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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 40  |  Issue : 3  |  Page : 113-120

Evaluation of CD69 expression as a prognosticator in chronic lymphocytic leukemia


1 Department of Internal Medicine, Ain Shams University, Cairo, Egypt
2 Department of Clinical and Chemical Pathology, Ain Shams University, Cairo, Egypt

Date of Submission21-Mar-2015
Date of Acceptance16-Apr-2015
Date of Web Publication8-Sep-2015

Correspondence Address:
Emad A Abd El-hadi
Department of Internal Medicine, Ain Shams University, 10 Ahmed Saman Street, Nasr City 11762, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.164725

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  Abstract 

Introduction Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the western world. It is a malignancy of mature B cells involving the blood, bone marrow (BM), and lymphoid tissues, and its cells arise from polyclonal expansion of CD5+ B lymphocytes transformed into a monoclonal population by mutational agents. CD69 is an integral membrane protein belonging to the lectin family. It is expressed after activation in all BM-derived cells except erythrocytes. CLL exhibits features of activated and antigen-experienced B lymphocytes and CD69 overexpression. CD69 is significantly correlated with poor clinical and biological prognostic factors, and this supports its introduction into routine laboratory assessment and, possibly, in a prognostic scoring system for CLL after an adequate standardization process.
Objective The aim of this study was to detect CD69 expression in newly diagnosed patients with CLL by flow cytometry and correlate it with clinical and laboratory parameters to evaluate it as a prognostic factor.
Patients and methods This study was conducted on 40 B-CLL patients who attended Ain Shams University Hospitals over 1 year. All patients were subjected to full medical history and clinical examination, RAI staging according to disease burden and the degree of BM involvement, abdominal ultrasonography, complete blood count with examination of peripheral blood smears, BM aspiration with morphological examination, and immunophenotyping of BM or whole peripheral blood applying monoclonal antibodies CD20, CD79b, FMC7, serum IgM, CD5/CD19, CD10, CD103, CD123, CD23, and CD38, and κ and λ light chains and CD69 expression.
Results In the current study all of the studied B-CLL patients expressed CD69. Among the 40 studied patients 23 had high CD69 expression (group I) and 17 had low CD69 expression (group II). A highly significant elevation in group I patients compared with group II patients was found (P = 0.000). A highly significant reduction in hemoglobin (Hb) level (P = 0.001), elevation in lactate dehydrogenase concentration (P = 0.006), elevation in RAI staging, and elevation in CD38 expression (P = 0.005) were observed in group I. A highly significant negative correlation was found between CD69% and Hb level (P = 0.008) and platelet count (P = 0.009). A highly significant positive correlation was found between CD69% and hepatomegaly (P = 0.008) and RAI stage (P = 0.008) and significant positive correlation was found between CD69% and CD38% expression (P = 0.012). An association study was conducted between CD69% expression and all the standard prognostic factors in B-CLL patients. There was a highly significant association between CD69% expression and presence of hepatomegaly (P = 0.002) and a significant association between CD69% expression and presence of splenomegaly (P = 0.028) and low Hb levels (P = 0.013).
Conclusion Several clinical and biological variables have been reported to predict the outcome of CLL patients, such as advanced patient age, male sex, higher absolute lymphocyte count, greater extent of lymphadenopathy, and raised serum β2-microglobulin levels, all of which are associated with inferior prognosis. In the current study all of the studied B-CLL patients expressed CD69. CLL patients were divided into two subsets with significantly different prognosis: those with high CD69 (group I) (≥30%) and those with low CD69 (group II) (<30%) expression; both were compared with respect to the different studied parameters. There was highly significant elevation of CD69 in group I compared with group II. There was a highly significant reduction in Hb level and elevation in lactate dehydrogenase concentration in group I patients in comparison with group II patients. A highly significant relation was found between the two groups with respect to RAI staging: an advanced RAI stage was found among group I patients in comparison with group II patients. The current study evaluated CD69 as a prognosticator and studied the significant association of its high expression with the standard prognostic factors, notably splenomegaly (P = 0.028) and hepatomegaly (P = 0.002), low Hb level, low platelet count, and advanced RAI stage. CD69 expression is associated with both immunoglobulin variable heavy chain mutation status and survival. It is recommended to perform a larger prospective study on CD69 expression in B-CLL patients, studying its relation to overall survival and progression-free survival and its re-evaluation during the course of treatment as we recommend assessment of this marker by flow cytometry among independent prognostic markers in B-CLL.

