The Prevalence of Chronic Lymphoproliferative Diseases in Patients with Borderline Lymphocytosis in Community Practice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4975-4975
Author(s):  
Zuhair Y. Ghanem ◽  
Mahmoud Q. Moammar ◽  
Sherif A. Nasr ◽  
Maher Albitar
Keyword(s):  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
Early Diagnosis ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Disease ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Community Practice ◽  
Lymphoproliferative Diseases

Abstract Introduction: The standard criterion for diagnosing chronic lymphocytic leukemia (CLL) is clonal lymphocytosis of >5×10 9/L. Cases of CLL with normal lymphocyte count have been diagnosed by flow cytometry based on the presence of clonal CD19+/CD5+/CD23+ cells. Therefore, it is not unexpected that a proportion of patients with borderline lymphocytosis (>3.5 and <5.0x10 9/L) will have CLL. The aim of our study is to establish the prevalence of CLL in patients with borderline “4.0 to 5.0x109/L” lymphocytosis in the adult population (age >40 years) seen in community practice. Methods: Using flow cytometry we analyzed a total of 157 sequential peripheral blood samples collected from patients older than 40 years presented with borderline lymphocytosis (4 to 5 x109/L). Majority of these patients (#106) were detected incidentally during routine CBC and 51 samples were submitted to rule out lymphoproliferative diseases. Results: Forty of the 157 (26%) patients had clonal B-cell disease meeting the criteria for chronic lymphoproliferative disease. The disease was classified as CLL in 35 patients (87.5%), hairy cell leukemia in 1 patient (2.5%), Waldenstrom’s macroglobulinemia in 1 patient (2.5%) and marginal zone B-cell lymphoma in 3 patients (7.5%). This data suggests that patients older than 40 year with lymphocyosis >4x10 9/L have high probability of having chronic lymphoproliferative disease. This disease could be other than CLL and should be thoroughly investigated. DISCUSSION: In our study the prevalence of low grade lymphoproliferative disorders in patients with borderline lymphocytosis (4–5 x109/L) above the age of 40 is 26%. This number may be positively skewed considering our selection criteria (including a subset of patients retrospectively included). Currently, there is no data to support that early intervention is beneficial for CLL, even for patients with unfavorable prognosis (e.g., those with ATM and P53 deletions). Early diagnosis of CLL will create more opportunity to study the disease in its early stages.[Shanafelt TD, Geyer SM, Kay NE: Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL. Blood. 2004 Feb 15;103(4):1202–10. Epub 2003 Oct 23. Review.], [ Hamblin TJ: Achieving optimal outcomes in chronic lymphocytic leukemia. Drugs. 2001;61(5):593–611. Review.]. Since lymphocyte doubling time (LDT) is a prognostic factor (the prognostic utility of LDT is most important for patients with early stage disease who typically are treated by watchful waiting [ Shanafelt TD, Call TG. Current approach to diagnosis and management of chronic lymphocytic leukemia. Mayo Clin Proc. 2004 Mar;79(3):388–98. Review. ] ). early diagnosis may help to better segregate low from high-risk patients. Finally, in today’s cost containment pressures, it is beneficial to have an expectation for the cost/benefit ratio of performing a test. Knowing the prevalence of disease at decision limits may help us to better justify establishing testing guidelines.

scholarly journals Detection of CD5 in B-cell chronic lymphoproliferative diseases by flow cytometry: a strong expression in B-cell chronic lymphocytic leukemia

2005 ◽  
Vol 20 (suppl 1) ◽  
pp. 56-62
Author(s):  
Geraldo Barroso Cavalcanti Júnior ◽  
Valeria Soraya de Farias Sales ◽  
Dany Geraldo Kramer Cavalcanti e Silva ◽  
Maria Cleide de Araújo Lopes ◽  
Aldair de Souza Paiva ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphoproliferative Disease ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
B Cell Malignancies ◽  
Prolymphocytic Leukemia ◽  
Chronic Lymphoproliferative Diseases ◽  
Cell Chronic Lymphocytic Leukemia

