL?
Experts are still recommending that outside clinical trials that the only prognostic indicator that makes any sense is the clinical stage. In other words, if you have Rai stage 0 or Binet stage A then that should be enough; you have a long period of life ahead of you.
I disagree.We know very clearly that Binet stage A patients who have unmutated IgVH genes will live on average 8 years (range 4-12 years). With better treatment this may be prolonged some, but it contrasts with an average survival of 25 years for those with mutated IgVH genes.
If any prognostication is to be done then the experts rely on the lymphocyte doubling time. Now, there is no doubt that unlike clinical stage, this is a dynamic indicator; it tells you something about the rate of progression. But it only tells you that when the disease progresses and it is unreliable. Because the blood compartment is only one of those where CLL cells accumulate, it does not tell you that your marrow cavity is filling up, nor that the lymph nodes that you cannot feel (like retroperitoneal nodes) are enlarging. In fact even the experts won’t prognosticate on lymphocyte doubling times if the absolute lymphocyte count is less than 30.
The mutational status of the IgVH genes, on the other hand is a given characteristic of the disease, available at diagnosis.
Now this doesn’t mean that I advocate that everyone with CLL should go out and get their IgVH genes done. If you are 90-years old, it hardly makes sense and people have to make their own decisions on how much information they want. Remember that these survival curves only predict averages and there is no such thing as an average person. Stephen J Gould, the Biology Professor at Harvard wrote a brilliant piece entitles ‘The Median is not the Message’ when he was diagnosed with mesothelioma and given less than a year to live. He survived for 17 years and died of something else.
It does make sense for the doctor looking after the patient to have this information since it could influence management, but I see no compelling reason that the patient should be burdened with it unless it is going to be acted on or unless he demands it.
In my previous article “You can’t handle the Truth” I explained how difficult I found it to handle information about my CT scan. Patients want to be given hope and not despair. Too much openness is sometimes harmful. It used to be the case that the patient would leave the worrying to the doctor and in Japan they still do. Perhaps that’s why people live longer in Japan.
If prognostic tests are to be done, which ones are useful?
For most tests, the results are not set in stone. In fact, the only unchanging test is the mutational status of the IgVH genes. The type of CLL you start with is the one you finish with. As far as I can determine this is not necessarily true for all other markers. But the effect of IgVH mutational status can be influenced by the other markers. It seems that the ability to signal through the B-cell receptor is what sets the pace of the disease, and in mutated IgVH cases this is impaired.
Proliferation in CLL occurs in proliferation centers in the marrow and lymph nodes and it is only when the cell is dividing that further genetic damage can occur. Every time a cell visits a proliferation center it up-regulates CD38 and possibly ZAP-70 as well. Every time it divides it shortens its telomeres and lays itself open to deletions and translocations on its chromosomes. There are simple serum tests like beta-2 M and thymidine kinase that give some indication of the rapidity of cell division, but they also measure tumor bulk, so that a high level might mean a slowly growing large tumor or a quickly growing small one.
This means that the baseline test that everyone who has full blown CLL should have done – whether or not they want to know the result – is the mutational status of their IgVH genes. Mutated and unmutated CLLs behave like two separate diseases and for the doctor not to know which one the patient has is like him saying the patient has lymphoma but time will tell us which type it is.
Why is it not done for everybody?
First, it is a matter of expense.The test costs $200 to do, though commercial labs charge $1000. You can get it done and interpreted in England for $200 plus the cost of the blood draw and a courier. Set next to the cost of one course of fludarabine let alone rituximab, this is peanuts.
What other reason? Sorry can’t think of one.
This isn’t a foolproof test. Being unmutated does not guarantee early treatment and being mutated doesn’t guarantee late treatment or no treatment. I have written before that there are some borderline cases with 97% homology who tend to include some cases that are effectively unmutated and of course, those who use the V3-21 gene behave as if they were unmutated even when they are mutated. There is also the influence of other prognostic markers. Having a high CD38 or ZAP-70 can make the disease behave more badly. However, when patients come to see me I get this test done because it gives me greater insight into the disease than any other.
