This is a draft of a paper that I am writing. I would appreciate comment from the CLL community. I have corrected some of the errors that crept in during cutting and pasting and have added the references
Is “Leukemia” an appropriate label for all patients who meet the diagnostic criteria of chronic lymphocytic leukemia?
In the new World Health Association (WHO) classification of hematological malignancies chronic lymphocytic leukemia (CLL) is recognized as a disease of neoplastic B cells, only distinguishable from small lymphocytic lymphoma by its presence in the blood [1]. The cells are characteristically small lymphocytes with a dense nucleus, showing partially aggregated chromatin with no obvious nucleolus, and a narrow rim of cytoplasm. The immunophenotype is specific: the cells are CD5, CD19, CD20 and CD23 positive and express surface immunoglobulin with light chain restriction [2]. The levels of CD20, CD79b and surface immunoglobulin are typically low compared with that of other B cells. Although NCI guidelines [3] published in 1996 required the lymphocytosis to be at an arbitrary threshold of 5 x 10 9/L, current custom and practice now merely requires an absolute lymphocytosis (in practice an absolute lymphocyte count greater than 3.5 x 10 9/L) with the characteristic morphologic and immunophenotypic profile [4].
At the same time a new entity of monoclonal B cell lymphocytosis (MBL) has been described [5]. It has been discovered that 3.5% of normal individuals over the age of 40 have monoclonal lymphocytes with the immunophenotypic characteristics of CLL cells at levels below 3.5 x 109/L in their blood [6], and that in first degree relatives of patients with familial CLL the prevalence of MBL is between 13.5% and 18% [7, 8].
On these criteria the only difference between CLL and MBL is the level of the absolute lymphocyte count and this is set at such a low level that minor fluctuations in the number of normal T cells, which comprise the majority of lymphocytes in a normal absolute lymphocyte count, could influence the distinction.
In “Guidelines on the diagnosis and management of chronic lymphocytic leukaemia” by the British Committee for Standards in Haematology [9] the statement is made: “A frequent dilemma is whether to convey the diagnosis of CLL to an elderly asymptomatic patient with low count stage A disease diagnosed on a routine blood count”. For many of these patients it is likely that therapy will never be needed. Many will have a life expectancy no different from that of age and sex matched controls. Nevertheless, the patient, despite the benign nature of the condition, is labeled as having a type of leukemia. Leukemia, whatever the type, is commonly regarded as a malignant disease with a poor outcome. Quite apart from the anxiety conveyed by the word “leukemia” to older people, younger individuals are faced with what may be unnecessary decisions and difficulties about their families, mortgages and life assurance.
The relationship between MBL and CLL is analogous to that between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. MGUS, which has a similar prevalence as MBL [10] is thought to transform to myeloma at a rate of 1% per year [11]. After many years of seeking defining characteristics to separate MGUS from myeloma an international working party has interspersed a third category, asymptomatic myeloma, between them [12]. This has the effect of ensuring that inappropriate treatment of asymptomatic disease is not undertaken.
We propose that a category that we call asymptomatic lymphocytosis should be interspersed between MBL and CLL
Most hematologists are well aware that among those diagnosed as having CLL are symptomless patients in whom the raised lymphocyte count is the only abnormal finding. In these cases, discovered by chance after a routine blood count, the lymphocytes are found to have the characteristic immunophenotype of CLL, but the rest of the blood count is normal; lymph nodes and spleen are not clinically enlarged. Within this “benign” group are a substantial number of patients in whom the clinical findings and white count remain substantially unchanged over many years. Attempts have been made in the past to recognize such patients [13, 14].
In the original paper describing Rai staging, stage 0 patients were reported to have an overall survival in excess of 10 years [15]. It should be remembered that at this time the diagnostic criteria for CLL required a lymphocyte count greater than 15 x 10 9/L. Subsequently, the French Co-operative group [16] recognized a type of smoldering Binet stage A’ CLL with Hb >120 g/L and lymphocyte count <30>130 g/L, lymphocyte count <30>/L, non-diffuse bone marrow histology and a lymphocyte doubling time of >12 months. The actuarial ten year progression-free survival for these was 78%.
