Prognostic Factors of Chinese Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4387-4387
Author(s):  
Jianyong Li ◽  
Wei Xu ◽  
Chun Qiao ◽  
Yu-Jie Wu ◽  
Kourong Miao ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Gene Families ◽  
Lymphocytic Leukemia ◽  
High Expression ◽  
Chinese Patients ◽  
Cytogenetic Abnormalities ◽  
Western Countries ◽  
Mutational Status ◽  
Clinical Stages

Abstract Abstract 4387 Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies in the Western countries, however, infrequent in Asian populations. Although the median survival is around 10 years, CLL is a disease with an extremely variable clinical course with overall survival times ranging from months to decades; some patients never need treatment, while others require intensive treatment early after diagnosis. Some factors, such as clinical stages, IGHV mutational status, cytogenetic abnormalities, ZAP-70, and the expression of CD38 in leukaemic cells, were strong indicator of prognosis in CLL. However, the prognostic factors of Chinese patients with CLL compared with the Western countries have not yet been clarified. The aim of this study was to explore the influence of factors on the prognosis of Chinese patients with CLL. One hundred and twenty-nine patients with CLL were enrolled in this study. Multiplex PCR and sequencing, fluorescence in situ hybridization (FISH), and flow cytometry were used to detect IGHV mutational status, cytogenetic abnormalities, and the expression of ZAP-70 and CD38, respectively. A panel of FISH probes included 13q14 (D13S319), 17p13 (p53 gene), 11q23 (ATM gene), 6q23(MYB gene), the centromere of chromosome 12 (D12Z3) and 14q32 (IGHC/IGHV). In 129 CLL patients, according to the Binet clinical staging system, 65 (50.4 %) patients were in Binet A, 28 (21.7 %) in Binet B and 36 (27.9 %) in Binet C. Eighty-four (65.1%) patients had mutated IGHV, and 45 (34.9%) had unmutated IGHV. The most frequently expressed VH gene family was found to be VH3 (50.4%) followed by VH4 (32.6%), VH1 (10.9%), VH2 (2.3%), VH5(2.3%) and VH7 (1.6%), with no expression of VH6 gene families. VH1-69 and VH3-21 which commonly overused in Western CLL patients were very low in our cohort (0.8% and 3.1%, respectively). Molecular cytogenetic aberrations were found in 94 patients (72.9%) and 36 patients (27.9%) with more than two abnormalities. The most frequent abnormalities detected in our patients was del(13q14), with an incidence of 53.0%, followed by 14q32 translocation of 20.2%, +12 of 18.3%, del(11q23) of 10.8%, del(17p13) of 10.o%, and del(6q23) of 6.1%. Forty-one patients (31.8%) were positive for ZAP-70 (≥20%), and 51 patients (39.5%) were positive for CD38 (≥30%). With a median follow-up of 32 months (range, 4-58 months), eight patients (6.2%) died (CLL-related deaths). In univariate analysis for survival, advanced Binet stage (P=0.023), unmutated IGHV status (P=0.002), deletions of 17p13 or 11q23 (P=0.003), high expression of ZAP-70 (P=0.034), and high expression of CD38 (P=0.046) were poor prognostic factors. The prognostic factors with statistical significance were further used in a two-variables Cox analysis, which comparing unmutated IGHV status to other prognostic factors individually to show prognostic independence. The unmutated IGHV status were the independent prognostic factors and strongly associated with OS. This study demonstrates that the frequencies of IGHV gene families indicated significant difference in Chinese CLL patients compared with Western patients, suggesting involvement of ethnic and/or environmental factors in CLL disease initiation. The unmutated IGHV status, Binet clinical stages, Chromosomal aberrations of del(17p13) and del(11q23), high expression of ZAP-70 and CD38 have been shown highly predictive prognostic value for Chinese patients with CLL. Disclosures: No relevant conflicts of interest to declare.

