Predicting chronic leukaemias from assessment of complete peripheral blood counts

The chronic leukaemias include two distinct chronic neoplastic disease states, namely chronic myelogenous leukaemia (CML) and chronic lymphocytic leukaemia (CLL). The aim of this study was to assess the utility of leucocyte count, neutrophil percentage and absolute lymphocyte count from differential complete blood count analyses as indicators of the possible presence of CML and CLL. Blood counts from 102 patients with histopathologically confirmed CML and CLL were compared with counts for 858 cancer-free control subjects. Optimal cut-off values were identified by selecting values with the highest sensitivity-specificity combination for each blood count parameter for the two diseases. The results indicated that any individual with mature-appearing lymphocytes at a level > 6.65 x 10(9)/l in the peripheral blood should be examined further for CLL, and that any individual with a leucocyte count > 18.0 x 10(9)/l or a neutrophil proportion > 72.6% should be investigated for CML.     

Therapeutic cytapheresis in chronic lymphocytic leukemia

The role of therapeutic reductive lymphapheresis in 59 patients with chronic lymphocytic leukemia (CLL) was reviewed. Reduction in lymphocytosis, lymphadenopathy and hepatosplenomegaly was noted in 50%-60% of the patients studied. In addition to mobilization of the lymphoid tumor load, 40% of the patients showed an improvement in their hemogram. Although apheresis-induced anemia can occur, reported complications were minimal. These studies suggest that a majority of CLL patients might benefit from therapeutic lymphapheresis.     

Increased inducible heat shock protein 72 expression associated with PBMC isolated from patients with haematological tumours

Abstract Background. Heat shock protein 72 (Hsp72) is a highly inducible stress protein and molecular chaperone. Cancers have been shown to be associated with increased Hsp72 expression within the tumour itself and this may lead to resistance to apoptosis. Methods. Peripheral blood mononuclear cells (PBMC) were isolated from patients diagnosed with chronic lymphocytic leukaemia (CLL) (n =?27) and chronic myelomonocytic leukaemia (CMML) (n =?16) and Hsp72 expression was characterized on both the cell surface and intracellularly by flow cytometry. To allow for comparison PBMC from breast cancer patients (n =?25) and healthy volunteers (n =?19) were included. Results. Both lymphocytes and monocytes from CLL and CMML patients showed high levels of total Hsp72 expression (4-6 fold increase) in comparison to breast cancer and healthy subjects. The majority of Hsp72 in these tumours was determined to be cell-surface expressed (64-93% of cell total Hsp72). Conclusions. A correlation was observed between lymphocyte and monocyte total Hsp72 expression (p 相似文献   

Chronic lymphocytic leukemia--the old and the new

Chronic Lymphocytic Leukemia (CLL) is the most frequent lymphoproliferative disease and leukaemia in western countries. CLL occurs more frequently in men than women, the median age at diagnosis is 65 years. CLL is defined as a persisting chronic lymphocytosis > 5 G/l with classical morphological features (small lymphocytic cells with round nuclei, dense chromatin and small cytoplasmic rim) and a classical immunophenotype (CD5+, CD19+, CD20+, CD23+); however, deviations from classical morphology are frequent. In cases with classical diagnostic features in the peripheral blood, a bone marrow biopsy is not necessary for diagnosis. Prognostic features comprise the stage of the disease according to the Rai or Binet systems, laboratory markers such as LDH, beta-2-microglobulin, lymphocyte doubling time and CD38 expression by flow cytometry (and ZAP-70 expression if available) as well as the status on IgV(H) hypermutations and cytogenetic analysis. Up to 2/3 of patients do not need treatment at the time of diagnosis and can initially be followed using a watch and wait strategy. If therapy becomes necessary, initial standard treatment still is chlorambucil. Later, purine analogues and Alemtuzumab are treatment options for refractory or relapsing disease. Therapies with antibodies such as Alemtuzumab and Rituximab in combination with purine analogues are currently under clinical investigation. With recurrent or atypical infections, hypogammaglobulinemia should be searched for and immunoglobulins should be substituted if necessary. However, their prophylactic use is not recommended.     

