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  • 1
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    Array-CGH Based Genomic Profiling in B-Cell Chronic Lymphocytic Leukemia Reveals Specific Correlations of Genomic Imbalances and Prognostic Subgroups and Underlines the Consistency of Chromosomal Aberration Patterns within This Disease.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-01), p. 2083-2083
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2083-2083
    Abstract: Chronic lymphocytic leukemia of B-cell type (B-CLL) is characterized by a number of typical genomic aberrations. In comparison to patients with normal karyotypes or 13q deletions patients with high risk imbalances such as deletions of 11q, 17p or unmutated IgVH status have a higher risk for advanced disease and a significantly shorter survival. For a precise mapping of chromosomal imbalances as well as to verify the number of aberrations per case in different genetic subgroups of B-CLL (e.g. del11q, del13q, del17p, +12 or unmutated IgVH status) we performed high resolution genomic profiling using a genomic DNA-chip containing 2.800 probes. Target clones compriseda large genome-wide cluster of clones covering the genome at a distance of approx. 1.5Mb andclones mapping to genomic regions or genes of possible pathogenetic relevance in lymphoma. This chip covers approximately 10% of the human genome. In 93 (70%) of 133 analyzed B-CLL cases 171 genomic imbalances were identified (between 1–7 aberrations/case). Besides the confirmation of known recurrent chromosomal aberrations, previously unknown recurrent imbalances were detectable on 2p (8%), 4p (4%), 7p-q (5%), 10q (5%) and 20p (3%). Most of these imbalances were of larger extension ( 〉 10 Mb) and therefore impeded a further delineation of minimal aberrant regions and the identification of possible candidate genes. The mean number of chromosomal aberrations per case (= genomic complexity) in IgVH unmutated CLLs was approx. 2 times higher than in mutated cases (0,77 vs. 1,58 per case). 84% of samples with 〉 2 aberrations showed an unmutated IgVH status. Moreover, most of the previously unknown imbalances were identified within this group. A higher genomic complexity was also shown for samples with gain on 2p vs. balanced 2p status (2.2 times higher; 2.5 vs. 1.2) and in samples with del17p vs. balanced 17p status (3.7 times higher; 3.52 vs. 0.95). 11q aberrations had no impact on the number of genomic aberrations per case (1.6 vs. 1.2). Moreover, we found a strong association of 2p gains and an unmutated IgVH status (100%). Array based genomic profiling confirmes the chromosomal aberration structure and underlines the consistency of chromosomal aberration patterns of B-CLL. The biological and prognostic relevance of 2p gains and unmutated IgVH mutational status have to be further investigated.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2083.2083
    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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  • 2
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    Strikingly Homologous Immunoglobulin Gene Rearrangements and Poor Outcome in VH3-21-Utilizing Chronic Lymphocytic Leukemia Independent of Geographical Origin and Mutational Status.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 175-175
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 175-175
    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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.175.175
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
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  • 3
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    17p Deletion Predicts for Inferior Overall Survival after Fludarabine - Based First Line Therapy in Chronic Lymphocytic Leukemia: First Analysis of Genetics in the CLL4 Trial of the GCLLSG.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 715-715
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 715-715
    Abstract: The CLL4 trial evaluated first line treatment with fludarabine (F) or F + cyclophosphamide (FC) among 375 CLL patients up to 65 years enrolled between 1999 and 2003. FC resulted in a higher overall response rate (94% vs. 83%; P=0.001), longer median progression free survival (PFS) (48 vs. 20 months (m); P=0.001), but no difference in overall survival (OS) (Eichhorst et al., ASH 2003 and submitted). At enrollment, genomic aberrations and the VH mutation status have been analyzed for 307 and 280 cases thus far. The most frequent genomic aberrations were 13q-: 50.3%, 13q- single: 34.1%, 11q-: 20.3%, +12q: 13.7%, 6q-: 8.7%, 14q-: 6.1%, and 17p-: 4.9%. VH was mutated in 33.9% and unmutated in 66.1% of cases. The aberrations 13q- and 13q- single were more frequently