Keywords: CD69, chronic lymphocytic leukemia, prognostic factor


How to cite this article:
Abd El-hadi EA, El-Sakhawy YN, Osman AA. Evaluation of CD69 expression as a prognosticator in chronic lymphocytic leukemia. Egypt J Haematol 2015;40:113-20

How to cite this URL:
Abd El-hadi EA, El-Sakhawy YN, Osman AA. Evaluation of CD69 expression as a prognosticator in chronic lymphocytic leukemia. Egypt J Haematol [serial online] 2015 [cited 2018 Sep 25];40:113-20. Available from: http://www.ehj.eg.net/text.asp?2015/40/3/113/164725


  Introduction Top


Historically, chronic lymphocytic leukemia (CLL) was considered to be an indolent and incurable disease. Nonetheless, the clinical course is highly variable. Some patients survive for decades, whereas others develop aggressive disease and die within 23 years of diagnosis [1] .

CLL is the most common type of adult leukemia in the western world. It is a malignancy of mature B cells involving blood, bone marrow (BM), and lymphoid tissues, and its cells arise from polyclonal expansion of CD5+ B lymphocytes transformed into a monoclonal population by mutational agents [2] .

CLL is an indolent B-cell malignancy characterized by an infiltration of mature clonal B lymphocytes in the peripheral blood (PB) and BM. The clinical features of CLL include lymphocytosis, lymphadenopathy, hepatosplenomegaly, constitutional symptoms, propensity to infection, BM failure due to replacement of the hematopoietic compartment with malignant lymphocytes, and a predisposition to autoimmune cytopenias.

The molecular pathogenesis of CLL has not been fully understood. In contrast to other B-cell malignancies, CLL is not associated with recurrent balanced chromosomal translocations. For this reason, several biological parameters have been added to the staging systems to differentiate prognostic subsets [3] .

CD69 is an integral membrane protein belonging to the lectin family. It is expressed after activation in all BM-derived cells except erythrocytes [4] . CLL exhibits features of activated and antigen-experienced B-lymphocytes and CD69 overexpression [5] .

An association has been demonstrated between mutation status and CD69 expression [6] . Del Poeta et al. [7] performed a multivariate analysis for overall survival (OS) in CLL, in which CD69 was confirmed to be an independent prognostic factor and could allow the identification of early progressive patients, enabling timely therapeutic decisions.

A recent study reported that CD69 is significantly correlated with poor clinical and biological prognostic factors and this supports its introduction into routine laboratory assessment and, possibly, in a prognostic scoring system for CLL after an adequate standardization process [7] .


  Objective Top


The aim of this study was to detect CD69 expression in newly diagnosed patients with CLL by flow cytometry and correlate it with clinical and laboratory parameters to evaluate it as a prognostic factor.


  Patients and methods Top


The present study was conducted on 40 newly diagnosed B-CLL patients who attended Ain Shams University Hospitals between June 2013 and June 2014. The patients were selected for the study on the basis of standard clinical, hematological, and immunophenotypic criteria for diagnosis of B-CLL. The group comprised 30 men and 10 women, with a male to female ratio of 3:1. Their ages ranged from 40 to 83 years, with a mean of 58.63 ± 9.1 years.

Methods

All patients were subjected to the following:

  1. Full medical history and clinical examination.
  2. RAI staging according to disease burden and degree of BM involvement [8] .
  3. Investigations including abdominal ultrasonography, complete blood count on a Coulter LH750 Cell Counter (Coulter Electronics, Hialeah, Florida, USA) with examination of PB smears stained with Leishman's stain, BM aspiration with morphological examination of Leishman-stained smears, immunophenotyping of BM or whole PB using a Coulter EPICS-XL flow cytometer (Coulter Electronics), applying monoclonal antibodies (MoAbs) CD20, CD79b, FMC7, serum IgM, CD5/CD19, CD10, CD103, CD123, CD23, and CD38, as well as κ and λ light chains labeled with either fluorescein isothiocyanate or phycoerythrin (PE). Samples were considered positive for a marker if 20% or more of cells expressed that marker, except for CD38 positivity, which was considered positive only at 30% or more staining.
  4. Measurement of CD69 expression by flow cytometry using Coulter EPICS-XL (Coulter Electronics). Samples were considered positive for CD69 if 30% or more of cells expressed it.


