scholarly journals Clinical Impact of Stereotyped Antigen Receptors in Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3280-3280
Author(s):  
Panagiotis Baliakas ◽  
Anastasia Hadzidimitriou ◽  
Lesley-Ann Sutton ◽  
Evangelia Minga ◽  
Andreas Agathangelidis ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clonal Evolution ◽  
Molecular Classification ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Molecular Diagnostic ◽  
Median Percentage ◽  
Molecular Features ◽  
Mutational Status ◽  
Ighv Gene

Abstract In chronic lymphocytic leukemia (CLL), the molecular features of the clonotypic B-cell receptor immunoglobulins (BcR IG) are set from the birth of the clone and in contrast to genetic aberrations, remain stable overtime, rendering the BcR IG a reference biomarker that is usually not significantly affected by clonal evolution. Approximately 30% of CLL cases carry quasi-identical BcR IGs and can be assigned to distinct stereotyped subsets. While preliminary evidence alludes to BcR IG stereotypy being relevant from a clinical viewpoint, this aspect has never been explored systematically or in a cohort of adequate size to enable meaningful conclusions. In order to assess the clinical implications of BcR IG stereotypy, we evaluated clinicobiological data from 8593 CLL patients, particularly focusing on 14 major stereotyped subsets of cases with unmutated (U-CLL) or mutated IGHV genes (M-CLL). The largest subset was #2 (n=254, 3%), within which 156 and 98 cases were M-CLL and U-CLL, respectively, followed by U-CLL subsets #1 (n=173, 2%) and #7 (n=123, 1.4%). Amongst M-CLL, the largest subsets were #4 (n=94, 1.1%) and #148 (n=92, 1%). Stereotyped subsets, even of the same mutational category i.e. U-CLL or M-CLL, exhibited significant clinicobiological differences regarding: age at diagnosis (median age ranging from 53-68 years, p<0.001); gender distribution (male/female ratios ranging from 0.85-4.4, p<0.001); the frequency of advanced stage disease (Binet C) at diagnosis (ranging from 9-21%, p<0.001); CD38 positivity (median percentage of positive cells ranging from 2-73%, p<0.05). Moving to cytogenetic findings, we detected subset-biased spectra of FISH-detected aberrations which can be summarized as follows: (i) isolated del(13q) varied from 10% in subset #8 (U-CLL), to 29% in subsets #59 (U-CLL) and #16 (M-CLL), and >75% in M-CLL subsets #77 and #148 (p<0.001); (ii) trisomy 12 was absent in subsets #31 (U-CLL) and #77 (M-CLL), in 20% of subset #201 (M-CLL) and, 60% in subset #8 (U-CLL) (p<0.001); (iii) del(11q) ranged from 69% in subset #31 (U-CLL) to 12% in subset #8 (U-CLL) and 0% in M-CLL subsets #16 and #201 (p<0.001); (iv) del(17p): absent from all M-CLL subsets except #148 (7.5%); absent from U-CLL subsets #5 and #59, and present in 19% and 17% of stereotyped subset #8 and #6 cases, respectively (p<0.05). We considered subset #2 separately since it included both M-CLL and U-CLL and identified a distinctive clinicobiological profile characterized by a constellation of features, including high incidence of Binet stage C disease (21%), CD38 positivity (41%) and certain cytogenetic abnormalities i.e. del(13q) (56%) and del(11q) (23%) and, in contrast, low frequency of del(17p) (4.5%). Notably, no differences were found between U-CLL versus M-CLL subset #2 cases regarding the incidence of these parameters. Survival analysis for time-to-first-treatment (TTFT) revealed that each stereotyped subset exhibited a distinct clinical course, different from that of other subsets even with similar IGHV gene mutational status and/or expressing the same IGHV gene. Interestingly, subsets #1 and #2 demonstrated a similar TTFT to that of del(17p) positive cases, while within subset #2 the clinical outcome was independent of IGHV mutational status. By integrating BcR IG stereotypy into the Döhner cytogenetic prognostication model, we found that subsets #1, #2 and #4, collectively accounting for ~7% of our series, and representing both U-CLL and M-CLL, constituted distinct clinical entities, with the latter exhibiting a particularly indolent disease even when compared to isolated del(13q) cases or cases with no cytogenetic aberrations. Finally, in multivariate analysis for TTFT, assignment to subset #2 emerged as a new independent unfavorable factor (p=0.002); furthermore, when restricting the analysis to Binet A cases, subset #2 exhibited the second highest hazard ratio after U-CLL. In conclusion, the molecular classification of CLL based on BcR IG stereotypy refines prognostication beyond IG mutational status and improves the Döhner hierarchical model. Hence, we suggest that a compartmentalized approach focusing on and comparing different subsets sheds light on CLL clinical behavior and biology and that BcR IG stereotypy represents a companion molecular diagnostic for personalized medicine in CLL. Disclosures Montillo: Janssen: Honoraria.