We propose that the term asymptomatic lymphocytosis be used for conditions where the absolute lymphocyte count is less than 30 x 10 9/L and the Hb and platelet count are normal, where there are no palpable lymph nodes, spleen or liver, and the patients has no symptoms referable to the lymphoid proliferation.
For MGUS three prognostic factors have been defined which predict progression: a serum paraprotein of at least 15 g/L, a monoclonal immunoglobulin other than IgG, and an abnormal serum free light-chain ratio. If all three risk factors are present there is a 58% risk of progression over 20 years, if two are present the risk is 37%, if one is present the risk is 21% and if none are present the risk is 5% [18].
In recent years several prognostic factors have been identified for CLL (Table 1)
Table 1
Prognostic factors associated with progressive disease in CLL
Lack of somatic mutations in the immunoglobulin VH genes [19, 20]
Aberrations of chromosomes 11 and 17 [21]
Expression of surface CD38 [22]
Expression of cytoplasmic ZAP-70 [23-25]
Elevated serum thymidine kinase [26]
Elevated serum CD23 [27, 28]
and some of these are able to predict progression at an early stage of disease. CD38 expression is independent of both VH gene mutations and ZAP-70 expression and provides extra prognostic information when used in combination with either [29, 30]. A recent study [31] examined 150 patients, who satisfied the smoldering criteria of the French Collaborative Group [16] at presentation, for unmutated VH genes, ZAP-70 and CD38 expression, and 11q or 17p deletions. None of the patients who were negative for all these criteria has progressed so as to require treatment after follow up of between one and 35 years (median 6 years). The single most useful measurement was CD38 expression; CD38 negative cases had a progression rate of 11.6% over the period of observation and none had died of CLL.
Currently, prognostic tests need to be standardized and evaluated in prospective trials. However, the natural history of asymptomatic lymphocytosis is so long that guidelines are necessary now for the management of such patients. There is no evidence that such patients should be treated. We believe that such individuals should be offered the full range of prognostic markers and the frequency of follow up should be determined by the results of these. The word “leukemia” should only be used either when there is sign of progression or if there is strong evidence of the likelihood of progressions from the results of prognostic marker studies.
References
1. Jaffe ES, Harris NL, Stein H, Vardiman JW. Eds Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001.
2. Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A et al. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 1994;8:1640-1645.
3. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87: 4990-4997.
4. Binet J-L, Caligaris-Cappio F, Catovsky D, Cheson B, Davis T, Dighiero G et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia Blood 2006;107:859-861.
5. Marti GE, Rawstron AC, Ghia P, Hillmen P, Houlston RS, Kay N et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol, 2005;130:325-332.
6. Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans Pa et al. Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood 2002; 100:635-639.
7. Rawstron AC, Yuille MR, Fuller J, Cullen M, Kennedy B, Richards SJ Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood 2002;100:2289-2290.
8. Marti GE, Carter P, Abbasi F, Washington GC, Jain N, Zenger VE et al. B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Cytometry B Clin Cytom 2003;52:1-12.
9. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Brit J Haematol 2004;25:294-317.
10. Kyle RA, Therneau TM, Rajkumar SV. Larson DR, Plevak MF, Offord JR et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362-1369.
11. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002;346:564-569.
12. Durie BG, Kyle RA, Belch, Bensinger W, Blade J, Boccadoro M et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J 2003;4:379-398.
13. Han T, Ozer H, Gavigan M, Gajera R, Minowada J, Bloom ML et al. Benign monoclonal B cell lymphocytosis--a benign variant of CLL: clinical, immunologic, phenotypic, and cytogenetic studies in 20 patients. Blood 1984;64:244-252.
14. Chanarin I, Tidmarsh E, Harrisingh D, Skacel PO. Significance of lymphocytosis in adults. Lancet 1984;2:897-899.
15. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood 1975;46:219-234.
16. French Cooperative Group on Chronic Lymphocytic Leukaemia. Natural history of stage A chronic lymphocytic leukaemia untreated patients. Br J Haematol, 1990;76, 45-57.