Serum Thymidine Kinase Level in Chinese Chronic Lymphocytic Leukemia and Its Correlation with Other Prognostic Factors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4189-4189
Author(s):  
Jianyong Li ◽  
Wei Xu ◽  
Hui Yu ◽  
Hongxia Qiu ◽  
Chun Qiao ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Thymidine Kinase ◽  
Pcr Amplification ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Mutation Status ◽  
Cytogenetic Aberrations ◽  
Mutational Status

Abstract Objective To investigate serum thymidine kinase (TK) level in Chineses patients with chronic lymphocytic leukemia (CLL) and its correlation with other prognostic factors, including Binet stages, absolute lymphocyte count (ALC), lactate dehydrogenase (LDH), immunoglobulin heavy-chain variable region (IgVH) gene mutation status, ZAP-70 protein and CD38 expression level, and cytogenetic aberrations. Methods Serum TK1 level in 39 CLL patients was detected by TK monoclonal antibody (Anti-TK mAb) and enhanced chemiluminecence (ECL). IgVH mutation status was detected by multiplex PCR and sequencing of purified PCR amplification products. A panel of monoclonal antibodies and multiparametic flow cytometry were employed to immunophenotype and determine the expression of ZAP-70 protein and CD38. A panel of probes and interphase fluorescence in stu hybridization (FISH) were used to detect cytogenetic aberrations including 6q-, 11q-, +12, 13q-,17p- and IgH translocation. Results The level of TK1 was higher in CLL patients that in normal control (P<0.05). TK1 level was not signifigantly correlated with sex, age, Binet stages, CD38, and cytogenetic aberrations. Patients with higher level of ALC, LDH, ZAP-70 and unmutated IgVH genes had higher levels of TK1 than those with lower level of ALC, LDH, ZAP-70 and mutated IgVH genes (P=0.018, P=0.018, P=0.038 and P=0.030, respectively). Conclusions Serum TK1 level significantly correlates with ALC, LDH, ZAP-70 and IgVH mutational status, and could be a predictive marker of IgVH mutation status. Serum TK1 might be applied for the assessment of prognosis in Chinese patients with CLL.

scholarly journals Chronic Lymphocytic Leukemia in Kuwait

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5467-5467
Author(s):  
Salem Alshemmari ◽  
Ramesh Pandita ◽  
Abdulaziz Hamadah ◽  
Ahmad Alhuraiji
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Mutational Analysis ◽  
Staging System ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Western Countries ◽  
Mutational Status ◽  
Study Results ◽  
History Of

Background :Chronic lymphocytic leukemia (CLL) is common malignancy in Western countries. However, little known about this disease entity in our area. This study exploring the biology in out patients' population. Method:Patients with confirmed CLL under IGHV and TP53 mutational analysis at presentation or during follow up. We also integrated other clinical and biological parameter in this study. Results: A total of 137 cases were analyzed, median age 61 years (range:34-89); 30% of the cases age was<55 years at presentation. There was 108 males vs. 29 females M:F ratio 3.7. Two patients gave a family history of CLL, while 1 patient gave a history of other lymphoproliferative disorders. Binet staging system available in 134 cases, A: 109 (81.3%), B: 12 (9%), C:13 (9.7%). B2 macroglobulin elevated in 40/112 (36%) cases and 10/103 (10%) had M-spike. CD38 positivity reported in 37/112 (33%) of cases. Cytogenetics data evaluable in 85 cases: isolated del(13q): 35%, isolated trisomy 12 (16.5%), del(11q) (4.5%), del(17p)(2.4%). IGHV mutational status mutated vs unmutated: 40% vs 60%. Cases with available treatment information on 132 cases. Fifty cases required treatment due to disease progression. First line treatment Bendamustine-Rituximab (BR) 3 cases, Fludarabine Cyclophosphamide Rituximab (FCR) 30 cases and Chlorambucil with anti-CD 20 antibody 6 cases. At the time of review, 3 cases on ibrutinib (2 in 3rdline and 1 case in the 4thline). Conclusion: This is the first study to shed light on CLL in our area. There are biological differences between our patients' population and the western countries. Disclosures Pandita: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Prognostic Significance of Molecular Cytogenetics in Chinese Patients with Chronic Lymphocytic Leukemia: A Prospective Unicentric Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4690-4690
Author(s):  
Wei Xu ◽  
Jianyong Li ◽  
Li Li ◽  
Yujie Wu ◽  
Hui Yu ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Survival Time ◽  
Gene Deletion ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Molecular Cytogenetic ◽  
Western Countries ◽  
Cytogenetic Aberrations ◽  
Atm Gene