Sampling

Samples were collected from each patient under completely aseptic conditions using sterile vacutainers and were divided as follows:

  1. PB samples of 2 ml were obtained on ethylenediaminetetraacetic acid dipotassium salt (K 2 -EDTA), in vacutainer tubes (at a final concentration of 1.5 mg/ml) for complete blood count, flow cytometric immunophenotyping, and CD69 measurement.
  2. BM aspirate of 0.5 ml was obtained; smears were prepared and stained with Leishman's stain for morphological examination.


Flow cytometric immunophenotyping

Principle

Flow cytometry is the measurement of numerous cell properties (cytometry) as the cells move in a single file (flow) in a fluid column and interrupt a beam of laser resulting in light scattering. Antibodies specific for various cellular antigens can be labeled with different fluorochromes that can absorb and emit laser light, allowing simultaneous multicolor flow cytometric analysis of two or more cell-associated antigens.

Reagents

  1. MoAbs supplied by Coulter Electronics: the lymphoproliferative diseases panel include CD20, CD79b, FMC7, serum IgM, CD5/CD19, CD10, CD103, CD123, CD23, and CD38, and κ/λ light chains.
  2. Negative isotypic control for determining the nonspecific binding of the MoAbs.
  3. PBS, pH 7.2, containing 0.09% sodium azide and 0.2% (w/v) bovine serum albumin (BSA).
  4. PE-conjugated MoAb (anti-CD69) supplied by BioLegend (San Diego, California, USA).


Sample processing

BM aspirates or PB samples were processed within 24 h of collection, being preserved at room temperature.

CD69 expression analysis

  1. For each sample, two tubes were labeled for the antibody used and the negative control.
  2. A volume of 50 ml of samples (diluted if total leucocytic count (TLC) >5 × 10 3 mm) was delivered into each tube.
  3. A volume of 5 μl of anti-CD69 was added to the respective tubes of sample and isotypic control.
  4. The tubes were vortexed and incubated in the dark at room temperature for 15 min.
  5. The tubes were centrifuged at 3000 rpm for 5 min and the supernatant was discarded.
  6. Cells were suspended in 500 μl PBS to be ready for acquiring data by the flow cytometer.


Interpretation

In cases where CD19-positive cells constituted less than 85% of the patient's lymphocytes, gating on CD19-positive cells using PE-labeled CD19 was performed. Monoclonality was confirmed by either κ/λ ratios of more than 3 or less than 0.4 or absence or coexpression of both light chains. Expression data for CD69 were reported as a percentage of CD5+ CD19+ CLL cells displaying specific fluorescence intensity. Positivity threshold for CD69 was defined as expression of 30% or more of lymphocytes for the marker, and patients testing positive were designated as group I patients, whereas those below this level were designated as group II patients.

Statistical analysis

Data were collected, revised, coded, and entered into the statistical package for social science (SPSS, version 19; SPSS Inc., Chicago, Illinois, USA). Qualitative data were presented as numbers and percentages, whereas quantitative data were presented as mean, SD, and range when the data were parametric and as median with interquartile range when the data were nonparametric.

Analytical statistics

  1. The χ2 -test was used for comparing qualitative data.
  2. The independent test (t-value) was used for comparing quantitative data.
  3. Pearson's correlation coefficient (r) was used in correlation studies.
  4. Significance was evaluated as follows:
    1. P value 0.05 or more was considered nonsignificant (NS).
    2. P value less than 0.05 was considered significant (S).
    3. P value less than 0.01 was considered highly significant (HS).



