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Andy C Rawstron - One of the best experts on this subject based on the ideXlab platform.
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monoclonal b cell Lymphocytosis and chronic lymphocytic leukemia
The New England Journal of Medicine, 2008Co-Authors: Andy C Rawstron, Fiona Bennett, Sheila J M Oconnor, Marwan Kwok, James A L Fenton, Marieth Plummer, Ruth M De Tute, Roger G Owen, Stephen J Richards, Andrew JackAbstract:Background A diagnosis of chronic lymphocytic leukemia (CLL) requires a count of over 5000 circulating CLL-phenotype cells per cubic millimeter. Asymptomatic persons with fewer CLL-phenotype cells have monoclonal B-cell Lymphocytosis (MBL). The goal of this study was to investigate the relation between MBL and CLL. Methods We investigated 1520 subjects who were 62 to 80 years of age with a normal blood count and 2228 subjects with Lymphocytosis (>4000 lymphocytes per cubic millimeter) for the presence of MBL, using flow cytometry. Monoclonal B cells were further characterized by means of cytogenetic and molecular analyses. A representative cohort of 185 subjects with CLL-phenotype MBL and Lymphocytosis were monitored for a median of 6.7 years (range, 0.2 to 11.8). Results Monoclonal CLL-phenotype B cells were detected in 5.1% of subjects (78 of 1520) with a normal blood count and 13.9% (309 of 2228) with Lymphocytosis. CLL-phenotype MBL had a frequency of 13q14 deletion and trisomy 12 similar to that of C...
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disease progression in monoclonal b cell Lymphocytosis is independent of vh mutation status
Blood, 2006Co-Authors: Fiona L Bennett, James A L Fenton, Sheila J M Oconnor, Peter Hillmen, Andy C RawstronAbstract:A monoclonal B-cell Lymphocytosis (MBL) is detected in the peripheral blood of around 3% of otherwise healthy adults, the majority of these have a CLL immunophenotype. We have previously demonstrated that the cells in MBL are indistinguishable from good risk CLL, sharing the same immunophenotypic profile, genetic aberrations and IgVH gene usage. MBL exerts an increasing burden on haematology clinics with over 100 new patients diagnosed per annum in our regional haemato-oncology laboratory. This is largely as a result of the increased tendency to investigate patients with a mild lymphocyosis although 10,000/μL and included 3 patients who progressed to a clinical stage requiring treatment. VH gene usage was different in each of these 3 patients was with VH3-7, VH4-34 and VH5-51 identified, the levels of SHM were 5.8, 4.0 and 5.3% respectively. Follow-up data shows that a deletion of ATM was detected at progression in one of these patients. In conclusion, we show that MBL is predominantly mutated and that progression to CLL is independent of mutational status. Other prognostic markers, particularly assessment of chromosomal aberrations, may be informative but this would probably require cell selection to increase sample purity. Our data suggests that current prognostic markers are not effective at predicting outcome in MBL and periodic monitoring is required.
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monoclonal b cell Lymphocytosis mbl in cll families substantial increase in relative risk for young adults
Leukemia, 2006Co-Authors: R De Tute, Peter Hillmen, Daniel Catovsky, Martin Yuille, Richard S Houlston, Andy C RawstronAbstract:Monoclonal B-cell Lymphocytosis (MBL) in CLL families: substantial increase in relative risk for young adults
Neil P Shah - One of the best experts on this subject based on the ideXlab platform.
