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  • 11
    Online Resource
    Online Resource
    Auto-Immune Origin of B Cells from HCV-Associated Lymphoma
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1464-1464
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1464-1464
    Abstract: Hepatitis C virus (HCV) infection is a well-established risk factor for the development of B cell non-Hodgkin lymphoma (B-NHL). Two main pathways have been proposed to explain the role of the virus in lymphomagenesis: 1) transformation of B cells either directly by oncogenic viral proteins, or by a hit-and-run mechanism inducing a mutator phenotype, and 2) chronic antigenic stimulation through the B cell receptor (BcR) in conjunction to the binding of the viral E2 protein to its receptor CD81. There are however conflicting data regarding whether the BcR of the lymphomatous cells are capable of directly recognizing viral proteins or, rather, they possess a rheumatoid factor (RF) activity, binding instead polyclonal immunoglobulin (IG) within immune complexes trapping the virus. To further elucidate the role of antigenic stimulation in the natural history of HCV-associated B-NHL, we analyzed the IG gene repertoire of both heavy and light chains expressed by neoplastic cells in 41 cases of HCV-associated NHL, including: 29 marginal zone lymphoma (MZL); 7 diffuse large B-cell lymphoma (DLBCL) of which 3 originated from transformed MZL ; and 5 other low-grade B-cell NHL. Tumor cells were obtained from blood in 39 cases, bone marrow and a lymph node biopsy in 1 case each. Forty-three productive IGHV-IGHD-IGHJ gene rearrangements were obtained, which displayed a clear biased gene composition as 3 IGHV genes contributed to almost half of the repertoire: IGHV1-69 (11/43, 25,6%), IGHV3-7 (5/43, 11.6%), IGHV3-21 (4/43, 9.3%). This was also true for both IGHD genes (IGHD3-22: 12/43, 27.9%), and IGHJ genes (IGHJ4: 17/43, 39.5%; IGHJ3: 17/43, 25.6%). All but 3 sequences carried somatic hypermutations (SHM) in their IGHV genes with a median identity to the germline of 97.6% (range 86.5-100%). Thirty-eight productive IG light chain rearrangement sequences were obtained from 36 cases, of which 30 (78.9%) were IGK. Similarly, they exhibited strong gene usage bias with an over-representation of IGKV3-20 (9/30, 30%), as well as IGKJ1 (11/30, 33.3%) and IGKJ2 (6/30, 20%). IG light chain sequences were found to harbor similar SHM load with a 97% median identity to germline (range 91-100%). As previously described, we observed preferential pairing of heavy and light chain genes, with 6 of the 9 IGHV1-69 cases (with available light chain sequence data) being associated with IGKV3-20. Using established criteria, we found 5 cases (11.6%) carrying stereotyped BcR i.e. IGHV-IGHD-IGHJ gene rearrangements with quasi-identical amino-acid (AA) sequences, including the highly variable complementary determining region 3 (CDR3). Three cases concerned IGHV3-7/IGHD3-22/IGHJ3 rearrangements with an 18 AA-long CDR3, and 2 concerned IGHV1-69/IGHD3-22/IGHJ4 rearrangements with a 13 AA-long CDR3. Identity within the CDR3 extended to AA encoded by randomly inserted N-region nucleotides. We failed to establish correlations between histological categories and IG repertoire, probably due to the uneven distribution of lymphoma subtypes within our cohort. In contrast, most if not all sequences with biased IG gene usage, including the 5 stereotyped BcR ones, were found amongst the 28/41 cases (68.3%) with mixed cryoglobulinemia type II and/or positive for RF (MC/RF+). These two categories of patients differed also regarding the SHM load of their IGHV genes since MC/RF+ cases were signlificantly less mutated than MC/RF- cases (median identity to germline: 97.9% vs 95.9%, p= 0.048). We then searched for similar sequences in public databases and collaborative studies. Stereotyped BcR sequences similar to those of our cases were detected in HCV-associated lymphoma, but also in other HCV-negative B-cell maligancies e.g. MALT lymphoma (some associated with RF) and chronic lymphocytic leukemia, non malignant B cells with RF activity, and non malignant marginal zone splenic B cells. Sequence similarity extended to some shared AA replacements, e.g. identical AA introduced by HSM at the same positions. In conclusion we confirm the highly biased IG repertoire of HCV-associated lymphoma. However this feature seems to be linked essentially to the presence of a MC and/or RF. As quasi-identical sequences are found in HCV-negative malignant and normal B cells, our data support the hypothesis that HCV-associated lymphomatous cells originate from precursors endowed with auto-immune properties rather than B cells expressing an anti-virus BcR. Disclosures Stamatopoulos: Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1464.1464
