Distinctive IgVH gene segments usage and mutation status in Chinese patients with chronic lymphocytic leukemia

Chen, Lijuan; Zhang, Yaping; Zheng, Wei‐Shi; Wu, Yu‐Jie; Qiao, Chun; Fan, Lei; Xu, Wei; Li, Jianyong

doi:10.1016/j.leukres.2008.02.005

Cited by 47 publications

(42 citation statements)

References 33 publications

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“…The methods for analysis of IGHV and p53 gene mutation status, ZAP-70 status, CD38 status and cytogenetic abnormalities by interphase FISH testing were as previously described. [13][14][15][16] Two percentage deviation from a germline VH sequence was used to determine the mutation status of IGHV gene. The cut-off point for ZAP-70-positive and CD38-positive in CLL cells was >20% and >30%, respectively.…”

Section: Evaluations and Follow-upmentioning

confidence: 99%

“…Patients with CLL cells that have high expression of ZAP-70 or CD38, unmutated IGHV, mutated p53, or adverse cytogenetic features, achieved OR at rates that appeared similar to those who did not have such disease characteristics. With a median followup of 12 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) months, the median OS and PFS have not been achieved.…”

Section: Cancer Therapymentioning

confidence: 99%

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Enhancing the action of rituximab by adding fresh frozen plasma for the treatment of fludarabine refractory chronic lymphocytic leukemia

Miao

Zhu

et al. 2011

Intl Journal of Cancer

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Complement deficiencies have been identified in many chronic lymphocytic leukemia (CLL) patients. Supplying fresh frozen plasma (FFP)-derived complement can enhance complement-dependent cell lysis by the rituximab. The objective of our study was to evaluate the clinical efficacy and safety of the treatment by adding FFP to rituximab in fludarabine refractory CLL patients. Twenty-two patients were treated with two units of FFP followed with rituximab, 375 mg/m 2 , as a single agent, repeated every 1-2 weeks. Patients received a median of four courses of the combined FFP and rituximab treatment (range: 2-6). Sixteen patients (72.7%) responded to treatment and seven (31.8%) achieved a complete remission. Three (13.6%) of which had no evidence of minimal residual disease after treatment. Patients with high expression of ZAP-70 or CD38, unmutated immunoglobulin heavy chain variable region, mutated p53, or adverse cytogenetic features, achieved response to treatment at rates that appeared similar to those who did not have such characteristics. With a median follow-up of 12 (4-19) months, the median overall survival and progression free survival have not been achieved. Toxicity was minimal, and the treatment was well tolerated. Our data suggest that the adding FFP to rituximab is an effective nonmyelotoxic regimen for the treatment of fludarabine refractory CLL patients.

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Section: Evaluations and Follow-upmentioning

confidence: 99%

Section: Cancer Therapymentioning

confidence: 99%

Enhancing the action of rituximab by adding fresh frozen plasma for the treatment of fludarabine refractory chronic lymphocytic leukemia

Miao

Zhu

et al. 2011

Intl Journal of Cancer

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“…38 Recent studies have shown that patients with progressive CLL do not have mutations, and have considerably short survivals and short duration of treatment after diagnosis when the cut-off values were considered as 98%. [39][40][41] In our study, in the cases with mutations, VH5-51, VH3-21 and VH6-1 genes were used, and the most frequently used was VH3-21 gene. Unlike the finding that M-CLL had a slow clinical course and a favorable prognosis in other studies, we found that the cases displaying mutation had in Binet stage B and C and required treatment early after diagnosis, which can be attributed to the fact that the rate of VH3-21 gene mutation was higher, associated with short survival.…”

Section: Prognosismentioning

confidence: 82%

“…There are only a few small studies in Japan, China and Iran. 39,40,43 This can be due to the lower incidence of CLL in Asian populations compared to Western countries. The skewness for the use of IgVH gene in CLL patients from different ethnic populations suggests that pathogens and autoantigens which have not been identified yet may play a role in the development of CLL.…”

Section: Prognosismentioning

confidence: 99%

Prognostic Significance of the IgVH Mutation Status and Immunohistochemical Analysis of ZAP70 and CD38 in Bone Marrow Biopsies in Chronic Lymphocytic Leukemia

