Fishing For Answers

The old ways are changing. But if you read any of the short and sweet patient information brochures and on-line write-ups, the ones that do not update their content on a regular basis, you could come away with the impression that the "Watch & Wait" approach is still the unquestioned best way to treat CLL patients. CLL Topics begs to differ. Slowly but surely, that approach ruled by the one-size-fits-all perspective is giving way to more risk-adapted therapy decisions in treating CLL patients. Sure, you will still find old school local oncologists who have not kept up with the latest information and would prefer to stick to the old ways. In that case, it is up to you to read, understand and decide for yourself and perhaps change your oncologist's perspective as well.

Background

The Rai and Binet classification systems have been the underpinnings of CLL treatment for more than a decade. They provided a rational way of looking at the disease, a yardstick with which to measure the level of tumor load and therefore a rational way of deciding when to end the "Watch & Wait" phase. In their time, they were both extremely useful in guiding therapy decisions. We have discussed the details of the Rai and Binet staging in a previous article. We have also reviewed many of the modern prognostic indicators that are useful in segregating CLL patients into different risk categories in our article "What Type of CLL do you have?" . If you have not read it before, I urge you to do so now. In that article we discussed the role of IgVH gene mutation status, CD38 levels on CLL cells, and ZAP-70 as well as other popular indicators.

The bad news is that tests such as IgVH gene mutation status and ZAP-70 are still not available commercially, and there is still a degree of controversy on how exactly they relate to each other and to the other prognostic indicators. The jury is still out on CD38 expression, some experts think this changes over time just like B2M (concurrently with the disease), and therefore is not a good indicator of future prognosis.

The good news is that the specific chromosomal aberrations you have are at the very heart of what makes your CLL tick and many of the other prognostic indicators are derivatives of this fundamental cytogenetic flaw. A few years ago, "FISH CLL panel" was an expensive procedure carried out only at top-rated research labs. But now, modern FISH analysis is rapidly becoming a standardized test. Unfortunately it is still not a fully FDA-approved test procedure, not yet. However, it is feasible right now to get this test done, if you are willing to "push" the issue. I am willing to bet FISH analysis will be within reach of most of us in the next year or two, fully approved by the FDA and as automatic as a regular CBC.

Rationale for FISH Testing Ahead of Therapy Decisions

This is where rubber meets the road. Life was simple a decade ago, when there were few diagnostic tools and fewer therapy choices. Watch-and-wait was a good strategy then since there was no point in undergoing high toxicity chemotherapy before you absolutely needed it to take care of nasty b-symptoms, especially since it did not add to overall survival. Ten years from now, life may get simple again, with better understanding of the exact nature and risks of each variety of CLL matched with well defined and optimized therapy strategies for patients in the different risk groups. Right now we are in that uncomfortable, in-between stage. The technology is available, the research findings are pretty clear and we can differentiate patients into different risk "buckets" with a reasonable degree of confidence. What is missing is the general percolation of this information and insight down to the level of the local healthcare provider and the insurance companies that sometimes use the FDA lethargy in the approval process as a fig leaf for not covering reasonable procedures. Several years ago, there was no choice. But for patients today, making therapy choices without knowing their chromosomal aberration can be the equivalent of shooting in the dark. You may get lucky, but there is also the chance that you may end up shooting yourself in the foot or some other place where it hurts even more.

Let's make this discussion up close and personal. You have recently been diagnosed with CLL. The shock is just wearing off and you are now in the learning mode, trying your best to come to grips with the situation. The monthly CBC says your absolute lymphocyte count is not all that high and you have a couple of lymph nodes that are just beginning to bump out. No fevers or infections, no night sweats, no B-symptoms yet, thank your stars. Old school conventional wisdom says do nothing and stay in Watch-and-wait mode until you start feeling the effects of the disease and your shirt collar no longer fits because of expanding nodes under your jaw, until you have to change your PJ's in the middle of the night because of night sweats, or until CLL-related fatigue gets you out of having to invent excuses for not attending to the honey-do list. When you reach that stage, the old-schoolers tell you, that is when you initiate fludarabine therapy, the current gold standard for CLL.