  Results Top


The clinical and laboratory features of all B-CLL patients are shown in [Table 1]. Their ages ranged from 40 to 83 years with a mean of 58.63 ± 9.1 years; 30 (75%) patients were male and 10 (25%) were female, with a male to female ratio of 3:1. Regarding the clinical data, 27/40 (67.5%) patients had lymphadenopathy, 34/40 (85.0%) patients had splenomegaly, and 29/40 (72.5%) had hepatomegaly. As for the clinical staging 2/40 (5.0%) patients were classified as RAI stage 0, no cases were classified as RAI stage I, 21/40 (52.5%) patients were classified as RAI stage II, 9/40 (22.5%) were classified as RAI stage III, and 8/40 (20.0%) were classified as RAI stage IV. As for the hematological data, 72.5% cases were anemic with hemoglobin (Hb) concentration ranging from 3.9 to 15.6 g/dl (mean 10.8 ± 2.8, median 11.5), 42.5% cases were thrombocytopenic (<140 × 10 3 /μl) with platelet count ranging from 45.0 to 800.0 × 10 3 /μl (mean 190.0 ± 130.0, median 165), TLC ranged from 3.0 to 400.0 × 10 3 /μl (mean 90.4 ± 90.7, median 56.1), the absolute lymphocytic count ranged from 2.1 to 350.0 × 10 3 /μl (mean 75.4 ± 80.6, median 48.6), and BM lymphocytes ranged from 30 to 90% (mean of 53.7 ± 18.0, median 49). The lactate dehydrogenase (LDH) concentration ranged from 90 to 955 IU/l (mean 474.4 ± 242.0, median 535.0).
Table 1 Clinical and laboratory data of the studied B-cell chronic lymphocytic leukemia patients


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In the current study all of the studied B-CLL patients expressed CD69. CD69% expression in B-CLL patients ranged from 1 to 78% with a mean of 31.2 ± 21.4 (median 31. 23). Of the 40 studied patients, 57.5% had high CD69 expression (group I); their values ranged from 30 to 78 with a mean of 46.74 ± 13.3 (median 45). Seventeen (42.5%) patients had low CD69 expression (group II); their values ranged from 1 to 26 with a mean of 10.24 ± 7.7 (median 8). A highly significant elevation was found in group I patients compared with group II patients (P = 0.000). A highly significant reduction in Hb level (P = 0.001), elevation in LDH concentration (P = 0.006), and elevation in CD38 expression (P = 0.005) were observed in group I patients in comparison with group II patients. A highly significant elevation was found between the two groups according to RAI staging (P = 0.001), in which there was an advanced RAI stage among group I patients in comparison with group II patients. However, no significant difference was observed between the two groups regarding other clinical and laboratory data - namely, age (P = 0.612), platelet count (P = 0.995), TLC (P = 0.978), absolute lymphocytic count (P = 0.496), percentage of BM lymphocytes (P = 0.837), and CD23 expression (P = 0.464) ([Table 2]).
Table 2 Comparison between group I and group II patients as regards some clinical and laboratory data in addition to CD69%


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A highly significant negative correlation was found between CD69% and Hb level (P = 0.008) and platelet count (P = 0.009). A highly significant positive correlation was found between CD69% and hepatomegaly (P = 0.008) and RAI stage (P = 0.008) and significant positive correlation was found between CD69% and CD38% expression (P = 0.012) ([Table 3]).
Table 3 Correlation between CD69% expression and clinical and laboratory data among the studied patients


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An association study was conducted between CD69% expression and all standard prognostic factors in B-CLL patients. The cutoff values for age, sex, hepatomegaly, splenomegaly, lymphadenopathy, Hb level, TLC, and platelet count were taken according to Sagatys and Zhang (2012), whereas the cutoff values for absolute lymphocytic count and percentage of BM lymphocytes were taken according to their median. There was a highly significant association between CD69% expression and presence of hepatomegaly (P = 0.002) and a significant association between CD69% expression and presence of splenomegaly (P = 0.028) and low Hb levels (P = 0.013) ([Table 4]).
Table 4 Association between CD69% expression and the standard prognostic factors among group I and group II patients


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  Discussion Top


CLL is distinguished from other indolent B-cell malignancies by a characteristic immunophenotype, which allows the diagnosis to be established by flow cytometric analysis of the PB in the majority of cases [9] .

CLL is a heterogeneous disease with a highly variable clinical course. Some patients have a life expectancy that resembles that of the age-matched general population, whereas others progress and need treatment within a few months of diagnosis. Several clinical and biological variables, some of which have been validated in prospective studies, have been reported to predict the outcome of CLL patients when assessed at presentation of the leukemia [10] .

Useful prognostic information can be derived from readily available clinical and laboratory data. Advanced patient age, male sex, higher absolute lymphocyte count, greater extent of lymphadenopathy, and raised serum β2-microglobulin levels are all associated with inferior prognosis on multivariate analysis [1] .