PURPOSE: CD5 is a T cell marker, aberrantly express in B cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL). Other chronic B cell malignancies including hairy cell leukemia (HCL) and B cell prolymphocytic leukemia (B-PLL) are CD5 negative or express this antigen in a weak way. In this study, CD5 expression was investigated in leukemic cells from 42 patients with chronic B cell lymphoproliferative disease. METHODS: We studied the CD5 expression in leukemic cells from 42 patients with chronic B-cell malignancies by flow cytometry. Demographic features such as age, sex and clinical date were also analyzed. RESULTS: There were 22 males and 20 females. The immunophenotyping showed that 35 cases were B-CLL, 3 B-PLL and HCL and one patient was MCL. CD5 expression was present in all B-CLL and MCL. Low expression of CD5 was observed in one patient with B-PLL and negative in all cases of HCL. CONCLUSION: Our date demonstrated that CD5 expression can help distinguish among B-CLL from HCL and B-PLL, but is similar expressed in MCL.

scholarly journals Histiocytic Sarcoma: Review, Discussion of Transformation From B-Cell Lymphoma, and Differential Diagnosis

2018 ◽  
Vol 142 (11) ◽  
pp. 1322-1329 ◽  
Author(s):  
Stephanie L. Skala ◽  
David R. Lucas ◽  
Rajan Dewar
Keyword(s):  
Differential Diagnosis ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Histiocytic Sarcoma ◽  
Lymphocytic Leukemia ◽  
Western Hemisphere ◽  
Low Grade ◽  
Small Lymphocytic Lymphoma

Context.— Histiocytic sarcoma is a rare neoplasm of mature histiocytes with an aggressive clinical course that can arise de novo or from a low-grade B-cell lymphoma. In particular, chronic lymphocytic leukemia/small lymphocytic lymphoma is a very common malignancy in the Western hemisphere, and most cases of chronic lymphocytic leukemia/small lymphocytic lymphoma have an indolent course and behavior. However, 2% to 8% of chronic lymphocytic leukemia/small lymphocytic lymphoma cases transform. Histiocytic sarcomatous transformation is rare and portends poor prognosis. Objective.— To review the clinical features, morphology, and key points related to the differential diagnosis for histiocytic sarcoma. We discuss recent understanding of the biology underlying transformation. Data Sources.— University of Michigan case and review of pertinent literature about histiocytic sarcoma and morphologic differential diagnosis. Conclusions.— Histiocytic sarcoma is a rare histiocytic neoplasm that can arise as a result of transdifferentiation from low-grade B-cell lymphomas, and has a wide differential diagnosis including other histiocytic/dendritic cell neoplasms, myeloid neoplasms, lymphomas, melanoma, and carcinoma. However, some key morphologic and immunohistochemical features allow for accurate classification.

BAFF Accelerates Development of Chronic Lymphocytic Leukemia in TCL1 Transgenic Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1117-1117
Author(s):  
Thomas Enzler ◽  
George F. Widhopf ◽  
Jason Lee ◽  
Weizhou Zhang ◽  
Carlo M. Croce ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mononuclear Cells ◽  
Lymphoproliferative Disease ◽  
Lymphocytic Leukemia ◽  
Brdu Incorporation

