Research on the Characteristics of IGHV Gene In Chronic Lymphocytic Leukemia of China.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4609-4609
Author(s):  
Chun Qiao ◽  
Kourong Miao ◽  
Jianyong Li
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Conflicts Of Interest ◽  
Gene Families ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Ighv Gene ◽  
Significant Difference

Abstract Abstract 4609 Objective The usage, mutation status and prognostic impact of immunoglobulin heavy chain variable (IGHV) gene in Chinese patients with chronic lymphocytic leukemia (CLL) is unclear. We set out to define the characteristics of IGHV gene and its relevance to clinical and biological parameter in our patients. Methods IGHV gene mutations were detected by multiplex PCR in 202 Chinese CLL patients and the purified PCR amplification products were sequenced. IGHV somatic hypermutation status and gene usage were analyzed by IMGT/V-QUEST software. The association analysis between IGHV somatic mutation status and the clinical and biological features, including Binet staging, immunophenotype, cytogenetic aberrant, were also emphasized in this study. Results The results showed that 129 patients had mutated (M) IGHV, and the remaining 73 patients had unmutated (UM) IGHV according to the cutoff value of accordance rate 98%. The most frequent VH gene family was found to be VH3 (47.5%), followed by VH4 (34.7%), VH1 (11.4%), VH2 (2.5%), VH5(1.5%), VH7(1.5%) and VH6(0.9%) gene families, which was similar to other Asian populations. The overall survival (OS) time of UM IGHV group was significant shorter than M IGHV group (P=0.025). Significance was found in the expression of CD38 and ZAP-70 between patients with and without IGHV mutations (P<0.0001 and P=0.015, respectively). Binet staging was significantly different with IGHV mutation status (P<0.001). “Unmutated” sequences had significantly longer heavy chain complementarity-determining region 3 (HCDR3). Seven of these patients used VH1-69, which was similar to other Asia countries, but in striking contrast to those in Western countries, where VH1-69 was one of the most frequently used genes. FISH was performed in 117 cases, del(11q22) was considered as high risk factors, and 10(10/42, 23.8%) cases with UM IGHV gene. On the other hand, there were 7(7/75, 9.3%) cases with M IGHV gene (P=0.033). No significance was found in del(17p),del(13q),del(6q),add(12),IGH translocation between IGHV mutation and unmuatioan patients. A total of five stereotyped BCR were identified, IGHV3-21/IGHD3-9/IGHJ6, IGHV4-34/IGHD2-15/IGHJ6, IGHV1-3/IGHD6-19/IGHJ4, IGHV4-59/IGHD3-22/IGHJ6 and IGHV4-39/IGHD6-13/IGHJ5. Conclusions The usage of IGHV gene families indicates significant difference in Chinese CLL patients compared with Western patients, suggesting involvement of ethnic and/or environmental factors in CLL disease initiation. In the development course of CLL, BCR play an important role in the immunological recognition and selection. There are intimate relationships between mutation status of IGHV gene and prognosis. The usage of IGHV provides enlightment for the occurrence mechanism of CLL. Disclosures: No relevant conflicts of interest to declare.

Distinctive IgVH Gene Segments Usage and Mutation Status in Chinese Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4708-4708
Author(s):  
Lijuan Chen ◽  
Yaping Zhang ◽  
Wenjuuan Zheng ◽  
Jianyong Li ◽  
Changgeng Ruan
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Family ◽  
Gene Families ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Chain Gene ◽  
Mutation Status ◽  
Significant Difference ◽  
Variable Heavy ◽  
Vh Gene