Is this the right choice? That depends. If you were lucky enough to have one of the more benign chromosomal aberrations, say a sole 13q deletion which puts you squarely in Bucket A, this approach is not a bad one. You get to delay the inevitable day of therapy for as long as possible - and when you can no longer put it off, fludarabine will probably work well for you. But what if you were not one of the lucky ones? What if you did not have a sole 13q deletion and instead you had the dreaded 17p deletion (deletion of the TP53 tumor suppressor gene)? Would it still be prudent to let the CLL tumor load get ever higher, with lymph nodes to match? Would fludarabine still be the right choice as front-line therapy? In the next section I would like to lay out the logic that says it would not be a good choice to wait out a 17p deletion case till the disease becomes bulky and fludarabine is most likely not the best choice in such a case. How can you tell what to do and when to do it, if you don't even know what type of CLL you have in the first place? That is the nature of this debate.

What the Experts Say

Dohner, Stilgenbauer, et. al., provide some of the first clear indications of cytogenetics and response to conventional therapy. Fifty patients received therapy with purine analogs (fludarabine or pentostatin). The response to therapy depended strongly on the presence of a 17q (TP53 gene) deletion. None of the 12 patients with 17q deletion responded to therapy with fludarabine (7 patients) or pentostatin (5 patients), while 20 out of 36 (56%) patients without a deletion achieved a remission. The median survival time after start of therapy in the patients with a p53 gene deletion was only 7 months, whereas the median survival time of the patients without a deletion had not yet been reached at 72 months.

If you were one of the unlucky ones with TP53 deletion as your chromosomal aberration, two points stand out - you are not likely to respond to fludarabine or pentostatin (another purine analog similar to fludarabine); and once therapy starts, you may not have a lot of time to re-think options and implement a brand new game plan.

As you can read below, options other than fludarabine or pentostatin may be your best bet. If you were one of these unfortunate Bucket C folks and you followed the conventional wisdom of yesteryear, by staying in Watch-and-wait until onset of heavy duty B-symptoms and then treating with fludarabine, in my opinion you would be up the proverbial creek without a paddle. Standard chemo drugs may not work well for you, and by that time your lymph nodes may be so large that the monoclonals have a hard time doing the job adequately (see "Campath Looking Better and Better"). How would you know what to do, whether or not you have the 17p (TP53 gene) deletion, unless you get the FISH test done at the time of diagnosis?

Abstract:

p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias.

Dohner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G, Diehl D, Schlenk R, Coy J, Stilgenbauer S, et al.
Medizinische Klinik, University of Heidelberg, Germany.

Conventional cytogenetic analysis in B-cell chronic lymphocytic leukemia (B-CLL) has been very difficult, and the prognostic significance of specific chromosome aberrations is under discussion. Recent improvements in fluorescence in situ hybridization (ISH) techniques have provided an alternative approach for the detection of chromosome aberrations. Here, an interphase cytogenetic study was performed to analyze the incidence and prognostic significance of a p53 gene deletion in B-CLL and related disorders. We studied mononuclear cells from 100 patients with chronic B-cell leukemias [B-CLL, 90 patients; B-prolymphocytic leukemia (B-PLL), 7; Waldenstrom's macroglobulinemia (WM), 3] by fluorescence ISH with a genomic p53 DNA probe. In a subset of patients, additional G-banding analysis and single strand conformation polymorphism (SSCP) analysis was performed. Seventeen of the 100 patients [17%; B-CLL], 11 of 90 (12%); WM, 1 of 3; B-PLL, 5 of 7] exhibited a monoallelic p53 gene deletion by ISH. G-banding analysis demonstrated abnormalities of chromosome 17 in 13 of these 17 patients, all leading to loss of band 17p13. SSCP analysis showed aberrant bands in 9 of 14 patients with a p53 gene deletion. None of 12 patients with a p53 gene deletion compared with 20 of 36 patients (56%) without a deletion responded to therapy with fludarabine or pentostatin (P < .001). The difference in survival probabilities from the time of diagnosis and from the start of treatment with purine analogs between the two groups was highly significant (P < .001). In multivariate analysis, p53 gene deletion was the strongest prognostic factor for survival. In conclusion, p53 gene deletion predicts for non-response to therapy with purine analogs and for poor survival in chronic B-cell leukemias.