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 12
    Online Resource
    Online Resource
    The Total Amount of Kappa Plus Lambda Serum Immunoglobulin Free Light Chains (sFLC κ+λ) Is a Powerful Independent Predictor of Time to First Treatment In Chronic Lymphocytic Leukemia (CLL) and Allows Definition of a Novel Prognostic Scoring System: A Study of 449 Therapy-naïve Patients
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2437-2437
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2437-2437
    Abstract: Abstract 2437 Clinical course in individual CLL patients (pts) is highly heterogeneous. Several pts show an indolent disease and other experience an aggressive course rapidly succumbing to disease-related events. Different biomarkers have been developed to identify pts with evolving disease but their application is mostly limited to clinical trials. It has been shown that measurement of clonal serum free light chains (sFLC) levels, through a straightforward assay validated for plasma cell disorders, could independently identify CLL pts with progressive disease. By analyzing the largest cohort of CLL pts ever reported, we wished to: i) determine the independent predictive value of sFLC abnormalities in the context of established biomarkers; ii) define the predictive hierarchy of these markers; iii) incorporate sFLC into a novel prognostic system. Cryopreserved sera at diagnosis from 449 untreated pts (282 males and 167 females, median age 65 yrs; r 33–89) were collected for analysis at two reference laboratories. After quantization (Freelite, The Binding Site, Ltd., UK) of sFLC k and l levels (r, k: 3.3–19.4 mg/mL; l: 5.71–26.3 mg/mL), their ratio was calculated as sFLC k/l (r: 0.26–1.65). An abnormal sFLCk/l was found in 150/449 cases (132 k/18 l). A significant correlation emerged between sFLCk/l and CD38, ZAP70, unmutated IgHV and unfavourable FISH but not with Binet stage (Table). At a median follow up of 3 yrs (r 1–20), 149 of 449 pts were treated due to progressive disease (NCI Guidelines). Treatment-free survival (TFS) was significantly shorter (p 〈 0.0001) in pts with abnormal sFLCk/l (median TFS 14.2 yrs) as compared to cases with normal ratios (median TFS 4.4 yrs). Abnormal sFLCk/l remained independently associated with TFS after adjustment for CD38, ZAP70, IgVH and stage (HR=2.2, 95% C.I. 1.5–3.3, P 〈 0.0001). In this model, ZAP70 (HR=3.2, 95% C.I. 2.0–5.1, P 〈 0.0001), IgVH (HR=2.1, 95% C.I. 1.2–3.5, P=0.006) and stage (HR=2.7, 95% C.I. 1.7–4.2, P 〈 0.0001) but no longer CD38 retained a significant association with risk of being treated. To further dissect the predictive value of sFLC testing, absolute levels of k and lFLCs were summed in a new variable named sFLCk+l (median value 39.0 mg/mL; r 8.2–1430.4). A higher sFLCk+l value was observed in pts who required treatment and ROC analysis disclosed that 60.6 mg/mL was the optimal cut-off value for distinguishing pts who required treatment from those who did not (AUC=0.62, P 〈 0.0001). At 3 yrs, the probability of being therapy-free was 84.1% and 51.8% for pts with sFLCk+l below or above the threshold, respectively (Chi Square of log-rank 85.6, P 〈 0.0001). Cox multivariate analysis demonstrated that a sFLCk+l value 〉 60.6 mg/mL (HR=2.5, C.I. 2.6–3.9), remained the strongest independent predictor of TFS together with ZAP70 (HR=2.8, C.I. 1.8–4.6) and stage (HR=2.5, C.I. 1.6–3.8), while CD38 and IgVH status lost their predictive power. Most intriguingly, it emerged that sFLCk/l is irrelevant in predicting TFS if sFLCk+l is above cut-off and that cytogenetic risk remains significantly associated with sFLCk+l (P=0.047) but not FLCk/l. sFLCk+l retained an independent association with TFS together with cytogenetics, ZAP70 and stage. A novel prognostic model was then constructed with 1 point for each of these unfavorable marker and a score given by their sum. On 260 pts scores were: 104=0, 79=1, 56=2, 19=3, 4=4. The 3 year