Immune Thrombocytopenia in Patients with Chronic Lymphocytic Leukemia Is Associated with Stereotyped B-Cell Receptors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2847-2847
Author(s):  
Francesco Maura ◽  
Carlo Visco ◽  
Elisabetta Novella ◽  
Ilaria Giaretta ◽  
Giacomo Tuana ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Immune Thrombocytopenia ◽  
Initial Level ◽  
Conflicts Of Interest ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Mutational Status ◽  
Ighv Gene ◽  
Cytotoxic Treatment

Abstract Abstract 2847 Chronic lymphocytic leukemia (CLL) is frequently complicated by autoimmune disorders, primarily autoimmune hemolytic anemia and immune thrombocytopenia (ITP). In order to investigate biological features related to ITP development, we retrospectively analyzed 463 CLL patients characterized for immunoglobulin heavy-chain variable (IGHV) gene mutational status, cytogenetic features and B-cell receptor (BCR) configuration (HCDR3) at the time of diagnosis. Thirty-six patients (7.7%) had developed ITP, according to our previously reported criteria (Visco et al, Blood 2008): i) an otherwise unexplained rapid (< 2 weeks) and severe fall (at least half of the initial level and below 100*109/L) of the platelet count; ii) normal or augmented number of megakaryocytes in the bone marrow; iii) no or limited (not palpable) splenomegaly and iv) no cytotoxic treatment in the last month. Stereotyped BCR configuration was defined by means of pair-wise alignment with known stereotyped sequences available from different public databases (Stamatopoulos et al, Blood 2007; Bomben et al, Br J Hematol 2009; Murray et al, Blood 2008), specifically excluding pairs of sequences whose length differed more than 3 amino acids and sharing more than 60% identity on alignments showing less than 3 gaps, as described by others and by our group (Stamatopoulos et al, Blood 2007; Maura et al, Plos One, in press). Our results indicated that the occurrence of ITP was strongly associated with unmutated (UM) IGHV (p<0.0001), unfavorable cytogenetic lesions (P =0.005), and interestingly, the occurrence of stereotyped HCDR3 (P =0.006). Additionally, the UM IGHV mutational status, unfavorable cytogenetic lesions, or stereotyped BCR were significantly associated with shorter time to ITP development (P <0.0001, P =0.02 and P =0.005 respectively) compared to other patients. As regards to the most represented HCDR3 subsets, we observed that subsets #1 (IGHV1-5-7/IGHD6-19/IGHJ4; 16/16 UM) and #7 (IGHV1-69 or IGHV3-30/IGHD3-3/IGHJ6; 13/13 UM) were significantly associated with ITP development (P =0.003 and P =0.001, respectively). Moreover, restricting the analysis to UM patients, subset #7 retained a significant association with the occurrence of ITP (P =0.02). Time to ITP development was also significantly shorter in subsets #1 and #7 patients than in all others patients (P =0.0076 and P <0.0001, respectively). Overall, our data suggest that patients with CLL and peculiar BCR conformations are at higher risk of developing secondary ITP, and that stereotyped BCR may be involved in the pathogenesis of this complication. Disclosures: No relevant conflicts of interest to declare.