We know that whatever clinical stage you are in the mutational status of IgVH genes affects your time to first treatment, length of remission and overall survival, and it has a bigger effect than which type of treatment you get. So far this applies whatever type of treatment you receive, though there may come a time when there is a cure-all that acts well whatever your mutational status is – but we’re not there yet.
Should other tests be done?
You can make a case for CD38, ZAP-70, and Beta-2M. The trouble with CD38 is that the cut-off between positive and negative is disputed, Should it be 7%, 20% or 30%? And what about bimodal cases? In practice I do it because it can be incorporated into the flow cytometry picture necessary for diagnosis, but I find it most useful for cases of MBL. MBL with a CD38 less than 30% will almost never transform to CLL. The other thing about CD38 is that the percentage of positive cells tends to change during the course of the disease – in at least a quarter of patients – frequently when the disease relapses after treatment.
The trouble with ZAP-70 is finding a method that everyone can agree on. The concordance with IgVH mutations was over 90% using the first two published methods, but only 76% when the method developed in Tom Kipps lab was used. That paper suggested that it was a better prognosticator than IgVH mutations, but when it was adopted by commercial labs, very strange results indeed were apparent. Not only that, the Spanish group found that ZAP-70 levels changed in about 10% of patients during the course of the disease. Nowadays most labs don’t trust ZAP-70.
Beta-2M is a good test except in renal failure. It is not just a test of disease activity since it also measures bulk. However I would do this test on all my patients.
The next test we should consider is FISH. This stands for Fluorescent In-Situ Hybridization, and it is a way for looking for particular chromosomal aberrations. It is not a perfect test and for 25 years in Bournemouth we preferred to do conventional karyotyping as well, since FISH only picks up the common abnormalities (del 13q, del 11q, del 17p and trisomy 12 – though sometimes del 6q is added). Conventional karyotyping also picks up the rarer abnormalities – trisomy 18, trisomy 19 for example and the unusual translocations – t(14;18) and t(14;19).
Although there is a famous hierarchical model which ranks cases according to prognosis according to FISH findings, this is not always helpful. It is very dependent on mutational status. Del 13q as an isolated finding mainly occurs in mutated cases, and the severity of trisomy 12 depends on whether the patient has mutated or unmutated IgVH genes. In clinical trials del 11q and del 17p almost universally occur in unmutated cases, but in untreated mutated cases we do see both of these FISH patterns in patients who do not have an aggressive disease, and indeed, may never need treatment.
Where FISH is important is in giving some idea of what is going to happen in patients who are treated. Patients who need treatment who are given either fludarabine or chlorambucil or any combination of purine analogue and alkylating agent, are not going to respond well if they have either del 11q or del 17p. Remissions are short with del 11q and almost non-existent with del 17p. If rituximab is added to the mixture then the adverse effect of del 11q seems to be removed, but it does nothing for del 17p cases.
Therefore FISH should be done before treatment since this could be determined by the FISH findings. Very few drugs work well with del 17p. High dose steroids, Alemtuzumab (Campath), flavopiridol and perhaps revilimid. A new drug in clinical trials, acadesine, also looks promising. Some people think that ofatumumab might also be helpful, but this is not proven.
Del 11q and del 17p are almost always secondary findings and some years ago a German study showed that almost always they developed in the unmutated cases rather than the mutated cases. All this reinforces my view that for most patients with CLL their doctors would benefit from knowing the mutational status of the disease.
45 comments on "Prognosis Markers in CLL"
Thank you Chaya for this article. Thank you Dr. Hamblin.
One year ago I had a routine physical and bloodwork, all results were unremarkable. Six months ago, I switched jobs and had to take a routine bloodtest, this time my results were abnormal and I was diagnosed with CLL.
I had a gamut of tests run during my workup: FISH, IgVH, CTs, MRIs, flow cytometry, CBCs, etc by CLL specialists at the Ohio State University Medical Center.
Ohio State has run an IgVH test on me twice and both times my results have been non-diagnostic. What do you make of this?
(The exact results say: ‘The clonal B-cell population was not detected in this sample and correlation with flow cytometry is recommended.’)
