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We analysed COVID-19 infection outcomes of 129/241 chronic lymphocytic leukaemia (CLL) (53.9%) and 22/55 monoclonal B-lymphocytosis (MBL) (40.0%) patients following multiple vaccine doses aiming for maximum measured anti-spike antibody response. Throughout the pandemic to date, there were 8/129 CLL (6.2%) patients hospitalised, with one death (0.8%). No MBL patients were hospitalised or died. CLL patients with COVID-19 had lower anti-spike levels (3778.8 AU/mL) than those without (13 486.8 AU/mL; p = 0.0061). Anti-nucleocapsid antibody was detected in 29.8% within 2 months and 17.5% >6 months. Of COVID-19-infected CLL patients, 47.3% received anti-viral therapy. A multiple vaccine dosing strategy to achieve measured maximum antibody is highly effective in preventing severe COVID-19., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Chronic lymphocytic leukaemia (CLL) is associated with immunocompromise and high risk of severe COVID-19 disease and mortality. Monoclonal B-cell lymphocytosis (MBL) patients also have immune impairment. We evaluated humoural and cellular immune responses in 181 patients with CLL (160) and MBL (21) to correlate failed seroconversion [<50 AU/ml SARS-CoV-2 II IgG assay, antibody to spike protein; Abbott Diagnostics)] following each of two vaccine doses with clinical and laboratory parameters. Following first and second doses, 79.2% then 45% of CLL, and 50% then 9.5% of MBL patients respectively remained seronegative. There was significant association between post dose two antibody level with pre-vaccination reduced IgM (p < 0.0001), IgG2 (p < 0.035), and IgG3 (p < 0.046), and CLL therapy within 12 months (p < 0.001) in univariate analysis. By multivariate analysis, reduced IgM (p < 0.0002) and active therapy (p < 0.0002) retained significance. Anti-spike protein levels varied widely and were lower in CLL than MBL patients, and both lower than in normal donors. Neutralisation activity showed anti-spike levels <1000 AU/ml were usually negative for both an early viral clade and the contemporary Delta variant and 72.9% of CLL and 53.3% of MBL failed to reach levels ≥1000 AU/ml. In a representative sample, ~80% had normal T-cell responses. Failed seroconversion occurred in 36.6% of treatment-naïve patients, in 78.1% on therapy, and in 85.7% on ibrutinib., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

The clinical significance of low-frequency deletions of 17p13 [tumour protein p53 (TP53)] in patients with chronic lymphocytic leukaemia (CLL) is currently unclear. Low-frequency del17p clones (<25%) were identified in 15/95 patients in the Australasian Leukaemia and Lymphoma Group (ALLG)/CLL Australian Research Consortium (CLLARC) CLL5 trial. Patients with low del17p, without tumour protein p53 (TP53) mutation, had significantly longer progression-free survival and overall survival durations than patients with high del17p clones. In 11/15 cases with low-frequency del17p, subclones solely with del17p or del13q were also noted. These data suggest that low-frequency del17p does not necessarily confer a poor outcome in CLL and challenges the notion of del13q as a founding event in CLL., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL. With recent advances in therapy it is increasingly important to stratify CLL patients according to risk. This has been highlighted by two recent studies, the first showing that immunoglobulin heavy chain mutational status predicts a durable response to frontline chemoimmunotherapy and the second showing that complex karyotype is a stronger predictor of poor response to ibrutinib and venetoclax therapy than TP53 deletion. In this review we discuss the molecular features of CLL and how technological advances can identify patient subsets and stratify them according to risk., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA). Binimetinib was also significantly more toxic towards CLL cells cultured in the presence of either anti-IgM antibody or stroma-derived factor-1α (SDF-1α) and reduced CLL cell cycle progression and proliferation. Furthermore, binimetinib significantly increased the sensitivity of CLL cells co-cultured with CD40 ligand (CD40L)-expressing fibroblasts to the BH3-mimetics ABT-737 and Venetoclax (ABT-199) via a mechanism involving down-regulation of Mcl-1 (MCL1) activity and Bim (BCL2L11) and Bcl-xL (BCL2L1) expression. Collectively, these data suggest that binimetinib may have both cytotoxic and cytostatic effects on CLL cells by blocking microenvironment-derived signals known to drive survival and proliferation. The combination of binimetinib with a BH3 mimetic may be an effective treatment strategy for CLL, particularly against the proliferative fraction of the disease within the tumour microenvironment., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Immune dysfunction attributed to hypogammaglobulinaemia is common in chronic lymphocytic leukaemia (CLL) and infection is a major contributor to morbidity and mortality. A higher incidence of multiple immunoglobulin and immunoglobulin G (IgG) subclass deficiency was associated with more advanced disease (P < 0·001 and P < 0·001, respectively) in a cohort of 147 CLL patients. Multiple immunoglobulin and IgG subclass deficiency were significantly associated with shorter treatment-free survival (TFS) (P < 0·001 and P = 0·006, respectively). The association between disease stage and immune dysfunction demonstrated by these data suggest aspects of immune deficiency correlate with disease severity and may be associated with shorter TFS in CLL., (© 2018 John Wiley & Sons Ltd.)