Usage of IGHV4-39 with Stereotypic B Cell Receptor Is An Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 778-778
Author(s):  
Davide Rossi ◽  
Valeria Spina ◽  
Michaela Cerri ◽  
Clara Deambrogi ◽  
Lorenzo De Paoli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Control Analysis ◽  
Ighv Gene ◽  
Gene Usage

Abstract Richter’s syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma, mainly occurring as diffuse large B-cell lymphoma (DLBCL). The biology of CLL transformation to RS is poorly understood and knowledge on risk factors of RS development is scant. We tested whether IGHV gene usage and stereotypic B cell receptor (BCR) at CLL diagnosis have an impact on RS transformation. The first step of the study consisted of a case-control analysis comparing IGHV gene usage and prevalence of stereotypic HCDR3 in RS (n=69; all DLBCL) versus a control group (n=715) of CLL that had not transformed to RS. The second step consisted of an actuarial assessment of the impact of IGHV gene usage and stereotypic HCDR3 at CLL diagnosis, on the risk of subsequent transformation to RS in a cohort of 754 CLL, of which 39 had transformed to RS. Comparison of IGHV usage in unmutated RS versus unmutated control CLL documented that IGHV4-39 was the sole gene preferentially utilized (6/48, 12.5% vs 5/277, 1.8%, respectively, p=.002) by RS. Prevalence of stereotypic HCDR3 was significantly higher in RS compared to non-transformed CLL when considering all cases (RS: 50.7% vs non-transformed CLL: 22.2%; p<.000001), unmutated cases only (RS: 58.3% vs non-transformed CLL: 35.7%; p=.003), and mutated cases only (RS: 33.3% vs non-transformed CLL: 13.7%; p=.022). Compared to non-transformed CLL, RS preferentially utilized BCR belonging to a subset characterized by rearrangement of unmutated IGHV4-39/IGHD6-13/IGHJ5 genes (2/159, 1.2% vs 5/35, 14.3%, respectively; p=.002). All cases with stereotypic IGHV4-39 carried +12 as the sole FISH abnormality. After a median follow-up of 41.1 months, 39/754 CLL had transformed to RS. Univariate analysis documented: shorter time to transformation in CLL utilizing IGHV4-39 (5-year risk: 35.4%) compared to CLL utilizing other IGHV genes (5-year risk: 5.6%) (p<.000001); higher risk of RS in CLL utilizing stereotypic HCDR3 (5-year risk: 14.2%) compared to CLL without stereotypic HCDR3 (5-year risk: 3.9%) (p<.00001). CLL with stereotypic HCDR3 and IGHV homology 98% showed a significantly higher risk of transformation (5-year risk: 18.4%) compared to CLL with IGHV homology 98% but without stereotypic HCDR3 (5-year risk: 6.8%) (p=.006). Also, stereotypic HCDR3 identified a CLL subgroup that, despite presenting with IGHV homology <98%, showed an increased risk of RS (p=.040). This observation indicates that stereotypic HCDR3 is not a surrogate of IGHV homology for RS prediction. We then tested the independent predictive value for RS transformation of IGHV4-39 usage and of stereotypic HCDR3. Multivariate analysis selected IGHV4-39 usage (HR: 4.25; p=.002) and stereotypic HCDR3 at CLL diagnosis (HR: 3.08; p=.002) as independent predictors of RS transformation. The observation that all RS utilizing IGHV4-39 carried stereotypic HCDR3 prompted investigation of the interaction between IGHV4-39 usage and stereotypic HCDR3 in the model. Multivariate analysis selected the interaction between IGHV4-39 usage and stereotypic HCDR3 at CLL diagnosis as the strongest independent predictor of RS transformation (HR: 5.13; p=.001). The relevance of the interaction between IGHV4-39 and stereotypic HCDR3 was confirmed by bivariate log rank analysis. Accordingly, CLL utilizing both IGHV4-39 and stereotypic HCDR3 were identified as the disease category with highest risk of transformation (5-year risk: 68.7%). Transformation to RS and progression to symptomatic disease according to NCI Working Group guidelines are distinct events in CLL. Accordingly, neither IGHV4-39 usage nor stereotypic HCDR3 affected the risk of CLL progression occurring without transformation to RS. IGHV4-39 usage and stereotypic HCDR3 may be appropriate biological markers for RS prediction since: these markers predict RS in a fashion that is independent of other clinical and biological features; given the widespread use of IGHV sequencing for CLL prognostication, information on IGHV4-39 and stereotypic HCDR3 may be obtained at CLL diagnosis without additional testing; and importantly all CLL with concomitant IGHV4-39 usage and stereotypic HCDR3 ultimately transform to RS. A close monitoring and a careful biopsy policy may be of help for early recognition of RS transformation in patients carrying IGHV4-39 usage and stereotypic HCDR3.