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the relentless accumulation of monoclonal B cells with the appearance of small mature lymphocytes and a characteristic CD5 and CD19 co-expression immunophenotype. The incidence of CLL in Asian countries is lower than that in the Western ones, where CLL is the most common leukemia. To evaluate the frequency and mutation status of immunoglobulin (Ig) variable heavy chain gene (IgVH) expression in Chinese patients with CLL. We investigated IgVH gene segments usage and mutation status by multiplex RT-PCR in 52 CLL patients, and analyzed the relationship between IgVH somatic mutation status and the expression of CD38, ZAP-70 and CLLU1. 38 patients had mutated IgVH, and 14 had unmutated IgVH. The most frequently expressed VH gene family was found to be VH3 (46.2%) followed by VH4 (40.4%), VH1 (5.8%), VH2 (5.8%) and VH7 (1.9%), with no expression of VH5 and VH6 gene families. VH1-69 and VH3-21 which commonly overused in Western CLL weren’t detected in our cohort. The frequency of IgVH gene families indicates significant difference in Chinese CLL patients compared with Western patients, suggesting involvement of ethnic and/or environmental factors in CLL disease initiation. IgVH gene mutation status was significantly associated with the expression of CD38 and CLLU1. The expression of them may be simple and reliable surrogates for the identification of IgVH mutations. VH gene family usage and mutation status VH family n Mutated VH gene Unmutated VH gene VH1 3 3 0 VH2 3 2 1 VH3 24 19 5 VH4 21 16 5 VH5 0 0 0 VH6 0 0 0 VH7 1 0 1

Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2246-2252 ◽  
Author(s):  
Göran Roos ◽  
Alexander Kröber ◽  
Pawel Grabowski ◽  
Dirk Kienle ◽  
Andreas Bühler ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Telomere Length ◽  
Inverse Correlation ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Ighv Gene ◽  
Genetic Complexity ◽  
Genomic Aberrations

Telomere length is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and clinical course in B-cell chronic lymphocytic leukemia (B-CLL). In a B-CLL cohort of 152 patients, we analyzed telomere length, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression to study the prognostic impact and associations among these factors. An inverse correlation existed between telomere length and IGHV homology (P < .001), CD38 (P < .001), and ZAP-70 expression (P = .01). Patients with telomere lengths below median (ie, “short telomeres”) and above median (ie, “long telomeres”) had similar incidences of genomic aberrations (74% vs 68%), 13q− (57% vs 49%), and +12q (5% vs 12%). In contrast, 13q− as a single aberration was more frequent in patients with long telomeres (51% vs 21%; P = .006), whereas 11q− (27% vs 9%; P = .014), 17p− (17% vs 0%; P < .001), and 2 or more genomic aberrations (39% vs 8%; P < .001) were more frequent in patients with short telomeres. Compared with patients with long telomeres, treatment-free survival (TFS) and overall survival (OS) was significantly shorter (P < .001 and P = .015, respectively) in the group with short telomeres, and telomere length was an independent prognostic indicator for TFS. These observations have biological and prognostic implications in B-CLL.

Distinct IGHV Repertoire Features In Chinese Chronic Lymphocytic Leukemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5279-5279
Author(s):  
Yi Xia ◽  
Wei Xu ◽  
Lei Fan ◽  
Chun Qiao ◽  
Li Wang ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Western World ◽  
Antigenic Difference ◽  
Mutational Status ◽  
Ighv Gene ◽  
Variable Heavy ◽  
Gene Usage