Although microscopically CLL cells appear as small resting cells, detailed phenotypic analyses reveal that they express a plethora of surface molecules associated with B-lymphocyte activation. In particular, two molecules CD38 and ZAP-70, expressed by activated T and B cells [11] and a subset of CLL cells [12] , have received special attention because of their ability to predict clinical outcome in CLL patients [13] . Recently, CD49d and other markers, such as CD25, CD26, and CD69, have been advocated as being predictive and reliable in identifying patients with peculiar molecular characteristics of disease and different prognoses [14] .

In the current study all B-CLL patients expressed CD69. CD69 is constitutively expressed on monocytes, platelets, Langerhans cells, and a small percentage of resident lymphocytes in the thymus. In addition, CD69 expression is induced very early upon activation of T and B lymphocytes, NK cells, macrophages, neutrophils, and eosinophils [15] . Literature data confirm that leukemic CLL cells bear the surface membrane phenotype of activated and antigen-experienced B lymphocytes with the overexpression of the activation markers CD23, CD25, CD69, and CD71 [5] .

Del Poeta et al. (2010) stated that the optimal cutoff for CD69 expression yielding the best separation of CLL patients into two subsets with significantly different prognosis was fixed at 30% of positive cells by applying the most commonly used methods to discriminate between CD69-high and CD69-low cases when testing the prognostic impact of CD69. They also confirmed its interlaboratory reproducibility and the stability of its expression over time. Also the studies done by Gattei et al. [3] , Del Poeta et al. [7] , and Degheidy et al. (2013) set the same cutoff value. Accordingly, patients in the present study were divided into two groups; a group with high expression of CD69 (group I) (≥30%) and another group with low expression (group II) (<30%); both were both compared with respect to the different studied parameters. On the basis of this cutoff value, 23 (57.5%) cases among the 40 studied patients had high CD69 expression. Their mean expression level ranged from 30 to 78, with a mean of 46.74 ± 13.3. Seventeen (42.5%) patients had low CD69 expression; their values ranged from 1 to 26 with a mean of 10.24 ± 7.7.

Similarly, Smilevska et al. [6] showed that 64.3% of their CLL cases were CD69 positive. This higher percentage may be due to the lower cutoff they used (20%). Grund et al. (2010) had obtained a mean CD69 of 35 ± 31 in their CLL patients. However, they used a different cutoff (50%), which could explain the lower mean percentage compared with our results.

The mean CD69 percentage was higher in B-CLL patients with high CD69 expression (mean% 46.74) compared with that in B-CLL patients with low CD69 expression (mean% 10.24). Both showed highly significant elevation in group I compared with group II. In the present study, no significant relation was found between CD69 expression and both age and sex, which was also not found by many other studies [7],[16],[17] . Although no previous study reported any significant relation between Hb level and LDH concentration in patients with high CD69 expression, there was a highly significant reduction in Hb level and elevation in LDH concentration in group I patients in comparison with group II patients. A highly significant relation was found between the two groups according to RAI staging in which there was an advanced RAI stage among group I patients in comparison with group II patients; this was in agreement with the results of Damle et al. [5] and Smilevska et al. [6] .

The current study evaluated CD69 as a prognosticator and studied its association with the standard prognostic factors. There was a significant association between the incidence of splenomegaly (P = 0.028) and the incidence of hepatomegaly (P = 0.002) among patients with high CD69 expression. However, a nonsignificant association was observed between lymph node enlargement and CD69 expression. This was partly in concordance with the results of Del Poeta et al. (2010), who found that CD69 overexpression was significantly correlated with splenomegaly. In the present study, there was high CD69 expression among advanced RAI stage patients, as all patients with high expression were in stage II, III, or IV, which is similar to the reports of other studies that reported that patients at RAI stages 0, I, and II had even lower CD69 expression compared with patients in RAI stage III and IV, who had relatively higher levels of CD69 expression [5],[6] . Del Poeta et al. (2010) also stated that CD69 overexpression was significantly correlated with more advanced RAI stages.