probability of avoiding treatment was 94.8%, 84.5%, 61.6% and 21.1% for pts scoring 0, 1, 2 and 3+4, respectively (P 〈 0.0001). While sFLCk/l predicts TFS by mirroring the size/activity of the dominant CLL clone, the higher predictive power of sFLCk+l may reflect activity of microenvironmental oligo/polyclonal B-cells, yet clonotypic or not to the main CLL population, undergoing continuous antigen-driven clonal evolution. A score system integrating sFLCk+l levels is proposed to Identify CLL pts likely to require early treatment. sFLC k/l in 449 untreated CLL pts Table 1. Death in complete remission by year sFLC k/l P Normal (%) Abnormal (%) CD38 − 234 (70.9) 96 (29.1) 〈 0.0001* + 37 (46.3) 43 (53.7) ZAP70 − 188 (72.5) 73 (28.0) 0.001* + 78 (55.7) 62 (44.3) IgVH Mut 177 (71.1) 72 (28.9) 0.038 Unmut 78 (60.0) 52 (40.0) Binet A 227 (68.6) 104 (31.4) 0.2* B+C 72 (61.0) 46 (39.0) FISH 13q14.3, normal (low risk) 186 (85.3) 32 (14.7) Trisomy 12 (int risk) 23 (71.0) 9 (28.1) 0.013** 11q22.3, 17p13.1 (hi risk) 37 (69.8) 16 (30.2) * Fischer's ET, **Pearson CS. * Fisher's ET, **Pearson CS. Disclosures: Amoroso: The Binding Site, LtD: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2437.2437
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 13
    Online Resource
    Online Resource
    Definition of a Prognostic Scoring System for Predicting Clinical Outcome in B-Cell Chronic Lymphocytic Leukemia.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-01), p. 2328-2328
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2328-2328
    Abstract: Patients whose cells utilize unmutated Ig VH region genes and/or express ZAP-70 or CD38 have a more aggressive course than patients whose cells have mutated Ig VH genes and/or do not express ZAP-70 or CD38. We have conducted here a study on 500 patients characterized for marker expression. By ROC curve analysis, we found 30% as the best cut-off value of CD38 which discriminates between mutated and unmutated cases in CLLs. CD38 expression, had low sensitivity (66%), but relatively high specificity (80%), with a positive and a negative predictive value respectively of 68% and 78% in anticipating VH mutational status. Moreover, the agreement between CD38 expression and VH mutational status was low although significant (K=0.46, p & lt; 0.001). ZAP-70 showed high sensitivity (76%) and specificity (75%), high negative (89%) but a low positive (54%) predictive value and a low, although significant, K statistic (0.45, p & lt; 0.001). Furthermore, we combined CD38 and Zap-70 expression to evaluate whether both variables provided more precise information in estimating VH mutational status. We found sensitivity, 42%; specificity, 97%; positive predictive value, 90%; negative predictive value, 72%; K statistic 0.43, p & lt; 0.001. In conclusion neither CD38 nor ZAP-70 by themselves or in combination were able to anticipate VH mutational status, meaning that CD38 and/or Zap-70 expression could surrogate the VH mutational status. In the second part of this study we wanted to validate this findings on clinical ground. Clinical information was available for 150/500 CLL cases investigated. After a median follow-up of 38 months, 83 cases remained untreated, while 67 cases received treatment. We show that these markers predict the clinical course by using time to first treatment (TTT) as a measure for disease progression. Each of the three markers was capable of discriminating two distinct groups of patients (p & lt; 0.0001 for CD38, p & lt; 0.00001 for ZAP-70 and Ig VH mutations) with different clinical behavior, although marker combinations provided a more precise definition of prognosis. Although many patients expressed all favorable or all unfavorable markers, there also were patients with different marker combinations. We devised a scoring system that subdivides patients based on the absence (score 0) or presence of 1 (score 1), 2 (score 2), or 3 (score 3) unfavorable prognostic markers. Using this scoring system, we have identified 3 groups with significantly different clinical courses: i.e., low- (score 0), intermediate-risk (score 1) and high-risk (score2–3) patients. This scoring system has potential utilization for prognostic stratification of CLL in designing prospective clinical trials.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2328.2328
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 14