Below is another blue-blood pedigree paper that comes to the same conclusion. Byrd, Flinn et al have provided one of the first analysis of response to Rituxan as a function of the FISH cytogenetic type. Unfortunately, the sample size is rather small, with as few as 3-4 patients in some of the categories, making the statistics less than robust. Nevertheless, this study does make a couple of important points: one of the poor prognosis groups, those with 11q (ATM gene) deletion, do respond well to Rituxan, while those with the 17p (TP53 gene) deletion do not respond to Rituxan. Perhaps this stance will be modified as larger retrospective studies are done. This is what the authors have to say, in terms of applying the new paradigm to better treat CLL patients:

"How can these results be applied to the treatment of patients with CLL? The data described herein extend the observation of others regarding the chemoresistance of del(17)(p13.1) to also include rituximab. This contrasts with preliminary findings of Stilgenbauer et al., who demonstrated in a small series that CLL patients with del(17)(p13.1) had clinical responses to Campath-1H. If the findings of Stilgenbauer et al. are confirmed in larger cohorts of patients, it would appear that Campath-1H, as opposed to fludarabine, chorambucil, or rituximab would be a more rational initial treatment choice for patients with del(17)(p13.1). This will be particularly true if new combination regimens of rituximab and fludarabine or fludarabine, cyclophosphamide, and rituximab cannot overcome the resistance associated with del(17)(p13.1). Studies examining this important clinical question are currently under investigation by our group."

I find the quote above from their paper almost a valuable as the actual statistics. This is the first clear-cut connection between therapy choices such as fludarabine, chlorambucil, Rituxan and Campath and cytogenetics voiced by some of the best minds in the business. Based on their results the authors conclude even Rituxan is not a good choice for the 17p deletion types, Campath may be better choice for them. And the authors leave the door open but raise the million dollar question, what about combination therapies like the popular "FRC" and "FR"? Would 17p deletion folks who do not respond to fludarabine, would they respond to fludarabine containing combos? Good question, don't you think? If you had 17p deletion, you would certainly want to know the answer, before you signed up for these combinations, I would think. If you did not even know your FISH cytogenetics, how do you even begin to make smart therapy choices? Just imagine, would you want to go through all the significant pain and toxicity of one of these therapies, if you had an only slim chance of getting a good response from the get go?

Too bad the sample size in this pivotal paper is small, it is time we got some clear answers to these very important questions. The authors say studies examining these clinical questions are currently under investigations in their lab. A heartfelt Amen! to that from this reporter and CLL spouse.

Abstract:

Interphase cytogenetic abnormalities in chronic lymphocytic leukemia may predict response to rituximab.

The Division of Hematology-Oncology, Ohio State University, Columbus, Ohio 43210, USA.

Select cytogenetic abnormalities such as del(17)(p13.1) and del(11)(q22-q23)predict rapid disease progression and inferior survival in chronic lymphocytic leukemia (CLL). We sought to determine the impact of the four most common interphase cytogenetic abnormalities in 28 CLL patients relative to response to three-times-a-week rituximab therapy. Abnormalities were noted in 25 of the 28 patients to include del(13)(q14.3) [n = 16 (57%)], del(11)(q22.3) [n = 10 (36%)], +12 [n = 6 (21%)], del(17)(p13.1) [n = 5 (18%)], and normal [n = 3 (11%)]. Only a minority of each of these occurred as sole abnormalities. To categorize patients into one specific group, we used the hierarchical order del(17)(p13.1) > del(11)(q22.3) > trisomy 12 > del(13)(q14.3) to prioritize. Response to rituximab was noted to vary by cytogenetic group: del(17)(p13.1), 0% [n = 5]; del(11)(q22.3), 66% [n = 9]; del(13)(q14.3), 86% [n = 7]; +12, 25% [n = 4], and normal, 0% [n = 3]. Response was significantly lower (P = 0.05) in patients with del(17)(p13.1) as compared with those with other abnormalities. These data suggest that interphase cytogenetics in CLL may be predictive of a response to rituximab therapy and provide support for additional studies validating risk-adapted therapy in this disease.

