Chronic Lymphocytic Leukaemia in Tropical Africa: A Review

Chronic lymphocytic leukaemia (CLL) has a male:female (M:F) ratio 1:1 in tropical Africa. Below the age of 45 years, the M:F is 1:2, while above 45 years; it is 2:1 CLL in younger adults is associated with low socio-economic status (SES) and rural habitation. Clinical and haematological features are the same as in other continents, except that many patients have gross splenomegaly and two populations of lymphocytes in the peripheral blood on light microscopy: it is postulated that with the altered immunity of CLL, recurrent malaria causes a secondary but benign lymphoid hyperplasia.

It is hypothesised that the probability of B-cell mutation is increased in an enlarged pool of B-cells resulting from recurrent malaria and other infections. The greatest enhancement occurs in subjects of low SES, who are more exposed to infections, and in grandemultiparae, whose cell-mediated immunity has been depressed repeatedly during pregnancies. A second event could follow transmission of an unidentified virus: transmission is more likely with overcrowding and proliferation more rapid with depression of immunity by malaria and pregnancy. HTLV-1 is associated with CLL, but does not appear to contribute significantly to the peculiar epidemiology of CLL in Africa.     

Management of Early-stage Hodgkin Lymphoma: A Practice Guideline

In the past, treatment for patients with early-stage Hodgkin lymphoma consisted mainly of radiotherapy. Now, chemotherapy alone and chemoradiotherapy are treatment options. These guidelines aim to provide recommendations on the optimal management of early-stage Hodgkin lymphoma. We conducted a systematic review searching MEDLINE, EMBASE, the Cochrane Library and other literature sources from 2003 to 2015, and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Two authors independently reviewed and selected studies, and appraised the evidence quality. The document underwent internal and external review by content, methodology experts, a patient representative and clinicians in Ontario. We have issued recommendations for patients with classical Hodgkin lymphoma and with nodular lymphocyte predominant Hodgkin lymphoma; with favourable and unfavourable prognosis; and for the use of positron emission tomography to direct treatment. We have provided our interpretation of the evidence and considerations for implementation. Examples of recommendations are: ‘Patients with early-stage classical Hodgkin lymphoma should not be treated with radiotherapy alone’; ‘chemotherapy plus radiotherapy or chemotherapy alone are recommended treatment options for patients with early-stage non-bulky Hodgkin lymphoma’; ‘The Working Group does not recommend the use of a negative interim positron emission tomography scan alone to identify patients with early-stage Hodgkin lymphoma for whom radiotherapy can be omitted without a reduction in progression-free survival’. Through the use of GRADE, recommendations were geared towards patient important outcomes and their strength reflected the available evidence and its interpretation from the patients’ point of view.     

Expression and Production of Interleukin 4 in B-Cell Chronic Lymphocytic Leukaemia

Interleukin (IL) 4 is a T-cell derived pleiotropic cytokine whose properties include alterations of B-cell function. In B-cell chronic lymphocytic leukaemia (B-CLL), IL4 is involved in the mechanism of survival of the leukaemic B-cells. The present study examines the expression and production of IL4 by B- and T-lymphocytes derived from patients with B-CLL and provides evidence that IL4 is not an autocrine factor in B-CLL. Freshly isolated B-CLL cells enriched for B- and T-cells did not express mRNA for IL4 but expressed mRNA for IL4 receptor (IL4R). Activation of B-cells with phorbol ester and calcium ionophore and of T-cells with phytohaemaglutinin (PHA) upregulated IL4 mRNA expression. However phorbol ester and calcium ionophore did not affect the mean level of IL4 production by either B-CLL or normal B-cells. Furthermore, in the presence or absence of activation, the amount of IL4 synthesised by B-CLL B-cells was not significantly different than that observed with peripheral blood B-cells isolated from normal individuals (with activation: P=0.239; without activation: P=0.565). Also, there was no significant difference between normal and B-CLL B-cells in the level of cytoplasmic IL4 (P=0.47).

PHA-activated enriched B-CLL T-cells produced significantly higher levels of IL4 compared to normal control T-cells (P=0.0136). In addition, in 47% of cases with B-CLL T-cells, a significant higher level of intracellular IL4 was observed (P=0.0027). The levels of production of IL4 by the T-cell-enriched preparations correlated positively with the intensity of cytoplasmic IL4 in CD4⁺ and CD8⁺ cells in tested samples (r=0.49 and r=0.76, respectively).

The significant differences observed in the production of IL4 by B-CLL B- and T-lymphocytes may suggest a paracrine function of IL4 in B-CLL.     