Soluble factor(s) released by Concanavalin A activated lymph node lymphocytes induce proliferation and maturation of chronic lymphocytic leukaemia (CLL) B lymphocytes

An active supernatant (Ly Con A) was prepared by stimulating the normal human lymph node lymphocytes with Concanavalin A (Con A). Peripheral blood lymphocytes (PBL) from 3 healthy subjects and from 8 patients with chronic lymphocytic leukaemia (CLL) were cultured in the presence of Con A and Ly Con A. The latter induced a significant DNA synthesis both in normal and CLL lymphocytes. A proliferative response was still present in CLL after T lymphocytes depletion. The Con A and Ly Con A treatment also induced morphological changes in CLL lymphocytes consistent with plasma cell differentiation. In 3 cases the appearance of cytoplasmic light chains was detected by immunofluorescence. These findings suggest that peripheral blood B lymphocytes from CLL patients can be stimulated to maturation when helper factor(s) released by mitogen activated lymph node lymphocytes are provided.     

A case of CLL that was successfully treated resulted in the immediate development of AML from a coexistent myeloid line that had been suppressed

An 83 year‐old Caucasian male presented to the emergency room with confusion and lethargy. A complete blood count revealed lymphocytosis, anemia, and thrombocytopenia. A bone marrow examination revealed chronic lymphocytic leukemia (CLL), along with a small population of abnormal immature myeloid cells. Chemotherapy for CLL was started. After one cycle, repeat bone marrow examination revealed normalization of the lymphocyte count and a proliferation of the previously noted myeloid population, consistent with acute myeloid leukemia (AML). This report presents the microscopic, immunophenotypic, and cytogenetic evidence to document the development of AML after one cycle of chemotherapy for CLL.     

Shifting ecologies of malignant and nonmalignant cells following BRAF inhibition

Clinical vignette: A 49-year-old man with stage IV BRAF^V600E-driven melanoma was initiated on twice-daily 960 mg of vemurafenib for treatment of progressive and recurrent subcutaneous metastatic disease of the left lower extremity. The patient’s melanoma responded well to targeted BRAF inhibition. At treatment onset, hematologic parameters were all within normal limits; however, within three months of initiating therapy, wbc were found to be elevated (to 20 K) with sustained lymphocytosis of mature phenotype. Immunophenotypic analysis was consistent with chronic lymphocytic leukemia (CLL), and FISH results revealed presence of the CLL-associated deletion in chromosome 13q14 as well as in 2p33. Vemurafenib was withdrawn after approximately one year of therapy, and subsequently, his peripheral lymphocytosis resolved and CLL regressed. Nevertheless, a monoclonal B cell population persisted even 732 days after discontinuation of vemurafenib.In this issue, Yaktapour et al. describe a patient with metastatic melanoma harboring the BRAF^V600E mutation who, upon treatment with the BRAF inhibitor vemurafenib, developed a sustained lymphocytosis that was ultimately diagnosed as del13q14 chronic lymphocytic leukemia (CLL) without mutations in IGHV. Notably, Yaktapour and colleagues demonstrate that SYK-mediated B cell receptor (BCR) signaling in CLL in the presence of drug-bound BRAF is a putative driver of the paradoxical MEK/ERK activation that has been occasionally observed in response to BRAF inhibition (1).     

An itchy vesiculobullous eruption in a patient with chronic lymphocytic leukaemia

Exaggerated reactions to insect bites are characteristic of patients with haemoproliferative disorders, particularly chronic lymphocytic leukaemia (CLL). Skin lesions usually appear after the diagnosis of leukaemia and seem unrelated to laboratory findings, disease course or therapy. Rarely, the eruption may precede the diagnosis of the haematologic malignancy. The patients usually do not recall of insect bites, and the diagnosis may require histological and laboratory investigations to exclude specific lesions or autoimmune bullous diseases. Lesions may run a chronic course and represent a therapeutic challenge. Here, we report an adult patient with CLL who developed itchy recurrent papulovesicular and bullous lesions. Differential diagnosis was made with cutaneous specific lesions of CLL, bullous pemphigoid and pemphigus vulgaris, but laboratory and histological investigations confirmed the diagnosis of an insect bite reaction. The patient was treated with oral H1 anti-histamines and topical corticosteroids under occlusion, with marked improvement after 10 days.     

Immunoglobulin profiles and antibacterial antibody levels in hairy cell leukaemia.

Serum immunoglobulin and natural antibody concentrations to environmental antigens have been determined in 26 hairy cell leukaemia (HCL) patients. The serum IgG, IgA and IgM levels as well as the concentration of antibodies to the majority of intestinal bacteria were found to be normal in both groups of HCL patients. In contrast to the data on the impaired humoral immunity of chronic lymphocytic leukaemia (CLL) patients, our results show that in HCL the studied aspects of humoral immunity are normal. Serum IgE levels were found to be significantly decreased in HCL when all patients were taken as a group. The difference was due to the decreased serum IgE concentration of splenectomized HCL patients, while IgE levels of untreated HCL patients did not differ statistically from that of the healthy controls.     