scholarly journals ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia

Leukemia ◽  
2006 ◽  
Vol 21 (1) ◽  
pp. 1-3 ◽  
Author(s):  
P Ghia ◽  
◽  
K Stamatopoulos ◽  
C Belessi ◽  
C Moreno ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Mutational Status ◽  
Ighv Gene ◽  
Status Analysis

scholarly journals Intraclonal Diversification Occurs in Chronic Lymphocytic Leukemia Expressing B Cell Receptors Belonging to the IGHV4 Gene Family

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 944-944
Author(s):  
Filippo Vit ◽  
Francesca Maria Rossi ◽  
Tiziana D'Agaro ◽  
Tamara Bittolo ◽  
Antonella Zucchetto ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Excision Repair ◽  
Lymphocytic Leukemia ◽  
Mrna Levels ◽  
Direct Role ◽  
Region Gene ◽  
Mutational Status ◽  
Ighv Gene

Abstract Background. The pivotal role of the Immunoglobulin (Ig) receptor and antigenic stimulation have been proven to be landmarks for the understanding of the ontogeny and evolution of chronic lymphocytic leukemia (CLL). In addition, the mutational status of the Immunoglobulin Heavy-Chain Variable region gene (IGHV) was confirmed to be a reliable prognostic factor, supporting an antigen-driven model of CLL development. To clarify aspects regarding an antigenic involvement in CLL evolution, studies focusing on intraclonal diversification (ID) of Ig genes have provided relevant information, although mainly conducted in a pre-Next Generation Sequencing (NGS) era. Aim. To apply a NGS approach to investigate ID in CLL. Methods. IGHV genes from 530 CLL patients with Royal Masden Hospital score 4-5 (Fig. 1A) was sequenced using NGS (Lymphotrack). The bio-informatic pipeline was based on the pRESTO/ChangeO packages. Specific pathological clones were selected based on the presence of same IGHV, junction genes and with similar HCDR3 sequence according to Hamming's distance. Through the R-Alakazam package, we generated rarefaction curves to evaluate the clonal diversity inside the pathological clone (Fig. 1B). Focusing on the Simpson index (represented by the Hill number of order q=2), which gives more weight to larger clones minimizing the smaller ones (Fig. 1B), we selected a Diversity Score (DS) of 4 for the definition of cases without ID (clonal; DS <4) and cases with ID (intraclonal; DS ≥4) (Fig. 1B). Results. Using the reported threshold we identified 469 (88.5%) clonal cases, expressing a single clone (Fig. 1C), and 61 (11.5%) cases with ID (median DS 9.2, range 4.4-66.0) characterized by the presence of two or multiple pathological clones expressing the same IGHV gene and HCDR3 (Fig. 1C). Notably, cases with ID expressed both a mutated (M) (39/61, 63.9%) and an unmutated (UM) (22/61, 36.1%; p=0.066) IGHV gene configuration (Fig. 1C). Of note, we observed a significant skewing toward the usage of VH4-family genes when comparing cases with ID (38/61, 62.3%) vs. cases without ID (78/469, 16.6%; p<0.0001, Fig 1D). Moreover, the IGHV4-39 and IGHV4-34 genes were the most used genes in the context of cases with ID (Fig. 1E), although none of them belonging to known stereotyped subsets. By focusing on VH4-family only cases, we observed that cases with ID and UM IGHV genes displayed higher mutation frequencies in WA/TW motifs, a mutational signature which suggests an involvement of both Activation-Induced (Cytidine) Deaminase (AID) and error-prone polymerase eta (Fig. 1F), a pattern not observed in its counterpart with UM IGHV genes but without ID (Fig. 1F). Conversely, in cases with ID and M IGHV genes, mutations preferentially clustered in AID hotspots (WRC/GYW motifs), suggesting a direct role of AID and the Base Excision Repair machinery in the mutational overload (Fig. 1F). Consistently, M IGHV cases with ID expressed significantly higher AID mRNA levels than M IGHV cases without ID (p=0.0024; Fig. 1G). These expression levels were overall comparable with those found in UM IGHV cases, irrespective to the evidence of ID (Fig. 1G), which however were not associated with an increased number of mutations in AID-specific hotspots (Fig. 1F). Conclusions. By taking advantage of a new method for ID assessment in CLL, we demonstrated that ID prevalently affects VH4-family cases which display different mutational patterns dependent to the IGHV gene status. This data are in keeping with previous reports indicating the IGHV4 genes as particularly prone to generate immunoglobulin subjected to continuous/persistent stimulation by external/auto-antigens, hence particularly prone to generate features of ID. Further experiments in selected cases with ID through a non-random barcode strategy are needed. Disclosures Zaja: Sandoz: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria.