    Online Resource
    Online Resource
    Microenvironment Regulation of IL23R/IL-23 Axis Drives Chronic Lymphocytic Leukemia (CLL) Progression
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 616-616
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 616-616
    Abstract: Background : CLL displays a considerable degree of clinical heterogeneity, which is in part ascribable to clone-intrinsic biological features and that are also influenced by clone-extrinsic events related to the microenvironment. Among the dynamics-taking place within the CLL microenvironment, those finalized to the induction of an overly inflammatory milieu may significantly impact on the CLL natural history by hijacking the immunological microenvironment at the same time fostering clone fitness. IL-23 acts as a prototypical pro-inflammatory mediator representing a promising therapeutic target. We analyzed the ability of CLL cells to sense IL-23 through the IL-23R complex (consisting of IL12Rß1 and IL23R subunits) expression and correlated this feature with clinical outcome. Moreover, we investigated the synthesis of IL-23 within the CLL microenvironment, and tested the biological effects of the IL-23/IL-23R axis engagement and of its interference in vitro and in vivo. Methods : IL23R complex was detected by quadruple flow cytometry staining with CD19, CD5, IL23R, and IL12Rβ1 in prospectively enrolled CLL cases (O-CLL1 protocol, clinicaltrial.gov identifier NCT00917540). On human tissue specimens, lymph node and bone marrow samples from 16 CLL patients were selected for in situ immunolocalization analyses. NOD/Shi-scid/γcnull (NSG) mice were used for in vivo xenografts, in which activated autologous T cells (AAT), obtained by adding anti-CD3 and CD28 Dynabeads and rIL2 were co-injected with CLL cells. MiRNA analysis was performed by Agilent's Human V2 platform and by quantitative PCR. MirVANA microRNA mimics and inhibitors were purchased from Ambion, Inc. For 3'UTR luciferase reporter experiments, miRNA target reporter vectors were purchased from Origene. Results : By flow cytometry, circulating CLL cells of 281 cases variably expressed IL23R side chain while consistently lacking IL12Rß1 chain expression. The engagement of the uncoupled IL23R complex expression (i.e. IL23R but not IL12Rb1 expression) by IL23 did not activate downstream signaling pathways, such as the up-regulation of pSTAT3. The 3-year TTFT probability of patients with low IL23R expression (IL23R-low) was 91% as compared to 75% of IL23R-high cases [χ2 9.1, P=.003; HR=3.2, 95%CI (1.4-7.1)] ; in a multivariate model, IL23R expression still remained independently associated with TTFT. We explored the potential control of IL23R expression in CLL cells by miRNA and found 15 miRNAs inversely associated with IL23R expression, five of which predicted as regulators (miRNA-146b-5p, miRNA-155, miRNA-324-5p, miRNA-532-3p and miRNA-630). Among these, miR-324-3p and miR-146b-5p were demonstrated to functionally regulate the expression of IL23R and IL12Rβ1 proteins in CLL cells, respectively. Within lymphoid tissues, in situ, CLL clones expressing IL23R side chain also showed expression of IL12Rß1, which varied according to the density of CD40L-expressing bystander elements suggesting a microenvironment-driven regulation of the IL-23R complex. To functionally test this hypothesis, CLL cells were co-cultured in the presence of NIH-3T3 transduced with CD40L or with AAT cells. A significant up-regulation was observed for both the IL12Rß1 and IL23R side chains, suggesting the environment co-stimulation as a mechanism of IL-23R complex regulation. Consistently, the IL-23R complex was upmodulated in CLL cells expressing IL-23R but not IL12Rß1, upon xenograft with autologous T cells into NOD-Scid mice. We then investigated the effect of IL-23R engagement by IL-23 in CLL cells and found that IL-23R activity correlated with CLL cell proliferation and survival in vitro via STAT3 phosphorylation. The trophic nature of IL-23-mediated stimuli over CLL cells was further demonstrated in vivo through the adoption of an anti-IL23p19 monoclonal antibody for clinical use, which proved to be effective in eradicating the xenografted CLL clone in the infiltrated tissues (spleen, liver and BM) by inhibiting proliferation and inducing apoptosis. Noteworthy, the therapeutic effect of IL-23 antagonism was demonstrated by histopathology, flow cytometry and BCR clonality. Conclusions : Overall, we demonstrated that IL-23/IL-23R axis is a novel microenvironment-regulated determinant in CLL pathobiology representing a strong prospect in disease prognostication and treatment. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.616.616