(My flow cytometry results: immunophenotypic analysis demonstrates a monoclonal lambda population of B lymphocytes, consistent with a B cell lymphoproliferative disorder. The immunophenotype is consistent with CLL. My FISH results: normal signal numbers for BCL6, 6q21, MYB, CMYC, ATM, TP53, chromosome 12 centromere. 57.4% cells had one signal for D13S319 indicating a deletion at 13q14.3, FISH with 14q32 break-apart probes was negative for rearrangement and had normal signal numbers in this sample.)
As an aside, my mother has had CLL for more than ten years and is stage 0. She has not had an IgVH test performed.
THANK YOU!
Thank you Chaya and thank you Dr. Hamblin,
As usual a very interesting article, and doubly so, being as Dr. Hamblin not only is a most emminent authority on CLL, but because he has “walked a mile in my shoes” and also still believes in medicine as an artform as well as a science…and he knows that patienets are first and foremost people. Just like you do, Chaya!
Thank you and stay well, both of you,
Mette
Thank you Dr.Hamblin for again sharing your expertise here; your SLL discussion was as water in the desert to me.
This discussion of prognostics is again a very sensitive issue personally as I have yet to match my diagnosis (SLL Rai 4A) and average 10 year life expectancy with material I have read subsequently. In the patient continuum I fall at the extreme- I find ‘smell the flowers/carpe diem’ advice patronizing; I want a relevant factor to track. The closest I can get to hard data is being 38 neg without description of percentage of cells, bone marrow involvement is ‘extensive'(no percent given),no deletions on FISH,flow cytometry: CD19/5,11c,23(but not 20).
As a body of evidence, should I rely on this as adequate for prognosis or does considerable merit still rest with trying to find some means of having the IgVH test done on my own IF it is possible outside the government health system?
Your clear exposition of the basics of this disease and this helpful guidance through prognostic indicators is more welcome than can be adequately expressed.
Thank you for your generous spirit.
Dear Dr Hamblin,
Thank you SO much for this clear and comprehensive article.
Doreen
Thank you Dr. Hamblin for sharing the information on mutational status.
Do you have any information on the success of bone marrow transplants for unmutated patients who fall into the “younger” patient category? and would you treat and transplant earlier based on mutational status alone?
Thank you
Having had my diagnosis of CLL well completed, I would like simply to get the Mutation test done next time I’m in the UK without having to pay a consultant to start from square one. How would I go about this, or which UK agency would I ask? My difficulty is that the mutation status test is not yet available in the Province of Ontario, or as far as I know, anywhere in Canada. Any advice that Dr. Hamblin or anyone else here could offer would be most welcome. Thanks! :)
Hi Patrick- I live in Manitoba and was able to find out my mutational status by joining a clinical trial.
Hope this helps!
Chaya,
Excellent….excellent….article.
Very informative.
William Bates
Chaya and Dr. Hamblin:
As always, a very informative and insightful article.
PLEASE keep the information flowing – we (the CLL community) very much appreciate your efforts!
Thank you!
Alan
Dr. Hamlin
One year ago at age 63 on a routine CBC Lymphocytes= 7.3 Platelets = 146
Last month Lymphocytes = 12,333 Platelets = 129
Your thoughts please?
Denis
dhkalf@aol.com
Thank you Dr. Hamblin and thank you Chaya
Very good article. I, too, hope to find out my mutational status via the clinical trial route.
I’m curious, has anyone else had a del 13q abnormality show up at a fairly low frequency in one FISH test, and not be found in a later one? Unfortunately, the VA did not record detail results like the first results I had obtained six months earlier. I’m sure the same lab ran both panels, but I’m also pretty sure that the interpretation/review was done by different doctors.
Perhaps the threshold for a positive probe result varies if a standard is run each time. Does anyone know?
Jim
Thank you, Chaya and Dr. Hamblin. I have two questions. The first is about the reliability of the IGVH test. Are all of the commercial labs equally reliable or is it necessary to go to one of the CLL consortium sites? The second is about the FISH test. I’ve been googling and googling and can’t find what the cut-off percentages are for having a deletion. For example, if 1% of cells show the 11q deletion, that’s under the cut-off. But does it mean that that patient will likely develop the deletion?
