Treatment options for high-risk chronic lymphocytic leukaemia

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BlankTreatment options for high-risk chronic lymphocytic leukaemia

1.. Saman Hewamana

1.. Department of Haemato-Oncology, The Royal Marsden NHS Foundation Trust and

The Institute of Cancer Research, Sutton, UK

1.. Dearden

1.. Department of Haemato-Oncology, The Royal Marsden NHS Foundation Trust,

Downs Road, Sutton, Surrey SM2 5PT, UK

1.. claire.dearden@...

Abstract

Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in the

Western world. The natural history of CLL is extremely variable with a survival

time from initial diagnosis that ranges from 2 to more than 20 years.

Understanding the clinical diversity and allowing the subclassification of CLL

into various prognostic groups not only assists in predicting future outcome for

patients, but also helps to direct treatment decisions. Chlorambucil and

fludarabine were the standard therapy for CLL for decades. Randomized studies

have reported superior overall response and progression-free survival (PFS) for

fludarabine compared with alkylator-based therapy and for the

fludarabine–cyclophospamide (FC) combination over fludarabine alone. More

recently the addition of rituximab to the FC regimen (R-FC) has shown

significant improvement in overall response, PFS and overall survival compared

with FC alone. However, there are patients for whom this regimen still provides

less satisfactory results. Within the above studies CLL patients who have some

of the poorer prognostic markers, such as unmutated IgVH genes and/or high

beta-2 microglobulin (B2M), and those who fail to achieve a minimal residual

disease (MRD) negative remission are likely to have a shorter PFS compared with

those without these features. Various strategies have been explored to improve

the outcome for such patients. These include the addition of agents to a

frontline R-FC regimen, use of consolidation and consideration of maintenance.

The only group that can be clearly identified pretreatment for whom conventional

fludarabine-based therapies produce significantly inferior response rates, PFS

and overall survival are the patients who harbour a genetic fault; deletion or

mutation or a combination of deletion and mutation of tumour protein p53 (TP53).

TP53 inactivation is a less common finding at first treatment but becomes much

more common in fludarabine-refractory patients. Alemtuzumab and high-dose

corticosteroids have been shown to be effective in this group of CLL patients.

Trials combining these two agents have shown improved responses, particularly

for those patients with bulky nodal disease for whom alemtuzumab alone may be

insufficient. Since the duration of responses remains relatively short, suitable

patients should be considered for allogeneic stem cell transplantation according

to the European Group for Blood and Marrow Transplantation (EBMT) guidelines.

Furthermore, there are a number of other new treatments on the horizon,

including humanized antibodies directed against novel targets and small-molecule

inhibitors.