observed in the VH mutated subgroup (45.4% vs. 32.7% and 35.5% vs. 18.8%, respectively), while 11q- (26.9% vs. 12.2%) and 6q- (14.2 vs. 1.7%) were more common in the VH unmutated subgroup. Clinical outcome was evaluated in subgroups defined by genomic aberrations and VH status for both treatment arms combined. In univariate analyses, significant associations were found for the following parameters: the overall response rate was significantly lower in the subgroup with 17p- (53.8% vs. 89.6%, P=0.001), the median PFS was significantly shorter in the subgroups with 11q- (17.4 vs. 26.8 m, P=0.044), 14q- (14.5 vs. 24.5 m, P=0.018), and 17p- (11.0 vs. 24.1 m, P=0.002), and the median OS was significantly shorter in the subgroup with 17p- (15.9 m vs. not reached, 75% survival at 43.8 m, P & lt;0.001, Figure 1). Multivariate analysis was performed including the treatment arms, specific genomic aberrations, and the VH mutation status as possible prognostic factors: the parameters with significant adverse impact were F monotherapy (HR 1.70, 95%CI 1.12-2.58, P=0.013) and 17p- (HR 3.67, 95%CI 1.66-8.14, P=0.001) regarding PFS, but only 17p- (HR 7.32, 95%CI 2.44-21.90, P & lt;0.001) regarding OS. In conclusion, this first analysis of the prospective CLL4 trial shows that 17p- CLL is characterized by a short OS after F-based first line therapy. In future trials, alternative primary treatment strategies of proven efficacy in 17p- CLL such as alemtuzumab should be considered for these patients. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.715.715
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 4
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    Protein Expression Patterns of Candidate Genes Involved in Apoptosis and Cell Cycle Control in Genetic Subgroups of Chronic Lymphocytic Leukemia.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 2796-2796
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2796-2796
    Abstract: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a highly variable clinical course. Genomic aberrations (such as 13q−, 11q−, +12q, 17p−) can be found in about 80% of CLL cases and define pathogenic as well as clinical subgroups. Similarly, the mutational status of the variable region of the immunoglobulin heavy-chain gene (VH) identifies subgroups with different maturation stage and clinical outcome. In this study protein expression levels of candidate genes involved in cell cycle and apoptosis control (p53, ATM, Akt1, PI3-K, p21, p27, cdk4, Cyclin-D1, D2, D3, Bax, Bcl-2, Apaf-1, Smac, XIAP, cIAP2, survivin) were examined by Western Blotting. A total of 87 CLL cases derived from the subgroups with 11q- (n=22), 17p-/p53 mutation (n=18), +12q (n=24), 13q- (n=8) or a normal karyotype (n=15) were studied and compared to the cell lines EHEB and JVM-2. VH-mutation status was available for 65 cases (unmutated n=48, mutated n=17). Due to limitations in sample availability not all proteins could be examined in all cases. A highly homogenous expression pattern for all the proteins studied was observed in the CLL subgroup with a normal karyotype. This pattern was independent of the VH-status. CLL samples with normal karyotype, +12q and 13q deletion showed equal levels of ATM as compared to EHEB and JVM-2. As compared to cases with a normal karyotype the ATM level within the 11q- subgroup was reduced in 5 cases and absent in 1 case among 11 evaluable 11q- cases. The 17p- subgroup was comprised of 3 cases with concomitant 17p- and 11q- and 15 cases with 17p- but no 11q-. The latter group showed ATM protein levels comparable to the levels of the normal karyotype group. In the group with 17p- and 11q- there was an ATM expression level similar to the groups with 17p- and normal karyotype in two cases while one case had a reduced ATM protein level comparable to the 11q- subgroup. All cases with 17p- exhibited a stronger expression of p53 as compared to the cell lines and all other cases, except for one case with normal karyotype and one with an 11q-. No p53 mutations could be detected in exons 5–9 by sequencing in these two cases. High levels of survivin protein were found in all cases with 17p- and/or 11q-, 13q-, +12q while the subgroup with a normal karyotype showed lower levels. High levels of cdk4 protein were expressed in cases with 17p-, 11q- and 13q- while cdk4 protein levels were low in the subgroup with +12q and normal karyotype. Regarding p21, p27, Bcl2, Bax, Smac, Apaf-1, Cyclin D1–D3, cIAP2, XIAP, Akt1 and PI3K no variation in the expression levels were observed across the genetic CLL subgroups. Comparing the CLL cases to the cell lines the differences in expression levels were found for the cell cycle regulators Cyclin D1, D2, D3, p21 and p27. While the cell lines showed strong protein levels for Cyclin D1, D2, D3 and p21, they were nearly absent in the CLL cases. Expression of p27 was higher in all CLL cases as compared to JVM-2 and EHEB. In conclusion, the 17q- subgroup was the only group with a high level of p53 protein expression indicating that p53 is the affected gene in this subgroup. In contrast, the ATM protein levels are reduced only in a part of the 11q- cases indicating a possible role of additional candidate genes. Cases with +12q and normal karyotype showed weak expression of cdk4 pointing out a possible function in these subgroups.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.2796.2796