Abstract B-cell chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western countries, however, infrequent in the Eastern. It is characterized by a highly variable clinical course; some patients survive more than 20 years, whereas others die within a few months of diagnosis. The characteristics of Chinese patients with CLL compared with the Western countries have not yet been clarified. The aim of this study was to prospectively explore characteristics and prognostic significance of molecular cytogenetic aberrations in Chinese patients with CLL. Interphase fluorescence in situ hybridization (FISH) and a panel of probes (LSI D13S319,LSI p53,LSI ATM,CEP 12,LSI MYB,LSI IGHC/IGHV) were used to detect cytogenetics abnormalities in 95 patients with CLL. Cytogenetics aberrations and their association with some other prognostic factors were analyzed. Kaplan-Meier was used for survival time. Out of the 95 CLL patients, molecular cytogenetic aberrations were found in 69 (72.6%) cases and 25 (26.3%) patients showed more than two kinds of abnormalities. The most frequent abnormalities detected were del(13q14) in 46 cases (48.4%), followed by trisomy of chromosome 12 in 22 patients (23.2%), 14q32 rearrangement in 21 patients (22.1%), del(17p13) in 16 patients (16.8%), del(11q22) in 9 patients (9.5%) and del(6q23) in 5 patients (5.3%). There were no significant differences of molecular cytogenetic aberrations in sex, age, Binet stages, peripheral lymphocyte count, and the levels of lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), and ZAP-70. The TP53 and ATM gene deletion rates were higher in the group of CD38 high expression than that in the group of low expression (P=0.047 and P=0.001). No patient with TP53 and ATM gene deletion achieved complete response (CR) among 41 patients received treatment with fludarabine. The survival time was shorter in patients with high levels of LDH (P=0.028), β2-MG (P=0.012), and CD38 (P=0.000), and with TP53 gene deletion (P=0.000). Patients with sole del(13q14) had longer survival time than those with other abnormalities (P=0.044). It was showed that panel FISH has greatly increased the sensitivity of cytogenetic analyses and del(13q14) was the most frequent abnormality in CLL. Detection of molecular cytogenetic aberrations with FISH had important prognostic significance in CLL. The patients with sole del(13q14) had favorable outcome, and with del(17p13) had poor outcome.

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

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

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

The Prognostic Significance of Positive Direct Antiglobulin Test in Chinese Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4183-4183
Author(s):  
Wei Xu ◽  
Jianyong Li ◽  
Xin Cao ◽  
DAN-Xia Zhu ◽  
Lin Yao ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
Direct Antiglobulin Test ◽  
Chinese Patients ◽  
Prognostic Impact ◽  
Antiglobulin Test ◽  
Positive Direct

Abstract Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemias in the Western countries, however, infrequent in the Eastern. Autoimmune hemolytic anemia (AHA) is a complication in chronic lymphocytic leukemia (CLL). The direct antiglobulin test (DAT) may be positive at some time during the disease course in up to 35% of cases, but overt AHA occurs less frequently. The aim of the study was to explore the prognostic impact of positive DAT in Chinese patients with CLL and its correlation with other prognostic factors, including Binet stages, lymphocyte count in peripheral blood, lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), IgVH mutation status, ZAP-70, CD38 and cytogenetic abnormalities. Out of the 80 Chinese patients with CLL, positive DAT was found in 21 (30.6%) cases. The incidence of positive was 12.5% in Binet A, 23.8% and 44.4% in Binet B and C, respectively. The incidence of positive DAT was significantly increased at Binet C, compared with Binet A (P=0.006), and the presence of higher LDH and β2-MG levels correlated strongly with positive DAT (P=0.006 and P=0.004, respectively). Patients with unmutated IgVH genes had higher incidence of positive DAT than did patients with IgVH mutations (P=0.042), and positive DAT was also associated with higher level of ZAP-70 and CD38 (P=0.004 and P&lt;0.001, respectively). We also analyzed positive DAT in different cytogenetic subgroups. Higher incidence of positive DAT was found in patients with unfavorable cytogenetic aberrations (deletion in 17p13 or 11q22) in contrast to lower level in good risk cytogenetics (deletion in 13q as the sole abnormality) (P = 0.002). Positive DAT was associated with poor outcome. Survival analysis showed that the patients with positive DAT had significantly shorter OS (mean, 106.3 months) (95% CI, 74.7 to 137.8 months) than the patients negative DAT (mean, 151.5 months) (95% CI, 122.3 to 180.6 months) (P=0.024). Patients treated with fludarabine were not likely to remain DAT positive and to change from negative to positive (P=0.209). In conclusion, DAT status provides a new prognostic indicator and correlates with other clinical or laboratory prognostic factors, and might be applied for the assessment of prognosis in patients with CLL.