Insulin receptors in acute and chronic lymphoid leukaemias

Abstract. Normal lymphocytes lack insulin receptors. The binding of this hormone was studied in twelve patients with acute lymphoblastic leukaemia (ALL) and fourteen patients with chronic lymphocytic leukaemia (CLL). Lymphoblasts from ALL have been found to possess hormone receptors with properties identical to those of the known target cells for insulin: specificity, pH and temperature dependence, and ligand-induced increase in dissociation rate. All patients with ALL displayed insulin receptors on their lymphoblasts. The null-type cells possessed higher numbers of binding sites than the T-type cells, without overlapping of the values. In the fourteen patients with CLL, eight had low levels of insulin receptors on their lymphocytes while six showed a complete lack of such binding sites. Our results suggest that measurement of insulin binding might be a useful non-immunological marker for the classification of human leukaemias.     

Gene expression signature of chronic lymphocytic leukaemia with Trisomy 12

Background  The prognosis of chronic lymphocytic leukaemia (CLL) patients is largely determined by the karyotype of the malignant clone. We have investigated the gene expression profile associated with trisomy 12 (+12).
Design  Initially, unselected peripheral blood mononuclear cells of four patients with +12 were compared with 16 CLL controls using microarray analysis. Results were validated by quantitative real-time PCR with RNA from 61 patients (29 with +12, 32 CLL controls).
Results  Seven genes showing the strongest correlation with +12 in microarray analysis were selected for real-time PCR: HIP1R , MYF6 , SLC2A6 , CD9 (overexpressed); CD200 , P2RY14 , RASGRP3 (underexpressed). Four genes were significantly associated with +12: HIP1R ( P  < 0·0001), MYF6 ( P  = 0·007), P2RY14 ( P  = 0·014), CD200 ( P  = 0·028). Receiver Operating Characteristic curve analysis revealed that HIP1R expression was a highly sensitive and specific marker for +12 in CLL patients. MYF6 was exclusively expressed in normal or malignant B cells in peripheral blood but was poorly predictive for +12. As expected, a number of overexpressed genes are located on chromosome 12 ( HIP1R , MYF6 ). Interestingly, both significantly underexpressed genes ( P2RY14 , CD200 ) reside on the long arm of chromosome 3 pointing to trans-repression in this region.
Conclusions  Analysis of the molecular signature of trisomy 12 in CLL resulted in: (i) identification of a surrogate marker for PCR ( HIP1R ); (ii) observation of a gene dosage effect; and (iii) detection of specific underexpression of genes located on chromosome 3. These results should help to improve diagnosis and treatment decisions for patients with CLL and trisomy 12.     

Evaluating the impact of age and disease on survival of chronic lymphocytic leukaemia patients by a new method

Background: The impact of chronic lymphocytic leukaemia (CLL) on survival may be different in younger patients, but this remains controversial. Objectives: The aim of the study was to examine the effect of age on survival in CLL using an original method. Methods: Clinical, laboratory and survival data of 87 CLL patients treated in our institute were analysed. The survival of patients in different age groups was determined and compared, as related to the expected survival of age‐ and gender‐matched general population obtained from national statistical data. Results: The mean age in the younger (≤ 65 years, n = 37) and older (> 65 years) age groups was 56 and 74 years (p < 0.001). The younger group had more unfavourable presentation, with advanced stage (Rai 2–4) in 46% vs. 16% (p = 0.002), and diffuse involvement of bone marrow in 60% vs. 18% (p = 0.03), compared with the older group, and were more likely to require treatment (p = 0.02). The Kaplan–Meyer curve showed a more favourable survival for the younger group. However, the loss of expected survival exposed a reversed pattern: while the older patients lost only 13%, the survival loss in the younger patients was 44% (p < 0.001). Conclusions: Chronic lymphocytic leukaemia had a more unfavourable presentation and a more severe clinical course in the younger patients. Our method of evaluating the negative impact of disease on expected survival reveals that their survival also is significantly more affected than that of older patients. We suggest calculating the loss of expected survival as a new criterion for assessing disease impact.     