scholarly journals EXPRESSION OF LIPOPROTEIN LIPASE AND c-MYC ONCOGENE IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AFFECTED BY THE CHORNOBYL ACCIDENT

2020 ◽  
Vol 25 ◽  
pp. 421-429
Author(s):  
N. Bilous ◽  
◽  
I. Abramenko ◽  
A. Chumak ◽  
I. Diagil ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lipoprotein Lipase ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
Expression Levels ◽  
Myc Oncogene ◽  
Mutational Status ◽  
Ighv Gene ◽  
Lpl Gene ◽  
Myc Gene

Objective. to determine the association between the expression of lipoprotein lipase (LPL) and c-MYC genes in peripheral blood cells of chronic lymphocytic leukemia (CLL) patients affected by the Chornobyl catastrophe depending on the mutational status of IGHV genes. Methods. Analysis was performed in the group of 69 CLL patients irradiated due to the Chornobyl NPP accident (58 clean-up workers of 1986 year, 6 inhabitants of radionuclide contaminated areas, and 5 evacuees). The IGHV gene mutational status was studied by polymerase chain reaction (PCR) followed by direct sequencing. LPL and c-MYC expression was evaluated by Quantitative Real-time PCR. Data were analyzed with the SPSS software package, version 20.0. Results. Relative LPL expression levels in CLL samples ranged from 0 to 1663.5 (mean 138.47 ± 30.69, median 26.1). A strong correlation between individual LPL expression levels and IGHV mutational status was found (r = 0.684; p < 0.0001). The average relative c-MYC expression level was 5.7 ± 0.87 (median 2.86; range 0–48.5). No association between c-MYC expression and IGHV mutational status was found. Among unmutated IGHV cases, a correlation between LPL and c-MYC gene expression levels was identified: r = 0.351; p = 0.013. Conclusions. Our data confirm the dominant concept that unmutated IGHV CLL cases are more sensitive to the action of proliferative stimuli compared to mutated IGHV CLL cases. This is manifested by an increase in the expression of a functionally significant LPL gene, is one for the strongest negative prognostic markers in CLL. Key words: lymphocytic leukemia, LPL, c-MYC, IGHV genes, Chornobyl NPP accident.

scholarly journals Are surrogates of IGHV gene mutational status useful in B-cell chronic lymphocytic leukemia? The example of Septin-10