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Lymphocytosis after treatment with dasatinib in chronic myeloid leukemia effects on response and toxicity
Cancer, 2016Co-Authors: Charles A Schiffer, Satu Mustjoki, Jorge E Cortes, Giuseppe Saglio, Philipp Le Coutre, Kimmo Porkka, Hesham Mohamed, Andreas Hochhaus, Neil P ShahAbstract:The proliferation of clonal cytotoxic T-cells or natural killer cells has been observed after dasatinib treatment in small studies of patients with chronic myeloid leukemia (CML).The incidence of Lymphocytosis and its association with response, survival, and side effects were assessed in patients from 3 large clinical trials. Overall, 1402 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP), CML-CP refractory/intolerant to imatinib, or with CML in accelerated or myeloid-blast phase were analyzed.Lymphocytosis developed in 32% to 35% of patients and persisted for >12 months. This was not observed in the patients who received treatment with imatinib. Dasatinib-treated patients in all stages of CML who developed Lymphocytosis were more likely to achieve a complete cytogenetic response, and patients who had CML-CP with Lymphocytosis were more likely to achieve major and deep molecular responses. Progression-free and overall survival rates were significantly longer in patients with CML-CP who were refractory to or intolerant of imatinib and had Lymphocytosis. Pleural effusions developed more commonly in patients with Lymphocytosis.Overall, Lymphocytosis occurred and persisted in many dasatinib-treated patients in all phases of CML. Its presence was associated with higher response rates, significantly longer response durations, and increased overall survival, suggesting an immunomodulatory effect. Prospective studies are warranted to characterize the functional activity of these cells and to assess whether an immunologic effect against CML is detectable. Cancer 2016;122:1398-1407. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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the association of dasatinib induced Lymphocytosis with treatment outcome in patients with chronic myeloid leukemia cml
Blood, 2013Co-Authors: Jorge E Cortes, Satu Mustjoki, Giuseppe Saglio, Philipp Le Coutre, Kimmo Porkka, Hesham Mohamed, Neil P ShahAbstract:Background Clonal proliferation of T/NK cells has been noted after the treatment of CML patients with dasatinib. Previous reports have suggested that persistent expansion of clonal cytotoxic T cells or NK cells in dasatinib-treated patients may be associated with higher response rates and increased occurrence of pleural effusions. This retrospective study analyzed the incidence of Lymphocytosis and its association with response, progression-free survival (PFS) and overall survival (OS), and pleural effusion in a large sample of dasatinib-treated patients. Methods Analyses were conducted using dasatinib-treated patients from three large studies with ≥3 years of follow-up: CA180-056 (DASISION), which included 258 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP); CA180-034, which included 662 dasatinib-treated patients with CML-CP who were previously treated with imatinib; and CA180-035, which included 316 dasatinib-treated patients with CML in accelerated phase (CML-AP) and 148 dasatinib-treated patients with CML in myeloid blast phase (CML-MBP) who were previously treated with imatinib. Results Lymphocytosis, as defined by ≥2 consecutive lymphocyte counts > 3600/µl after 28 days of treatment, was present in 33% of patients (85/258) with newly diagnosed CML-CP in DASISION (median time to onset, 4.6 months) and 31% of patients (206/662) with imatinib-resistant or -intolerant CML-CP in CA180-034 (median time to onset, 3.0 months). The median on-treatment follow-up times were 36.8 months and 29.3 months for DASISION and CA180-034, respectively. For CA180-035, the median on-treatment follow-up time was 6.1 months, and Lymphocytosis developed in 35% of patients (110/316) with CML-AP and 34% of patients (51/148) with CML-MBP. Lymphocytosis persisted for >12 months in 64% of patients (54/85) with newly diagnosed CML-CP, in 52% of patients (107/206) with imatinib-resistant or -intolerant CML-CP, in 42% (46/110) with CML-AP, and in 18% (9/51) with CML-MBP. The proportion of newly diagnosed patients with complete cytogenetic response (CCyR) or major molecular response (MMR) at any time was higher among those with vs. without Lymphocytosis: 89% (76/85) vs. 80% (138/173) for confirmed CCyR and 74% (63/85) vs. 67% (116/173) for MMR. Patients who developed Lymphocytosis during treatment with second-line dasatinib were more likely to achieve CCyR, regardless of disease phase; the proportion of patients who achieved CCyR with vs. without Lymphocytosis was 62% (127/206) vs. 49% (222/456) for CML-CP, 46% (51/110) vs. 27% (55/206) for CML-AP, and 31% (16/51) vs. 14% (14/97) for CML-MBP. In landmark analyses of patients with CML-CP in DASISION who were still on first-line dasatinib at 3 or 8 months, Lymphocytosis status did not significantly affect PFS or OS. Similar results were found in the second-line studies, when considering patients with CML-CP, -AP, or -MBP who were still on study treatment (second-line dasatinib) at 3 months. Pleural effusions (all grades) developed more often in newly diagnosed patients with Lymphocytosis (28% [24/85] vs. 16% [27/173] without Lymphocytosis) and in imatinib-resistant or -intolerant patients with CML-CP (38% [79/206] vs. 30% [136/456]) or CML-AP (53% [58/110] vs. 31% [64/206]). The proportion of patients with CML-MBP developing pleural effusions was 27%, regardless of the presence of Lymphocytosis (14/51 with