Thank you.
Thanks Tess and mjw.Sadly I know of no trials underway at the moment in Ontario.:(
Thank you Chaya and Dr. Hamblin for this article. I have some questions for Dr. Hamblin.
I am 56, male, diagnosed with SLL/CLL on February 1, 2010 after noticing some enlarged lymph nodes. They did a CAT scan, lymph node biopsy (picked the largest one as right axilliary lymph node: 2.5 cm aggregate of fat with at least four lymph nodes 0.3 to 0.5 cm)), and bone marrow biopsy (marrow lymphocytes 30%) and aspirate. On flow cytometry the lymphoid cells are negative to CD38 and ZAP-70. The cytogenetic analysis of bone marrow aspirates shows the presence of an abnormal cell clone characterized by an interstitial deletion of 14q which is very rare. Are you aware of any other cases with 14q deletion?
On May 28th I had a follow up visit. My CBC seems in the normal range (absolute lymphocytes 2.3). I would like to do the mutational status of the IgVH gene but I do not know where or whether choosing the lab is critical or not.
Is there a metric (similar to the doubling time on ALC) to determine how fast lymph nodes are growing?
Thank you
When I asked my doctor about getting the IgVH test, she simply said that we already knew the answer, since my doubling time was in the order of 5 years. Is this a fair assumption??
Again, thank you for a very imformative article. Since you mentioned the retroperitoneal lymph nodes, I have to ask is that the same as the mesinteric lymph nodes or am I dealing with something new? After my last ct scan it showed the mesinteric lymph nodes – size of 5-6 cms.
Q: Ohio State has run an IgVH test on me twice and both times my results have been non-diagnostic. What do you make of this?
Terry: There are a few patients for whom the IgVH test does not work. We are not sure why this should be so; most likely it is because of mutations at the side where the PCR primers are supposed to bind. We usually do not have any luck when we repeat the test. All that can be done is to look at other markers for which there is a high concordance with IgVH mutations and hope that you are not one of the unlucky ones.
Q: As an aside, my mother has had CLL for more than ten years and is stage 0. She has not had an IgVH test performed.
Terry: There is no indication that mother and child will have the same sort of CLL
Q: Trying to find some means of having the IgVH test done on my own IF it is possible outside the government health system?
Terry: For SLL patients IgVH testing can be done on a marrow aspirate, but this is a big procedure to undertake if other indicators suggest benign disease. It should be up to the patient though.
Q: Do you have any information on the success of bone marrow transplants for unmutated patients who fall into the “younger” patient category? and would you treat and transplant earlier based on mutational status alone?
Terry: We know that with autografting that the mutated patients live far longer than the unmutated ones. Allografting may overcome the unmutated disadvantage though. I think that I would be more reluctant to allograft someone who was mutated unless there were compelling reasons. I wouldn’t allograft someone just because they were unmutated
Q: Having had my diagnosis of CLL well completed, I would like simply to get the Mutation test done next time I’m in the UK without having to pay a consultant to start from square one. How would I go about this, or which UK agency would I ask? My difficulty is that the mutation status test is not yet available in the Province of Ontario, or as far as I know, anywhere in Canada. Any advice that Dr. Hamblin or anyone else here could offer would be most welcome. Thanks!
Terry: The service is offered in Bournemouth, UK, by Rachel Ibbotson at the Royal Bournemouth Hospital, Castle Lane, Bournemouth. Her e-mail is Rachel.Ibbotson@rbch.nhs.uk . Mention my name and she would be happy to give you details of how to send samples and how much they now charge. It used to cost £155.00. I am fully retired now and have no part in it, but I would be happy to interpret any results for free. We have received samples by Courier from all over Europe, North America, including Canada, and from Australia and New Zealand.
Q: I’m curious, has anyone else had a del 13q abnormality show up at a fairly low frequency in one FISH test, and not be found in a later one? Unfortunately, the VA did not record detail results like the first results I had obtained six months earlier. I’m sure the same lab ran both panels, but I’m also pretty sure that the interpretation/review was done by different doctors.
