Constantine S Tam
John F Seymour
MB BS FRACP
H Miles Prince
MB BS MD FRACP FRCPA
University of Melbourne
Peter MacCallum Cancer Centre
Chronic lymphocytic leukaemia (CLL) frequently presents in elderly patients and is a relatively indolent disease with a median age at presentation of 65 years.(1) As early intervention with alkylating agents in patients without cytopenias or other indicators for immediate treatment(2) does not improve survival,(3) a “watch-and-wait” strategy is often initially advocated. Patients who present with or develop symptoms usually receive alkylating agents such as chlorambucil or cyclophosphamide,(4) and indeed, many such patients die “with CLL” rather than “of CLL”. Such a strategy makes no attempt at maximally eradicating disease and remains entirely appropriate for older patients who are unlikely to tolerate moderate doses of chemotherapy, particularly those with an established indolent disease course.
However, with the development of new therapies for CLL, there has been exploration of treatments with the objective of prolonging remission duration and survival. Patients suitable for a more aggressive approach include younger patients who can tolerate these treatments, particularly those destined to have more aggressive disease.
Advances in the understanding of CLL biology
During the last decade, significant advances in the understanding of CLL pathogenesis identified for the first time important biological features predictive of aggressive disease course. Foremost of these is the recognition that patients with CLL can be divided into two groups based on their immunoglobulin variable (IgV) gene somatic mutation status: patients with mutated IgV genes usually had indolent disease and prolonged survival (>20 years), while those with unmutated IgV genes had a more aggressive disease course and shortened survival (<10 years).(5,6) Other novel prognostic predictors to emerge include cytogenetic abnormalities (as assessed by fluorescent in-situ hybridisation analysis),(7) dysfunction of the p53 tumour suppressor gene(8) and cell surface expression of CD38 and cellular ZAP-70,(8,9) all of which have varying degrees of correlation with IgV mutational status. The evaluation of the cellular expression of ZAP-70 is the most convenient and cost-efficient means of evaluation in routine clinical practice, although cytogenetics also adds additional independent prognostic information.(10) Taken together, these new tools assist the clinician to identify patients with biologically aggressive disease who may be appropriate candidates for the early application of disease-modifying strategies.
Changing role of purine nucleoside analogues
The purine nucleoside analogues fludarabine, cladribine and pentostatin were the first agents to be active against alkylator-refractory CLL.(11) Fludarabine, the most extensively studied purine nucleoside analogue, significantly improves response rates and prolongs remission when compared with alkylating-agents as front-line therapy.(12,13)
Importantly, combinations of fludarabine and a DNA- damaging agent demonstrate impressive in- vitro and in-vivo synergy,(14) leading to the development of the potent regimens fludarabine–cyclophosphamide (FC)(15,16) and FC–mitoxantrone (FCM);(17) both regimens demonstrate significantly more activity than fludarabine alone, with little or no additional toxicity.(18) Early experience with combinations involving cyclophosphamide and cladribine(19) or pentostatin(20) have shown similar promise.