Çetin¹,

Döger²,

Kurtgöz³

et al. 2014

Turkiye Klinikleri J Med Sci

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A AB BS ST TR RA AC CT T O Ob bj je ec ct ti iv ve e: : Chronic lymphocytic leukemia (CLL) is one of the most common leukemia type among adults in the industrialized countries. Due to the nature of CLL, it is important to recognize patients with a more rapid course of disease. The goal of our study was to study ZAP70 and CD38 antibodies along with immunglobulin heavy chain variable region (IgVH) mutation status, which have been associated with rapid progression and aggressive clinical course in CLL, and to correlate the expression of these molecules with patterns of bone marrow infiltration. M Ma at te er ri ia al l a an nd d M Me et th ho od ds s: : We included 84 bone marrow biopsy samples into the study to determine ZAP70 and CD38 status using immunohistochemistry. Expression patterns for both antibodies were then correlated with the bone marrow infiltration patterns. We also analyzed IgVH mutations in 20 patients using DNA obtained from paraffin-embedded formalin-fixed bone marrow biopsies. These findings were then correlated with immunohistochemical results. R Re es su ul lt ts s: : We identified a positive correlation between the expression patterns of ZAP70 and CD38, factors that were previously identified as poor prognostic factors (p<0.001). However, there was no correlation between these two markers and IgVH mutation status (p=1.000 and p=0.931). In addition, we showed a statistically significant positive correlation with ZAP70 immunostaining, and the necessity for an early intervention (p=0.046). ZAP70 and CD38 expressions were statistically significantly correlated with the diffuse pattern infiltration of bone marrow (p<0.001 and p<0.001, respectively). C Co on nc cl lu us si io on n: : Despite small number of our patients, the findings of our study suggested that ZAP70 and CD38 expression patterns as well as IgVH mutation status might be helpful to determine the course of the disease, and the risk of progression. Particularly ZAP70 immunopositive patients appear to have a faster disease progression, and may require earlier intervention and a closer follow up.K Ke ey y W Wo or rd ds s: : Leukemia, lymphocytic, chronic, B-cell; somatic hypermutation, immunoglobulin; ZAP70 protein, mouse; CD38 protein, mouse Ö ÖZ ZE ET T A Am ma aç ç: : Kronik lenfositik lösemi (KLL), batı toplumunda erişkinlerde en sık görülen lösemi türüdür. KLL'nin klinik seyrinden dolayı, hızlı seyredecek hastaları önceden belirlemek önemlidir. Bu çalışmada amaç, KLL'de hızlı progresyon ve agresif gidişle ilişkileri çeşitli çalışmalarla belirlenen ZAP70 ve CD38 antikorları ile İmmünglobu-lin ağır zincir değişken bölgesi (IgVH) mutasyon durumu arasındaki ilişkileri değerlendirmek, ve bunların ekspresyonunun kemik iliği infiltrasyon paternleri ile bağlantısını ortaya koymaktır. G Ge er re eç ç v ve e Y Yö ön nt te em ml le er r: : Çalışmaya retrospektif olarak alınan 84 olguya ait kemik iliği biyopsi örneklerinin parafin bloklarından elde edilen kesitlere avidin-biotin peroksidaz yöntemiyle ZAP70 ve CD38 antikorları uygulandı. Tümör ...

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“…Sequencing of IGHV was carried out as previously described. (16) A germline homology of 98% was used as the cut-off between IGHV mutated and non-mutated cases.…”

Section: Methodsmentioning

confidence: 99%

High levels of CD20 expression predict good prognosis in chronic lymphocytic leukemia

et al. 2013

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Heterogeneity of CD20 expression exists in chronic lymphocytic leukemia (CLL), therefore, we explored the prognostic significance of CD20 expression in Chinese patients with CLL. Multiparameter flow cytometry was used to detect the expression of CD20 in CD5 + CD19 + cells. In 172 CLL patients, the median expression percent of CD20 was 97.82% (range, 0-100), and the median mean fluorescence intensity (MFI) of CD20 in CLL cells was 731.45 (range, 0.00-9071.90). The percentage of CD20 + cells in the patient group with mutated variable region of immunoglobulin genes (IGHV) was higher than in the non-mutant IGHV group (mean, 92.1% vs 80.4%, P < 0.001). There were no differences in the MFI of CD20 + cells in all prognostic factor groups. Representation of the data using a receiver operating characteristic plot reflected separation between the two IGHV groups, with an area under the curve of 0.661 (95% confidence interval, 0.569-0.753). At the cut-off value of 60.3% for percentage of CD20, the sensitivity and specificity were 90.00% and 38.46%, respectively. Patients whose percentage of CD20 antigen was above 60.3% had longer treatment-free survival (hazard ratio, 0.452; 95% confidence interval, 0.232-0.884, P = 0.020). Percentage and MFI of CD20 were the variables not associated with treatment-free survival by multivariate Cox regression analysis (P < 0.05). High level of CD20 expression in de novo CLL appears to be associated with a good prognosis. (Cancer Sci 2013; 104: 996-1001) C hronic lymphocytic leukemia (CLL), the most frequently occurring leukemia in adults in North America and Europe, is a heterogeneous disease with variable clinical presentation and evolution.(1) In recent years, the significant increase in understanding the pathogenesis of CLL has been translated into a biologically oriented assessment of prognosis. In particular, there has been major progress in the identification of both molecular and cellular markers that may predict disease progression.(2,3) Two major molecular subtypes can be distinguished, characterized by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes (IGHV) that features in CLL. However, IGHV gene sequencing remains a demanding technique, so many studies have focused on the identification of alternative markers with similar prognostic significance, and whose expression is easier to investigate, such as CD38 and zeta-associated protein-70 (ZAP-70). (4,5) A great deal of renewed interest in CD20 membrane protein has emerged since 1997, when the chimeric anti-CD20 mAb rituximab was approved for use in relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma. Rituximab is commonly incorporated into CD20-positive B-cell lymphoma therapy, including CLL, to improve response and prognosis. The CD20 expression level might correlate with treatment outcome in CLL patients. Tam et al. (6) showed that CLL patients with trisomy 12 showed strong expression of CD20 and had a high rate of response to rituximab-based therapy. H...

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Distinctive IgVH gene segments usage and mutation status in Chinese patients with chronic lymphocytic leukemia

Cited by 47 publications

References 33 publications

Enhancing the action of rituximab by adding fresh frozen plasma for the treatment of fludarabine refractory chronic lymphocytic leukemia

Enhancing the action of rituximab by adding fresh frozen plasma for the treatment of fludarabine refractory chronic lymphocytic leukemia

Prognostic Significance of the IgVH Mutation Status and Immunohistochemical Analysis of ZAP70 and CD38 in Bone Marrow Biopsies in Chronic Lymphocytic Leukemia

High levels of CD20 expression predict good prognosis in chronic lymphocytic leukemia

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