Molecular Diagnostics and Risk-stratification in Chronic Lymphocytic Leukaemia
Molecular Diagnostics and Risk-stratification in Chronic Lymphocytic Leukaemia
European Oncological Disease 2006 Issue ll
Published: October 2008
Published: October 2008
Chronic lymphocytic leukaemia (CLL) is the most frequent type of leukaemia in the Western world and is characterised by a highly variable clinical course. As none of the currently available conventional treatment options can offer a cure, therapeutic procedures have traditionally been aimed at palliation and were instituted only for advanced stages or symptomatic disease.
Some patients suffer from organomegaly, cytopenia or B-symptoms at diagnosis, or soon thereafter, necessitating therapy. Others have no or minimal signs and symptoms during their entire disease course and have a survival time similar to agematched healthy individuals. Over the recent years, innovative and highly effective approaches such as antibody-chemotherapy and targeted therapy have been developed. Modern treatments can induce remission rates in over 90% of CLL patients and result in median survival time estimates of approximately 10 years.
Some patients are primary refractory or develop treatment resistance during the course of the disease, a situation with a particularly poor prognosis and median survival times in the range of only one year.
Over the recent years, there has also been dramatic progress in our understanding of molecular pathogenesis and outcome prediction in CLL. Genetic parameters such as genomic aberrations (11q-, 17p-), the mutation status of the variable segment of immunoglobulin variable heavy chain (VH) genes and surrogate markers (CD38, ZAP-70, LPL) provide prognostic information for individual patients independently of clinical disease characteristics.
Some markers have been associated with rapid disease progression (+12, 11q-, 17p-, unmutated VH, ZAP-70), resistance to treatment (17p-), short remission duration (11q-, 17p-, unmutated VH), and short overall survival (11q-, 17p-, unmutated VH, ZAP-70). These molecular markers are about to enter the stage of risk-stratification for individual patients in clinical trials.
Risk-stratification in CLL
The standard clinical procedures to estimate prognosis in CLL are the staging systems developed by Binet and Rai.1,2 There is heterogeneity in the course of the disease between individual patients within a single stage group. Other markers, such as clinical parameters (age, lymphocyte doubling time), the serum levels of beta 2-microglobuline or thymidine kinase 3,4 and genetic markers of the tumour cells, such as genomic aberrations,5 gene abnormalities (p53, ataxia telangiectasia mutated (ATM) kinase) and the VH mutation status can refine outcome prediction as they may give prognostic information independently of the stage of the disease.6
Genomic aberrations can be identified in about 80% of CLL cases.5 Specific aberrations, such as a deletion 17p- or 11q-, are associated with aggressive disease as evidenced by rapid progression, resistance to treatment (17p-) and short overall survival. Other important molecular genetic parameters to dissect pathogenic and prognostic subgroups of CLL are the mutation status of the VH genes and its surrogate marker ZAP-70.
References:
1. Binet J L, Auquier A, Dighiero G, et al., “A new prognostic classification of chronic lymphocytic leukaemia derived from a multivariate survival analysis”, Cancer (1981); 48(1): pp. 198–206
2. Rai K R, Sawitsky A, Cronkite E P, et al., “Clinical staging of chronic lymphocytic leukaemia”, Blood (1975); 46(2): pp. 219–234
3. Di Giovanni S, Valentini G, Carducci P, et al., “Beta-2-microglobulin is a reliable tumor marker in chronic lymphocytic leukaemia”, Acta Haematol (1989); 81(4): pp.181–185
4. Hallek M, Langenmayer I, Nerl C, et al., “Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukaemia”, Blood (1999); 93(5): pp. 1732–1737
5. Dohner H, Stilgenbauer S, Benner A, et al., “Genomic aberrations and survival in chronic lymphocytic leukaemia”, N Engl J Med (2000); 343(26): pp. 1910–1916
6. Kröber A, Seiler T, Benner A, et al., “V (H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukaemia”, Blood (2002); 100(4): pp. 1410–1416
7. Kröber A, Bloehdorn J, Hafner S, et al., “Additional Genetic High-Risk Features such as 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukaemia”, J Clin Oncol; in press
8. Rai K R, Peterson B L, Appelbaum F R, et al., “Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukaemia”, N Engl J Med (2000); 343(24): pp. 1750–1757
9. Eichhorst B F, Busch R, Hopfinger G, et al., “Fludarabine plus cyclophosphamide versus fludarabine alone in first line therapy of younger patients with chronic lymphocytic leukemia”, Blood (2005)
10. Keating M J, O’Brien S, Albitar M, et al., “Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukaemia”, J Clin Oncol (2005); 23(18): pp. 4079–4088
11. O’Brien S M, Kantarjian H M, Cortes J, et al., “Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukaemia”, J Clin Oncol (2001); 19(5): pp. 1414–1420
12. el Rouby S, Thomas A, Costin D, et al., “p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression”, Blood (1993);82(11):pp. 3452–3459
13. Stilgenbauer S, Dohner H, “Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy”, N Engl J Med (2002); 347(6): pp. 452–453
2. Rai K R, Sawitsky A, Cronkite E P, et al., “Clinical staging of chronic lymphocytic leukaemia”, Blood (1975); 46(2): pp. 219–234
3. Di Giovanni S, Valentini G, Carducci P, et al., “Beta-2-microglobulin is a reliable tumor marker in chronic lymphocytic leukaemia”, Acta Haematol (1989); 81(4): pp.181–185
4. Hallek M, Langenmayer I, Nerl C, et al., “Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukaemia”, Blood (1999); 93(5): pp. 1732–1737
5. Dohner H, Stilgenbauer S, Benner A, et al., “Genomic aberrations and survival in chronic lymphocytic leukaemia”, N Engl J Med (2000); 343(26): pp. 1910–1916
6. Kröber A, Seiler T, Benner A, et al., “V (H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukaemia”, Blood (2002); 100(4): pp. 1410–1416
7. Kröber A, Bloehdorn J, Hafner S, et al., “Additional Genetic High-Risk Features such as 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukaemia”, J Clin Oncol; in press
8. Rai K R, Peterson B L, Appelbaum F R, et al., “Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukaemia”, N Engl J Med (2000); 343(24): pp. 1750–1757
9. Eichhorst B F, Busch R, Hopfinger G, et al., “Fludarabine plus cyclophosphamide versus fludarabine alone in first line therapy of younger patients with chronic lymphocytic leukemia”, Blood (2005)
10. Keating M J, O’Brien S, Albitar M, et al., “Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukaemia”, J Clin Oncol (2005); 23(18): pp. 4079–4088
11. O’Brien S M, Kantarjian H M, Cortes J, et al., “Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukaemia”, J Clin Oncol (2001); 19(5): pp. 1414–1420
12. el Rouby S, Thomas A, Costin D, et al., “p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression”, Blood (1993);82(11):pp. 3452–3459
13. Stilgenbauer S, Dohner H, “Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy”, N Engl J Med (2002); 347(6): pp. 452–453