scholarly journals Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Fortunato Morabito ◽  
Giovanni Tripepi ◽  
Riccardo Moia ◽  
Anna Grazia Recchia ◽  
Paola Boggione ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Doubling Time ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Prognostic Role ◽  
Mutational Status ◽  
Binet Stage ◽  
Time To First Treatment

The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone’s biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT &gt;12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHVunmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ2 = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell’C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT’s explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHVunmut and LDT&gt;12months group showed a predominant prognostic role over IGHVmut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients.

MicroRNA-29c and 223 Are Powerful Prognostic Factors for Chronic Lymphocytic Leukemia and Improve Risk Stratification When Combined with ZAP70 and LPL in a qPCR Score.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1066-1066
Author(s):  
Basile Stamatopoulos ◽  
Nathalie Meuleman ◽  
Dominique Bron ◽  
Benjamin Haibe-Kains ◽  
Pascale Saussoy ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Lymphocytic Leukemia ◽  
Early Therapy ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Binet Stage

Abstract Background: MicroRNAs (or miR) are a novel class of small noncoding RNA involved in gene regulation. Aberrant microRNA expression has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Currently, the heterogeneous evolution of this disease can be predicted by several prognostic factors. Nevertheless, a better individualization of the outcome in a given patient is still of utmost interest. Methods: In the current study, we investigated the expression of two microRNAs, miR-29c and miR-223, compared them to other biological or clinical markers and proposed a quantitative real-time PCR (qPCR) score to better assess CLL outcome. All cut-offs were calculated by ROC curve analysis maximising the correlation with the immunoglobulin variable heavy chain (IgVH) mutational status; statistical differences were evaluated by Mann Whitney test or Kruskal-Wallis test ; treatment-free (TFS) and overall (OS) survival differences were investigated by log-rank test or Cox proportional hazard ratio (HR). Results: miR-29c and miR-223 expression decreased significantly with progression along Binet Stage A to C (P=0.0010 and P=0.0183, respectively), and were significantly lower in poor prognosis subgroups defined by cytogenetic abnormalities, IgVH mutational status, lymphocyte doubling time, solubleCD23, β2-microglobulin, ζ-associated protein 70 (ZAP70), lipoprotein lipase (LPL) and CD38 expression. Furthermore, miR-29c and miR-223 could predict TFS (n=110, P=0.0015 and P&lt;0.0001, respectively) and OS (n=110, P=0.0234 and P=0.0008, respectively). Regarding all these results, we developed a qPCR score (from 0 to 4 poor prognostic markers) combining miR-29c, miR-223, ZAP70 and LPL in order to stratify treatment and death risk in a 110 patient cohort with a median follow-up of 72 months (range, 2–312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of &gt;312, 129, 80, 36 and 19 months, respectively (HR=17.00, P&lt;0.0001). Patient with a score of 0–1/4, 2–3/4 and 4/4 had a median OS of &gt;312, 183 and 106 months, respectively (HR=13.69, P=0.0001). Interestingly, during the first 50 months after diagnosis, only 10% of patients with a 0/4 score required a treatment, when compared to 100% of the 4/4. Furthermore, during the total follow-up (312 months), patients with a 4/4 score had a 27-fold higher risk to be treated and a 31-fold higher risk to die comparing to patients with a 0/4 score. This score was validated by a 10-fold cross-validation (prediction accuracy of 82%). Finally, in Binet stage A patients (n=77), this score remained relevant and significant for TFS and OS prediction (HR=18.56, P&lt;0.0001 and HR=12.5, P=0.0068, respectively). Conclusions: we showed that (i) miR-29c and miR-223 levels were decreased in poor prognosis patients regarding several well-known prognostic factors; (ii) a low level of these two microRNAs is thus associated to disease aggressiveness, tumor burden and poor clinical evolution; (iii) we also showed that these two microRNAs could predict TFS and OS; (iv) we proposed a qPCR score to better individualize evolution of a particular CLL patient. This score will help to identify patients who will need early therapy and require thus a closer follow-up.