Sudden Onset Deafness as a Presenting Manifestation of Chronic Lymphocytic Leukemia

An unusual patient with typical Rai Stage 2 (Binet Stage A) chronic lymphocytic leukaemia (CLL), who presented with sudden onset deafness as the initial manifestation of disease is reported. This sensorineural hearing loss improved dramatically after the administration of chemotherapy. This unique observation was also associated with reduction of the circulating B-CLL cells and with the achievement of a partial response, lasting for almost three years. Recently there was another episode of sudden deafness, associated with a rising leukocyte count, and disease activity followed once again by recovery after chemotherapy. Audiograms were recorded showing positive findings on presentation and recovery after therapy. This very rare manifestation of CLL was presumed to be due to infiltration of the cochlear duct or the 8th cranial nerve although all imaging techniques were negative, because of the rapid relief and recovery achieved after specific chemotherapy. The importance of early diagnosis and therapy is stressed in the light of the rapid clinical recovery observed here.     

2D-Gel Analysis of Protein Synthesis Profiles of Different Stages of Chronic Lymphocytic Leukaemia

Protein synthesis profiles of leukaemic cells from 15 chronic lymphocytic leukaemia (CLL) patients were analysed by 2D-electrophoresis of ³⁵S-methionine labelled proteins. This series of CLL included patients with stage A (7), B (4) and C (4) disease. Although the protein synthesis profiles were similar in all cases, some consistent differences were noted between the different stages. The levels of synthesis of three proteins (approximately 35 kD size) were of particular interest. Two of these were always expressed in stage C CLL but either infrequently or not at all in stage A or B CLL. By contrast a third protein was expressed at a much reduced level in stage C compared to stages A or B. This type of analysis could prove invaluable for identifying proteins whose expression was intimately associated with the evolution of CLL.     

An Analysis of Circulating CD4 Lymphocyte Subpopulations in B-Cell Chronic Lymphocytic Leukaemia

The distribution of circulating CD4 lymphocyte subpopulations determined by reactivity with monoclonal antibodies anti-2H4 (CD45RA), anti-UCHL1 (CD45RO), anti-4B4 (CD29) and anti-Leu8, and analysed by dual colour immunofluorescence flow cytometry is described in a series of patients with B-CLL and in age-matched control subjects. The percentages and absolute numbers of CD4 cells reactive with anti-CD45RA, anti-CD45RO and anti-CD29 reagents were similar in the patient and control groups. In contrast, CD4+ Leu8+ cells (percentages and absolute numbers) were significantly reduced in B-CLL patients resulting in an inversion of the normal CD4+ Leu8+ :CD4+Leu8- ratio. The patients' clinical or therapeutic status did not appear to influence the levels of the respective CD4 subpopulations; nor was evidence of hypogammaglobulinaemia associated with specific numerical alterations in any of the CD4 subpopulations studied. It is proposed that, in B-CLL, the alterations in the CD4Leu8 subpopulations are associated with the disease process, whereas the distributions of CD4+CD45RA+, CD4+ CD45RO+ and CD4+ CD29+ cells reflect the normal physiological levels of these subpopulations in elderly subjects.     

Contribution of Nitric Oxide to the Apoptotic Process in Human B Cell Chronic Lymphocytic Leukaemia

B cell chronic lymphocytic leukaemia (B-CLL) is characterised by defective apoptosis that cannot be explained solely on the basis of the known chromosomal abnormalities. We and other have now reported that the leukemic cells spontaneously display the inducible isoform of nitric oxide synthase, iNOS. Inhibition of the iNOS pathway leads to increased apoptosis of the tumoral cells in vitro, indicating that the endogenous release of NO contributes to their resistance to the normal apoptotic process. The factors that induce the expression of iNOS in vivo in the leukemic cells are not yet identified. Yet, as interaction of B-CLL leukemic cells with bone marrow stromal cells promotes their survival, the involvement of adhesion molecules and integrins may be suspected. The engagement of CD23 stimulates iNOS activation in the tumoral cells, suggesting that in vivo interaction of CD23 with one of its recognised lig-ands may contribute to iNOS induction. A role for CD40-CD40 ligand interaction may also be hypothesised.

The mechanisms involved in the anti-apoptotic role of NO are not fully understood, but may implicate the inhibition of caspase activity, hence the impairment of the Fas pathway. In addition, the mitochondrial membrane potential disruption appears to be a NO-sensitive step in the apoptosis cascade. The presence of a NOS displaying anti-apoptotic properties has now been recognised in different cell types, including various leukaemia. A better knowledge of the mechanisms governing the ultimate fate of NO, anti-versus pro-apoptotic would allow the development of new therapeutic approaches for the treatment of these diseases.     