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 15
    Online Resource
    Online Resource
    Expression of CD10 by Human T Cells That Undergo Apoptosis Both In Vitro and In Vivo
    American Society of Hematology ; 1999
    In:  Blood Vol. 94, No. 9 ( 1999-11-01), p. 3067-3076
    Details
    In: Blood, American Society of Hematology, Vol. 94, No. 9 ( 1999-11-01), p. 3067-3076
    Abstract: This study shows that human postthymic T cells express CD10 when undergoing apoptosis, irrespective of the signal responsible for initiating the apoptotic process. Cells from continuous T-cell lines did not normally express CD10, but became CD10+ when induced into apoptosis by human immunodeficiency virus (HIV) infection and exposure to CD95 monoclonal antibody, etoposide, or staurosporin. Inhibitors of caspases blocked apoptosis and CD10 expression. Both CD4+ and CD8+ T cells purified from normal peripheral blood expressed CD10 on apoptotic induction. CD10 was newly synthesized by the apoptosing cells because its expression was inhibited by exposure to cycloheximide and CD10 mRNA became detectable by reverse transcription-polymerase chain reaction in T cells cultured under conditions favoring apoptosis. To show CD10 on T cells apoptosing in vivo, lymph node and peripheral blood T cells from HIV+ subjects were used. These suspensions were composed of a substantial, although variable, proportion of apoptosing T cells that consistently expressed CD10. In contrast, CD10+ as well as spontaneously apoptosing T cells were virtually absent in peripheral blood from normal individuals. Collectively, these observations indicate that CD10 may represent a reliable marker for identifying and isolating apoptosing T cells in vitro and ex vivo and possibly suggest novel functions for surface CD10 in the apoptotic process of lymphoid cells.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V94.9.3067.421a32_3067_3076
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1999
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 16
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    Online Resource
    Polyreactive Monoclonal Antibodies Synthesized by Some B-CLL Cells Recognize Specific Antigens on Viable and Apoptotic T Cells.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 2813-2813
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 2813-2813
    Abstract: B-cell chronic lymphocytic leukemia (CLL) is a disease characterized by uncontrolled clonal expansion of a CD5+/CD19+ B cell. Clones from different patients often express receptors/mAbs with remarkably similar VHDJH rearrangements, suggesting that the same antigen(s) or epitope(s) led to the initial clonal expansion. Although the specific antigens and epitopes remain to be identified, recent data indicate that B-CLL mAbs often bind autoantigens. In certain systemic autoimmune diseases, autoantibodies can react with cell surface molecules of viable lymphocytes (anti-lymphocyte mAbs) and with intracellular molecules of apoptotic cells that are transported to the cell membrane and function as autoantigens. Therefore, we expressed recombinant antibodies from B-CLL cells as IgG1 mAbs and tested them by flow cytometry for immunoreactivity with surface molecules on irradiated (apoptotic) and non-irradiated Jurkat cells, a human T-cell line. We chose to use T cells as our target for analysis to avoid difficulties that might arise from binding to FcgRIIb on B lymphocytes. Initial screening indicated that 5 of 25 mAbs showed intense binding. Antibodies from CLL Nos. 141 and DO8 bound to live but not apoptotic cells; in contrast, CLL Nos. 014, 114, and DO13 bound to apoptotic but not live cells. These five antibodies express unmutated VH genes. CLL 141 and DO8 express VH4-34. CLL 014 expresses VH1-69, CLL 114 VH4-39 and DO13 VH1-02. Other antibodies expressing VH1-69 in its unmutated form also bound Jurkat cells, albeit weaker than CLL 014, whereas mAbs expressing different unmutated genes from the VH1 family did not react. Among the mAbs expressing VH1-02 that were tested, only DO13 