Increased inducible heat shock protein 72 expression associated with PBMC isolated from patients with haematological tumours

Abstract

Background. Heat shock protein 72 (Hsp72) is a highly inducible stress protein and molecular chaperone. Cancers have been shown to be associated with increased Hsp72 expression within the tumour itself and this may lead to resistance to apoptosis. Methods. Peripheral blood mononuclear cells (PBMC) were isolated from patients diagnosed with chronic lymphocytic leukaemia (CLL) (n =?27) and chronic myelomonocytic leukaemia (CMML) (n =?16) and Hsp72 expression was characterized on both the cell surface and intracellularly by flow cytometry. To allow for comparison PBMC from breast cancer patients (n =?25) and healthy volunteers (n =?19) were included. Results. Both lymphocytes and monocytes from CLL and CMML patients showed high levels of total Hsp72 expression (4–6 fold increase) in comparison to breast cancer and healthy subjects. The majority of Hsp72 in these tumours was determined to be cell-surface expressed (64–93% of cell total Hsp72). Conclusions. A correlation was observed between lymphocyte and monocyte total Hsp72 expression (p <?0.001) suggesting a common stress response pathway may exist in these blood cells and there are stress conditions present within the circulation. Hsp72 expression was not found to be related to white blood cell count.     

Current approach to diagnosis and management of chronic lymphocytic leukemia

The care of patients with chronic lymphocytic leukemia (CLL) has changed dramatically during the past decade. This review summarizes the work-up of lymphocytosis and the current diagnostic criteria and management of CLL. Although clinical staging (Rai and Binet) remains the foundation for determining prognosis, 50% of patients with early-stage disease at diagnosis will experience an aggressive course of disease with early progression and premature death due to CLL. New laboratory techniques (CD38, fluorescence in situ hybridization [FISH]) can identify some patients with early-stage CLL at high risk of rapid disease progression. The array of treatment options has expanded in recent years and now includes monoclonal antibodies used alone or in combination with purine nucleoside analogues and alkylating agents, which have culminated in dramatically improved response rates. Supportive care guidelines now include vaccination strategies, surveillance for secondary malignancies, and aggressive management of infectious complications. An early hematology consultation is recommended for all patients at diagnosis to identify and counsel high-risk patients with early-stage disease who may benefit from more frequent follow-up or early treatment as part of a clinical trial.     

Chronic lymphocytic leukemia: a review of some new aspects of the biology, factors influencing prognosis and therapeutic options.

This review provides some basic information on chronic lymphocytic leukemia (CLL) and attempts to present some of the newer data which have accumulated in recent years including those relating to familial aggregation of CLL and the detection of monoclonal CD5+ lymphocytosis in the general population and families of CLL patients. Novel data on the pathogenesis and concepts of cell origin in CLL are also reviewed stressing the fact that there is biased IgVH gene usage, and the importance of mutational status of the CLL cell, as reported in recent years by different authors. A brief review of the significance of the microenvironmental interactions between stromal cells and other accessory cells, and the leukemic CLL cells is also provided. Other clinical aspects are discussed including diagnostic criteria, clinical staging, and the newer prognostic factors which influence survival and timing of therapy for CLL patients. We also attempt to outline the therapeutic options available and the principles of planning risk and age-adapted treatment, stressing the importance and the necessity for participating in ongoing and future international clinical trials.     

Density of Demodex folliculorum in haematological malignancies

We aimed to investigate the incidence and density of Demodex folliculorum in adults with leukaemia or lymphoma. Fifty patients with haematological malignancy and 50 healthy controls were studied. Patients had been diagnosed with acute lymphocytic leukaemia (12%), acute myelocytic leukaemia (32%), chronic lymphocytic leukaemia (4%), chronic myelocytic leukaemia (10%), Hodgkin's lymphoma (4%) or non-Hodgkin's lymphoma (38%). Standardized skin surface biopsies were taken and > or = 5 living parasites/cm2 of skin was defined as an infestation. The difference in infestation rates between patients and controls was statistically significant. The highest incidences of D. folliculorum were found in patients with acute myelocytic leukaemia (10%), non-Hodgkin's lymphoma (6%), acute lymphocytic leukaemia (4%), chronic lymphocytic leukaemia (4%) and chronic myelocytic leukaemia (4%). Demodicidosis should be included in the differential diagnosis of facial eruptions in patients with haematological malignancies who are receiving chemotherapy, and a standardized skin surface biopsy should be performed.     

