Survival and prognostic factors in chronic lymphocytic leukemia

The survival of 137 consecutive chronic lymphocytic leukemia patients, diagnosed between 1960 and 1982 and followed up at the Hematology Clinic of the Chaim Sheba Center, was correlated with demographic, clinical and laboratory data. The median survival time of the whole group was 104 months. Older age, hepatomegaly, anemia, thrombocytopenia and increased percent of lymphocytes in the peripheral blood at diagnosis were all associated with shorter survival. On the other hand, splenomegaly or lymph node enlargement did not influence survival. When divided according to both Rai's and the International Workshop staging systems, the survival of our patients seemed to be better than that reported in most previously published series of similar patients. We assume that this is related to a conservative approach to the treatment of chronic lymphocytic leukemia patients in this center.     

Investigation of nuclear clefts as a prognostic parameter in chronic lymphocytic leukemia

The importance of cell morphology with respect to the presence or absence of nuclear clefts (NC) in peripheral blood lymphocytes has been investigated in 86 previously untreated chronic lymphocytic leukemia (CLL) patients. Cleaved cells were considered to be present in significant numbers when they exceeded 5% of the peripheral blood lymphocytes. On this basis patients could be divided into two morphological groups. Age, sex and distribution of stages, as well as mode of clinical presentation were alike in the two groups of patients. In contrast, lymph node involvement was more frequently encountered in patients with NC greater than 5% (p less than 0.01). Both survival and treatment-free period probabilities were not statistically correlated to the quantitative changes in the percent value of NC. We further confirm that Binet's clinical staging is a significant predictor of survival irrespective of NC.     

Concomitant chronic lymphocytic leukemia and acute myeloid leukemia with an uncommon immunophenotype

We report a case of simultaneous diagnosis of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), in which the use of flow cytometry analysis allowed the demonstration of two different cell populations and the study of both immunophenotyping patterns with a large panel of monoclonal antibodies (MoAbs). CLL cells showed a typical immunophenotype with coexpression of B cell markers with CD5, CD23, CD43, and weak surface immunoglobulin light chain restriction expression, whereas the AML population had a very uncommon phenotype with expression of myeloid markers and CD56 and lack of expression of other natural killer (NK) antigens, CD34 and HLA-DR. After chemotherapeutic treatment of AML with two induction courses, the patient achieved complete remission of the AML with persistence of a CD19/CD5 positive population. After consolidation chemotherapy, this latter population was no longer detectable despite the presence of lymphoid nodules in a bone marrow biopsy. Six months after diagnosis, the patient relapsed with AML and died shortly afterwards. Am. J. Hematol. 56:281–287, 1997. © 1997 Wiley-Liss, Inc.     

Lipoprotein lipase in chronic lymphocytic leukemia: function and prognostic implications

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation of a clonal population of B cells in peripheral blood, bone marrow, and lymphoid organs. More than 10 years ago, lipoprotein lipase (LPL) mRNA was identified as being strongly expressed in patients experiencing a more aggressive phenotype, while CLL patients with an indolent disease course lack expression of this marker. Since then, several reports confirmed the capability of LPL to predict CLL disease evolution at the moment of diagnosis. In contrast, data on the functional implications of LPL in CLL are scarce. LPL exerts a central role in overall lipid metabolism and transport, but plays additional, non‐catalytic roles as well. Which of those is more important in the pathogenesis of CLL remains largely unclear. Here, we review the current knowledge on the prognostic and biological relevance of LPL in CLL.     

Prognostic value of nucleoli and cell size in chronic lymphocytic leukemia

In an effort to improve prediction of duration of survival in chronic lymphocytic leukemia, correlations between blood-cell morphology and survival were investigated. Blood films made on 108 patients at the time of diagnosis of chronic lymphocytic leukemia were reviewed by a single hematologist. Lymphocyte diameter and the fraction of lymphocytes containing nucleoli were both found to have an inverse correlation with survival. Bone-marrow aspirate films were available for 64 patients. Differential leukocyte counts showed that the median for marrow lymphocytes was 64%. Those patients with a greater than median proportion of lymphocytes on marrow aspirate had a shorter survival time than those with less than median.     