I will wrap up this section with a discussion of the third paper I would like to bring to your attention. This time the experts are of the caliber of Flinn, Grever, Byrd et al, no slouches in the whole pack. This article is focused on Campath, the other big monoclonal antibody in the CLL universe. The authors agree that while ZAP70 and IgVH mutation status are interesting and important, it is still the cytogenetics that are likely to have the most direct correlation to clinical outcome. Unlike purine analogs such as fludarabine and pentostatin, Campath was found to have significant activity even in 17p deleted "Bucket C" patients. The quote below is from the full paper, and the highlighted sentence says it in blunt terms. Fludarabine, chlorambucil, even Rituxan, may not be rational choices as therapy for 17p (TP53 gene) deleted patients, Campath would be a better choice.

"How can these results be applied to the treatment of patients with CLL? While recently identified prognostic factors such as VH mutational status and associated ZAP-70 expression are predictive of disease progression and inferior survival, one preliminary study did not relate this to resistance to conventional CLL therapies. This contrasts with del(17)(p13.1)/p53 abnormalities that become increasingly common with disease progression and are associated with resistance to most conventional therapies used in the treatment of CLL. The data described support the case report of Stilgenbauer and colleagues who demonstrated a complete response in a single CLL patient with del(17)(p13.1) and p53 mutation. Similar to the results reported in this single case report, several patients included in our series had durable remissions that ranged from 3 to 17 months with three having complete eradication of the del(17)(p13.1) clone in the bone marrow post-therapy. If our collective findings are confirmed in larger prospective cohorts of patients, it would appear that alemtuzumab, as opposed to fludarabine, chorambucil, or rituximab would be a more rational initial treatment choice for patients with p53 mutations and/or del(17)(p13.1). In addition, these data would provide preliminary evidence for screening all patients at time of initial and subsequent therapies for the presence of del(17)(p13.1) and p53 mutations to avoid administration of otherwise ineffective therapy for this disease."

Abstract:

Alemtuzumab is an Effective Therapy for Chronic Lymphocytic Leukemia with p53 Mutations and Deletions.

Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC.

The presence of p53 mutation or deletion predicts for poor response to conventional therapy in chronic lymphocytic leukemia (CLL). We sought to determine if the humanized anti-CD52 antibody alemtuzumab was effective in this patient group. Thirty-six patients with fludarabine refractory CLL were treated with alemtuzumab, fifteen (42%) of which had p53 mutations or deletions. Clinical responses in patients with p53 mutations and/or deletions were noted in 6 of 15 (40%) versus 4 of 21 (19%) of patients without. The median response duration for this subset of patients was 8 months (range 1-17 months). These data suggest that alemtuzumab may be an effective therapy for CLL patients with p53 mutations or deletions.

You might ask, what is wrong with trying out fludarabine even with a 17p (TP53 gene) deletion, the worst that can happen is that you don't get a good response and you may have to raise the stakes and move on to Campath. Well, the risk is higher than just not getting a good response. TP53 gene and the ATM gene are the gatekeepers of your genome. You can read a lot more about them on our recent article, "Cytogenetics of ATM and P53". When these two important genes are not working well, you can make the situation a lot worse by exposure to DNA-damaging agents such as fludarabine. The following is an oversimplification, but it helps to make the point: chemotherapy drugs such as alkylating agents (chlorambucil, cyclophosphamide) and purine analogs (fludarabine, pentostatin) work by causing severe DNA damage to cancer cells. The damage is often so severe that the cells' own internal mechanisms kick in and order the cells to die. The problem is that two of the most important internal mechanisms we are talking about are functions of the ATM and TP53 genes. In other words, with poor functioning of the ATM and TP53 gene, not only is the damaged cancer cell not ordered to kill itself, it may in fact continue living in its even more mangled and damaged form. What does this mean to the patient? One of the consequences could be risk of secondary cancers down the road, such as multiple myeloma. The abstract below by Morrison, Rai, et. al., describes potential risks of this type.

Please be sure you get this point right: just because you have had fludarabine therapy and you have also got ATM and/or TP53 gene defects does not guarantee that you will have secondary cancers. It may, however, mean you have a higher risk of developing these secondary cancers than patients with similar cytogenetics who were not exposed to DNA-damaging drugs. Cancer is all a matter of statistics and balancing risk / reward ratios. If you are looking for absolute answers and guarantees, this website may not be your cup of tea and perhaps you had better invest in a crystal ball! And do me a favor, please do not shoot the messenger if I am bringing you bad news.

