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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]

Abstract: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in cancer patients. The literature is sparse on the incidence in the most common lymphoid malignancy, chronic lymphocytic leukaemia (CLL). We calculated the incidence rates for VTE in an unselected UK CLL clinic population at 1.45% per patient year. This represents a tenfold increase over previously published estimates of incidence in the general population and a twofold increase over that of the local hospital inpatient population. In our cohort, the risk of VTE was related to stage C disease. Clinicians should be aware that CLL patients are at risk of VTE. [Copyright &y& Elsevier]

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.

Background: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Combination immunochemotherapy such as fludarabine, cyclophosphamide and rituximab is the standard first line therapy in fit patients, but there is limited evidence regarding the optimal treatment of patients after relapse. Ofatumumab as monotherapy has been proven to be effective in the treatment of relapsed, refractory CLL, and as it is not myelotoxic, it is an ideal drug to combine with chemotherapy. However, the optimal dose of ofatumumab in this setting is not known. The Chemotherapy plus Ofatumumab at Standard or Mega dose in relapsed CLL (COSMIC) trial will assess the efficacy and safety of standard and high (mega) doses of ofatumumab combined with bendamustine or a combination of fludarabine and cyclophosphamide to determine which, if either, schedule should progress to a phase III trial.Methods/design: COSMIC is a phase II, multi-centre, randomised, open, parallel group trial for patients with relapsed CLL who are not refractory to fludarabine-based chemotherapy. Participants will be randomised to receive either standard dose or mega dose ofatumumab. Both doses will be given in combination with either bendamustine or fludarabine and cyclophosphamide chemotherapy backbone. The primary objective is to assess the proportion of participants achieving a complete remission following therapy with the two treatment arms (mega versus standard), as assessed at 3 months post treatment. The treatment groups will be assessed independently to determine whether the level of response is acceptable in relation to pre-specified criteria. If both treatment groups show an acceptable level of response, selection criteria will be used to determine which to take forward to a confirmatory phase III trial. A key secondary objective is to assess the dynamics of minimal residual disease (MRD) levels in relapsed disease. Eighty-two participants are planned to be recruited from 18 research centres in the UK.Discussion: Currently there is limited evidence regarding the optimal treatment of patients with relapsed or refractory CLL, and so suitable therapies are urgently needed. The COSMIC trial will identify whether ofatumumab given in combination with chemotherapy is safe and effective in this population, and will identify the optimal doses for further investigation.Trial Registration: ISRCTN51382468 . Registered on 21 September 2011. [ABSTRACT FROM AUTHOR]

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]

Abstract: We conducted an analysis of the effect of monocytosis at diagnosis of CLL on subsequent overall (OS) and treatment-free survival (TFS). Monocyte counts were performed using the Sysmex XE2100™ analyser. A monocyte count >0.91×109 L−1 at the time of diagnosis was associated with a shortened OS and TFS. Monocytosis at diagnosis was associated with lymphocyte count, deletions of chromosomes 17p and 11q, the extent of IgVH somatic hypermutation and Binet stage. A multivariate analysis model which excluded somatic hypermutation found only monocyte count and age to be independently predictive of OS. The automated monocyte count is predictive of OS and TFS in newly diagnosed CLL. [Copyright &y& Elsevier]