Lymphocytosis and 26/97 without Lymphocytosis). Conclusions Lymphocytosis develops very commonly after treatment with dasatinib and persists for >1 year in an appreciable fraction of patients. Immunophenotyping was not done, but it can be presumed that this represents a large granular lymphocyte proliferation in most patients, based on other studies. Lymphocytosis was associated with higher CCyR rates in all stages of CML, as well as higher rates of pleural effusions in CML-CP and -AP. Lymphocytosis was also associated with higher MMR rates in patients with CML-CP receiving first-line dasatinib. There appears to be no significant association, however, between Lymphocytosis and PFS or OS in this analysis. Prospective studies are warranted to more carefully characterize the functional activity of these cells and to help assess whether an immunologic effect against CML is detectable in some patients, particularly advanced phase patients with unexpected long responses to treatment with dasatinib alone. Disclosures: Schiffer: Novartis: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Teva: Consultancy; Eisai: Consultancy; Ariad: Research Funding; Pfizer: Research Funding. Cortes: Ariad: Consultancy, Grant to institution Other, Honoraria; BMS: Grant to institution, Grant to institution Other; Novartis: Grant to institution, Grant to institution Other; Pfizer: Consultancy, Grant to institution, Grant to institution Other, Honoraria; Teva: Consultancy, Grant to institution Other, Honoraria; Tragara: Membership on an entity’s Board of Directors or advisory committees; Ambit: Grants/grants pending for institution Other; Astellas: Grants/grants pending for institution, Grants/grants pending for institution Other; Incyte: Grants/grants pending for institution, Grants/grants pending for institution Other; Arog: Grants/grants pending for institution Other; Celgene: Grants/grants pending for institution, Grants/grants pending for institution Other; sanofi: Grants/grants pending for institution, Grants/grants pending for institution Other. Saglio: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria. Porkka: BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mustjoki: BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mohamed: BMS: Employment, Stock/stock options; travel/accommodations/meeting expenses unrelated to activities listed Other. Shah: BMS: Consultancy, Grants/grants pending to institution for costs related to clinical research Other; Ariad: Consultancy, Grants/grants pending to institution for costs related to clinical research, Grants/grants pending to institution for costs related to clinical research Other.
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Lymphocytosis following first line treatment for cml in chronic phase with dasatinib is associated with improved responses a comparison with imatinib
Blood, 2010Co-Authors: Charles A Schiffer, Francois Guilhot, Jorge E Cortes, Giuseppe Saglio, Philipp Le Coutre, Erkut Bahceci, David Dejardin, Neil P ShahAbstract:Abstract 358 Background: Persistent expansion of clonal cytotoxic T cells or NK cells has been described in patients with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) receiving dasatinib. These small studies have suggested a relationship between the development of T/NK Lymphocytosis with both toxicity and improved response. A recent analysis of CML patients who were resistant to or intolerant of imatinib indicated that Lymphocytosis occurs in ∼30% of patients in all stages of CML after treatment with dasatinib (Schiffer 2010 ASCO abstract #6553). In addition, Lymphocytosis was associated with improved cytogenetic response and an increased incidence of pleural effusions. The DASISION study (CA180-056) compared dasatinib with imatinib in patients with newly diagnosed, previously untreated chronic phase CML. This subanalysis of the DASISION data was undertaken to determine the safety profile, responses, and outcomes in those patients with sustained Lymphocytosis. Method: Patients enrolled in the DASISION study were retrospectively evaluated for Lymphocytosis (N=516). Lymphocytosis was defined as lymphocytes >3.6 × 10 9 /L on ≥2 occasions after 28 days of treatment. Immunophenotyping was not done as part of these studies. Rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were measured in those with and without Lymphocytosis. The median follow-up was 14.0 and 14.3 months for dasatinib and imatinib, respectively. Result: Lymphocytosis occurred more frequently and sooner in patients treated with dasatinib compared with imatinib (23.6% vs 5.4% and 3.0 months vs 4.7 months, respectively). Dasatinib-treated patients who developed Lymphocytosis had lower baseline Hasford risk scores, whereas imatinib-treated patients who developed Lymphocytosis had high Hasford risk scores. In the presence or absence of Lymphocytosis, MCyR and CCyR occurred more frequently with dasatinib as compared with imatinib. In dasatinib treated patients, Lymphocytosis was associated with a higher MCyR rate (91.8% with vs 83.3% without) and CCyR rate (83.6% with vs 75.1% without). In imatinib-treated patients, Lymphocytosis was associated with a lower MCyR rate (50.0% with vs 82.8% without) and CCyR rate (50.0% with vs 69.7% without). Patients with Lymphocytosis, compared with those without it, had higher rates of pleural effusion (any grade) on dasatinib (18.0% vs 7.6%, respectively). Only 1 patient treated with imatinib, who did not have Lymphocytosis, experienced pleural effusion. Dasatinib-treated patients with Lymphocytosis, compared with those without it, had higher rates of fatigue (16.4% vs 9.1%,); this trend was reversed for imatinib-treated patients (7.1% vs 11.9%). Patients with Lymphocytosis, compared with those without it had lower rates of myalgias and arthralgias (all grades) on both the dasatinib arm (11.5% vs 18.8%) and the imatinib arm (7.1% vs 24.2%). Conclusion: Lymphocytosis occurred much more frequently and sooner in patients treated with dasatinib than with imatinib. Lymphocytosis was associated with improved responses (MCyR and CCyR) in dasatinib-treated patients. An apparent inverse relationship was observed in imatinib-treated patients, although the number of patients with Lymphocytosis was small. It remains to be determined how Lymphocytosis, baseline Hasford risk score, and response are correlated. It is possible that some of the antileukemic effects of dasatinib are produced by an immunomodulatory mechanism. Lymphocytosis in dasatinib-treated patients was associated with an increased rate of pleural effusion and a possible decrease in myalgias and arthralgias. Longer follow-up is needed to assess whether Lymphocytosis has an effect on PFS. Disclosures: Schiffer: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Cellgenix: Consultancy; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Cortes: Bristol-Myers Squibb: Research Funding. Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. le Coutre: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Guilhot: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Bahceci: Bristol-Myers Squibb: Employment. Dejardin: Bristol-Myers Squibb: Employment. Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy.
Jianing Zheng - One of the best experts on this subject based on the ideXlab platform.
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cytogenetic aberrations and immunoglobulin vh gene mutations in clinically benign cd5 monoclonal b cell Lymphocytosis
American Journal of Clinical Pathology, 2007Co-Authors: Dominick Amato, David Oscier, Zadie Davis, Sarah Mould, Elena Kolomietz, Jianing Zheng, Chen WangAbstract:: The finding of monoclonal B-cell Lymphocytosis (MBL) raises questions on the nature of clonal cell expansion and its risk of progression. We identified and characterized 7 cases of clinically benign clonal B-cell Lymphocytosis. The clonal lymphocytes were clearly of CD5- and non-chronic lymphocytic leukemia (CLL) phenotype. All cases had mild to moderate absolute Lymphocytosis. The clonal population accounted for 95% to 99% of B cells. For a follow-up period of 4 to 16 years, clonal Lymphocytosis was persistent but virtually not progressing. Patients' conditions remained clinically stable and asymptomatic. The clonal populations had somatic hypermutations of the VH gene in 6 cases, indicating a germinal center or post-germinal center B-lymphocyte origin. Clonal cytogenetic aberrations were found in 5 of 6 cases, with 2 clones bearing isochromosome 17q that resulted in loss of p53 and 2 other clones with 7q abnormalities. By the presence of absolute Lymphocytosis, this series differs from MBL cases identified by sensitive flow cytometry in normal populations. The phenotypic profiles are distinct from that of benign CLL. We suggest these CD5-B-cell Lymphocytosis cases may represent an intermediate condition between covert clonal expansions and overt malignancy.
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cytogenetic aberrations and ig vh gene mutations of clinically benign cd5 monoclonal b cell Lymphocytosis mlus
Blood, 2006Co-Authors: Chen Wang, Dominick Amato, David Oscier, Zadie Davis, Sarah Mould, Elena Kolomietz, Jianing ZhengAbstract:Clonal expansion of lymphocytes is a hallmark of lymphoproliferative disorders. However, the finding of clonal lymphocytes may not be diagnostic of a defined lymphoid malignancy. In this study, we had an opportunity to identify and characterize a series of 7 patients with clinically benign clonal B-cell Lymphocytosis. The clonal lymphocytes were clearly of CD5 − and non-CLL phenotype. All patients were elderly and identified with a mild to moderate absolute Lymphocytosis (lymphocytes range 3.6–9.4 ×10 9 /L). The clonal population accounted for 95–99% of total B cells. For a follow-up period of 4–16 years, clonal Lymphocytosis was persistent but virtually not progressing. All patients remained clinically stable and totally asymptomatic. The clonal CD5 − B cells were shown to have somatic hypermutations of V H gene in 6 of the 7 patients, indicating a cell origin of germinal center B lymphocytes. Karyotypic aberrations were found in 5 of 6 patients examined. Two clones were found to have an isochromosome 17q, one as the sole abnormality and one as part of a complex karyotype. The loss of the short arm of chromosome 17 resulted in loss of p53, which was confirmed by the FISH analysis in both cases. The finding of p53 loss is unusual in such a benign condition. Two other clones were shown to have 7q abnormalities; one 7q31–34 deletion and one t(2;7)(p11;q22), the latter is impliated in dysregulation of the CDK6 gene. Even though deletion of 7q is strongly associated with, and t(2;7) is confined to splenic marginal zone lymphoma (SMZL), neither patients were hematologically or clinically diagnostic for SMZL. It remains to be determined whether additional cytogenetic and molecular changes may occur to lead to progression to a clinical malignancy. The patients in this study differ from those clonal CD5 − monoclonal B-cell populations identified by sensitive flow cytometry in the normal population, by the presence of absolute Lymphocytosis. In addition, the phenotypic profile is distinct from that of benign variant CLL. These clinically benign lymphocytoses may represent an intermediate between covert clonal expansion and overt malignancy.