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 5
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    Short Telomeres Are Associated with Genetic Instability and the Occurrence of High Risk Genomic Aberrations in Chronic Lymphocytic Leukemia.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1178-1178
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1178-1178
    Abstract: Telomere length has been associated with the mutation status of the immunoglobulin variable heavy chain (VH) gene and the clinical course in chronic lymphocytic leukemia (CLL). In an unicentric CLL cohort of 108 patients, we have analyzed the telomere length by quantitative real time PCR, genomic aberrations by FISH with a comprehensive set of DNA probes (11q, 12q, 13q, 14q, 17p), the VH mutation status by DNA sequencing, ZAP-70 expression (clone 2F3.2, Upstate, according to Crespo et al., NEJM 2003) and CD38 expression by flow cytometry, to further study the prognostic impact and associations among these factors. A relative telomere-single-copy-gene ratio (T/S) was calculated for each sample, where low and high T/S values correspond to short and long telomere lengths, respectively. The median T/S value was 0.33 (range 0.06–1.18). There was an inverse correlation between telomere length and the following parameters: 1. VH homology (r=−0.56, p & lt;0.001), 2. CD38 expression (r=−0.44, p & lt;0.001) and 3. ZAP-70 expression (r=−0.25, p=0.01). Cases with T/S values below the median of 0.33 (short telomeres) and cases with T/S values above the median (long telomeres) had similar incidences of genomic aberrations (76 vs. 67%), 13q- (54 vs. 52%) and +12q (9 vs. 9%). In contrast, 13q- as a single aberration was significantly more frequently observed in cases with long telomeres (43 vs. 17%, p=0.006), whereas 11q- (30 vs. 9%, p=0.014), 17p- (24 vs. 0%, p & lt;0.001) and cases with two or more genomic aberrations (26 vs. 6%, p & lt;0.001) were significantly more frequent in cases with short telomeres. Compared to cases with long telomeres the treatment free survival from diagnosis (TFS) and overall survival (OS) in the group with short telomeres were significantly shorter (TFS: 29 vs. 67 months, p=0.002; OS: last observed death at 100 months, survival probability 57% vs. last observed death at 141 months, survival probability 77%, p=0.02). In conclusion, telomere length was inversely correlated with the VH mutation status, CD38 expression and ZAP-70 expression. Short telomeres were associated with genomic instability indicated by a high number of aberrations and the occurrence of 11q- and 17p- in CLL. These observations have biological and prognostic implications in CLL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1178.1178
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
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  • 6
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    VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome
    American Society of Hematology ; 2003
    In:  Blood Vol. 102, No. 8 ( 2003-10-15), p. 3003-3009
    Details
    In: Blood, American Society of Hematology, Vol. 102, No. 8 ( 2003-10-15), p. 3003-3009
    Abstract: Immunoglobulin variable heavy chain gene (VH) mutation status and VDJ rearrangement structure were analyzed in 141 patients with mantle cell lymphoma (MCL) and correlated with biologic and clinical characteristics; 29% of the MCLs displayed mutated VH using a 98% germline homology cutoff. Striking differences occurred in the VH mutation subgroups with respect to the use of specific V genes. Rearrangements involving V4-34 and V3-21 were almost exclusively unmutated, whereas rearrangements using V4-59 and V3-23 were typically mutated. Significant association occurred between mutated VH with shorter CDR3 lengths and the use of JH4b. V3-21 and V4-59 were involved in highly characteristic rearrangements, implying that antigen specificity might have been involved in MCL development. There was no evidence for isotype switch recombination or Bcl-6 expression in any MCL. ZAP70 expression was not different in VH-mutated or -unmutated MCL. Although the deletions 11q– and 17p– showed a balanced distribution, an overrepresentation was observed for trisomies +3q, +8q, and tetraploidy in the VH-unmutated subgroup and +12q in the VH-mutated subgroup. Clinically, mutated VH was associated with a higher rate of complete remission, but there was no correlation between VH mutation status and other clinical characteristics or overall survival.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2003-05-1383