Terry: We sometimes do see chromosomal abnormalities disappear in subsequent tests; but they may re-appear later.
Q: Perhaps the threshold for a positive probe result varies if a standard is run each time. Does anyone know?
Terry: Generally levels less than 5% are disregarded because of the nature of the tests. Individual labs should publish their own thresholds, though and they can be as high as 10%
Q: The first is about the reliability of the IGVH test. Are all of the commercial labs equally reliable or is it necessary to go to one of the CLL consortium sites?
Terry: There is a standard methodology for the IgVH test so all labs that adhere to it should get the answer right. Early on we found that some commercial labs weren’t doing the test right and got wrong answers, but I would hope that people have sorted this out by now.
Q: The second is about the FISH test. I’ve been googling and googling and can’t find what the cut-off percentages are for having a deletion. For example, if 1% of cells show the 11q deletion, that’s under the cut-off. But does it mean that that patient will likely develop the deletion?
Terry: See above, but the answer is No.
Q:I am 56, male, diagnosed with SLL/CLL on February 1, 2010 after noticing some enlarged lymph nodes. They did a CAT scan, lymph node biopsy (picked the largest one as right axilliary lymph node: 2.5 cm aggregate of fat with at least four lymph nodes 0.3 to 0.5 cm)), and bone marrow biopsy (marrow lymphocytes 30%) and aspirate. On flow cytometry the lymphoid cells are negative to CD38 and ZAP-70. The cytogenetic analysis of bone marrow aspirates shows the presence of an abnormal cell clone characterized by an interstitial deletion of 14q which is very rare. Are you aware of any other cases with 14q deletion?
Terry: Yes. There is often a submicroscopic deletion in the t(14;18) translocation cases.
Q: On May 28th I had a follow up visit. My CBC seems in the normal range (absolute lymphocytes 2.3). I would like to do the mutational status of the IgVH gene but I do not know where or whether choosing the lab is critical or not.
Terry: For SLL it usually means either a marrow sample or a FNA of the lymph node. Both need the co-operation of your physician. All labs should be able to do it.
Q: Is there a metric (similar to the doubling time on ALC) to determine how fast lymph nodes are growing?
Terry: Not really. You can try to do it on CT scans, but usually people rely on a size threshold to start treatment, and it does mean a lot of radiation.
Q: When I asked my doctor about getting the IgVH test, she simply said that we already knew the answer, since my doubling time was in the order of 5 years. Is this a fair assumption??
Terry: The longer you go the more likely she is to be right, but we have seen unmutated cases take longer than 5 years to gear into activity; it is rare though.
Q: Again, thank you for a very imformative article. Since you mentioned the retroperitoneal lymph nodes, I have to ask is that the same as the mesinteric lymph nodes or am I dealing with something new? After my last ct scan it showed the mesinteric lymph nodes – size of 5-6 cms.
Terry: Retroperitoneal nodes are further back in the abdomen than mesenteric ones.
I too would like to thank Dr. Hamblin and Chaya for this article. I am one of those people who do better knowing all the facts. However; the first Dr. I went to told me “he was the Dr and don’t bring him any thing I find on the internet.” I now have a Dr who allows me to bring my questions to her and her PA and whenever they go to seminars on CLL they send me all the information they obtain at their seminars. It is funny because my husband will look at the information and say he doesn’t understand it and I usually come back with something like that is ok, I’m already onboard and understand it from the articles that Chaya presents to us. I do better knowing the facts and trying to make sense of it. It really does help me. Thank you again
Thanks for this article, packed full of info. From a patient’s point of view, having this knowledge is so important. Being able to estimate the progress and amount of time we have to left to live, directly affects the quality of that allocation. We know what we’re dealing with, it’s like having a reliable weather forecast.