Dominick Amato - One of the best experts on this subject based on the ideXlab platform.
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cytogenetic aberrations and immunoglobulin vh gene mutations in clinically benign cd5 monoclonal b cell Lymphocytosis
American Journal of Clinical Pathology, 2007Co-Authors: Dominick Amato, David Oscier, Zadie Davis, Sarah Mould, Elena Kolomietz, Jianing Zheng, Chen WangAbstract:: The finding of monoclonal B-cell Lymphocytosis (MBL) raises questions on the nature of clonal cell expansion and its risk of progression. We identified and characterized 7 cases of clinically benign clonal B-cell Lymphocytosis. The clonal lymphocytes were clearly of CD5- and non-chronic lymphocytic leukemia (CLL) phenotype. All cases had mild to moderate absolute Lymphocytosis. The clonal population accounted for 95% to 99% of B cells. For a follow-up period of 4 to 16 years, clonal Lymphocytosis was persistent but virtually not progressing. Patients' conditions remained clinically stable and asymptomatic. The clonal populations had somatic hypermutations of the VH gene in 6 cases, indicating a germinal center or post-germinal center B-lymphocyte origin. Clonal cytogenetic aberrations were found in 5 of 6 cases, with 2 clones bearing isochromosome 17q that resulted in loss of p53 and 2 other clones with 7q abnormalities. By the presence of absolute Lymphocytosis, this series differs from MBL cases identified by sensitive flow cytometry in normal populations. The phenotypic profiles are distinct from that of benign CLL. We suggest these CD5-B-cell Lymphocytosis cases may represent an intermediate condition between covert clonal expansions and overt malignancy.
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cytogenetic aberrations and ig vh gene mutations of clinically benign cd5 monoclonal b cell Lymphocytosis mlus
Blood, 2006Co-Authors: Chen Wang, Dominick Amato, David Oscier, Zadie Davis, Sarah Mould, Elena Kolomietz, Jianing ZhengAbstract:Clonal expansion of lymphocytes is a hallmark of lymphoproliferative disorders. However, the finding of clonal lymphocytes may not be diagnostic of a defined lymphoid malignancy. In this study, we had an opportunity to identify and characterize a series of 7 patients with clinically benign clonal B-cell Lymphocytosis. The clonal lymphocytes were clearly of CD5 − and non-CLL phenotype. All patients were elderly and identified with a mild to moderate absolute Lymphocytosis (lymphocytes range 3.6–9.4 ×10 9 /L). The clonal population accounted for 95–99% of total B cells. For a follow-up period of 4–16 years, clonal Lymphocytosis was persistent but virtually not progressing. All patients remained clinically stable and totally asymptomatic. The clonal CD5 − B cells were shown to have somatic hypermutations of V H gene in 6 of the 7 patients, indicating a cell origin of germinal center B lymphocytes. Karyotypic aberrations were found in 5 of 6 patients examined. Two clones were found to have an isochromosome 17q, one as the sole abnormality and one as part of a complex karyotype. The loss of the short arm of chromosome 17 resulted in loss of p53, which was confirmed by the FISH analysis in both cases. The finding of p53 loss is unusual in such a benign condition. Two other clones were shown to have 7q abnormalities; one 7q31–34 deletion and one t(2;7)(p11;q22), the latter is impliated in dysregulation of the CDK6 gene. Even though deletion of 7q is strongly associated with, and t(2;7) is confined to splenic marginal zone lymphoma (SMZL), neither patients were hematologically or clinically diagnostic for SMZL. It remains to be determined whether additional cytogenetic and molecular changes may occur to lead to progression to a clinical malignancy. The patients in this study differ from those clonal CD5 − monoclonal B-cell populations identified by sensitive flow cytometry in the normal population, by the presence of absolute Lymphocytosis. In addition, the phenotypic profile is distinct from that of benign variant CLL. These clinically benign lymphocytoses may represent an intermediate between covert clonal expansion and overt malignancy.