Abstract The B cell- activating factor of the tumor necrosis factor family (BAFF) is a potent regulator of normal B cells. We recently showed that BAFF supports chronic lymphocytic leukemia (CLL) B cell survival in vitro through activation of the canonical NF-kB pathway. To study the influence of BAFF on CLL development, we crossed BAFF transgenic (Tg) mice with mice that express human TCL1 under a B cell specific promoter/enhancer, and that are known to develop a lymphoproliferative disease resembling human B-CLL. BAFF/TCL1-Tg mice had a shorter mean survival than either TCL1-Tg or BAFF-Tg mice (12 mice each; BAFF/TCL1-Tg mice 9.6±3.4 months; TCL1-Tg 17.2±3.9; BAFF-Tg 17.9±3.6; B6 wildtype (wt) >19.2). To monitor for the development of CLL, mice were bled at 6-week intervals starting at 3 months of age, and blood mononuclear cells (PBMC) were analyzed via flow cytometry using fluorochrome-conjugated antibodies for murine CD5, CD3, CD45R, and human TCL1. Whereas all BAFF/TCL1-Tg mice began to develop a pathological CD5+CD3−CD45Rlo cell population at 3 months of age, such a population was not observed in TCL1-Tg mice before 6 months of age. BAFF-Tg or wt mice did not develop CD5+CD3−CD45Rlo cells over the entire observation period (26 months). CD5+CD3−CD45Rlo B cells expressed the TCL1 transgene. Over time, the CD5+CD3−CD45Rlo population increased in BAFF/TCL1-Tg mice, coming to represent >99% of the total PBMC of 9-month-old animals. To examine the capacity of these cells to propagate, 1x106 CD5+CD3−CD45Rlo B cells were transferred i.v. into either BAFF-Tg or wt mice that previously were irradiated with 600 rad. Ten days after transfer, CD5+TCL1+ cells were detected in BAFF-Tg, but not in wt recipients. Most CLL cells were located in the liver and spleen, as assessed by bioluminescent-based imaging of mice that received luciferase expressing CLL cells. Subsequent examination upon autopsy at 6 months of age, however, revealed that the majority of CLL cells populated the spleens of the recipient mice, which were massively enlarged. At this age, CLL cells also were found in wt recipient mice, although tumor burden was less than 20% of that of BAFF-Tg recipients (n=3 per group). We found that BAFF did not promote CLL cell proliferation in vitro or in vivo using assays to measure BrdU incorporation and flow cytometry to evaluate for enhanced intracellular expression of Ki67. However, BAFF induced CLL cells to express high levels of several anti-apoptotic proteins (e.g. Bcl-XL, Bcl-2, Bim, and A1/Bfl1). Also, while death-associated protein kinase 1 was repressed in CLL cells of TCL1-Tg mice, CLL cells of BAFF/TCL1-Tg mice expressed high-levels. Because of this, we examined whether treatment with BAFF-neutralizing BR3-Fc could influence the survival of CLL cells that were adoptively transferred into BAFF-Tg mice. We found that i.p. injection of 200 ug BR3-Fc into the recipient animals reduced the numbers of circulating CLL cells by nearly 20% (18.2%±5.3%; n=3) within 6 days. These data indicate that BAFF can accelerate the development of CLL cells in TCL1-Tg mice by promoting their survival. Because BAFF can similarly promote survival of human CLL cells, BAFF, and the signaling pathways it activates in neoplastic B cells, could be targeted for the development of novel therapies for this disease.

Impact of Interleukin-10 Gene Promoter Polymorphisms on Clinical Course of Chronic Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4168-4168
Author(s):  
Ewa Lech-Maranda ◽  
Tadeusz Robak ◽  
Miroslaw Majewski ◽  
Monika Lewandowska ◽  
Grazyna Nowak ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Course ◽  
Gene Promoter ◽  
B Cell Lymphoma ◽  
Interleukin 10 ◽  
Lymphocytic Leukemia ◽  
Rank Test ◽  
Control Group ◽  
Low Grade