showed reactivity. This indicates that the VH1-02 gene was not solely responsible for the observed binding, and that DJ and/or VLJL segments were also involved. Remarkably, none of the tested mAbs belonging to VH3 family recognize antigens on Jurkat cells; all of these VH3 mAbs were mutated. Only CLL 114 belongs to a previously identified stereotypic set. Of interest, although CLL 014 and 141 are polyreactive, binding ssDNA, dsDNA, insulin, LPS, and HEp-2 cell lysates, their reactivities with surface antigens were specific in that CLL 141 bound only live cells and CLL 014 reacted solely with apoptotic cells. Our results indicate that, despite their inherent polyreactivity, certain B-CLL mAb bind specifically to antigenic epitopes on the surface of live as well as apoptotic Jurkat cells. The identity of these autoantigens is currently being investigated. These data highlight the importance of autoreactivity in the promotion and evolution of B-CLL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2813.2813
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 17
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    Online Resource
    Incidence of Cytogenetic Abnormalities in Newly Diagnosed Binet Stage A B-CLL and Relationship with Prognostic Biomarkers: Preliminary Results On 305 Patients Included in the Prospective O-CLL1 GISL Study.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2341-2341
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2341-2341
    Abstract: Abstract 2341 Poster Board II-318 Background. The clinical heterogeneity of chronic lymphocytic leukemia (CLL) requires parameters to stratify patients into prognostic subgroups to adapt treatment ranging from ‘watch and wait’ to allogeneic stem cell transplantation. To this end, several parameters such as lymphocyte doubling time, β-2 microglobulin, CD38 and ZAP-70 expression, immunoglobulin variable heavy chain (IgVH) mutation status and genetic abnormalities, as assessed by fluorescence in situ hybridization (FISH), have been integrated in clinical practice. Aims. In the present study, we investigated by FISH the incidence of the known major cytogenetic alterations (+12 and 13q14, 17p13, 11q23 deletions) in a series of Binet A B-CLL patients included in the prospective O-CLL1 GISL study started in April 2007. Methods. Molecular markers characterization and FISH analyses were performed as previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. GCC, 2008). A cut-off value of 2% was used to distinguish mutated and unmutated patients. CD38 and ZAP-70 were determined by flow-cytometry and a 30% cut-off was used to distinguish between positive or negative cases. Results. Up to date, 326 patients have been enrolled in the trial and FISH data concerning trisomy 12 and 13q14, 17p13, 11q23 deletions were available in 305 patients. At least one abnormality was found in 197 (64%) cases. The most frequent was del(13)(q14) (150/305, 49%), followed by +12 (40/303, 13%) (in one and three cases accompanied by 17p13 and 13q14 deletions, respectively), del(17)(p13) (7/305, 2%) and del(11)(q23) (17/305, 5%). 13q14 deletion was found as a sole abnormality in 134 patients; in the remaining cases, it was combined with +12 (3 pts) and 17p13 (3 pts) or 11q23 (10 pts) deletions. Among patients with 13q14 deletions, 99 were monoallelic, 12 biallelic and 39 showed a combination of the two patterns. Biomarkers data were available in all of the patients: 95/305 (31%) cases had unmutated IgVH genes; ZAP-70 and CD38 were positive in 117/305 (38%) and 72/305 (23%) cases, respectively. Concerning the distribution of cytogenetic aberrations, the unmutated IgVH group included 29/150 (19%) 13q14 deleted cases, 23/40 (57%) cases with trisomy 12 and 4/7 (57%) and 16/17 (94%) with 17p13 and 11q23 deletions, respectively. ZAP-70-positive groups included 43/150 (28%) 13q14 deleted cases, 26/40 (65%) cases showing trisomy 12 and 5/7 (71%) and 12/17 (70%) with 17p13 and 11q23 deletions, respectively. Finally, CD38-positive cases included 18/150 (12%) 13q14 deleted cases, 26/40 (65%) cases carrying trisomy 12 and 5/7 (71%) and 7/17 (41%) with 17p13 and 11q23 deletions, respectively. The percentages of IgVH mutations significantly correlated with cytogenetic alterations; namely, 5.8±0.3 for cases with del(13)(q14), 4.6±0.4 for normal karyotype, 2.6±0.5 in +12, 0.3±0.2 in del(11)(q23), and 1.7±0.9 