Abstract Mounting evidence indicates that immunoglobulin variable heavy-chain (IGHV) repertoire and mutational status in chronic lymphocytic leukemia (CLL) patients are prognostically relevant. However, rare data is available in Chinese CLL population. Our group investigated 270 Chinese CLL patients for their IGHV sequences and discovered significant differences between Chinese and European CLL patients. First of all, 169 (62.6%) patients in our group got mutated IGHV and 101 (37.4%) were unmutated, rendering a considerable higher percentage of mutated subgroup compared with European patients (55%) (Figure 1). While IGVH3 is still the most frequently used IGVH gene in Chinese CLL patients (135/270, 50%), discrepancy occurs in the usage of IGVH1 gene, which only presents in 13.7% (37/274) patients in our cohort whereas 23.79% for European (Figure 2). Regarding IGHV subgroups, IGHV3-23 and IGHV4-34 are more often used in Chinese CLL patients (10.7% and 10.4%, respectively). Remarkably, IGHV1-69, the most prevalent IGHV subgroup in European CLL patients (12.81%), only accounts for 5.2% (14/270) Chinese cases.Figure 1Higher percentage of mutated IGHV in Chinese CLL patientsFigure 1. Higher percentage of mutated IGHV in Chinese CLL patientsFigure 2Different IGHV gene usage between Chinese and European CLL patients, with IGVH1 gene accounts for 23.79% of European CLL patients and for only 13.70% of Chinese CLL patients.Figure 2. Different IGHV gene usage between Chinese and European CLL patients, with IGVH1 gene accounts for 23.79% of European CLL patients and for only 13.70% of Chinese CLL patients.Figure 3IGVH1-69 is the most prevalent IGHV gene among European CLL patients(12.81%), however, only 5.20% Chinese CLL patients use VH1-69. IGVH4-39 and IGVH4-59 are more often used in Chinese CLL patients (7.80% vs 3.73% and 5.60% vs 2.75%, respectively).Figure 3. IGVH1-69 is the most prevalent IGHV gene among European CLL patients(12.81%), however, only 5.20% Chinese CLL patients use VH1-69. IGVH4-39 and IGVH4-59 are more often used in Chinese CLL patients (7.80% vs 3.73% and 5.60% vs 2.75%, respectively). We further studied the distribution of stereotyped BCR in our cohort. Thirty-eight patients (14.07%) with stereotyped BCR that belonged to 21 subsets were identified, with 1 to 7 sequences contained each. Among them, subset 1 and subset 8 are the most common types with 6 and 7 cases respectively. Three new subsets were discovered (Table 1). Notably, only 1 case belonged to subset 2, the subset with largest group size in western world. Hence, we conclude that Chinese CLL patients show unique IGHV repertoire features compared to patients from western countries. While the mechanism within remains unknown, the discrepancy might due to antigenic difference in geographically remote areas.Table 1Three new subsets of BCR stereotypy in Chinese CLL patientsNO.IGHVIGHDIGHJM/UMIdentityHCDR3 AA sequenceLengthNovel 1NJ-15IGHV4-59*083-22*016*03UM100,00%ARGNYYDSSGYYYVGYYYYYMDV23NJ-31IGHV4-59*013-22*016*03UM99,65%ARGDYYDSSGYYYVGYYYYYMDV23Novel 2NJ-186IGHV3-23*013-22*014*02M96.60%AKGYRDNYDGDQSSVFDS18NJ-23IGHV3-23*012-21*014*02M96,53%AKGYRDNYDGDQSSVFDS18Novel 3NJ-36IGHV4-34*016-6*015*02M93,33%AKLMAGRPNWFDP13NJ-123IGHV4-34*016-6*015*02M91,67%AKLMAGRPNWFDP13 Disclosures: No relevant conflicts of interest to declare.

The Repertoire of Heavy Chain Immunoglobulin Genes in B-Cell Chronic Lymphocytic Leukemia in Russia and Belarus