Leukemia ◽  
2007 ◽  
Vol 22 (1) ◽  
pp. 224-226 ◽  
Author(s):  
D Benedetti ◽  
R Bomben ◽  
M Dal-Bo ◽  
D Marconi ◽  
A Zucchetto ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Mutational Status ◽  
Ighv Gene ◽  
Cell Chronic Lymphocytic Leukemia

Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3726-3736 ◽  
Author(s):  
Nagaja Capitani ◽  
Orso Maria Lucherini ◽  
Elisa Sozzi ◽  
Micol Ferro ◽  
Nico Giommoni ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Apoptosis ◽  
Group Analysis ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Expression Of Genes ◽  
Mutational Status ◽  
Survival Pathways

Abstract Intrinsic apoptosis defects underlie to a large extent the extended survival of malignant B cells in chronic lymphocytic leukemia (CLL). Here, we show that the Shc family adapter p66Shc uncouples the B-cell receptor (BCR) from the Erk- and Akt-dependent survival pathways, thereby enhancing B-cell apoptosis. p66Shc expression was found to be profoundly impaired in CLL B cells compared with normal peripheral B cells. Moreover, significant differences in p66Shc expression were observed in patients with favorable or unfavorable prognosis, based on the mutational status of IGHV genes, with the lowest expression in the unfavorable prognosis group. Analysis of the expression of genes implicated in apoptosis defects of CLL showed an alteration in the balance of proapoptotic and antiapoptotic members of the Bcl-2 family in patients with CLL. Reconstitution experiments in CLL B cells, together with data obtained on B cells from p66Shc−/− mice, showed that p66Shc expression correlates with a bias in the Bcl-2 family toward proapoptotic members. The data identify p66Shc as a novel regulator of B-cell apoptosis which attenuates BCR-dependent survival signals and modulates Bcl-2 family expression. They moreover provide evidence that the p66Shc expression defect in CLL B cells may be causal to the imbalance toward the antiapoptotic Bcl-2 family members in these cells.

Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997

2007 ◽  
Vol 25 (7) ◽  
pp. 799-804 ◽  
Author(s):  
Michael R. Grever ◽  
David M. Lucas ◽  
Gordon W. Dewald ◽  
Donna S. Neuberg ◽  
John C. Reed ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Variable Region ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Therapeutic Trial ◽  
Cd38 Expression ◽  
Molecular Features ◽  
Mutational Status

Purpose Genomic features including unmutated immunoglobulin variable region heavy chain (IgVH) genes, del(11q22.3), del(17p13.1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome. Patients and Methods We prospectively evaluated the prognostic significance of a comprehensive panel of laboratory factors on both response and progression-free survival (PFS) using samples and data from 235 patients enrolled onto a therapeutic trial. Patients received either fludarabine (FL; n = 113) or fludarabine plus cyclophosphamide (FC; n = 122) as part of a US Intergroup randomized trial for previously untreated CLL patients. Results Complete response (CR) rates were 24.6% for patients receiving FC and 5.3% for patients receiving FL (P = .00004). PFS was statistically significantly longer in patients receiving FC (median, 33.5 months for patients receiving FC and 19.9 months for patients receiving FL; P < .0001). The occurrence of del(17p13.1) (hazard ratio, 3.428; P = .0002) or del(11q22.3) (hazard ratio, 1.904; P = .006) was associated with reduced PFS. CR and overall response rates were not significantly different based on cytogenetics, IgVH mutational status, CD38 expression, or p53 mutational status. Expression of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 was not associated with either clinical response or PFS. Conclusion These results support the use of interphase cytogenetic analysis, but not IgVH, CD38 expression, or ZAP-70 status, to predict outcome of FL-based chemotherapy. Patients with high-risk cytogenetic features should be considered for alternative therapies.