Shorter Telomeres Are Associated with the Unfavourable Chromosomal Aberrations Del 17p and Del 11q in Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3131-3131
Author(s):  
Ludger Sellmann ◽  
Dirk de Beer ◽  
Marius Bartels ◽  
Holger Nueckel ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Telomere Length ◽  
Chromosomal Aberrations ◽  
Germ Line ◽  
Average Length ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Snp Chip ◽  
Mutational Status

Abstract BACKGROUND: In chronic lymphocytic leukemia (CLL) short telomeres were shown to be associated with mutational status, progression free survival (PFS) and overall survival (Damle et al., 2004). Chromosomal instability increases with shortening of telomeres. Recently, a relationship between telomere length and number of chromosomal aberrations has been shown if telomere length was investigated by quantitative real-time polymerase chain reaction (Tel-PCR) (Roos et al., 2008). The aim of the present study was to correlate average telomere length of individual cells measured by multicolor flow-FISH to established prognostic factors and genomic aberrations. PATIENTS and METHODS: Blood samples from 64 patients with CLL were analyzed. Flow cytometry was performed for quantification of ZAP-70 and CD 38 expression with a cut off at 20%. Immunoglobulin variable heavy chain (IGVH) genes were sequenced. An IGVH gene sequence with less than 98% homology with the corresponding germ-line sequence was considered to be mutated. Chromosomal alterations were investigated by fluorescence in situ hybridization (FISH) with the following gene probes: LSI 13q14, LSI 13q34, CEP 12, LSI 17p13, LSI 11q22–23. Copy number changes were also detected in 18 samples by SNP-chip analysis. The average length of telomere repeats at chromosome ends was measured by multicolor flow-FISH. Values of telomere length from CLL cells were correlated to values of telomere lengths of B lymphocytes from healthy age matched individuals (delta telomere length=Δtel). RESULTS: The average telomere length of the clonal B-cells was short. Patient samples from advanced Binet stages (B/C) had significantly shorter telomeres (Δtel −4.8 ± 1.0 kb) than patients samples from Binet A (Δtel −3.4 ± 1.2 kb, p=0.03). The average telomere length was significantly shorter for ZAP-70+ (Δtel −5.0 ± 0.5 kb) and CD38+ (Δtel −4.9 ± 0.7 kb) patient samples than for ZAP-70− (Δtel −2.4 ± 0.8 kb) and CD38− (Δtel −3.0 ± 1.0 kb) patient samples, respectively (p&lt;0.005, p&lt;0.005). IGVH unmutated CLL samples exhibited significant shorter telomere lengths (Δtel −4.8 ± 0.4 kb) than mutated samples (Δtel −2.8 ± 0.9 kb, p&lt;0.005). Interestingly CLL samples harbouring del 17p and del 11q had significantly shorter average telomere length (Δtel −5.3 ± 0.2 kb, n= 8) than samples without these aberrations (Δtel −4.0 ± 1.2 kb; n= 56, p&lt;0.005). Furthermore we found a tendency of an increase in the number of chromosomal aberrations detected by SNP-chip with shorter telomeres. DISCUSSION: We are able to confirm significant shorter telomeres in CLL samples with unfavourable prognostic factors like advanced Binet stage, positivity for ZAP-70 or CD38 and unmutated IGVH genes compared to their favourable counterparts. CLL samples with the chromosomal aberrations del 17p and del 11q are associated with bad clinical outcome. CLL with these aberrations of the present study demonstrated significantly shorter telomeres compared to cases without these abnormalities. Additional studies relating impact of telomere length on genomic instability detected by SNP-chip are ongoing.

Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy

2006 ◽  
Vol 24 (3) ◽  
pp. 437-443 ◽  
Author(s):  
John C. Byrd ◽  
John G. Gribben ◽  
Bercedis L. Peterson ◽  
Michael R. Grever ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Prognostic Factors ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Interphase Cytogenetics ◽  
Mutational Status ◽  
The Impact

Purpose Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig VH mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy. Methods We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712. Results Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig VH mutational status to classify risk, there was no association between complete response rate with either unmutated Ig VH mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig VH unmutated patients as compared with the Ig VH mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk. Conclusion These data demonstrate that high-risk CLL patients characterized by Ig VH unmutated (≥ 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig VH mutational status and interphase cytogenetics on treatment outcome.

Sign in / Sign up

Export Citation Format

Share Document