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4579-4579
Author(s):  
Bella Biderman ◽  
Eugene Nikitin ◽  
Tatiana Sergienko ◽  
Alexandra Bakun ◽  
Irina Taras ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Conflicts Of Interest ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Antigen Receptors ◽  
Mutation Status ◽  
The Uk ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abstract 4579 Introduction. Mutation status of the heavy chain variable region genes is known as an important factor in long-term prognosis in B-cell chronic lymphocytic leukemia (B-CLL). A more detailed study of the gene sequences of immunoglobulin heavy chain (IgVH) led to the discovery of stereotyped antigen receptors (SAR) - receptors that have the same set of VH-, D- and JH- genes used. SARs have been found almost in a quarter of all B-CLL cases. Since this study there have been no data available concerning VH-gene usage and SARs in Russian and Belarusian B-CLL patients. Patients and methods. DNA or cDNA was amplified in 6 separated reactions using primers specific for VH-families, and a consensus JH primer [Campbell et al. 1992] or primer sets recommended by the BIOMED-2 [van Dongen et al. 2003]. PCR products were sequenced using family-specific primers and Big Dye Terminator v3.1 kit (Applied Biosystems). Sequences were analyzed with IgBlast (http://www.ncbi.nlm.nih.gov/igblast). 98% homology cutoff was used to discriminate between mutated and unmutated cases. Results. Total of 547 patients with B-CLL where analyzed; 192 patients with mutated IgVH-genes (35%) and 355 patients with unmutated ones (65%). We have identified 65 stereotyped receptors (SARs) in 198 of 491 Russian patients (40%). Twenty one SARs (confirmed) appeared in more than 3 patients (110 out of 198, 55%), 44 SARs (potential) found in 2 patients (88 out of 198 cases, 45%). The vast majority of confirmed SARs were found in the subgroup of patients without mutations in IgVH genes (95%). Among the potential SARs 15 pairs were from patients with and without mutations (34%), seven pairs from patients with mutations (16%) and 22 pairs from patients without IgVH mutations (50%). The most common SARs were: VH1–69/D3-3/JH6 (24 patients, 5%); VH1–69/D3–16/JH3 (8 patients); VH1–69/D2-2/JH6 (8 patients); VH1–69/D3–10/JH6 (6 patients). Among 56 Belarusian patients we have identified only 4 SARs, one confirmed SAR (4 cases) and 3 potential ones. Confirmed (VH1–69/D3-3/JH6) and one potential (VH1–69/D3–16/JH3) were also found in Russia while other two potential (VH1–69/D2–15/JH6 and VH2–5/D2-2/JH6) were not observed in Russia. Discussion. In Russia and Belarus, VH1–69 gene is found in 20% of all cases of B-CLL, and almost always (95%) in unmutated cases. This finding well correlates to the data obtained by [Kryachok et al. 2012] concerning high VH1–69 usage in Ukrainian patients. In other European countries, this gene is less common: about 14% of cases in Sweden, France and Spain, 11% in the UK and about 6–7% in Greece and Italy [Ghia et al. 2005; Tobin et al. 2004; Duke et al. 2003]. In all these countries, this gene is also prevalent in patients with unmutated VH-genes. Nordic countries are characterized by very frequent use of gene VH3–21 - 9%, while in Russia and the countries of central and southern Europe, it occurs at least 3 times less (about 3%), and was not found in Belarusian samples. This gene is also associated with poor prognosis of B-CLL, regardless of mutation status of IgVH genes. Interestingly, in Asia (China, Japan, Iraq) VH1–69 and VH3–21 genes are almost not observed [Nakamura et al. 1999; Farsangi et al. 2007; Lijuan Chen et al. 2008]. Narrowing of the repertoire of IgVH genes - specific feature of B-CLL indicatites that influence of antigen (at least in some cases) occurs during the development of the disease. Also, factors of genetic background as well as geographical environment could be important. It is possible that future treatment decisions will be based not only on the IgVH mutation status, but also on the characteristics of certain antigen receptor. Disclosures: No relevant conflicts of interest to declare.

Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1524-1533 ◽  
Author(s):  
Fiona Murray ◽  
Nikos Darzentas ◽  
Anastasia Hadzidimitriou ◽  
Gerard Tobin ◽  
Myriam Boudjogra ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Distinctive Features ◽  
Ighv Gene ◽  
Gene Usage

Abstract Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, “stereotyped” amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).

scholarly journals V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 100 (4) ◽  
pp. 1410-1416 ◽  
Author(s):  
Alexander Kröber ◽  
Till Seiler ◽  
Axel Benner ◽  
Lars Bullinger ◽  
Elsbeth Brückle ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Expression Level ◽  
Chain Gene ◽  
P Value ◽  
Prognostic Impact ◽  
Survival Times ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Genomic Aberrations

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (VH) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed VH mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q−, +8q, 11q−, +12q, 13q−, t(14q), 17p−) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of VH mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (Pcor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% VH homology (95% confidence interval [CI], 96%-98% homology,Pcor &lt;.001) and at 7% CD38 expression (95% CI, 20%-71% expression, Pcor = .02). In univariate analyses, unmutated VH genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in theVH unmutated and VHmutated subgroups. High-risk genomic aberrations such as 17p− and 11q− occurred almost exclusively in the VHunmutated subgroup, whereas favorable aberrations such as 13q− and 13q− as single abnormalities were overrepresented in theVH mutated subgroup. In multivariate analysis, unmutated VH, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of VH mutation status and genomic aberrations to predict outcome in CLL.

scholarly journals Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin

Blood ◽  
2010 ◽  
Vol 115 (19) ◽  
pp. 3907-3915 ◽  
Author(s):  
Charles C. Chu ◽  
Rosa Catera ◽  
Lu Zhang ◽  
Sebastien Didier ◽  
Briana M. Agagnina ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Lymphocytic Leukemia ◽  
Apoptotic Cells ◽  
Nonmuscle Myosin ◽  
Cell Of Origin ◽  
Poor Clinical Outcome ◽  
Mutation Status ◽  
Poor Patient Survival

Abstract Many B-cell chronic lymphocytic leukemia (CLL) monoclonal antibodies (mAbs) can be grouped into subsets based on nearly identical stereotyped sequences. Subset 6 CLL mAbs recognize nonmuscle myosin heavy chain IIA (MYHIIA). Herein, we report that during apoptosis, MYHIIA becomes exposed on the cell surface of a subgroup of apoptotic cells, allowing subset 6 CLL mAbs to bind with it. Because other non–subset 6 CLL mAbs interact with apoptotic cells, 26 CLL mAbs, including 24 not belonging to subset 6, were tested for reactivity with MYHIIA-exposed apoptotic cells (MEACs). More than 60% of CLL mAbs bound MEACs well; most of these mAbs expressed unmutated IGHV (15 of 16) and belonged to a stereotyped subset (14 of 16). Binding to MEACs inversely correlated with the degree of IGHV mutation. Interestingly, high binding to MEACs significantly correlated with poor patient survival, suggesting that the basis of IGHV mutation status as a CLL prognostic factor reflects antigen binding. Finally, natural antibodies from human serum also reacted with MEACs. Taken together, our data indicate that a large proportion of CLL clones emerge from natural antibody-producing cells expressing immunoglobulins that recognize MEACs, and that this reactivity is associated with poor clinical outcome.

Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia

2006 ◽  
Vol 24 (6) ◽  
pp. 969-975 ◽  
Author(s):  
Alexander Kröber ◽  
Johannes Bloehdorn ◽  
Sebastian Hafner ◽  
Andreas Bühler ◽  
Till Seiler ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Variable Region ◽  
Multivariate Regression Analysis ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Characteristic Modes ◽  
Genomic Aberrations ◽  
Vh Gene

Purpose Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. Patients and Methods We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. Results ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. Conclusion There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

Comparative Efficacy of First-Line Chemotherapy-Free Combinations in Chronic Lymphocytic Leukemia (CLL): A Network Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Philip A Haddad ◽  
Nowell Ganey ◽  
Kevin M. Gallagher
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
English Language ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Meta Analysis ◽  
The Elderly ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Significant Difference ◽  
Anti Cd20

