Search

Keywords: chronic lymphocytic leukaemia; chemotherapy; clinical trial; monoclonal antibody; minimal residual disease EN chronic lymphocytic leukaemia chemotherapy clinical trial monoclonal antibody minimal residual disease 646 650 5 07/29/21 20210801 NES 210801 Chemoimmunotherapy (CIT) comprising cytotoxics and anti-CD20 monoclonal antibodies (mab) has long been the therapeutic mainstay for chronic lymphocytic leukaemias (CLL). COSMIC, c hemotherapy plus o fatumumab at s tandard or m ega-dose i n c hronic lymphocytic leukaemia, a phase II randomised study. [Extracted from the article]

The article reports that genetic alterations in the ataxia telangiectasia‐mutated (ATM)‐TP53 DNA damage response (DDR) pathway represent an important mechanism of chemoresistance to conventional chemotherapeutic agents and also drive genomic instability. It mentions that ATM protein plays a critical role in the DNA damage response to double strand breaks. It presents use of olaparib in patients with relapsed chronic lymphocytic leukaemia, T‐prolymphocytic leukaemia or mantle cell lymphoma.

Abstract: CLL is an incurable disease with variable prognosis. The hyper reactivity of the B-cell receptor (BCR) to unknown antigen ligation plays a pivotal role in CLL-cell survival. We aimed to investigate the BCR signalling pathway using proteomics to identify novel proteins which may have clinical relevance in this disease. Three CLL samples were selected based upon BCR responsiveness, demonstrated by upregulation of phospho-ERK following in vitro stimulation. The differential expression of proteins, upon artificial stimulation of the BCR, was examined in these samples using two-dimensional gel electrophoresis in combination with mass spectrometry. Proteins of interest were subsequently examined using immunoblotting. Proteomic analysis revealed that kininogen, a critical protein of kinin–kallikrein system, was upregulated in all 3 clinical samples upon BCR stimulation. There are 2 forms of kininogen: HMWK and LMWK. The upregulation of LMWK upon BCR stimulation was confirmed by immunoblotting in all 3 of these samples. In a pilot series of 52 unselected CLL samples, 71% demonstrated basal LMWK expression. There was a trend towards shorter median survival in LMWK positive cases (147months versus 253months for LMWK negative cases; p =0.125). Kininogen may be a novel therapeutic target in CLL and the possible association with prognosis warrants further investigation. Biological significance: We have identified the upregulation of LMWK upon BCR stimulation of CLL samples. There is no previous published research to suggest a link between kininogen and normal B-cells or CLL cells. In 52 unselected CLL samples, 71% demonstrated basal LMWK expression. There was a trend towards shorter median survival in LMWK positive cases. The absence of LMWK protein expression on normal B-cells suggests that this could be a biomarker for CLL and further research should be undertaken. [Copyright &y& Elsevier]