Serum insulin-like growth factor is not elevated in patients with early B-cell chronic lymphocytic leukemia but is still a prognostic factor for disease progression

OBJECTIVES: Insulin-like growth factor 1 (IGF-1) is an important growth and anti-apoptotic factor for the cancer cells in several malignancies and in multiple myeloma recent studies support the hypothesis of a role for IGF-1 in disease progression; however, clinico-biological relevance of IGF-1 was never studied in B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Using a quantitative sandwich immunoassay technique (ELISA) (Quantikine, Human IGF-1 and IGFBP-3, R&D Systems), we measured the concentration of IGF-1 and its major binding protein IGF-binding protein 3 (IGFBP-3) in serum drawn at the time of diagnosis from 77 Binet stage A CLL patients. RESULTS: Either IGF-1 or IGFBP-3 were significantly decreased compared with healthy age- and sex-matched controls (P < 0.0001 for both; Mann-Whitney test). Serum levels of IGF-1 and IGFBP-3 paralleled each other (P = 0.002); in contrast, no significant correlation was found between serum levels of IGF-1 and clinico-hematological variables including age (P = 0.253), sex (P = 0.270), Rai clinical substages (P = 0.140), lactate dehydrogenase (P = 0.956), beta2-microglobulin (P = 0.368), lymphocyte count (P = 0.703) and lymphocyte doubling time (LDT, P = 0.233). When correlation were attempted with circulating levels of angiogenic cytokines such as vascular endothelial growth factor (P = 0.971), basic fibroblastic growth factor (P = 0.695), angiogenin (P = 0.282) or adhesion molecules such as vascular cell adhesion molecule-1 (P = 0.318), intercellular adhesion molecule-1 (P = 0.883) and platelet endothelial cell adhesion molecule-1 (P = 0.772) similar results were found. Serum levels of IGF-1 were further evaluated as a dichotomous variable with respect to progression-free survival (PFS), an endpoint surrogate for overall survival in early B-cell CLL. The best separation of curves was seen with the cutoff point at the 75th percentile of IGF-1 levels (i.e., 93 pg/mL). Median PFS was 63 months in the patient group with low IGF-1, compared with a median PFS of 40 months in the remaining patients (P = 0.03). In the multivariate analysis performed including variables significant at univariate analysis [i.e. Rai substage (P = 0.002); LDT (P = 0.004), IGF-1 (P = 0.01)], only Rai substage retained prognostic significance (P = 0.006). However, after removing from analysis LDT (only six of 77 had an LDT < 12 months), either IGF-1 or Rai substage entered the model at a significant level (P = 0.03 and P = 0.01, respectively). CONCLUSIONS: IGF-1 did not correlate with markers of tumor burden or clinical status in CLL thus suggesting that levels of this cytokine do not reflect the intrinsic malignancy of disease. Results of the present study highlight, however, its involvement in mechanisms of disease progression in early CLL.     

New prognostic markers in chronic lymphocytic leukemia

The prognosis of patients with chronic lymphocytic leukemia (CLL) is extremely variable. Prognostication of patients with CLL has been classically based on clinical parameters. In the last few years, several biologic markers such as cytogenetics, IgVH mutations, CD38 and ZAP-70 expression in leukemic cells have shown to offer important prognostic information. However, before being incorporated into daily practice these markers require standardization and validation in prospective trials. Meanwhile, prognosis of patients with CLL should remain to be based on clinical stages and other easily obtainable clinical parameters. An important area of research is the identification of markers useful for predicting response to therapy. Among them, 17p- reflecting p53 abnormalities is particularly important. Also relevant is 11q- pointing out to ATM defects. The correlation of IgVH mutations, ZAP-70 and CD38 expression with response is unclear and needs further investigation. Finally, there is increasing evidence that response to therapy, particularly when all measurable disease is eradicated, is associated with longer survival.     