B-cell Chronic Lymphocytic Leukemia in Chronic Immune Thrombocytopenic Purpura: a Case Report

A patient suffering from chronic immune thrombocytopenia developing B-cell chronic lymphocytic leukemia seventeen years later, is reported. The possible mechanisms of association between the two disorders are discussed.     

B-Type Lymphocytic Leukaemia Developing Seven Years after Chemoradiotherapy for Hodgkin's Disease: Report of a Case and Review of the Literature

This report describes the development of B-cell lymphocytic, leukemia, probably a leukaemic phase of non-Hodgkin's lymphoma, in a patient with Hodgkin's disease (HD) who was successfully treated and cured with MOPP combination chemotherapy and mantle radiotherapy. The leukaemia occurred seven years after the completion of chemoradiotherapy, and manifested as peripheral blood and bone-marrow involvement alone without any initial evidence of lymphadenopathy, organomegaly or extranodal disease at the time of diagnosis. The occurrence of B-lymphocytic leukaemia in a cured patient with HD is rare, and the association of these two disorders is reviewed and discussed in the light of current knowledge.     

TNF Receptors in Chronic Lymphocytic Leukemia

Two transmembrane receptors for tumor necrosis factor (TNF) with different molecular weight, 55 kD (p55) and 75 kD (p75), have been identified. In addition, the extracellular part of both receptors are shedded by proteolytic cleavage and exist as soluble receptors which bind to TNF in plasma and other biological fluids. Normal B cells produce TNF and express TNF receptors (R), mainly p75, upon stimulation. TNF costimulates DNA synthesis via the p75 receptor in normal B cells. The B cells from patients with chronic lymphocytic leukemia (CLL) produce TNF and have the capacity to express both receptor types. Also in malignant B cells the p75 receptor is dominant. TNF induce DNA synthesis in CLL cells via both receptors. CLL patients have elevated serum levels of soluble (s) TNFR and this is more pronounced in advanced disease. In conclusion, there is considerable support for TNF as an autocrine growth factor in CLL. However, the net effect of TNF is determined by the quan titative relationship between TNFR on the cell surface, TNF in plasma and sTNFR in plasma, and the affinities between TNF-p55 and TNF-p75. Due to increasing serum levels of sTNFR the significance of TNF as a growth factor is probably less important in advanced disease.     

Intraventricular and Intravenous Treatment of a Patient with Refractory Primary CNS Lymphoma using Rituximab

The treatment of primary central nervous system lymphoma (PCNSL) with chemo- and radiotherapy is efficient in terms of tumor response. However, time to tumor progression often is of short duration and leptomeningeal relapse is common [1]. We present a 66-year-old man in third relapse of a CD20-positive PCNSL. After treatment with intravenous and intraventricular administration of the chimeric anti-CD20 monoclonal antibody rituximab, a total clearing of lymphoma cells in the cerebrospinal fluid (CSF) was achieved. There was no change in the size of the parenchymal tumor mass but there was slight improvement of clinical symptoms after therapy. Rituximab infusions (375 mg/m²) were first given systemically on days 1 and 8. Intraventricular injections of rituximab via Ommaya reservoir were given on days 16 (10 mg), 17 (40 mg), 24 (25 mg) and 25 (25 mg). Reversible side effects such as nausea, chills and hypotension were observed only immediately after intraventricular administration of 40 mg rituximab. Antibody levels in CSF were measured at 7 timepoints during and after the treatment period. These data suggest that intraventicular treatment with rituximab is safe and feasible with a potential activity on leptomeningeal tumor manifestation. Efficacy and pharmacokinetics of rituximab in PCNSL should be investigated in future trials.     

A Phase II Trial of Rituximab Combined With Pegfilgrastim in Patients With Indolent B-cell Non-Hodgkin Lymphoma

Background

To explore the role of augmenting neutrophil function in B-cell lymphoma, we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low-grade CD20⁺ B-cell non-Hodgkin lymphoma (B-NHL).

慢性中性粒细胞白血病伴多发性骨髓瘤1例合并文献复习

目的 分析慢性中性粒细胞白血病(CNL)伴多发性骨髓瘤的临床病理特征.方法 回顾性分析1例CNL伴多发性骨髓瘤患者的临床病理资料,并结合相关文献,进行分析.结果 患者中性粒细胞显著上升,脾脏肿大,中性粒细胞碱性磷酸酶积分增高,无Ph染色体及BCR/ABL融合基因,骨髓粒系有明确增生,未见病态造血和纤维化改变,排除类白血病反应等其他可能导致中性粒细胞增多的因素,合并多发性骨髓瘤.结论 CNL临床少见,其发病有一定特殊性,具体机制及干预方法需要进一步研究.     