In addition, no significant association was found between CD23 and CD69 expression by flow cytometry on comparing the two groups. However, Del Poeta et al. [16] mentioned a significant association between CD23 expression and CD69 expression, and in 2010 they mentioned a significant association between soluble CD23 expression and CD69 expression. High levels of CD23 are associated with diffuse BM infiltration and rapid lymphocyte doubling time [18] . Also CD23 may predict OS or progression-free survival (PFS) [19] . In the present work, a highly significant association between CD69 expression and CD38 was obtained wherein patients with high CD69 expression had significantly higher CD38 expression. This finding was strongly confirmed by Del Poeta et al. (2010), who reported that CD69 expression was significantly correlated with CD38, CD49d, and ZAP-70 and immunoglobulin variable heavy chain (IgVH) mutational status; they also demonstrated in a large series of CLL patients that CD69 protein expression was an independent risk factor for PFS and OS.

In the current study the significant association between high CD69 expression and many standard prognostic factors such as incidence of hepatomegaly, splenomegaly, low Hb level, low platelet count, and RAI staging recommends its use as an independent prognostic factor in B-CLL and its application as a prognosticator. Herishanu et al. (2011) and Walsby et al. (2013) stated that CD69 has been shown to be a strong predictor of CLL prognosis and to be upregulated by microenvironmental contact.

In a study conducted by Grund et al. (2010), all mutated cases belonged to the low CD69 expression group, and all unmutated cases except one belonged to the high expression group. The concordance between CD69 positivity and mutation status was 96%. It is well known that patients with unmutated IgVH genes have a decreased survival compared with patients with mutated IgVH genes, and thus CD69 expression is associated with both IgVH mutation status and survival.

Interestingly, Gattei et al. [3] made a combined analysis of CD69 with CD38 or CD49d or ZAP-70 and demonstrated that CD69 expression had true additive properties, allowing us to identify CLL subsets (CD69- CD38-; CD69- CD49d-; CD69- ZAP-70-; CD69- M IgVH) presenting a very good outcome with regard to PFS and OS. Conversely, double-positive (CD69+ CD38+, CD69+ CD49d+, CD69+ ZAP-70+) subsets and CD69+ unmutated IgVH patients showed the worst outcome. Moreover, CD69 was also necessary to correctly prognosticate the active/progressive disease status within selected subsets of patients. Also, Grund et al. (2010) stated that CD69 is a better surrogate marker for IgVH mutation status compared with CD38 and ZAP-70.

Del Poeta et al. [7] in a multivariate analysis of PFS and OS found age, RAI modified stages, ZAP-70, lymphocyte doubling time, β2-microglobulin, CD38, CD69, and CD79b to be independent prognostic factors. Unfortunately, the current study lacks information about PFS and OS because of the short duration and failure to follow up the studied patients as the majority continued their treatment and follow-up in places other than Ain Shams University Hospitals. Thus, multivariate analysis of PFS and OS could not be applied.

MoAb CD69 promotes NK-cell cytolytic activity in the presence or absence of the tumor microenvironment. Consequently, in vivo treatment with anti-CD69 MoAbs, in either preventative or therapeutic settings, is efficient in promoting NK-cell-dependent tumor elimination [20] . Furthermore, CD69 targeting by a nondepleting anti-CD69 antibody similarly increases antitumor responses by enhancing NK-cell activity, and treatment of NK cells with this antibody results in increased cytotoxic activity and IFN-γ production. CD69 thus regulates antitumor immune responses by modulating the expression of various cytokines, including TGF-β and IFN-γ [21] .


  Conclusion Top


Recent risk parameters were defined as prognostic markers that appear to be clearly related to the biology of B-CLL, including defects detectable on fluorescence in situ hybridization, IgVH mutational status, surface marker CD38, and intracytoplasmic ZAP-70 levels.

We concluded that CD69 determined by flow cytometry could be considered a novel important independent prognostic parameter in B-CLL. It is easy and rapid laboratory evaluation allows early identification of progressive patients, enabling timely therapeutic decisions.