in del(17)(p13) cases (p for trend 〈 0.0001). A significant correlation was also found for ZAP-70 expression: namely 32±1.8 for cases with del(13)(q14), 38.6±2.2 for normal karyotype, 47.6±3.7 for +12, 55.8±7.0 for del(11)(q22) and 42.4±11.7 for del(17)(p13) (p 〈 0.0001). Similarly, CD38 percentages were (mean value ± sem) 9.3±1.7, 16.9±2.1, 52.9±5.7, 26.8±6.2, 37.0±12.7 for del(13)(q14), normal karyotype, +12, del(11)(q23) and del(17)(p13) alterations, respectively (p for trend 〈 0.0001). Finally, cytogenetic abnormalities were clustered in 3 risk groups [i.e. low del(13)(q14) and normal; intermediate (+12); and high risk del(11)(q23) and del(17)(p13)] and significantly correlated (p 〈 0.0001) with a scoring system in which cases were stratified in 4 different groups according to the absence (group 0) or presence of 1 (group 1), 2 (group 2) or 3 (group 3) biomarkers (Morabito et al., BJH, 2009, voce). Interestingly, 147/154 cases scoring 0, gathered in the low FISH group, whereas 17/22 high FISH risk cases clustered in scoring 2-3. Conclusions. Our preliminary results indicate that in Binet stage A B-CLL patients at diagnosis cytogenetic abnormalities with an expected negative clinical impact are relatively few (7.2%) but significantly associated with prognostic biomarkers which negatively predict the clinical outcome in B-CLL. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2341.2341
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 18
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    BOTH MD Anderson Cancer Center MODEL and German Score Work in Predicting Time to First Treatment in EARLY Chronic Lymphocytic Leukemia: Results of an External Validation Analysis
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3934-3934
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3934-3934
    Abstract: Abstract 3934 In chronic lymphocytic leukemia (CLL) there has been a limited published work on the development of models predicting time to first treatment that incorporate traditional and novel prognostic factors. We wondered whether the nomogram recently proposed by M D Anderson Cancer Center (MDACC) investigators that includes clinical and newer prognostic variables (i.e., three or more involved lymph node sites, increased size of cervical lymph nodes, presence of 17p deletion or 11q deletion by FISH, increased serum LDH, and unmutated IGHV mutation status) could work when applied to a prospective community-based CLL patient cohort. We considered suitable for the purpose of this study 328 previously untreated patients with newly diagnosed asymptomatic Binet stage A CLL from different primary hematology centers registered on a prospective basis during the period 2006–2010 on an observational database of Gruppo Italiano Studio Linfomi (GISL). Using the formula proposed by Wierda et a total point score was calculated for each patient. A value ranging between 0 and 69.5 (median, 19.9) - therefore similar to total point scores reported by the MDACC group (median, 21.0; range, 0 – 87.4) – was found. As a continuous variable (i.e., measuring the risk of each point increase), total point score was associated with time to first treatment (HR 1.04; 95% CI 1.02–1.05; P 〈 0.0001). Receiver Operating Characteristic analysis identified a point score of 25 [area under curve (AUC) 0.64, sensitivity 61.5 specificity 72.1; P 〈 0.0001)] as the best threshold capable of separating patients who needed therapy from patients who did not (HR, 3.27; 95% CI, 2,07–5.18; P 〈 0.0001). The prognostic index category remained a predictor of time to first treatment also when analysis was limited to patients in Rai stage 0 (HR,4.05; 95% CI: 2.25–7.52; P 〈 0.0001). Finally, the goodness of fit showed that the nomogram model had significant good fit at 2 years (r2=0.966; P=0.002). We next wondered whether the German score based on 7 prognostic variables (i.e., age, gender, b2-microglobulin, sTK, IGVH mutational status, ECOG performance status and hierachic type of FISH abnormalities) and originally designed for predicting overall survival could forecast time to first treatment in patients with early disease. Since sTK was not available a slightly modified version of German model based on 6 prognostic variables was used. The risk score calculated in each patient by summing single ratings of adverse factors, allowed the identification of two different risk categories scoring respectively 0–2 and 3–5 whose clinical outcomes were different with respect to time to first treatment (HR 2.19, 95% CI: 1.15–2.20; P=0.005). In conclusion, this analysis shows that both models proposed by MDACC investigators and German group provide interchangeable tool for assessing time to first treatment. Interestingly, in this validation analysis the pattern of distribution of patients into a low and high-risk category revealed a high degree of concordance between models (P 〈 0.0001; Mann-Whitney test). Disclosures: Morabito: Celgene: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3934.3934