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2003
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  • 7
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    High ZAP-70 and Differential Expression of B-Cell Receptor Related Genes in Chronic Lymphocytic Leukemia with V3-21 Gene Usage.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 773-773
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 773-773
    Abstract: V3-21 gene usage defines a distinct genetic subgroup of chronic lymphocytic leukemia (CLL) characterized by a poor clinical outcome regardless of the VH mutation status. V3-21 cases exhibit a highly characteristic B-cell receptor (BCR) structure as demonstrated by homologous CDR3 sequences and a restricted use of VL genes implicating a common antigen involved in tumor pathogenesis of this specific CLL subgroup. To investigate the role of antigenic stimulation in the pathogenesis of V3-21 using CLL, we analyzed the quantitative expression of genes involved in BCR signaling (ZAP-70, SYK, BLNK, LYN, PI3K, PLCG2, FOS), B-cell activation (TRAF3, STAT6, NFKB), and cell cycle or apoptosis control (ATM, BCL-2, BAX, CDK4, CCND1, CCND2, CCND3, p27, E2F1, MYC) in V3-21 cases in comparison to VH mutated (VH MUT) and VH unmutated (VH UM) cases not using the V3-21 gene. To obtain native expression signatures we studied a non-CD19-purified (nPU) cohort (V3-21: 18 cases, equally divided into VH mutated and VH unmutated cases; VH MUT: 17; VH UM: 19) and, for verification, a CD19-purified (PU) cohort (V3-21: 10 cases, equally divided into VH mutated and unmutated; VH MUT: 12; VH UM: 16) to exclude a contamination of the results by non-tumor cells. All cases were analyzed by FISH for +3q, 6q-, +8q, 11q-, +12q, 13q-, 17p-, and t(11;14) to avoid major imbalances of genomic alterations between the subgroups under study. As expected, ZAP-70 expression was higher in VH UM as compared to VH MUT cases in the nPU (p=0.007) as well as the PU cohort (p=0.009). V3-21 cases showed a higher ZAP-70 expression as compared to VH MUT (nPU: p=0.033; PU: p=0.038). This applied also when restricting this comparison to V3-21 mutated cases (nPU: p=0.018). Median ZAP-70 expression in the PU cohort was 1.15 in VH MUT vs. 7.69 in VH UM cases, as compared to 7.05 in V3-21 cases (V3-21 mutated cases: 10.69; V3-21 unmutated: 6.7). Other genes differentially expressed between the V3-21 and VH MUT subgroups in nPU cases were PI3K (p=0.048), PLCG2 (p=0.007), CCND2 (p=0.003), p27 (p=0.003), BCL-2 (p=0.025), and ATM (p=0.006). In addition, a set of genes was detected with a differential expression between V3-21 and VH UM (nPU) including PLCG2 (p=0.014), NFKB (p=0.023), CCND2 (p=0.001), p27 (0.002), and BAX (p=0.028). Notably, except for ZAP-70, all of the differentially expressed genes showed a lower expression in V3-21 as compared to the other subgroups. When comparing the V3-21 mutated and V3-21 unmutated subgroups (nPU), there were no significant gene expression differences except for CDK4, which showed a lower expression in V3-21 unmutated cases. Therefore, cases with V3-21 usage appear to show a rather homogeneous gene expression pattern independently of the VH mutation status, which can be distinguished from VH MUT and VH UM cases not using V3-21. The expression differences observed suggest a role of differential BCR signaling in the pathogenesis of this distinct CLL subgroup. Deregulation of cell cycle, apoptosis, and candidate genes such as ATM indicate the involvement of additional pathways in the pathogenesis of CLL cases using V3-21.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.773.773
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 8
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    V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia
    American Society of Hematology ; 2002
    In:  Blood Vol. 100, No. 4 ( 2002-08-15), p. 1410-1416
    Details
    In: Blood, American Society of Hematology, Vol. 100, No. 4 ( 2002-08-15), p. 1410-1416
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V100.4.1410.h81602001410_1410_1416
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2002
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  • 9
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    Autologous graft-versus-host disease–like syndrome after an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation for chronic lymphocytic leukemia