Baff serum level predicts time to first treatment in early chronic lymphocytic leukemia

We analyzed the correlation between well‐established biological parameters of prognostic relevance in B‐cell chronic lymphocytic leukemia (CLL) [i.e. mutational status of the immunoglobulin heavy chain variable region (IgVH), ZAP‐70 and CD38 expression] and serum levels of B cell–activating factor (BAFF of the TNF family) by evaluating the impact of these variables on the time to first treatment (TFT) in a series of 169 previously untreated CLL patients in Binet stage A. Higher levels of BAFF were more frequently associated with female gender (P = 0.02), younger age (P = 0.01), Rai stage 0 (P = 0.002), higher platelet count (P = 0.005), mutated IgVH disease (P = 0.002), higher occurrence of normal cytogenetic profile or presence of 13q deletion (P = 0.02), low ZAP‐70‐ (P = 0.003), and CD38‐expression (P = 0.02). Maximally selected log‐rank statistic plot identified a serum BAFF concentration of 0.313 ng/mL as the best cut‐off (P < 0.0001). This threshold recognized two subsets of patients with different TFT (P < 0.0001). Because in multivariate analysis soluble BAFF [Hazard ratio (HR), 8.23; confidence Interval (CI) 95%,3.0–22.6, P < 0.0001] and mutational status of IgVH (HR = 2.60; CI 95% 1.10–6.14, P = 0.03) maintained the discriminating power their combined effect on clinical outcome was assessed. When three groups were considered: ( 1 ) low‐risk (n = 93), patients with concordant IgVH_mut and higher soluble BAFF; ( 2 ) intermediate‐risk (n = 50), patients with IgVH_mut and low BAFF levels or IgVH_unmut and soluble higher BAFF;( 3 ) high‐risk (n = 26), patients with concordant IgVH _unmut and low soluble BAFF, the 2‐yr TFTs were, respectively, 95%, 85%, and 41% (P < 0.0001). In conclusion, our results indicate that in early B‐cell CLL, the biological profile including among other parameters soluble BAFF may provide a useful insight into the complex interrelationship of prognostic variables.     

Chylothorax in chronic lymphocytic leukemia patient

Chronic lymphocytic leukemia (CLL) is rarely complicated by chylothorax: we present a 93-year-old woman with CLL who developed recurrent pleural effusions that were ultimately found to be chylous in nature. Despite eight repeated thoracenteses, she continued to experience re-accumulation of fluid, and therefore, video-assisted thoracotomy with mass ligation of the thoracic duct region plus pleurodesis was performed to resolve the chylothorax. Despite her age and underlying disease, she did well during follow-up. The etiology and management of chylothorax are also reviewed.     

A clinicopathologic analysis of chronic lymphocytic leukemia

Sixty consecutive patients with chronic lymphocytic leukemia (CLL) were studied from both a clinical and laboratory standpoint. Hypoimmunoglobulinemia was found in 45% of patients; many of these patients suffered from severe bacterial infections. Second primary malignancies were diagnosed in 20% of patient's; most of these predated the diagnosis of CLL. HLA-B17 typing was found in unexpectedly high frequency in a small group of Coombs'-positive patients. The Rai-staging system was found to be generally useful for determining prognosis of groups of patients, although less useful in any individual patient. Findings relating to surface membrane immunoglobulin-positive (B) and E-rosetting (T) lymphocytes are described. A patient with null-cell CLL is described. All patients with proliferation of gamma heavy-chain-bearing cells were diagnosed in early Rai stages suggesting that this marker may identify a subset of patients who present early and have a good prognosis. These data suggest that lymphocyte marker studies augment the Rai criteria in evaluating prognosis and may eventually be of value to the clinician in evaluating stage of disease and response to treatment.     

Splenectomy for thrombocytopenia in chronic lymphocytic leukemia

The role of peripheral platelet destruction as a reversible etiology of thrombocytopenia in chronic lymphocytic leukemia (CLL) was evaluated in nine patients with CLL and refractory thrombocytopenia who underwent splenectomy. The patients' ages ranged from 54 to 74 years. Progressive thrombocytopenia refractory to antineoplastic agents and corticosteroids had been present for a mean of 23.4 months. The platelet counts were 4,000-57,000/microliter, and were generally higher in those patients with larger spleens. The spleens ranged from 180 to 4050 gm. Seven patients responded completely to splenectomy, achieving platelet counts greater than 150,000/microliter, and in one other patient, the count rose to greater than 100,000/microliter. The platelet count of one patient failed to respond to surgery. Those patients with massive splenomegaly developed higher, more rapidly rising platelet counts postoperatively. No operative mortality was encountered. Median hospitalization was seven postoperative days. All patients experienced an increased sense of well-being. Median follow-up time is 9 months.     