Abstract:

Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011.

Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, Hines JD, Shepherd L, Larson RA, Schiffer CA.

Section of Hematology/Oncology, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin's lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication.
PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML.
RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P =.007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months).
CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.

The Need for Repeat FISH Analysis on a Regular Basis

Hopefully I have convinced you by now that getting a FISH analysis done is of major importance in determining your therapy choices. But why do you have to repeat it? Is it not enough to know once and for all what "Bucket" you belong to, and that is that? Not quite. CLL is not a static business. It evolves and changes over time. In some patients who have a truly smoldering disease, nothing much happens. They most often have the relatively benign 13q deletion going in, and they stay with that for the rest of their natural lives. Others, like our hypothetical patient Harvey ("The Difficult Case of the Round-headed Kid") undergo clonal evolution. Harvey too had a 13q deletion going in, clearly a resident of the lucky "Bucket A". His game plan was to stay cool, not worry too much about stuff because he had every option in the book available to him when he needed it, including the high response FRC type combo therapies. Then one fine day as a result of an annual FISH test he discovered his CLL clone had "evolved". A new variant raised its ugly head that had both the 13q deletion as well as a more dangerous 11q deletion added to it. Another repeat FISH analysis a few months later confirmed the more dangerous "double trouble" clone with both 11q and 13q deletions was rapidly gaining ground over the clone with just the 13q deletion. His game plan had to be changed - purine analogs were not his best bet anymore and he had to make sure he could get by with just monoclonals. For starters this meant he had to make sure his disease never got too bulky, since monoclonals do have a hard time dealing with bulky lymph nodes. Suddenly, he experienced a higher level of interest in "mobilizing agents" that can flush out the CLL cells from lymph nodes and bone marrow.

What happened to Harvey can happen to any patient. I do not know of any way to prevent clonal evolution, short of curing the underlying CLL. The best you can do is to monitor the situation. If the situation changes on you, and you have been lucky enough to find out about it in good time, you will be able to make the necessary course corrections. Fore-warned is fore-armed. You can read the technical abstracts and the logic of getting repeat FISH testing done at least on an annual base in our recent article on clonal evolution.

Where to Go, How to Get It Done

The "CLL FISH panel" test is not yet formally approved by the FDA. But then, neither is Rituxan approved as frontline and single agent therapy for CLL, and I think a lot of you have gotten over that hurdle. It does mean though that you have to work with your insurance companies and healthcare providers to get this test done and have it covered under your insurance policy. That part is up to you, but I will make this general comment: you get nothing if you are not even willing to ask, and it is amazing what you can get if you are willing to be determined and organized in your campaign. Contrary to popular thinking, the world out there does not think it owes you a free lunch.

We have identified two companies that will do the CLL FISH panel, which includes testing for 13q deletion, 12 Trisomy, 11q deletion and 17p deletion. These are the four major chromosomal aberrations under scrutiny right now. No doubt others such as 6q deletion will be added as time goes on. Make sure your test includes testing for each of these four major cytogenetic abnormalities. The cost of doing the test is approximately $450 dollars, roughly the same for both the labs. As I said above, you might want to make sure you know ahead of time how much of this your insurance will cover.

In addition to the two listed below, you might find that other providers are able to meet this need. If you obtain additional information on other providers or on applicable insurance coverage, please let us know by email:

. Widespread adoption of the test, FDA approval and competition from additional providers should make the cost more affordable and the insurance coverage better. But it all starts with you talking to your oncologist.

A. Mayo Medical Laboratories

Test # 83089, CLL FISH Panel (Cost $412.00)
Not approved by the FDA: Insurance carriers may not recognize this as a covered benefit.

Additional information: Richard Carlson, Supervisor, Cytogenetics Lab, 507-266-5349

It is possible to get the blood sample drawn locally, and then sent to Mayo Labs for testing.