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 6 ( 2006-09-15), p. 2127-2130
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 6 ( 2006-09-15), p. 2127-2130
    Abstract: A high incidence of autologous graft-versus-host-disease (auto-GVHD) was observed after an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation (auto-SCT) for chronic lymphocytic leukemia (CLL). Skin rash developed in almost all surviving patients (87%). In 7 patients (58%), a diagnosis of auto-GVHD was made (compared with 0% after TBI/Cy; P = .01). All patients with auto-GVHD required immunosuppression, and 3 of 7 were hospitalized because of GVHD. The median duration of GVHD was 517 days (range, 60-867 days). Auto-GVHD was associated with an abnormally high CD4/CD8 ratio because of severe depletion of CD8+ T cells, pointing to a potential pathomechanism. High non–relapse-related mortality led to the discontinuation of the trial. Current results do not support the use of high-dose alemtuzumab combined with total body irradiation (TBI) and autologous stem cell transplantation (auto-SCT). However, the addition of alemtuzumab led to improved disease control at the molecular level. Longer follow-up will show whether the GVHD-like syndrome may contribute to prolonged minimal residual disease (MRD) negativity.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2006-04-007898
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 10
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    The Receptor for Hyaluronic Acid Mediated Motility (RHAMM): Characterization as an Immunotherapeutical Target in Chronic Lymphocytic Leukemia (CLL) and First Results of RHAMM-Derived Peptide Vaccination Trial.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 2051-2051
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2051-2051
    Abstract: Background and Aims: The increased expression of receptor of hyaluronic acid mediated motility (RHAMM) was noted in CLL. The defective expression of RHAMM-exon4 splice variant that correlated with chromosomal instability was found to bear negative prognostic value in patients with multiple myeloma. Therefore, here we characterized expression of RHAMM with its splice variants and correlated it with prognosis in CLL. Moreover, based on our previous results we initiated a RHAMM-derived R3 peptide vaccination study for patients with B-CLL in early stages of disease. Methods: Messenger RNA expression of RHAMM/CD168 was assessed by quantitative RT-PCR in blood samples from 65 B-CLL patients, at the time of diagnosis. The splice variant expression was measured using fluorescence capillary electrophoresis. Three hundred mcg RHAMM R3 peptide (ILSLELMKL) emulsified with the incomplete Freund’s adjuvant (ISA-51) day 3, as well as GM-CSF days 1–5, was administrated four times subcutaneously at a biweekly interval. Results: The real-time RT-PCR results revealed higher RHAMM/TBP expression rates in patients with unmutated IgVH status compared with mutated CLL cases (0.047 vs. 0.029, p=0.012). Both splice variants RHAMMFL as well as RHAMM-exon4 showed significantly higher expression in unmutated CLL cases. Increased expression of RHAMM/TBP was noted in advanced stages of disease. A tendency towards higher RHAMM/TBP expression ratios was observed in B-CLL cases with del11q. CLL patients with a RHAMM/TBP ratio & gt;0.028 showed a significantly shorter median treatment-free survival (TFS) (16 vs. 38 months, p=0.0019). In a bivariate analysis, patients with VH mutated status and lower amounts of RHAMM presented longer TFS compared to unmutated cases with a high RHAMM expression (110 vs. 8 months, respectively). An enhanced RHAMM expression was observed in bone marrow samples of 5 B-CLL patients compared with the results obtained in blood (RHAMM/TBP 0.102 vs 0.032). Similar tendency to higher RHAMM/TBP ratios was observed after CD40L stimulation (RHAMM/TBP 0.025 vs.0.113). In five patients who completed all four doses of R3 peptide vaccine no toxicity related to vaccine was observed. Reduction of leukemic cells was noted in 3 patients but no clinical responses meeting NCI criteria was observed. Immunological responses were observed in patients who achieved hematological improvement. Conclusion: RHAMM/CD168 is a novel LAA in B-CLL patients, and its expression levels are correlated with the clinical course of the disease. RHAMM expression might indicate the proliferative potential of leukemic cells. First results of peptide vaccination using RHAMM-derived peptide showed limited reduction of tumor burden.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.2051.2051
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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