Clinical Practice Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL) in The Netherlands

Introduction

In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukemia (CLL), and new potent drugs have become available. Therefore, the CLL working party revised the Dutch guidelines. Not only efficacy but also quality of life and socio-economic impact were taken into account in the formulation of treatment recommendations.

γ-Linolenic Acid Induces Apoptosis in B-Chronic Lymphocytic Leukaemia Cells in Vitro

Gamma linolenic acid (GLA) is cytotoxic to many types of human cancer cells. Most chemotherapeutic agents are cytotoxic by inducing apoptosis. We examined the apoptotic activity of GLA on purified B-cells isolated from patients with B-cell chronic lymphocytic leukaemia (B-CLL) and from normal individuals. GLA significantly increased the degree of apoptosis in B-CLL B-cells after 24 hours of culture. The mean percentage of cells undergoing apoptosis when cultured in medium alone (spontaneous apoptosis) was 20% (range: 7 to 31%) (n=25) and in the presence of GLA (5μg-60μg) was: 42%-95%. In the presence of GLA 5μg/ml and dexamethasone the degree of apoptosis was 86% (range: 72 to 100%). GLA induced apoptosis in B-CLL B-cells at a higher level than that observed with normal B-cells at all lower concentrations tested 5, 10 and 15μg/ml: P=0.045; 0.027 and 0.022, respectively. At 30μg/ml of GLA, no significant difference in the percentage of cells displaying apoptosis between B-CLL and normal B-cells was observed (P=0.075). GLA induced apoptosis in B-CLL T-cells at both 10 and 30μg/ml. The degree of apoptosis in normal T-cells with GLA was also significant at the higher concentration of 30μg/ml. Interleukin 4 (IL4), a viability factor in B-CLL, and vitamin E, an anti-oxidant, protected B-CLL B-cells against GLA (20μg/ml)-induced apoptosis. These results demonstrate that GLA induces apoptosis in B-CLL B-and T-cells cells in-vitro and that they are more susceptible to GLA-induced apoptosis than normal peripheral blood B-and T-cells.     

Agar Capillary Clonogenic Microassays for Cellular Immunocytotoxic Activities in Human Leukaemia and Lymphoma

Current concepts of immunotherapeutic approaches in Ieukemias and lymphomas using activated cytotoxic lymphocytes and macrophages are briefly reviewed. Defective cellular immunocytotoxic activities and effects of interleukins and chemotherapeutic drugs thereupon are discussed. In vitro assays to measure lymphokine-activated killer (LAK) and natural killer (NK) cell activities suffer from various problems, depending on the quality of the endpoints. Our clonogenic microassay for LAK cell activity, using agar-containing glass capillaries, avoids some of the potential artifacts and offers several advantages that are discussed. As an example the stimulatory effect of low mafosfamide concentrations on the LAK cell activity versus K562 human myeloid Leukemia cells is demonstrated. Thus, our clonogenic LAK microassay provides a valid tool for preclinical screening of immunomodulatory agents.     

Grade 3 Follicular Lymphoma: Outcomes in the Rituximab Era

BackgroundFollicular lymphoma (FL) is heterogeneous. Although FL Grade 3B (FL3B) is treated as aggressive FL (aggFL), an optimal approach to FL Grade 3A (FL3A) remains unclear because few data exist on clinical outcomes on the basis of subclassification of FL Grade 3 (FL3) since the introduction of rituximab. We report outcomes of FL3 in the rituximab era.Patients and MethodsWe identified and analyzed a retrospective cohort of 53 patients with FL3A, 3B, and FL Grade 3 with areas of diffuse large B-cell lymphoma (DLBCL). They were divided into 2 groups: aggFL (n = 21) included patients with FL3B (n = 10) and FL3 (A or B) with concomitant DLBCL (n = 11); indolent lymphoma (n = 32) included only FL3A.ResultsBaseline characteristics did not differ between the groups. rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) was initial treatment in 15 (79%) of patients with aggFL and 21 (72%) of those with FL3A; rituximab was included in initial therapy in 18 (95%) and 24 (83%), respectively. Comparing aggFL and FL3A, 5-year overall survival was 90% versus 79% (P = .97) and 5-year progression-free survival (PFS) 44% versus 34% (P = .75), respectively.ConclusionWe conclude that outcomes for FL3, primarily treated with R-CHOP, do not differ between FL3A and aggFL (FL3B and FL3/DLBCL). The aggFL group showed a plateau in PFS confirming these should be treated with curative intent. FL3A patients, mainly managed with R-CHOP, also show an apparent plateau in PFS. Although longer follow-up and confirmation in other data sets is required, this indicates potential undertreatment of FL3A with less aggressive regimens often used for indolent lymphoma.