17. Montserrat E, Vinolas N, Reverter JC, Rozman C. Natural history of chronic lymphocytic leukemia: on the progression and progression and prognosis of early clinical stages. Nouv Rev Fr Hematol. 1988;30,359-361.
18. Rajkumar SV, Kyle RA, Therneau TM, Melton LJ 3rd, Bradwell AR, Clark RJ et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005;106:812-817.
19. Hamblin TJ, Orchard JA, Gardiner A, Oscier DG, Davis Z, Stevenson FK. Immunoglobulin V genes and CD38 expression in CLL. Blood 2000;95:2455-2457.
20. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999;94:1840-1847.
21. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916.
22. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764-1775.
23. Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet. 2004;363:105-111.
24. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004;351:893-901.
25. Hallek M, Langenmayer I, Nerl C, Knauf W, Dietzfelbinger H, Adorf D, et al. Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood. 1999;93: 1732-1737
26. Reinisch W, Willheim M, Hilgarth M, Gasche C, Mader R, Szepfalusi S et al. Soluble CD23 reliably reflects disease activity in B-cell chronic lymphocytic leukemia. J Clin Oncol 1994;12:2146-2152.
27. Sarfati M, Chevret S, Chastang C, Biron G, Stryckmans P, Delespesse G et al. Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia. Blood 1996;88:4259-4264.
28. Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002;99:1023-1029.
29. del Giudice I, Morilla A, Osuji N, Matutes E, Morilla R, Burford A et al. Zeta-chain associated protein 70 and CD38 combined predict the time to first treatment in patients with chronic lymphocytic leukemia. Cancer 2005;104:2124-2132.
30. .Hamblin TJ, Gardiner AC, Mould SJ, Glide S, Best G, Davis ZA et al. Can we predict which patients with early stage CLL will progress and require treatment. Leukemia Lymphoma 2005;46(suppl 1):S46 P24.
Terry,
ReplyDeleteYou put forward a good argument for "asymptomatic lymphocytosis." (AL?)
A major advantage I see to this designation is that it wards off unnecessary treatment by local oncologists who may be ignorant of how CLL progresses. Not that too many will treat at Stage 0 with an ALC of, say, 20,000, but I have heard of it happening.
You add that "We believe that such individuals should be offered the full range of prognostic markers." This has to go hand in hand with what you are proposing. Without the prognostics -- which can be expensive -- a determination of AL v. CLL cannot really be made. If this proposal encourages greater use of, and interest in development of, prognostics, then that is a good thing. One hopes that governments and insurance companies will cooperate; perhaps the adoption of this standard will encourage them to do so.
It sounds like asymptomatic lymphocytosis is a synonym for smoldering CLL - also, if the cut off is 30K for WBC, everyone with WBC higher would be out of the asymptomatic lymphocytosis category automatically. The other thought I have is the emphasis here on prognostic tests is good, however, does not always predict who is going to progress. I like the entire concept, as I would rather have asymptomatic lymphocytosis instead of CLL, but then I think...a rose by any other name. I guess I have mixed feelings but like that you are addressing this.
ReplyDeleteRather than spending money for prognostic tests,I would prefer a asymptomatic status coupled with relatively normal hemoglobin,platelets, ALC and ANC.
ReplyDeleteWhen and if these are exceeded by an arbitary set of levels or symptoms are noted,then would I do the expensive testing.
I can see the possibilty of problems for the Veterans who get assistance with health care because they have leukaemia.
ReplyDeleteOn the other hand it will help people facing employment issues because of a CLL dx.
How would you answer a patients question with say a 25,000 ALC if they ask "do I have cancer?"
Would a person with asymptomatic lymphocytosis have a compromised immune system.?
Would this be an international classification or could one person be dx with CLL while in another country a person with similar counts be dx as AL.
I think that irrespective of the term used most people will still worry.
I have spoken with several people about this after you discussed this before.. and Steve's argument was very valid for some of them.
ReplyDeleteThe word leukemia gives some kind of status in the medical world.
In my case, I think, the word is too heavy, I am very well , W & W, but I have to fill in forms to say , I have leukemia, albeit very mild, which people do not understand.
Leukemia is leukemia says the person, who has never been in contact with this strange illness..
