Consultation document

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.