Functions of T cells and recruitment of cellular response afterin vitro mitogenic stimulation of lymphocytes in chronic lymphocytic leukaemia

Summary In vitro stimulation of peripheral blood lymphocytes from ten patients with chronic lymphocytic leukaemia (CLL) was investigated under various culture conditions. It was confirmed that the mitogenic reactivity of whole cell populations (PBL) was delayed and depressed. When CLL rosette-forming cells (RFC) were stimulated, their³H-thymidine uptake was increased, but the pattern of the response was similar to that of whole PBL, thus suggesting some impairment of these cells. Furthermore, in order to evaluate the possible recruitment of B cells, generally thought to be unresponsive, some co-culture experiments were performed in which 10⁴ normal lymphocytes and 10⁵ CLL whole PBL or RFC-depleted cell populations were stimulated with mitogens. An amplified response of the CLL lymphocytes was obtained in all co-cultures, and this effect was more evident when specific T cell stimulants were used; autologous CLL T lymphocytes, on the contrary, failed to display such a ‘synergic’ effect. These results indicate that normal lymphocytes are able to recruit a large number of CLL lymphocytes in the mitogenic response; furthermore, the fact that in co-cultures of CLL T-depleted fractions a better response was obtained with T cell mitogens suggests that the definition of CLL as a clonal expansion of unresponsive ‘B’ lymphocytes may be inadequate.     

Acute renal failure due to leukaemic infiltration in chronic lymphocytic leukaemia: case report

A 73-year-old woman was presented with altered mental status and disorientation. She was diabetic and hypertensive, and she had experienced an ischemic cerebrovascular accident 3 years ago. Physical examination revealed the findings of chronic obstructive pulmonary disease, cor pulmonale and congestive heart failure. Hepatomegaly, splenomegaly and ascites were found and might be associated with postsinusoidal portal hypertension secondary to congestive heart failure. Laboratory tests showed uremia, lymphocytosis and thrombocytopenia. Neurologic findings were related with uremia and hypoxia. Multiple pathologic lymphadenopathies were seen in abdominal ultrasonography and thoracic computed tomography. Bone marrow histology indicated chronic lymphocytic leukaemia (CLL). The reason for acute renal failure was leukaemic infiltration of the kidneys due to CLL that was shown with renal biopsy. Blood urea nitrogen (BUN) and serum creatinine responded well to cyclophosphamide and methyl prednisolone treatment. In CLL, direct renal involvement is frequently seen in autopsy studies especially in advanced disease, however, renal failure due to leukaemic infiltration is extremely rare.     

慢性淋巴细胞白血病bcl-2基因表达与重排的研究

人类恶性肿瘤常伴有非随机性染色体异常,并由于使调控细胞生长的基因表达失控而在肿瘤的发生中发挥十分关键的作用。bcl-2基因由于t(14,18)染色体易位而激活在低恶度的非霍奇金淋巴瘤的发生和演变中的作用已举世公认。类似的重排和非重排引起的bcl-2过度表达也见于慢性淋巴细胞白血病。我们应用免疫组化染色和聚合酶链反应检测了11例慢性淋巴细胞白血病bcl-2基因表达和重排,结果发现所有病例均高度表达Bcl-2蛋白,1例有t(14,18)(q32,q21)染色体易位。结论提示慢性淋巴细胞白血病普遍存在bcl-2基因高表达,bcl-2基因在慢性淋巴细胞白血病的发生和发展中发挥着十分重要的作用。     

DAB389IL2 (ONTAK®) fusion protein therapy of chronic lymphocytic leukaemia

Despite multiple new therapeutic options for patients with chronic lymphocytic leukaemia (CLL), the prognosis of patients with relapsed disease is poor. After first-line therapy with fludarabine, alkylating agents, rituximab or combinations of these agents, most patients relapse within a few years. While second-line therapy with alemtuzumab, or other combinations of the above agents, have produced remissions, most of these are partial responses lasting months rather than years. Patients commonly die from progressive disease or infections related to the underlying disease or treatment. The authors sought to develop a novel therapeutic with the capacity to kill chemotherapy-resistant CLL cells and with reduced toxicities to normal tissues. Based on the presence of high affinity interleukin-2 receptor (IL-2R) on CLL cells, therapy of relapsed CLL patients with a diphtheria fusion protein targeting IL-2R – DAB₃₈₉IL2 (ONTAK^®,Seragen, Inc., Hopkinton, MA, USA) – was tested in a pilot Phase II study. Biological activity and a partial remission were observed with modest drug-related side effects. Based on these encouraging findings, alternative schedules and combinations with agents that may enhance CLL cell expression of IL-2R are being tested. Hopefully, the use of these targeted therapeutic approaches will provide additional therapeutic options with fewer side effects for this common and incurable condition.