Dr. Hamblin,
ReplyDeleteOnly you know where you are publishing this, so perhaps my comments are out of line with the intended audience. I don't think the rationale for change is strong enough. For those of us who are younger patients, the burden of the title generates profound havoc with employment, insurance, and ignorant oncologists. Some of us are blasted with Fludarabine based upon CD38+ only and abs lymphs only slightly out of range. The article as it is recognizes some of these things but doesn't grab me. Nevertheless, it is a issue worthy of publication and thanks.
Because many cases of what is now called CLL are not likely to progress, it is useful, and avoids confusion, to classify them differently than those that most likely will progress or have already done so. That is already done by using such qualifiers as indolent and aggressive. But surely it should only be called by an entirely different name if it is a fundamentally different disease, if we knew for sure, for example, that unmutated CLL is almost certain to get worse and that unmutated CLL will not do so (unless it changes, somehow, to the unmutated form), and that we can be certain of whether a patient’s CLL is one or the other. However, I get the impression, there is not yet any certainty about this. I think I have read that about half the indolent cases will need relief of symptoms after several years. Until medical science can arrive at clear cut criteria, are we not just fooling ourselves? Would we really better off with a new name than continuing to use indolent and aggressive?
ReplyDeleteIf the prognostic test shows the CLL immunophenotype, then surely we have a cancer of the blood. Is this not leukemia by definition, however benign it might be in a given case?
I was, of course, shocked when diagnosed with leukemia even though I was told it was indolent. Would I have felt differently if I had been told I had asymptomatic lymphocytosis which I would have quickly found out could possibly become worse and that it would then, due to a semantic twist, be called CLL?
By the proposed criteria I am in the asymptomatic lymphocytosis group. But not calling it leukemia will make no difference. If it has the CLL immunophenotype, I still have to enter a check mark on the questionnaire that asks if I have ever been diagnosed with cancer. Surely insurers know that CLL may be indolent. If that does not impress them now, how would a different name help?
While it is good that oncologists might be more aware that treatment may not be necessary (and it frightens me that any should automatically think it is), the flip side is the family doctor who does not think the initial test results of elevated WBC and lymphocytes are serious enough to refer the patient to an oncologist (or haematologist) to get the prognostic tests. At initial diagnosis just one year ago, my GP seemed to think that all CLL is indolent and would not have referred me to an oncologist or sent me for further tests (despite the recommendation of follow up on the lab report) without much higher levels than my WBC of 19.5 and lymphocyte level of 16.4. Only after I started reading up on CLL and showed him that some cases can develop quickly did he refer me. (Luckily for me, mine does appear to be indolent.)
Perhaps what is needed is agreed criteria for the use of the words indolent and aggressive.
I am with anonymous # 1 - "A rose ...." .
I have had a few thoughts looking at a newly diagnosed persons perspective. The majority of people are diagnosed by routine blood tests.
ReplyDeleteSo the doctor says you have an elevated white blood count and flow shows it is a monoclonal B lymphocytosis.
The patient asks what does that mean. The Doc. says well you have some lymphocytes that are all the same we need to run some more tests. Doc what kind of tests what does it mean.
Would the doc then have to explain that you have what used to be called completely ludicrous leukemia CLL but now we need to see how your prognostic indicators are because it now has a new name.
Would having asymptomatic lymphocytosis make people worry if they are in the 11% that may progress and would that be any different from w&w
I understand that the word leukaemia is largely misunderstood and before diagnosis I had visions of it meaning young kids with bald heads.
Maybe my mums attitude when diagnosed with CLL CD38- at age 74 is correct. "I have too many other things to worry about, I'm going to forget about CLL"
I find it interesting that changes to medical technology are leading to these interesting questions.
ReplyDeleteThis year I have had a series of ear infections. As part of the treatments I have had several hearing tests. I have learnt that some aspects of my hearing are below normal. If I was to have examinations of my heart, liver and other organs, comparable to the tests described in the draft essay, I suspect that I would be found to have the early signs of all sorts of problems. But without the tests I am kept from visits to all the hospital specialists and all the attendant worries. I do not consider this ignorance an ethical problem.