Excellent info – thanks Chaya and Terry,
Labs vary in quality of testing and methods used. For example: Commercial labs, being profit driven, may use a smaller number of interphase cells in testing since it costs more to test more there by lowering the bottom line. In some cases a patient may not have a sufficient disease burden in the peripheral blood (think SLL or early stage low WBC CLL) to obtain an adequate testing sample. Failure to obtain a test result may occur from the lab’s inability to amplify the test sample with the primer sets used in the assay.
Having said that, I have been tested in both commercial and CLL consortium labs with the same result of 6% mutated IgVH using the more favorable VH4-34 family/location. This “Good” finding is in conflict with my rather aggressive disease progression which raises the question of how best to accurately subtype patients for optimal treatment in the era of expanding drug options.
With more “Markers” being discovered and the resolution of array CGH scanning increasing, would it be feasible to scan patients at diagnoses to develop a record of chromosomal translocations, deletions and additions which could be monitored at appropriate intervals?
How important are translocations as compared with deletions and additions? Can these markers be meaningful taken separately?
Some studies have also indicated that it is not just the cytogenetic deletion or aberration (i.e. 13q,11q,17p etc)that determines prognosis but the percent of cells containing the defect(s).
If this wide spread scanning of patients is not a good way to crack the Nut of heterogeneity what should be the method to properly subtype patients for best therapy application?
Many questions and maybe too much to answer in this forum but I thought I’d toss them on the table.
Thanks in advance – You both have given so much to the patient Community.
WWW
Wayne
We don’t have this cracked yet. A lot of the chromosomal abnormalities turn out to be unimportant and just noise. Much of what goes wrong is epigenetic. The exceptions to the IgVH rule are the really interesting ones. They give us clues as to what else is going on. We need to do as many prognostic markers as possible, but funstional studies are also important. Thank you for offering your body for medical research! :-)
Thank you Chaya and Dr. Hamblin. My husband was diagnosed less than a year ago, and he is IgVh unmutated. His counts have already doubled, and his FISH does not reveal any other of the negative prognostic indicators.
He has signed up for a study through Ohio State, and they are repeating the bone marrow this week. Our doctor feels doing this trial will be beneficial for him.
My question is, for those that have that (IgVH unmutated) as the only ‘negative’ indicator, what is really the best course of action? He is going to be starting treatment next Monday, 6/21 with this trial:
http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=584205&version=HealthProfessional&protocolsearchid=7748826
We will find out that day which arm of the trial and which drugs he will receive. If you have any recommendations, we’d appreciate it!
Dr Hamblin: Thanks for your answer.
I just need more clarification on the 14q deletion since I understand is very rare. Is this chromosome abnormality considered a “good”, “not so good”, or “we do not know” prognostic indicator? How common is this “submicroscopic deletion in the t(14;18) translocation cases? And what does it mean?
In my case, asymptomatic, normal peripheral blood and 14q deletion, is it possible to have radiation to reduce lymph nodes or is it better to keep the “active monitoring” approach? I appreciate your comments.
Thank you
Thank you Chaya for keeping us so well inform.
Monique
Dr. Hamblin & Chaya – again bless you both for all your help and support for the CLL community. This was another excellent article. I found the data on ZAP-70 most informative as that is the one marker that has been causing me concern.
10/1/09 I was diagnosed with CLL by local doctor – (4.45% mutated IgVH 3-7, ZAP-70 +dim, CD5 +moderate, CD19 +moderate, CD20 +dim, CD10 negative, CD11C +moderate, CD23 +moderate). My FISH was negative for IGH Cyclin D1, Trisomy 12, 11q22.3, monosomy 13 & 17p13.1 (p53 gene)V. However my FISH showed positive for partial deletion of q13 on 10.5% of cells and partial deletions of BOTH copies of q13 in 65.5% of cells. My WBC was 12,000 & lymphocytes 6,800.
11/24/09 I saw Dr. Castro @ UCSD (CLL Consortium). They show 4.17% mutated IgVH 3-7, ZAP-70 5.74% negative, B2M 2.0
3/1/10 I again saw my doctor. Due different ZAP-70 results we re-tested. ZAP-70 now +moderate (was +dim), CD38 went from negative to +dim, CD45 went from +moderate to +bright. My WBC was now 14,300 & lymphocytes 8,300.