Free light chain: a novel predictor of adverse outcome in chronic lymphocytic leukemia

Objectives: Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. This retrospective study is planned to assess the prognostic value of serum free light chain (sFLC) levels and FLC ratio (FLCR) in CLL. Methods: Quantitative levels of sFLC were measured nephelometrically in sera collected at diagnosis. The expressions of ZAP70 and CD38 were quantified by flow cytometry. Chromosomal abnormalities were determined by interphase fluorescence in situ hybridization (FISH). Results: In a cohort of 101 patients with a median follow‐up of 29 (1–234) months, sFLC levels were found to be high in 55 patients (54.5%). An abnormal FLCR was found in 30 patients (29.7%). FISH‐based genetic risk groups did not differ significantly with respect to sFLC and FLCR (P > 0.05). Median time to first treatment was shorter in patients with high sFLC levels (P = 0.02). Median overall survival (OS) was shorter in patients with high sFLC levels (P = 0.01) and abnormal FLCR (P = 0.05). In patients with early stage disease, median OS was shorter in high sFLC (P = 0.03) and abnormal FLCR groups (P = 0.048). A relationship was observed between abnormal sFLC levels and CD38 positivity on logistic regression analysis (P = 0.003; OR: 4.44; 95% CI: 1.66–11.8). Conclusions: This study highlighted the adverse prognostic impact of high sFLC levels and abnormal FLCR with regard to survival in CLL, even in early stage patients. Prospective studies are warranted to validate the adverse impact of sFLC and FLCR on clinical outcome.     

Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA

Background

Zeta-associated protein 70 (ZAP70) is a widely recognized prognostic factor in chronic lymphocytic leukemia, but mechanisms by which its higher expression leads to a poor outcome must still be fully explained.

Design and Methods

In an attempt to unveil unfavorable cellular properties linked to high ZAP70 expression, we used gene expression profiling to identify genes associated with disparities in B cells from chronic lymphocytic leukemia patients expressing high versus low ZAP70 mRNA, measured by quantitative real-time PCR. Two groups of 7 patients were compared, selected on the basis of either high or low ZAP70 mRNA expression.

Results

Twenty-seven genes were differentially expressed with an FDR<10%, and several genes were significant predictors of treatment-free survival (TFS) and/or overall survival; PDE8A and FCRL family genes (down-regulated in ZAP70⁺ patients) could predict TFS and overall survival; ITGA4 mRNA (up-regulated in ZAP70⁺ patients) could significantly predict overall survival. Importantly, gene set enrichment analysis revealed overrepresentation of adhesion/migration genes. We therefore investigated in vitro adhesion/migration capacity of chronic lymphocytic leukemia cells into a stromal microenvironment or in response to conditioned medium. We showed that ZAP70⁺ cells had better adhesion/migration capacities and only ZAP70⁺ patient cells responded to microenvironment contact by CXCR4 downregulation.

Conclusions

We concluded that several prognostic factors are the reflection of microenvironment interactions and that the increased adhesion/migratory capacity of ZAP70⁺ cells in their microenvironment can explain their better survival and thus the aggressiveness of the disease.     

Prognostic importance of soluble CD23 in B‐cell chronic lymphocytic leukemia

Soluble CD23 (sCD23) was proposed as a marker of disease activity and as an important prognostic parameter in B‐cell chronic lymphocytic leukemia (B‐CLL). In this study, prognostic significance of sCD23 in B‐CLL was examined according to its temporal relationship with the known clinical parameters of the disease, CD38 and ZAP‐70. Serum sCD23 levels of 36 B‐CLL patients, followed up in our clinic between 1999 and 2005, and 15 healthy subjects were measured with enzyme‐linked immunosorbent assay. The mean serum sCD23 level of the B‐CLL patients (210.72 ± 193.67 and 6–600 U/ml) was significantly higher than the control group (18.20 ± 14.30 and 6–50 U/ml). Seventy‐eight percent of the B‐CLL patients with lymphocyte doubling time (LDT) <12 months and 24% of patients with LDT >12 months had high sCD23 levels (P = 0.008). Meanwhile, 81% of the patients with diffuse bone marrow infiltration and 33% of patients with nondiffuse infiltration had high levels of serum sCD23 (P = 0.029). A significant difference was found between B‐CLL patients with Binet stages A and C (P = 0.009). Peripheral blood flow cytometry of the patients revealed a significant CD38 expression in patients with high serum sCD23 levels (P = 0.002). Similarly, an increased bone marrow zeta‐chain associated protein kinase‐70 (ZAP‐70) expression was seen in patients with high serum sCD23 levels (P = 0.009, correlation co‐efficient was 0.714). Cumulative and the progression free survivals of the patients with low serum sCD23 levels were 60.1 ± 5.7 months [95% confidence interval (CI); 49.0–71.2] and 51.1 ± 6.6 months (95% CI; 38.0–64.1), respectively. However, they were 43.8 ± 6.5 months (95% CI; 31.0–56.6) and 26.5 ± 6.4 months (95% CI; 14.0–39.1) in patients with high levels. Serum sCD23 is increased in B‐CLL patients and can be used in the clinical follow‐up of the disease in prediction of the tumor mass and prognosis.     