I suspect that the essay is dealing with a similiar situation. Probably the diagnosis is an accident and everyone would be better of if had not been made. But once the diagnosis is made, even if it is accidental, then some kind of response is required. It is no longer acceptable for the doctor to keep it from the patient.
I support strongly the idea of intermediate classifications. A diagnosis of some precursor condition needs a response proportionate to its seriousness. It does not matter how it packaged a diagnosis of leukaemia and cancer is life changing and probably wholly disproportionate to the diagnosed condition.
I would like to make a couple of practical suggestions. Whilst the medicos will want meaningful names for these condition(s) I think it better to have something so bland that it is meaningless. Also if at all possible the follow-ups for people should avoid visits to hospital consultants. However infrequent, and whatever reassurances are offered, going to haematology clinics is in itself a message that the condition is serious. I would suggest occasional blood tests with, if necessary, a GP consultation would be more appropriate.
This is worthy discussion, but I'm reminded that patients and medical experts don't do gray areas very well. For example, I'm thinking about the many women who are told that "abnormal" cells have been found during a routine PAP test. So, is it cancer? No, just a little "pre-cancer," whatever that means! I'm not opposed to a renaming a condition as long as patients will have access to the appropriate care. I definately do not want a new label to mean "no big deal."
ReplyDeleteTerry,
ReplyDeleteI am not sure about another category for CLL. Do I think we need to differentiate? Yes. It all gets so messy as to whom needs treatment. Would a patient be less emotional upon learning he/she had Al instead of CLL? No. That is definately a part of your document that won't stand up to snuff. Every person with CLL that I have asked this question of has answered the same. No-they would still feel as if their life had been turned upside down--even more so if they were told it could get worse.
For medical reasons, you might have a winner. If this would help Dr.s with treatment decisions, etc. I don't know many people who will foot the bill for all the prognostic tests if they feel they would be AL. Therein lies the problem. You need these expensive tests to diagnose a non-disease?
Jenny Lou
ReplyDeleteI have had patients with asymptomatic myeloma survive for over 20 years - the normal median survival for myeloma is about 3 and a half. The aymptomatic keeps the oncology hands off, and it is the treatment that kills patients.
Dr. Hamblin,
ReplyDeleteSo how about including your specific statement to Jenny Lou in your article? It would give it more punch. CLLers certainly have the same problem. It IS OFTEN the treatment that kills.
Another thought, you state:
ReplyDelete(in practice an absolute lymphocyte count greater than 3.5 x 10 9/L) with the characteristic morphologic and immunophenotypic profile
With an ALC of 3.5 within normal range for almost all labs, would a GP order immunophenotyping?
The Asymptomatic Myeloma, Multiple Myeloma still uses the ...oma word indicating cancer.
Would there be resentment from the patient told they had AL and were unlucky to progress if they do need treatment.
Age at diagnosis is yet another issue...
A can of worms, good luck Terry.
Terry-
ReplyDeleteI understand the idea of renaming so as to give oncologists the "Keep Out" sign. But, if most of these patients never need treatment, live a life to normal age--then aren't we still naming a non-disease? In reality, maybe we should focus on that it is not a disease to be given any name and should not be diagnosed in the first place. Educate me on this please.
Dr. Hamblin
ReplyDeleteI question why you are spending your time, trying to put a finer point on the definition of CLL. Why not try and educate the large quantity of oncologists practising today that don't have a clue what CLL-2006 is or how to treat it.
Before reclassification, I suggest that the current tests be proven in open trials, before we start using them to slice the CLL loaf thinner. Research recently suggests that CD38 and Zap-70 do not correlate in all samples for example.
I think there are bigger fish to fry for the CLL community. Like why do some CLL patients have elevated levels of certain cytokines that cause them to experience fatigue for example when others have no fatigue at all.
Hope you like my mixed loaves and fishes metaphor...
No I don't want to join another blog so here is my name...Chris Dwyer
Prof. Hamblin,
ReplyDeleteYou state,"The single most useful measurement was CD38 expression; CD38 negative cases had a progression rate of 11.6% over the period of observation and none had died of CLL."
I have two questions:
1.How do you define a negative CD38 case, <3% or <1% CD38 expression?