Abstract Background: Interleukin-10 (IL-10) is an important immunoregulatory cytokine modulating the balance between cell-mediated and humoral response. It has been suggested that dysregulation and different IL-10 level resulting from single-nucleotide polymorphisms (SNPs) in IL-10 gene promoter play a role in pathogenesis of lymphoid disorders, and may increase a risk of non-Hodgkin lymphomas (NHL) development, especially diffuse large B-cell lymphoma subtype. The aim of this study was to investigate whether functionally important IL-10 promoter region SNPs IL-10: −1082A&gt;G and IL-10: − 3575T&gt;A contribute to the incidence and clinical course of B-cell chronic lymphocytic leukemia (CLL). Patients and Methods: We genotyped IL-10: −1082A&gt;G and IL-10: − 3575T&gt;A SNPs in 85 patients with B-CLL and 94 ethnically-matched healthy individuals by direct sequencing using 3130xl Genetic Analyzer (Applied Biosystems). Sequence data were based on the NCI SNP500 website http://snp500cancer.nci.nih.gov. Haplotype analysis was performed using version 2.0.2 PHASE software (http://www.stat.Washington.edu/stephens/). For the clinical features, p values were calculated using χ2 test. Survival probabilities were estimated using the Kaplan-Meier method and comparison of survival was based on log-rank testing. Results: The IL-10: −1082A&gt;G or IL-10: −3575T&gt;A allelic frequencies and distributions were consistent with Hardy-Weinberg equilibrium, and did not differ significantly between CLL patients and the control group. Four distinct haplotypes, including IL-10: −1082G, −3575A, IL-10: −1082A, −3575T, IL-10: −1082G, − 3575T, and IL-10: −1082A, −3575A, inferred in healthy controls and CLL patients. There were no significant differences in estimated frequencies of these haplotypes between CLL patients and controls. No association was found between IL-10: −1082A&gt;G or IL-10: − 3575T&gt;A allelic, genotype or haplotype distribution and clinical characteristics of CLL patients at diagnosis, including age, clinical stage according to Rai classification, surface CD38 expression, serum LDH and β2-microglobulin levels. In patients with IL-10: − 1082G allele (IL-10: −1082GG or IL-10: −1082GA genotypes) there was a trend towards higher frequency of autoimmune complications during CLL course as compared to those carrying IL-10: −1082AA genotype (13% vs 0%, p=0.04, χ2 test). The patients with IL-10: −1082G allele had significantly shorter time from diagnosis to treatment (log-rank test, p=0.02) as compared to individuals carrying IL-10: −1082AA genotype. However, neither of assessed IL-10 SNPs was associated with response to first-line treatment or freedom from progression time. With a median follow-up of surviving patients of 80 months (range 8–209), no correlation was found between IL-10: −1082A&gt;G or IL-10: −3575T&gt;A alleles, genotypes or haplotypes and overall survival in CLL patients. Conclusions: The study suggests the influence of IL-10: −1082G allele, predisposing to higher IL-10 production, on activation of immune system towards more aggressive course of CLL requiring earlier treatment intervention. Similarly to other low-grade NHL studies, our findings did not support an important role of IL-10 SNPs in CLL occurrence and survival however larger studies are needed to confirm these results.

scholarly journals The biology behind B-cell lymphoma 2 as a target in chronic lymphocytic leukemia

2016 ◽  
Vol 7 (6) ◽  
pp. 321-329 ◽  
Author(s):  
Valentín Ortíz-Maldonado ◽  
Pablo Mozas ◽  
Julio Delgado
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mitochondrial Pathway ◽  
Therapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Hallmarks Of Cancer ◽  
Lymphoid Malignancies

B-cell lymphoma 2 (BCL2)-type proteins are key regulators of the intrinsic or mitochondrial pathway for apoptosis. Since escape from apoptosis is one the main ‘hallmarks of cancer’, BCL2 inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). Multiple clinical trials have shown efficacy of these agents in patients with relapsed/refractory disease with a favorable toxicity profile. Moreover, some clinical trials indicate that combination with monoclonal antibodies and other novel agents may enhance their effect.

An unusual case of indolent B-cell lymphoma with distinct chronic lymphocytic leukemia and marginal zone differentiation according to the site of involvement

2005 ◽  
Vol 46 (9) ◽  
pp. 1369-1374 ◽  
Author(s):  
Lucile Baseggio ◽  
Sophie Gazzo ◽  
Evelyne Callet-Bauchu ◽  
Alexandra Traverse-Glehen ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Unusual Case ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia

scholarly journals Recurrent Mutations within the Nfkbie gene: A Novel Mechanism for NF-κB Deregulation in Aggressive Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 297-297
Author(s):  
Larry Mansouri ◽  
Lesley-Ann Sutton ◽  
Viktor Ljungstrom ◽  
Sina Bondza ◽  
Linda Arngarden ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mutant Allele ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
B Cell Lymphomas ◽  
Tlr Signaling ◽  
B Cell Malignancies ◽  
Recurrent Mutations ◽  
Genomic Aberrations