Molecular Cytogenetics Analysis of 13q14 Biallelic Deletion in Chronic Lymphocytic Leukemia: A Study on 250 Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1454-1454
Author(s):  
Alessandro Gozzetti ◽  
Giulia Papini ◽  
Rosaria Crupi ◽  
Adele Frasconi ◽  
Francesco Forconi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chromosomal Abnormality ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Strong Association ◽  
Lymphocytic Leukemia ◽  
The Other ◽  
Median Percentage ◽  
Mutational Status ◽  
13Q Deletion

Abstract Abstract 1454 Deletion 13q14 (13q-) detected by fluorescence in situ hybridization (FISH) is the most frequent chromosomal abnormality in chronic lymphocytic leukemia (CLL). When 13q- is detected as sole abnormality has a good prognosis, while aggressive outcome is registered when 13q- is combined with other chromosomal abnormalities such as del 11q or del 17p. A recent study evidenced also that patients with higher percentage of 13q-deleted cells (>70%) are at higher risk for aggressive disease. Some studies evidenced that 13q- deletion size (involving D13S319 +/−Rb1) seems to matter in terms of time to treatment (TTT) and prognosis (OS). Few studies evaluated so far the incidence and prognosis of a biallelic 13q- deletion, i.e. the deletion of both alleles of the minimal deleted region (MDR) of chromosome 13q.In particular prognosis has been reported controversial. We analyzed at single institution 250 CLL patients by FISH in order to evaluate the incidence and prognosis of biallelic 13q- by using probes for D13S319 and RB1 that map to DLEU2/MIR15A/MIR16-1 and RB1 loci. Results were correlated in terms of TTT and OS with IGHV mutational status (mutated vs unmutated), RAI/BINET stage, CD38 positivity and/ or ZAP-70 positivity, beta-2M, LDH, other chromosomal abnormality (+12, del17p, del11q). Deletion 13q was considered present if >10% of nuclei were deleted out of 300 nuclei scored by two different and independent observers. All biallelic cases were confirmed by FISH using a probe for LSI-D13S319 and 13q34 to exclude false positive results. 135/250 (52%) patients presented a monoallelic del 13q. 45/135 (32%) presented a monoallelic del of RB1 while 20/135 (15%) cases presented a biallelic 13q-.12/20 (80%) presented a biallelic 13q- as sole abnormality, while 8/20 presented a 13q- associated with other cytogenetic abnormalities (one 17p-, five 11q-, two +12). The median percentage of 13q-deleted cells was 50% (range 14–86). Median age was 65 (range 50–85), M/F 12/8; 80% of the patients were RAI stage 0–1, while only 10% were RAI stage 4. No differences were seen in patients with biallelic deletion of 13q when LDH, b2M, ZAP-70,IGHV were considered. CD38 was negative in 16/20 patients. Regarding the MDR of chromosome 13q, 11/20 patients presented a biallelic del of D13S319, while 5/20 had a biallelic deletion of RB1; 5/20 patients presented a mono+biallelic del of D13S319 while 3/20 a mono+biallelic deletion of RB1. When we analyzed clinical and biological characteristics comparing patients with biallelic13q-,monoallelic 13q- and with no 13q-, we did not find differences in terms of: stage (RAI-Binet), P=0.2,P=0.9; B2 M, P=0.4; LDH,P=0.1; CD38 positivity, P=0.2; ZAP-70, P=0,1; IGHV M vs UM,P=0.65; P53 mutated vs wild type, P=0.1; del 11q was significantly associated more with biallelic 13q-, P=0.02. TTT and OS were not significantly different between biallelic 13q- patients and the other two groups (164 vs 212 vs 211, P=0.9). 8/20 patients with biallelic 13q- have been treated, all 5 patients carrying also a 11q- received treatment, the other 3 patients had: 1patient RB1 deletion in 92% of cells and 2 deletion 13q- in>75% of cells. In conclusion, biallelic 13q- are present in about 8% of all cases of CLL and in 15% of 13q- patients. A strong association with del 11q was found and this correlated with disease progression and treatment.CD38 was negative in the majority of patients with biallelic 13q-. RB1 was deleted in 32% of 13q- patients. No differences were found in terms of clinical characteristics, TTT and OS with monoallelic 13q-. Disclosures: No relevant conflicts of interest to declare.

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