2.Elsewhere you imply that the mutation status of the immunoglobulin VH genes is the single most important prognostic marker. Which is more important then, mutation status or CD38 expression? Please clarify.
Thank you
Andy
The cut off for CD38 is 30% as in all the original publications. Although CD38 performed slightly better in theis articular group of patients, the difference between any single individual marker and any other (VH mutations, ZAP-70 and CD38) is not statististically significant. You need a combination of markers to pick out every benign case.
ReplyDeleteThanks to everybody for your comments. Keep them coming.
Why these markers?
ReplyDeleteI wonder why you have chosen the prognostic indicators you have. (CD38, Zap-70, IgVH mutation) Clearly there are others and some studies indicate they are superior to the aforementioned.
The Danish study of last year shows that Lipoprotein Lipase (LPL) to be more reliable than Zap-70 and equal to IGVH mutation status. (PMID: 16434371).
You state that "Although CD38 performed slightly better in theis articular group of patients, the difference between any single individual marker and any other (VH mutations, ZAP-70 and CD38) is not statististically significant."
This is contrary to a study in Journal of Clinical Oncology, 10.1200/JCO.2005.03.7184, shows that there can be a wide discordance between Zap-70 and IgVH gene mutation when other factors are considered. The study states "There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage."
A study at Duke University this year of 150 CLL patients showed that when predicting survival, Zap-70 had no significant relationship to survival. The study goes on to state "in contrast to other reports, cellular Zap-70 expression does not correlate with various parameters of disease severity (including survival) in our cohort of CLL patients"
Then we come to CLLU1. Clearly CLLU1 levels significantly predict the time from diagnosis until treatment in Zap-70 positive patients. The study states "CLLU1 expression levels contributed additional prognostic information to ZAP-70-positive patients. "
Since all prognostic markers are untested and unproven, why omit some of the news markers in favour of others that appear to be less reliable?
Chris Dwyer
This is a comment on some of the comments:
ReplyDeleteSometimes doctors treat because they think it is the best thing to do. Other times they treat because the patient makes them.
I like the idea of "asymptomatic," not for the purpose of discouraging doctors from treating, but because it may help reassure patients that no treatment is necessarily indicated.
There are many asymptomatic conditions which doctors treat: hypertension, hyperlipidemia, adjuvant therapy for certain cancers. In cancer, the idea is quite often to take care of the malignancy BEFORE it becomes symptomatic.
"Asymptomatic" does NOT mean "never treat." On the other hand, a test abnormality -- such as an elevated PSA or a monoclonal gammopathy or a lymphocytosis -- does not mean "always treat."
These issues ultimately require good clinical judgment based upon the circumstances of the individual case, bearing in mind the state of the research information available at that moment. One cannot "cookbook" it or be dogmatic.
Chris
ReplyDeleteThe reason I chose those 3 prognostic markers plus FISH for del 11q and del 17p is because these are the best established markers that have been confirmed by many laboratories. That is not to say that other markers will not emerge. The LPL story is still in the melting pot and we must see whether this wil emerge as a useful and convenient marker. The JCO paper is from the German group and the data were presented at the IWCLL last year. We immediately rushed home to see if their results applied to our series to explain the VH gene/ZAP-70 anomalies. I am afraid to say that they don't. We are preparing a paper to rebuff their findings.
In my experience you have to wait awhile when a new finding comes out to see whether other workers confirm the finding independently. This was the case for CD38 which proved not to be an exact surrogate for VH gene mutations, which was also true for ZAP-70.
The jury is still out on a number of other findings (including miR genes)and CLLU1 still needs to be confirmed by other labs.
Vance,
You are right, of course, that treating asymptomatic disease is sometimes the correct thing to do, though not in CLL according to our present knowledge. Things may change when we have the results of the early treatment of asymptomatic bad prognosis disease trials currently being conductd.
I think there is a message for some of our colleagues; not a few patients have contacted me becuase their oncologist has labelled their stage 0 CLL stage 4 in need of immediate treatment, because they were using Ann Arbor staging. But you are right that this idea is mainly for patients to remove the frightening word "Leukemia" and for their employers, relatives, mortgage companies etc who assusme a dire prognosis because of the name.