Chronic lymphocytic leukaemia (CLL) occurs rarely with pregnancy and monoclonal B-Lymphocytosis (MBL) has not previously been described in this setting. CLL is predominantly a disease of the elderly and affects men twice as often as women and hence only an estimated 2% of patients are females of childbearing age. We identified only five reported cases of CLL in pregnancy in the literature. We describe two additional cases, plus three other women with CLL dealing with pregnancy-related decisions. We review the literature and discuss proposals for management and issues that arise in this relatively uncommon occurrence. In contrast to many other haematological malignancies where longer remissions are typically associated with a lower risk of relapse, most patients with CLL who require treatment will ultimately relapse with current therapy. This complex setting requires careful consideration and well informed patients to assist with decisions related to pregnancy., (© 2014 John Wiley & Sons Ltd.)

Inhibitors of heat-shockprotein 90 (Hsp90) have been proposed as a novel therapeutic option for Chronic Lymphocytic Leukaemia (CLL), particularly as their mechanism of action appears independent of mutations of ATM or TP53. We investigated the activity of a novel Hsp90 inhibitor, SNX7081, against a panel of eight haematological cell lines and 23 CLL patient samples. SNX7081 displayed significant effects on cell cycle distribution, apoptotic rate and levels of ZAP-70 in the cell lines and in the patient samples, irrespective of TP53 status. Our findings suggest SNX7081 may represent a promising therapeutic option for aggressive CLL.

A novel antibody microarray has been developed that provides an extensive immunophenotype of leukaemia cells. The assay is a solid phase cell-capture technique in which 82 antigens are studied simultaneously. This paper presents the analysis of 733 patients with a variety of leukaemias and lymphomas from peripheral blood and bone marrow. Discriminant Function Analysis of the expression profiles from these 733 patients and 63 normal subjects were clustered and showed high levels of consistency with diagnoses obtained using conventional clinical and laboratory criteria. The overall levels of consensus for classification using the microarray compared with established criteria were 93.9% (495/527 patients) for peripheral blood and 97.6% (201/206 patients) for bone marrow aspirates, showing that the extensive phenotype alone was frequently able to classify the disease when the leukaemic clone was the dominant cell population present. Immunophenotypes for neoplastic cells were distinguishable from normal cells when the leukaemic cell count was at least 5 x 10(9) cells/l in peripheral blood, or 20% of cells obtained from bone marrow aspirates. This technique may be a useful adjunct to flow cytometry and other methods when an extensive phenotype of the leukaemia cell is desired for clinical trials, research and prognostic factor analysis.

Chronic lymphocytic leukaemia (B-CLL) is characterized by a progressive accumulation of B lymphocytes in blood and bone marrow and high concentrations of soluble CD23 and L-selectin are found in the serum of these patients. In this study lymphocytes from normal subjects and patients with B-CLL were allowed to undergo transendothelial migration across confluent layers of human umbilical vein endothelial cells. Lymphocytes in B-CLL samples showed an impaired capacity to migrate while the minor proportion of normal T cells was enriched by a mean of 2.5-fold in the transmigrated lymphocytes. In contrast, the ratio of B to T lymphocytes in normal preparations was unchanged in the transmigrated population. The expression of adhesion molecules on B-CLL lymphocytes before and after transendothelial migration was studied by flow cytometry which showed that 71 +/- 5% of L-selectin was lost from the surface of transmigrated lymphocytes. T and B cells from normal subjects also showed a major loss of L-selectin after transmigration. B-CLL lymphocytes and normal B cells expressed CD23 but this molecule was down-regulated following transendothelial migration, whereas the expression of VLA-4, ICAM-1, LFA-1 and CD44 was unchanged. Lymphocytes incubated with oxidized ATP, an irreversible inhibitor of P2Z/P2X7 purinoceptors, retained their capacity for transendothelial migration and showed the same loss of L-selectin as control leukaemic lymphocytes. Our results show that B-CLL lymphocytes have impaired ability for transendothelial migration compared to normal peripheral blood lymphocytes. Moreover, transendothelial migration involves a universal loss of L-selectin and CD23 from lymphocytes which suggests that the high serum levels of soluble L-selectin and CD23 observed in B-CLL may be generated by shedding during the process of transendothelial migration.