Recommendations

It is recommended to perform a larger prospective study on CD69 expression in B-CLL patients, studying its relation to OS and PFS and its re-evaluation during the course of treatment. We recommend assessment of this marker by flow cytometry among the independent prognostic markers in B-CLL.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Wierda WG, O'Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood 2007; 109 :4679-4685.  Back to cited text no. 1
    
2.
Hallek M. State-of-the-art treatment of chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Program 2009; 440-449. doi:10.1182/asheducation-2009.1.440. PMID: 20008230.  Back to cited text no. 2
    
3.
Gattei V, Bulian P, Del Principe MI, Zucchetto A, Maurillo L, Buccisano F, et al. Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia. Blood 2008; 111 :865-873.  Back to cited text no. 3
    
4.
Sancho D, Gómez M, Viedma F, Esplugues E, Gordón-Alonso M, García-López MA, et al. CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collagen-induced arthritis. J Clin Invest 2003; 112 :872-882.  Back to cited text no. 4
    
5.
Damle RN, Ghiotto F, Valetto A, Albesiano E, Fais F, Yan XJ, et al. B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. Blood 2002; 99 :4087-4093.  Back to cited text no. 5
    
6.
Smilevska T, Stamatopoulos K, Samara M, Belessi C, Tsompanakou A, Paterakis G, et al. Transferrin receptor-1 and 2 expression in chronic lymphocytic leukemia. Leuk Res 2006; 30 :183-189.  Back to cited text no. 6
    
7.
Del Poeta G, Del Principe MI, Zucchetto A, Buccisano F, Bomben R, Luciano F, et al. CD-69 and CD79B overexpression identity poor risk chronic lymphocytic leukemia. Haematologica 2010; 95 (Suppl 2):317.  Back to cited text no. 7
    
8.
Binet JL, Lepoprier M, Dighiero G, Charron D, D'Athis P, Vaugier G, et al. A clinical staging system for chronic lymphocytic leukemia: prognostic significance. Cancer 1977; 40 :855-864.  Back to cited text no. 8
[PUBMED]    
9.
Giannopoulos K, Dmoszynska A, Kowal M, Rolinski J, Gostick E, Price DA, et al. Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia. Leukemia 2010; 24 :798-805.  Back to cited text no. 9
    
10.
Rosenquist R, Cortese D, Bhoi S, Mansouri L, Gunnarsson R. Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand? Leuk Lymphoma 2013; 54 :2351-2364.  Back to cited text no. 10
    
11.
Nolz JC, Tschumper RC, Pittner BT, Darce JR, Kay NE, Jelinek DF. ZAP-70 is expressed by a subset of normal human B-lymphocytes displaying an activated phenotype. Leukemia 2005; 19 :1018-1024.  Back to cited text no. 11
    
12.
Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348 :1764-1775.  Back to cited text no. 12
    
13.
Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003; 101 :4944-4951.  Back to cited text no. 13
    
14.
Huang PY, Best OG, Belov L, Mulligan SP, Christopherson RI. Surface profiles for subclassification of chronic lymphocytic leukemia. Leuk Lymphoma 2012; 53 :1046-1056.  Back to cited text no. 14
    
15.
D'Arena G, Musto P, Nunziata G, Cascavilla N, Savino L, Pistolese G. CD-69 expression in B-cell chronic lymphocytic leukemia: a new prognostic marker? Haematologica 2001; 86 :995-996.  Back to cited text no. 15
[PUBMED]    
16.
Del Poeta G, Del Principe MI, Luciano F, et al. High CD-69 protein expression predicts a poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) (abstract 750). Atlanta, Georgia: Program and abstracts of the 49th Annual Meeting of the American Society of Hematology; 2007.  Back to cited text no. 16
    
17.
Moreno C, Montserrat E. New prognostic markers in chronic lymphocytic leukemia. Blood Rev 2008; 22 :211-219.  Back to cited text no. 17
    
18.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al.International Workshop on Chronic Lymphocytic Leukemia Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111 :5446-5456.  Back to cited text no. 18
    
19.
Lee KM, McNerney ME, Stepp SE, Mathew PA, Schatzle JD, Bennett M, Kumar V 2B4 acts as a non-major histocompatibility complex binding inhibitory receptor on mouse natural killer cells. J Exp Med 2004; 199 :1245-1254.  Back to cited text no. 19
    
20.
Esplugues E, Vega-Ramos J, Cartoixa D, Vazquez BN, Salaet I, Engel P, Lauzurica P. Induction of tumor NK-cell immunity by anti-CD-69 antibody therapy. Blood 2005; 105 :4399-4406.  Back to cited text no. 20
    
21.
Murata K, Inami M, Hasegawa A, Kubo S, Kimura M, Yamashita M, et al. CD69-null mice protected from arthritis induced with anti-type II collagen antibodies. Int Immunol 2003; 15 :987-992.  Back to cited text no. 21
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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[Pubmed] | [DOI]



 

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