Terry wrote:
ReplyDelete"But you are right that this idea is mainly for patients to remove the frightening word "Leukemia" and for their employers, relatives, mortgage companies etc who assusme a dire prognosis because of the name."
I would imagine that a diagnosis of AL, knowing there is a chance it could progress, would still be frightening. There is always the sword of Damocles hanging over the patient.
The bottom-line question, it seems, is: Are we dealing with what are essentially two different conditions? (CLL and AL)
If we are reasonably certain that the answer is yes, and that this difference can be accurately finessed by tests, then it makes sense to look at it that way.
. Recent reports state that 50% of patients with early-stage CLL experience rapidly progressive disease,4,5 require therapy,1,4 and have a median survival period that is significantly shorter than suggested by the original publications of the Rai and Binet staging systems.1 Most patients diagnosed as having CLL, including the majority of patients with early-stage disease, die of CLL or CLL-related complications.1,5
ReplyDeleteTerry-this is from Mayo on cll. I am hoping that the above mentioned patients had some b-symptoms when diagnosed. But could they be AL and should the Rai staging be updated? I am very interested in your text on research and immunoglobins concerning AL. Now that would really make sense..a real reason for the name AL. Can't wait to hear more on this subject.
Terry, Maybe one day we will find out that AL isn't really cancer. When I was diagnosed a year ago, I worked with an alternative MD to do some testing that my allopathic doctor wouldn't do. I found out that I have at least twice the mercury levels that I should have and 3 times the lead levels I should. I think lead can reside in the bones. What if the white cells are reacting to increased lead levels or some type of thing that we haven't discovered yet?
ReplyDeleteI am pretty sure that I have the benign form of this. I am still having trouble making long-term plans for my life because of the fear involved with a cancer diagnoses. On the other hand, I think sometimes people with poor prognoses are given false hopes at the beginning when they are told that they might have the benign form.
Thank you, Terry, for everything you do. I pray for you to have continued wisdom and revelation concerning this disease.
From a recently-diagnosed patient's perspective, I do not care what you call my disease - AL or CLL. I am still quite upset over having it. I would, however, feel much better if someone could tell me how long I am going to be okay, which apparently no one can. Dr. Hamblin, with all of your obvious expertise, I would rather see you spend your formidable talent trying to either pinpoint the prognostic markers more definitively or ascertain better treatment modalities for those of us who may need treatment someday. You remain, however, the best source of information and want you to continue to be there for us. We definitely need you.
ReplyDeleteTerry
ReplyDeleteI think what a lot of this is pointing to is a standardisation of tests, percentages and correct interpretation.
If this can be achieved then AL has merit, if it cannot it just extends the confusion.
Cheers
Steve
I understand the desire for the newly-diagnosed to understand the potential risk for dying from CLL.
ReplyDeleteHowever, the traditional indications that treatment will be necessary and that one will die from CLL are usually enough, really.
I for one would like the efforts put into fine-tuning these prognositic indicators be devoted instead to finding a cure for CLL. At that happy moment, then it wouldn't matter as much whether one was given a diagnosis of CLL or AL.
Some people present with an enlarged node. By definition, these people do not have 'smoldering' CLL. If one is diagnosed based upon blood tests, run a flow cytometry and find out the gross chromosomal abnormality. Then one will know.
Watch and wait is prescribed to all CLLers at diagnosis anyway. Indications to treat come with constitutional symptoms, all well known.
Until a curative therapy is discovered, even those with aggressive CLL aren't going to be treated at diagnosis anyway.
The only reason I see for this paper is to give the lucky few who won't die from CLL more peace of mind.
While the rest of us slowly (or more rapidly) decline and die from CLL.
More research into a cure, less into prognostic indicators, PLEASE!!!
Anonymous said "Watch and wait is prescribed to all CLLers at diagnosis anyway. Indications to treat come with constitutional symptoms, all well known."
ReplyDeleteMy husband was started on FCR3 within 2 months of diagnosis. He was not put on W&W. He was Rai Stage III high and terribly sick. So that statement is not always true. I also know many more cller's whom were treated quickly.
Thanks to all the contributors. This correspondance is now closed
ReplyDelete