You can get a lot more information from Mayo Medical Labs website: http://216.245.167.14:81/MALHTML/83089.html

The site gives precise instructions on sample size of blood, how it is to be collected, stored and shipped to the Mayo lab. It is important that your local blood draw station follows the instructions exactly, it is not a bad idea to print out the instructions and take them with you. If necessary, the supervisor at the draw station can call Mayo Labs on the phone and get clarifications. Make very sure the sample is sent over by the fastest mode, say FedEx overnight. It is suggested that you do not get the blood drawn on a Friday or even late in the week, since you would not want the sample languishing unattended over the weekend. The normal reference range, based on a 95% confidence interval, is <6.5%, <5.0%, <7.0%, and <8.5% for deletion in 6q, 11q, 13q, or 17p, respectively; <1.5% for trisomy 12. What that means is that if the percent of CLL cells with a particular abnormality is below the cutoff threshold, the test will not be able to measure it with a reasonable level of confidence.

If your doctor recommends a FISH analysis of bone marrow aspirate, Mayo Labs can do that as well. Again, go to the website and make sure you and your doctor follow the instructions precisely. Since the accuracy of the test does depend on getting a good and well preserved sample to the testing lab, it is in your interest to make sure it is done right.

B. Labcorp: Center for Molecular Biology and Pathology

CLL FISH Panel. LabCorp test #510594 (Cost $416.50)
Not approved yet by FDA; Because test is new it may not be recognized by carriers as a covered benefit for patients.

CLL FISH panel available targeting ATM (11q), 12 trisomy, 13q, and 17p (TP53) . Source of Information: Jeanetta (919-361-7700)

General company web address as well as the one specific to the oncology section are given below. You will have to scroll down almost to the bottom of the page for the oncology section before you get to the relevant information for CLL FISH panel.

http://www.labcorp.com/dos/
http://www.labcorp.com/datasets/labcorp/html/frontm_group/frontm/section/profonc.htm

For more information, call Oncology Customer Service at Labcorp at 800-533-0567.

Editorial

Someone told me there is an ancient Chinese curse that goes like this "May you live in interesting times". We are certainly living in interesting times, and it is not always a great deal of fun. Those of us who have been cursed by this disease for a while remember the not-so-good old days, when names like Rituxan and Campath were hardly ever heard. FISH was something you ordered for dinner, and good old Leukeran pills were the mainstay of CLL therapy. No choices, no decisions, no hassle. One size fits all. One third of all CLL patients smoldered for the rest of their natural life, one third needed treatment and did fine for some time with the chemotherapy drugs of the day, one third had no luck from the get go, nothing available worked for them. I wonder, did this very approximate segregation of CLL patients into thirds match our now more sophisticated "Buckets", did they pretty much follow the cytogenetic and other prognostic indicators we have now figured out?

Now things are a lot more complicated, but also a lot more optimistic. The third of the patients who were lucky to start with, they are still lucky and they can check their FISH status periodically and make sure their luck is holding. The middle group can try and finesse the situation, see if they can get by with less toxic and longer lasting therapy choices. We now know that roughly a quarter to a third of all CLL patients have the poor prognosis 11q and 17p deletions right from the beginning, or evolve into that position at a later date. These are the ones with massive lymph nodes, rapidly increasing counts and resistance to most chemotherapy drugs. In the past, they had short survival and complicated disease progression to look forward to. That is what has changed, thanks to better understanding of the underlying chromosomal aberrations. Once we figured out the function of ATM and TP53 genes, and that their malfunction is involved in 11q and 17p mutations and deletions, the emphasis is to keep away from further DNA damaging agents. Monoclonal antibodies, vaccine approaches, bone marrow transplants and the like have a much better chance of giving good results.

What about the patients who have already crossed the bridges, made the therapy choices that perhaps were not optimal for them, in the light of present day information? We can all play Monday morning quarterbacks, but there is little to be gained by going over could-haves and should-haves, or shooting the messenger that brings you bad news. Time can only go forward, and we all have to live with the choices we have made along the way, make the best of our today and our tomorrows. This website is dedicated to helping CLL patients find better solutions for themselves. It is not equipped to give detailed or specific medical advice. We cannot turn the clock back, invent miracle drugs, pills or potions, nor can we cure your CLL. What we can do is to find and present information that you can use, in a form that may be more useful to you as laypersons. It is up to you to make use of the information, to the extent that you and your healthcare team think appropriate.

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