In addition to cancer indications, there is exciting potential for PI3K inhibitors in other therapeutic contexts, particularly immune inflammation and cardiovascular PF-01367338 AG-014699 disease. It has been a fascinating journey so far with PI3K inhibitors. With the range of agents now coming through that have distinct and attractive profiles, in the next few months and years there should increasing opportunities to reveal further evidence of clinical utility. Chronic lymphocytic leukemia is the most common adult leukemia.1 At diagnosis, 85% of patients are older than 65 years of age. Therefore, this leukemia represents a significant challenge for healthcare systems of aging populations. Treatment of CLL has evolved significantly in recent years. In younger patients without co morbidities, treatment goals have shifted from symptom control to achieving long lasting remissions or even cure.
The advent of many new agents, in particular anti CD20 antibodies, has increased patients, choice of treatment and improved clinical outcomes. In particular, the addition of rituximab to the chemotherapy backbone has changed the natural history of CLL by improving overall survival. Bafetinib However, many issues remain unresolved: the increasing use of more toxic and expensive therapeutic regimens demands better risk stratification and response prediction. The question of early treatment versus active surveillance has re emerged as an area of research interest. Whether achieving eradication of minimal residual disease should become a treatment goal in younger patients and what the role of maintenance treatment should be remains unknown.
The treatment of patients with high risk and purineanalogue refractory CLL remains challenging in clinical practice and optimal strategies for older patients aimed at quality of life rather than overall survival, need to be developed. This review attempts to address some of these issues by providing a general introduction into CLL followed by a detailed description of the current management of both fit and frail patients with CLL. To this, we have focused in particular on the International Workshop for CLL and UK British Society of Haematology CLL guidelines.2,3 The third part of the review deals with some of the novel therapies currently under investigation. Molecular Pathogenesis in CLL It is generally accepted that CLL derives from antigen experienced mature B cells homing to secondary lymphoid organs.
Defects in the cell death machinery combined with the contribution from the stromal microenvironment and accessory cells lead to expansion of an abnormal lymphoid cell population. Antigenic input and B cell receptor signaling play an important role in this process. The BCR is the key survival molecule for normal and malignant B cells.4 Following antigen engagement of BCR, activation of intracellular protein kinases occurs which allows secondary downstream signalling involving pathways such as PI3 K/AKT/mTOR, ultimately mediating changes in cell proliferation and cell survival. Inhibition of BCR signalling is therefore an important mechanism of controlling the proliferation and survival of CLL cells. Prolonged survival of malignant B cells is a feature of CLL thought to result from an imbalance between pro and anti apoptotic members of the Bcl 2 family.