Monoclonal antibody therapy
The development of specific and active monoclonal antibodies (MAbs) against CLL provided novel agents for the management of multiply relapsed patients with compromised marrow reserve and resistant disease. Importantly, they show significant synergy with cytotoxic agents and, in combination with fludarabine-based regimens, result in disease reduction to levels undetectable by sensitive flow cytometry and molecular assays.(21)
The MAbs most extensively studied to date include the anti-CD20 MAb rituximab and the anti-CD52 MAb alemtuzumab. Rituximab is relatively nontoxic but shows only modest activity as a single agent at conventional doses;(22,23) its main role is in combination with chemotherapeutic agents to augment cytotoxicity. Alemtuzumab shows potent activity against resistant CLL but is associated with marked B- and T-cell depletion and the attendant risk of opportunistic infections.(24,25) In patients with small-volume residual disease following fludarabine- and rituximab-based therapy, “consolidation” therapy with alemtuzumab may further reduce disease to undetectable levels.(26)
Stem cell transplantation
Decreasing transplant-related morbidity and mortality has resulted in renewed interest in stem cell transplantation (SCT) as a therapeutic option for CLL. Autologous SCT, although limited by potential tumour contamination of stem cells, appears to be a promising treatment modality, particularly in patients with biologically high-risk disease, provided that adequate disease cytoreduction can be attained to allow collection of minimally contaminated autologous blood cell progenitors.(27) However, prior fludarabine use does impair peripheral blood stem cell mobilisation.(28) Allogeneic SCT avoids the problem of graft contamination, but such transplants using myeloablative conditioning regimens were historically associated with unacceptably high rates of transplant-related mortality.(29)
The recent development of nonmyeloablative allogeneic SCTs (“mini-allografts”) with significantly less peritransplant toxicity has renewed interest in allogeneic SCT for CLL.(30) Limited studies of such transplants have demonstrated a potent graft vs CLL effect, leading to the exploration of immune effector cells as a novel therapeutic strategy.(31)
Elimination of minimal residual disease
The emergence of highly potent fludarabine and MAb chemoimmunotherapy regimens and SCT strategies has led not only to achievement of complete remission by traditional morphologic criteria, but to reduction of CLL to levels undetectable by sensitive flow cytometry and molecular assays (“minimal residual disease” [MRD]).(21,30)
Although the full prognostic value of achieving MRD negativity has not been fully evaluated, it is intuitive that any potential cure for CLL must be preceded by the elimination of all detectable disease. Indeed, early historically controlled data have suggested that the frontline use of aggressive chemoimmunotherapy with the goal of eliminating MRD has resulted in improved survival for patients with CLL.(32)
Although still considered investigational, such an aggressive frontline approach is being explored in ongoing phase III randomised trials organised through the German CLL collaborative group, and may be particularly appropriate for young patients with biologically aggressive disease, where the results of current treatment strategies remain inadequate.
Recent advances in CLL biology and treatment include the identification of biological markers predictive of aggressive disease, the development of the purine nucleoside analogues and MAbs, and renewed interest in SCT strategies.
These new therapies not only have extended the repertoire of treatments for patients who have progressed following akylator-based therapy but also have the capacity to reduce the disease to levels undetectable by sensitive assays, leading to prolonged remissions and the early possibility of a cure for CLL.
- World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.
- Blood 1996;87:4990-7.
- N Engl J Med 1998;338:1506-14.
- Cancer 1974;33:555-62.
- Blood 1999;94:1840-7.
- Blood 1999;94:1848-54.
- N Engl J Med 2000;343:1910-6.
- Br J Haematol 2003;121:578-85.
- N Engl J Med 2003;348:1764-75.
- Blood 2004;103:1202-10.
- Blood 1989;74:19-25.
- Lancet 1996;347:1432-8.
- N Engl J Med 2000;343:1750-7.
- Clin Cancer Res 2001;7:3580-9.
- J Clin Oncol 2001;19:1414-20.
- Cancer 2004;100:2181-9.
- Leuk Lymphoma 2004;44 Suppl 2:S45 (Abstract 83).
- Blood 2004;104:139a (Abstract 475).
- Hematol J 2002;3:244-50.
- J Clin Oncol 2003;21:1278-84.
- Proc Am Soc Clin Oncol 2003;22:569 (Abstract 2289).
- J Clin Oncol 1998;16:2825-33.
- J Clin Oncol 2001;19:2165-70.
- Blood 2002;99:3554-61.
- J Clin Oncol 2002;20:3891-7.
- Proc Am Soc Clin Oncol 2003;22:569 (Abstract 2290).
- Blood 2004;103:2850-8.
- Leukemia 2004;18:1034-8.
- Ann Intern Med 1996;124:311-5.
- J Clin Oncol 2003;21:2747-53.
- Blood 2004;104:687a (Abstract 2508).
- Proc Am Soc Clin Oncol 2004;23:(Abstract 6565).
CLL Research Consortium
CLL Global Research Foundation
MD Anderson Leukemia Department
Australasian Leukaemia & Lymphoma group
International CLL Workshop
16–18 September 2005
European Hematology Association
2–5 June 2005 Stockholm
American Society of Hematology
3–6 December 2005