Membranous glomerulonephritis in chronic lymphocytic leukemia

We present a case of chronic lymphocytic leukemia associated with nephrotic syndrome. Renal biopsy revealed membranous glomerulonephritis accompanied by interstitial monoclonal lymphocytic infiltration. Combination therapy with cyclophosphamide, vincristine, and prednisone (COP) was successful in inducing an effective response in chronic lymphocytic leukemia. Improvement of renal function and proteinuria was also observed.     

Autoimmune hyperthyroidism and thrombocytopenia developing in a patient with chronic lymphocytic leukemia

A 56-year-old white man is described whose course of chronic lymphocytic leukemia (CLL) was complicated by the occurrence of the autoimmune hyperthyroidism/thrombocytopenia syndrome. The implications of this syndrome on the treatment of CLL are discussed.     

Coexistence of myelodysplastic syndrome and untreated chronic lymphocytic leukemia with development of acute myeloid leukemia immediately after treatment of chronic lymphocytic leukemia

A 72-year-old man originally seen for anemia and thrombocytopenia was determined to have chronic lymphocytic leukemia (CLL). Bone marrow examination at the time of CLL diagnosis revealed a small but significant population of atypical blasts. Cytogenetic analysis of the bone marrow aspirate disclosed chromosomal abnormalities (-7, +8) suggestive of a myelodysplastic syndrome. Shortly after treatment of the CLL, there was proliferation of the previously noted blast population, which cytochemical studies demonstrated to be of the myeloid series thus indicating acute myeloid leukemia superimposed on CLL. This report presents microscopic, cytogenetic, immunophenotypic, and cytochemical evidence to document the evolution of acute myeloid leukemia in the bone marrow of a patient with CLL after one course of chemotherapy.     

Staging and prognosis of chronic lymphocytic leukemia

Three hundred ninety-one cases of chronic lymphocytic leukemia (CLL) from the Tumour Registry of Manitoba, spanning a 20-year period from January 1960 to December 1979, were reviewed. Survival curves were developed using the staging systems of Rai and Binet. A clear separation in survival was found utilizing the system of Binet. Also, there was a significant increase in the development of secondary malignancies (observed, 53; expected, 31, p<0.01). However, there was no significant increase in secondary malignancies if only those malignancies occurring at least six months after the diagnosis of chronic lymphocytic leukemia was made were analyzed (observed, 38; expected, 29, p=0.26). This suggests that the increase in secondary malignancies is not treatment-related, and may be due to the underlying disease. Received from the Sections of General Internal Medicine and Oncology, Department of Internal Medicine, St. Boniface General Hospital, University of Manitoba, Winnipeg, Manitoba.     

CD8+ chronic lymphocytic leukemia: an extensive characterization of a bizarre hybrid neoplasia

Atypical chronic lymphocytic leukemia (CLL) expressing the CD8 antigen have a frequency of less than 0.5% of all cases, however, they are not yet been fully characterized. Herein a CD8+ CLL case was extensively studied. Besides the classical CLL antigen expression, an unusual presence of surface markers such as CD11c, CD56, and CD154 was observed. Moreover, gene expression of chemokine receptors belonging to the CCR family were clearly evidenced as well as mRNA for both, Th1 and Th2 cytokines. Likewise, granzyme A, B and perforin gene expression, cytotoxic T cell or NK enzymes were found. The intricate profile of membrane molecules and gene expression suggest that it could be favorable, rather than deletereous, for the maintainance of the neoplastic process.