Emerging drugs for chronic lymphocytic leukaemia

Abstract

Although the philosophy of management of patients with chronic lymphocytic leukaemia (CLL) has been altered with the advent of fludarabine-based therapies, impact on long-term survival is unclear and a significant proportion of patients will develop resistance to fludarabine. Similar to other haematological malignancies, a potential for 'cure' is likely to be achieved only if 'high-quality' complete remissions (CRs) are achieved. Treatment options for patients who develop resistance to fludarabine continue to be limited, with only a proportion obtaining a response (usually not CRs) with salvage therapies. This review summarises novel therapies that are being evaluated in patients with CLL, specifically those targeting the antiapoptotic Bcl-2 family of proteins and receptors (e.g., CD40, CD80, HLA-DR) involved in mediating survival signals from the microenvironment.

A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage display

“…In addition to its presence on the CD19 ϩ subpopulation and its absence on the CD19 Ϫ subpopulation of PBMCs, its absence on all B-cell lines tested excludes several cell-surface proteins that are currently investigated as targets for mAb therapy of B-CLL and other B-cell malignancies, including CD5, CD19, CD20, CD22, CD23, CD25, CD32B, CD37, CD38, CD40, CD45, CD52, CD74, CD79A, CD79B, CD80, CD200, HLA-DR, surface Ig, and ROR1. [2][3][4] Its distinct expression profile also excludes B-CLL cell-surface proteins to which post-alloHSCT or post-DLI serum antibodies were previously discovered, such as OFA/iLR and BCMA. 23,28 Notably, unlike SEREX, our method does not exclude non-peptidic epitopes, such as carbohydrates, lipids, and nucleic acids, which may or may not be associated with cell-surface proteins.…”

“…However, most preclinically and clinically investigated mAbs for the therapy of B-CLL target cell-surface antigens that are also expressed by healthy B cells and other blood cells of lymphoid and myeloid lineages. [2][3][4] By contrast, mAbs to cell-surface antigens that are unique to or at least overexpressed on B-CLL cells may be less toxic and more active by allowing selective intervention with powerful antibody-drug conjugates, immunotoxins, and radioimmunoconjugates. A few differentially expressed B-CLL cell-surface antigens that may be suitable for selective mAb therapy have been discovered through gene expression profiling.…”

Two novel aspirin analogues show selective cytotoxicity in primary chronic lymphocytic leukaemia cells that is associated with dual inhibition of Rel A and COX-2

“…Most CLL patients show initial responsiveness to frontline chemotherapeutic drugs and monoclonal antibodies, and introduction of agents such as purine nucleoside analogue fludarabine, and rituximab, has resulted in higher rates of remission (8–11). However, treated patients almost invariably develop drug resistance and, as a result, there has been little improvement in overall survival for patients with this condition (12,13). Consequently, there is much interest in identifying novel therapies that will add to the current therapeutic arsenal and reduce toxicities associated with combination chemotherapy/monoclonal antibody regimens.…”

Molecular basis of pathogenesis, prognosis and therapy in chronic lymphocytic leukaemia

“…For example, the Bcl2 inhibitor ABT 737 can cause CLL B-cell apoptosis in nanomolar concentration and is currently in clinical trial. 84,85 Inhibition of NFkB by dehydroxymethylepoxyq uinomicin can enhance the effect of fludarabine, with changes in the expression of other genes in NFkB pathways, including c-IAP (cellular inhibitors of apoptosis), Bfl-1, Bcl-X(L) and c-FLIP (cellular FADD-like ILb-converting enzyme inhibitory protein). 86 In the TCL1 CLL mouse model, rapamycin, an inhibitor of mTor, reduces mortality.…”