Chen Wang - One of the best experts on this subject based on the ideXlab platform.
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cytogenetic aberrations and immunoglobulin vh gene mutations in clinically benign cd5 monoclonal b cell Lymphocytosis
American Journal of Clinical Pathology, 2007Co-Authors: Dominick Amato, David Oscier, Zadie Davis, Sarah Mould, Elena Kolomietz, Jianing Zheng, Chen WangAbstract:: The finding of monoclonal B-cell Lymphocytosis (MBL) raises questions on the nature of clonal cell expansion and its risk of progression. We identified and characterized 7 cases of clinically benign clonal B-cell Lymphocytosis. The clonal lymphocytes were clearly of CD5- and non-chronic lymphocytic leukemia (CLL) phenotype. All cases had mild to moderate absolute Lymphocytosis. The clonal population accounted for 95% to 99% of B cells. For a follow-up period of 4 to 16 years, clonal Lymphocytosis was persistent but virtually not progressing. Patients' conditions remained clinically stable and asymptomatic. The clonal populations had somatic hypermutations of the VH gene in 6 cases, indicating a germinal center or post-germinal center B-lymphocyte origin. Clonal cytogenetic aberrations were found in 5 of 6 cases, with 2 clones bearing isochromosome 17q that resulted in loss of p53 and 2 other clones with 7q abnormalities. By the presence of absolute Lymphocytosis, this series differs from MBL cases identified by sensitive flow cytometry in normal populations. The phenotypic profiles are distinct from that of benign CLL. We suggest these CD5-B-cell Lymphocytosis cases may represent an intermediate condition between covert clonal expansions and overt malignancy.
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cytogenetic aberrations and ig vh gene mutations of clinically benign cd5 monoclonal b cell Lymphocytosis mlus
Blood, 2006Co-Authors: Chen Wang, Dominick Amato, David Oscier, Zadie Davis, Sarah Mould, Elena Kolomietz, Jianing ZhengAbstract:Clonal expansion of lymphocytes is a hallmark of lymphoproliferative disorders. However, the finding of clonal lymphocytes may not be diagnostic of a defined lymphoid malignancy. In this study, we had an opportunity to identify and characterize a series of 7 patients with clinically benign clonal B-cell Lymphocytosis. The clonal lymphocytes were clearly of CD5 − and non-CLL phenotype. All patients were elderly and identified with a mild to moderate absolute Lymphocytosis (lymphocytes range 3.6–9.4 ×10 9 /L). The clonal population accounted for 95–99% of total B cells. For a follow-up period of 4–16 years, clonal Lymphocytosis was persistent but virtually not progressing. All patients remained clinically stable and totally asymptomatic. The clonal CD5 − B cells were shown to have somatic hypermutations of V H gene in 6 of the 7 patients, indicating a cell origin of germinal center B lymphocytes. Karyotypic aberrations were found in 5 of 6 patients examined. Two clones were found to have an isochromosome 17q, one as the sole abnormality and one as part of a complex karyotype. The loss of the short arm of chromosome 17 resulted in loss of p53, which was confirmed by the FISH analysis in both cases. The finding of p53 loss is unusual in such a benign condition. Two other clones were shown to have 7q abnormalities; one 7q31–34 deletion and one t(2;7)(p11;q22), the latter is impliated in dysregulation of the CDK6 gene. Even though deletion of 7q is strongly associated with, and t(2;7) is confined to splenic marginal zone lymphoma (SMZL), neither patients were hematologically or clinically diagnostic for SMZL. It remains to be determined whether additional cytogenetic and molecular changes may occur to lead to progression to a clinical malignancy. The patients in this study differ from those clonal CD5 − monoclonal B-cell populations identified by sensitive flow cytometry in the normal population, by the presence of absolute Lymphocytosis. In addition, the phenotypic profile is distinct from that of benign variant CLL. These clinically benign lymphocytoses may represent an intermediate between covert clonal expansion and overt malignancy.