Introduction: Chronic Lymphocytic Leukemia (CLL) is an incurable B-cell malignancy which disproportionately affects the elderly. Although first-line chemoimmunotherapy (CIT) improved CLL clinical outcomes, recent randomized trials revealed superior outcomes with novel chemotherapy-free combinations (CFC) incorporating anti-CD20 monoclonal antibodies and inhibitors of BTK or Bcl-2. So far, these CFC have not been compared head-to-head. We conducted this network meta-analysis to evaluate their relative efficacy to each other. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of CLL; trials that explored the efficacy of first-line CFC with Obinutuzumab (O), Rituximab (R), Ibrutinib (IB), Acalabrutinib (ACAL), Venetoclax (VEN) compared to standard CIT that included Chlorambucil (CHLOR) with either R or O, Bendamustine+Rituximab, or Fludarabine+ Cyclophosphamide+R; and phase 3 randomized studies reporting responses, progression, death, and adverse (AE) events. A frequentists network meta-analysis was conducted using netmeta package and random-effects model. Results: Five studies comprising a total of 2,272 participants were included. When O-based CFC data was analyzed, only ACAL-O had a significant lower relative risk (RR) of progression and death (P&D). There were no significant differences with respect to overall response rates (ORR), complete remission (CR), minimal residual disease (MRD), or grade &gt;3 adverse events (Grd3+) among O-based CFC. When R-based CFC data was analyzed, IB and IB-R were not different with respect to RR of P&D, ORR, CR, MRD, or Grd3+. When the data was analyzed as CFC versus combined CIT, only ACAL-O was found to be significantly superior to other O- and R-based CFC with respect to RR of P&D. ORR and Grad3+ rates of O- and R-based CFC were not significantly different. While ACAL-O, IB-O, and VEN-O had superior CR and MRD rates compared to other CFC, there were no significant differences among each other. Conclusions: This network meta-analysis is the first to compare and rank first-line CFC therapies in CLL. It indicates that ACAL-O has a superior profile having the lowest RR of P&D without significant difference in Grd3+ among CFC. Disclosures No relevant conflicts of interest to declare.

Strikingly Homologous Immunoglobulin Gene Rearrangements and Poor Outcome in VH3-21-Utilizing Chronic Lymphocytic Leukemia Independent of Geographical Origin and Mutational Status.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 175-175
Author(s):  
Fiona Murray ◽  
Mia Thorselius ◽  
Alexander Krober ◽  
Ulf Thunberg ◽  
Gerard Tobin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Light Chain ◽  
Geographical Origin ◽  
Lymphocytic Leukemia ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Mutation Status ◽  
Mutational Status ◽  
Significant Difference ◽  
Vh Genes

Abstract We recently reported that Swedish VH3-21-utilizing chronic lymphocytic leukemia (CLL) patients showed restricted immunoglobulin gene features and poor prognosis despite VH mutation status. To investigate whether VH3-21+ CLLs have similar characteristics in different parts of the world, we analyzed the VH and VL gene rearrangements in 90 patients from Sweden, Germany, Italy, USA, Finland and Australia and correlated these data with survival. Sixty-three percent of cases exhibited mutated VH genes and 37% had unmutated VH genes. Fifty patients (56%) displayed a short and homologous heavy-chain CDR3, many of these with the amino acid motif, DANGMDV. Also, a highly biased Vλ2-14 usage was evident in 73% of patients with a restricted light-chain CDR3, QVWDS(S/G)SDHPWV. Combined restricted heavy- and light-chain CDR3s were found in patients from all included countries. Although VH3-21+ CLLs have a remarkably predominant λ-expression, analyses of kappa deleting element showed a conserved rearrangement order of the light-chain loci. The overall survival was poor in the VH3-21+ cohort (median survival 88 months) with no significant difference in relation to mutation status or homologous/non-homologous CDR3. In summary, highly restricted B-cell receptors and worse outcome characterize VH3-21+ CLLs independent of geographical origin and mutation status. VH3-21 usage should now be included in prognostic stratification of CLL when assessing mutation status.

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