Abstract Dysregulated NF-κB signaling appears to be particularly important in B-cell malignancies, with recurrent mutations identified within both the canonical and non-canonical NF-κB pathways, as well as in components of the B-cell receptor (BcR) and Toll-like receptor (TLR) signaling pathways. In chronic lymphocytic leukemia (CLL), although recurrent mutations have been identified in MYD88 (TLR signaling) and BIRC3 (non-canonical NF-κB pathway), their frequency is low (<3%) and hence the extent to which genetic aberrations may contribute to constitutional NF-κB activation remains largely unknown. To gain further insight into this issue, we designed a HaloPlex gene panel (Agilent Technologies) and performed targeted next-generation sequencing (NGS) (HiSeq 2000/Illumina) of 18 NF-κB genes in a discovery cohort of 124 CLL patients, intentionally biased towards poor-prognostic patients with either unmutated IGHV genes or high-risk genomic aberrations. Using a conservative cutoff of >10% for the mutant allele, we identified mutations (n=35) within 30/124 (24%) patients in 14/18 NF-κB genes analyzed. IκB genes, which encode for cytoplasmic inhibitor proteins, accounted for 20/35 (57%) mutations, with IκBε (encoded by NFKBIE) mutated in 8 patients; notably, 3/8 cases carried an identical 4bp deletion within exon 1 of NFKBIE. Prompted by these findings, we proceeded to validate our findings in an independent CLL cohort (n=168) using the same methodology as above and primarily focusing on cases with poor-prognostic features. We identified 30 mutations within 28 CLL patients in 11/18 NF-κB genes analyzed. Strikingly, 13/30 mutations were found within IκBε, with 10/13 patients carrying the same 4bp NFKBIE deletion. Notably, investigations into whether additional cases (within both the discovery and validation cohort) may harbor mutations of low clonal abundance (<10% mutant allele), led to the detection of the NFKBIE deletion in another 18 cases. Owing to the prevalence of this 4bp deletion within the NFKBIE gene, we developed a GeneScan assay and screened an additional 312 CLL cases. Collectively, 40/604 (6.6%) CLL patients were found to carry this frame-shift deletion within the NFKBIE gene, which is in line with a recent publication reporting that 10% of Binet stage B/C patients carried this mutation (Damm et al. Cancer Discovery 2014). Remarkably, the majority of these NFKBIE mutations (16/40) were found in a subgroup of patients that expressed highly similar or stereotyped BcRs and are known to have a particularly poor outcome, denoted as subset #1. This finding thus alludes to a subset-biased acquisition and/or selection of genomic aberrations, similar to what has been reported for subset #2 and SF3B1, perhaps as a result of particular modes of BcR/antigen interaction. We utilized proximity-ligation assays to test the functional impact of the NFKBIE deletion by investigating protein-protein interactions. This analysis revealed reduced interaction between the inhibitor IκBε and the transcription factor p65 in NFKBIE-deleted CLL cells; IκBε-knock-down shRNA experiments confirmed dysregulated apoptosis/NF-κB signaling. Finally, to assess whether the NFKBIE deletion could also be present in other B-cell malignancies, we screened 372 mature B-cell lymphoma cases using NGS or the GeneScan assay and found the deletion in 7/136 (5.1%) mantle cell lymphomas, 3/66 (4.5%) diffuse large B-cell lymphomas and 3/170 (1.8%) splenic marginal zone lymphomas. Taken together, our analysis revealed that inactivating mutations within the NFKBIE gene lead to NF-κB activation in CLL and potentially several other B-cell-derived malignancies. Considering the central role of BcR stimulation in the natural history of CLL, the functional loss of IκBε may significantly contribute to sustained CLL cell survival and shape the disease evolution. This novel data strongly indicates that components of the NF-κB signaling pathway may be prime targets for future targeted therapies not only in CLL but also other mature B-cell lymphomas. Disclosures No relevant conflicts of interest to declare.

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