We report 10 cases of B-cell chronic lymphocytic leukaemia (B-CLL) with expression of the T-cell antigen CD8. The majority of patients had typical B-cell CLL with stable and non-progressive stage A(O) disease except for more common expression of lambda light chain and CD25. Two patients had progressive disease and required therapy, one with atypical morphological and phenotypic features. The incidence of CD8 expression was approximately 0.5% of B-CLL patients from our institutions. Immunoprecipitation of the CD8 antigen from four of these B-CLLs showed identity to the CD8 antigen expressed on T cells with precipitation of CD8alpha bands of molecular weight approximately 34 kD. In view of the known intracellular signalling mechanism of CD8 using the tyrosine kinase p56-lck, we studied p56-lck expression by Western blot and found lack of consistent expression of the CD8 surface antigen, with most lacking p56-lck. Our report indicates that CD8 expression in B-CLL is probably underrecognized but is not a marker of disease progression. The CD8 on the B-CLL surface is immunochemically identical to the antigen on T cells, but is not accompanied by its usual signalling mechanism of p56-lck tyrosine kinase and therefore is unlikely to be a functionally active receptor.

Two hundred and twenty-six patients were diagnosed with myelodysplastic syndrome (MDS), according to the French-American-British (FAB) criteria, over a 13-year period, and studied retrospectively in a single institution in order to study indicators which were prognostically significant. Analysis of clinical and laboratory data indicated that the FAB classification, the Bournemouth, Dusseldorf, Goasguen, Sanz and FAB Scoring Systems were all good predictors of survival. We found advancing age, haemoglobin (Hb) < or = 9 g/dl, platelet count < or = 50 x 10(9)/l, increased peripheral total white cell count (WCC) and monocytosis, increased bone marrow blasts, dysgranulopoiesis, and bone marrow fibrosis were significant adverse prognostic variables. The commonest complication and cause of death was infection; however, infective episodes were not significantly associated with low neutrophil counts (either < or = 1.5 x 10(9)/l or < or = 0.8 x 10(9)/l) and there was also no significant association between neutropenia and survival. These findings indicate that neutrophil dysfunction plays an important role in the clinical progression of patients with MDS. The effect of new therapeutic modalities, such as the haemopoietic growth factors, on reducing infective episodes may be as significant as their effect on increasing neutrophil counts.

We studied the natural history and response to treatment in 50 patients with splenic lymphoma with villous lymphocytes followed for a minimum of 6 months and up to 15 years (median 3.7 years). The disease occurs in the elderly (median 68 years) and affects males more than females (M/F ratio 1.77). The median survival for the group was not reached but 82% were surviving at 3 years and 78% at 5 years. Twelve patients (24%) died, one-third of deaths were disease related (four patients) and one-half were due to cardiovascular disease or another malignancy (six patients). The outcome was worse for males (31% died) than females (11% died). Fourteen patients were not treated and 10 remain alive between 1 and 6 years from diagnosis. The remaining patients were treated by chemotherapy, splenic irradiation or splenectomy. The response to chemotherapy was poor and only eight of 22 (36%) patients treated achieved a good response. Splenic irradiation was employed in seven patients and three benefited from it. Splenectomy seems to be the treatment of choice, with significant improvement seen in 19 of 20 patients with one post-operative death. This response, lasting from 6 months to 7 years (median 4 years), was seen irrespective of whether splenectomy was the initial treatment or used later in management.

This report describes a patient with a large granular lymphocyte leukaemia (CD8 + lymphoproliferative disease) and severe neutropenia (less than 0.5 x 10(9)/l) in whom exercise resulted in a marked lymphocytosis, a phenomenon which has not previously been recorded. The lymphocyte count at rest was within normal limits (2.2 x 10(9)/l), then fell to the resting level within 15 min of cessation of exercise. The peripheral blood mononuclear cells showed the morphology of large granular lymphocytes (LGL) by light and electron microscopy both at rest (30%) and to a much greater extent during exercise (70%). Immunophenotyping of these lymphocytes during exercise demonstrated that the predominant cell was CD3+, CD8+, CD57+ (Leu7)/CD4-, CD16-, CD25-. In the resting state, despite a total lymphocyte count within the normal range, surface marker studies indicated an excess of cells with the CD8+/CD57 + T cell phenotype (26%; cf. normal range less than or equal to 10%). Functional assays revealed a minimal increase in natural killer (NK) activity during exercise. T cell receptor beta chain gene rearrangement was demonstrable in the peripheral blood at rest and during exercise. Although severe neutropenia was present, the growth of normal colony forming units, granulocyte-macrophage (CFU-GM) was not inhibited by patient lymphocytes and no anti-neutrophil antibodies were demonstrated. Finally, hyposplenism has developed and the relationship of this to the LGL leukaemia is discussed. In summary, the findings demonstrated large granular lymphocyte leukaemia as the primary disorder for which the primary manifestation, apart from the neutropenia, was a marked exercise-induced lymphocytosis.