I was concerned about the differing ZAP-70 results as my research indicated this was an important prognostic indicater. Then I read that ZAP-70 needs to be tested within 24-36 hours after the blood draw as the marker for ZAP-70 denigrates over time.
Dr. Hamblin – my two major concerns are
1) Does a q13 double deletion indicate a less favorable prognosis (the limited available data is conflicting)
2) Does my overall prognostic markers seem more favorable than unfavorable?
Thank you again & bless you both!!!
Patti Kruse
Terry and Chaya,
Thank you for the information. It is good to have the prognostic indicators looked at afresh.
Q. My question is, for those that have that (IgVH unmutated) as the only ‘negative’ indicator, what is really the best course of action?
Terry. But his doubling time is another adverse factor isn’t it? This trial is not for someone who has only unmutated IgVH – for those comparison is between doing something and doing nothing.
Q. I just need more clarification on the 14q deletion since I understand is very rare. Is this chromosome abnormality considered a “good”, “not so good”, or “we do not know” prognostic indicator? How common is this “submicroscopic deletion in the t(14;18) translocation cases? And what does it mean?
Terry. “We don’t know”. “We don’t know”. “We don’t know”.
Q. 1) Does a q13 double deletion indicate a less favorable prognosis (the limited available data is conflicting)
2) Does my overall prognostic markers seem more favorable than unfavorable?
Terry. 1) One paper suggested it was worse than a single deletion, but our larger data set shows no difference.
2) More favorable.
Thank you Chaya and Dr. Hamblin for this excellent article and information. As one with SLL and who has been in complete remission for 5 years and currently only has monthly IVIG infusions, is it possible to determine the IgVH status without any current disease? (Two BMBs and flow cytometries were also negative 4 years ago.) If so, how does one determine the IgVH status for an SLL patient? Thank you.
“Grifj”
grifj:
Unless you have detectable and sufficient disease in your blood, it is not possible to IgVH gene mutation status on a blood sample. There would be nothing to look at.
If you have enlarged nodes, I should think IgVH status can be determined on a biopsy sample. Same can be said for bone marrow aspirate, if there is sufficient concentration of CLL/SLL cells there. But it sounds like your bone marrow is clean as well.
The question arises, if you are in complete remission and your bone marrow is also squeaky clean, why bother getting this test at this time? Testing lymph node biopsy material is not as trivial as a blood test. In your shoes I would wait until something changes, therapy is looming on the horizon, before thinking about getting this test done.
As I continue to research factors influencing staging and prognosis for my SLL, I just came across this statement that completely confounds me. Is this Dr. Hamblin’s understanding as well?
“However, no prognostic significance has been found in BM histology in SLL.”
{Kumar S, Rau AR, Naik R, Kini H, Mathai AM, Pai MR, Khadilkar UN. Bone marrow biopsy in non-Hodgkin lymphoma: A morphological study. Indian J Pathol Microbiol [serial online] 2009 [cited 2010 Jun 16];52:332-8. Available from: http://www.ijpmonline.org/text.asp?2009/52/3/332/54987}
Thank you, Chaya. Just thinking ahead (and weighing potential options). This information confirms my hemonc’s position. See you Saturday.
Dr. Hamblin – Thank you so much for answering my questions about my CLL prognostic markers. I very much appreciate your thoughtfulness in taking the time to respond. Your answers are most helpful. This is the 2nd time on Chaya’s “CLL Topics” that you have been gracious enouh to answer a question for me.
Bless you for being one of the “better angels” that help make this a better world for all of us! I will be praying for your recovery from your current health situation.
Thank you again-
Patti Kruse
My lord, with men like Dr. Hamblin at the fore front of our understanding of CLL…how can any of us not know that help is on the way. Thank you doctor and most of all special thanks to Chaya.
She keeps the candle lite for all of us in the darkest of nights.
God bless all of you for keeping the faith.
Steve
Thank you Dr Terry Hamblin as the most emminent authority on CLL for sharing this informations and thank you also Dra Chaya with your fantastic work.
Stay well.