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
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  • 19
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    The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways
    American Society of Hematology ; 2008
    In:  Blood Vol. 111, No. 2 ( 2008-01-15), p. 517-524
    Details
    In: Blood, American Society of Hematology, Vol. 111, No. 2 ( 2008-01-15), p. 517-524
    Abstract: The clonal expansion of chronic lymphocytic leukemia (CLL) cells requires the interaction with the microenvironment and is under the control of several cytokines. Here, we investigated the effect of IL-15 and IL-21, which are closely related to IL-2 and share the usage of the common γ chain and of its JAK3-associated pathway. We found remarkable differences in the signal transduction pathways activated by these cytokines, which determined different responses in CLL cells. IL-15 caused cell proliferation and prevented apoptosis induced by surface IgM cross-linking. These effects were more evident in cells stimulated via surface CD40, which exhibited increased cell expression of IL-15Rα chain and, in some of the cases, also of IL-2Rβ. IL-21 failed to induce CLL cell proliferation and instead promoted apoptosis. Following cell exposure to IL-15, phosphorylation of STAT5 was predominantly observed, whereas, following stimulation with IL-21, there was predominant STAT1 and STAT3 activation. Moreover, IL-15 but not IL-21 caused an increased phosphorylation of Shc and ERK1/2. Pharmacological inhibition of JAK3 or of MEK, which phosphorylates ERK1/2, efficiently blocked IL-15–induced CLL cell proliferation and the antiapoptotic effect of this cytokine. The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2007-04-087882
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
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  • 20
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    Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells
    American Society of Hematology ; 2006
    In:  Blood Vol. 107, No. 9 ( 2006-05-01), p. 3708-3715
    Details
    In: Blood, American Society of Hematology, Vol. 107, No. 9 ( 2006-05-01), p. 3708-3715
    Abstract: Interleukin-21 (IL-21) is a member of the IL-2 cytokine family, which mediates proliferation or growth arrest and apoptosis of normal B cells, depending on their activation state. Here we demonstrate that surface IL-21 receptor (R) is expressed at variable levels by chronic lymphocytic leukemia (CLL) B cells freshly isolated from 33 different patients. IL-21R expression was up-regulated following cell stimulation via surface CD40. Therefore, IL-21 effects were more evident in CD40-activated CLL B cells. IL-21 induced an early signaling cascade in CLL B cells, which included JAK-1 and JAK-3 autophosphorylation and tyrosine phosphorylation of STAT-1, STAT-3, and STAT-5. IL-21 signaling failed to stimulate CLL B-cell proliferation, but induced their apoptosis. In addition, IL-21 counteracted the proliferative and antiapoptotic signals delivered by IL-15 to CLL B cells. IL-21-mediated apoptosis involved activation of caspase-8 and caspase-3, cleavage of Bid to its active form t-Bid, and cleavage of PARP and of p27Kip-1. Recent data indicate that CLL B cells require interaction with the microenvironment for their survival and expansion. The present findings thus provide a set of new mechanisms involved in the balance between cell-survival and apoptotic signals in CLL B cells.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2005-09-3535
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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    detail.hit.zdb_id: 80069-7
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