Jorge & Ana
I live in Ontario as do some of the others and my frustration with getting my genetic markers done recently led me to Combimatrix Molecular Diagnostics in California for HemeScan for CLL.
There were a few hoops to jump through and $$ of course but now I know that I have a 13q14 loss on my DNA. It’s been six years since my diagnosis and I have not needed treatment yet. They do not include IgVH status and when I asked about this I was told I am likely mutated based on CD38-ve Flow Cytometry results as well as the progression of my disease and the HemeScan results.
Dr Hamblin – any comments?
Thank you
Greetings to both Chaya and to you Dr Hamblin! This article cleared up so many questions I have about prognostic markers. I am however left with a question regarding trisomy 12. I never seem to get a straight answer on what it means to HAVE trisomy 12 and how it affects CLL. I am now considered stage 1 after being diagnosed in 2008 but we have traced it back to 2004 where my WBC started creeping up. I consider myself lucky as I have had it now for 6 years with being a stage 0 and am now only considered a stage 1 due to lymph node involvement. For someone with an unmutated status, I feel luckier than most! If you could explain the trisomy 12, in depth, I would be eternally grateful. Thanks to both of you for you diligence and help to all of us who struggle to understand the many complexities of this disease.
Wendy
I also have the mysterious Tri 12 and would like more info please, if it’s out there.
Molly
Chaya,
Would like to see your well-written CLL articles, like Dr. Hamlin’s discussion of prognostic indicators, be put into book form. Bet most of our fellow CLL patients would buy the book and keep on their bed stands for nighttime reading and ready reference. Also, believe that every local library should have a copy of CLL (could be titled “Everything You Want To Know About CLL”) as a reference book for those persons not savvy with computers.
The funding for editing the articles and publishing the book could come out of CLL Topics donations as a sponsored project. And who knows, this CLL book, could be a profitable venture for CLL Topics, even though the primary purpose is to help the patients get smart, and the money could be used to sponsor other CLL projects.
Annette
Chaya,
Do you know how is Dr. Hamblin doing ?
The last I saw on his blog 2 weeks ago, he was to have surgery again.
We all pray for him.
Annette D.
Dr. Hamblin just sent me an email. He is doing well, back at home and recovering from his surgery. I am glad to get this update on his health!
Thank you so much for sharing this good news!
ihial2
many thanks to you chaya and to Dr Hamblin for a very informative article. I am today at level 0 and my doctor told me that my doubling time was 3 and half years. Do I have to ask for any tests at this stage
especially the LGvh mutational status or to just carry on with my periodic follow up tests. I am seeing my doctor at the end of the week
and if it possible I would appreciate your answer.
i would like to seek an advice
if the fish test result indicates= All interphase nuclei observed showed a normal signal pattern for all parameters studied and Interpretation as Negative for cll panel.
what it means and imply and the PROGNOSIS,
my CD-38 is 19% and Zap-70 is 41%
i am from delhi ,india
sanesh
Perhaps I may be premature in asking this. I was diagnosed with CLL in 1965, based on a continuing Lymphocyte count in excess of 5000/cu mm B lymphocytes. The count has never been higher than ~ 6000 and I have no other symptoms. I have been on watch and wait since the initial diagnosis. My platelet count has dropped and then recovered to normal levels and my oncologist says that my “new normal” is stable and that I am Stage 0.
Recently it was discovered that I had a squamous cell carcinoma on the face which had invaded the perineural space and as a result, I had 20 radiation therapy treatments (electron beam-shallow dose) to the region. I am being followed by a head and neck surgical oncologist as well as the medical oncologist.
I have so far been very fortunate.
The question that has been on my mind has been; is there anything else I should be checking on (immunoology testing, cytopathology etc.)?
Should I continue “watch and wait” only?
As an aside, I have been exposed to several carcinogenic solvents, pesticides, and chronic low level radiaton during my career.
I know that there are many patients with greater problems and issues and I am not panicking or excessively worrying, I would just like to know if there are other things I should be watching.
Thank you.
JBO
Sorry, my diagnosis was in 2005, not 1965. It’s tought to get old but the alternative is worse.
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