Complex Karyotype in Patients with Chronic Lymphocytic Leukemia.

Abstract Chronic Lymphocytic Leukemia (CLL) is heterogeneous and there are two clinical forms with different outcome, in which initial stage and parameters of tumor burden, expression of CD38 and /or ZAP 70, chromosome abnormalities such as 11q23 and 17p13 are associated with a more aggressive course of disease. The aim of this study is to analyse clinical and biological characteristics and outcome of patients with complex karyotype, and to asses if there are differences with other genomic aberrations. Fifty patients diagnosed of CLL between 1980 and 1994 were studied (median age: 71 yrs; female/male: 18/32; median follow up 6.6 yrs.). Biological studies with flow cytometry and fluorescence in situ hybridization were done on cryopreserved blood cells. Clinical stages at diagnosis were: Rai stage 0: 56%; I: 20%; II: 16%; III: 6%; IV: 2%. Binet A: 72%; B: 20%; C: 8%. At the time of diagnosis 37% of patients needed treatment and 61% presented disease progression. At the time of this study, 10% of patients are alive with a median follow up of 15.3 yrs. Seven patients (28%) presented complex karyotype. At the time of diagnosis 43% patients needed treatment and clinical stages were: Rai stage O: 29%, I: 14%, II: 43%, III: 14%, IV: 0%. Binet A: 43%; B: 43%; C: 14%. Median overall median survival was 72 months. The most frequent genomic aberrations associated with complex karyotype were: del (17p13) and trisomy 12 (60 %). Cellular expression of CD38 and ZAP 70 was not able to separate this group. Compared with other chromosome abnormalities, there were not important differences in clinical stage at diagnosis or expression of CD38 or ZAP 70, but overall median survival could distinguish three groups: del 11q22-23 or del 17p13 (34 months, p < 0,05) complex karyotype (72 months), and trisomy 12 or del 13q14 (79 months, p > 0,05). In conclusion, complex karyotype is frequently formed by del 17p13 and trisomy 12 and identifies a subgroup of patients with better prognosis compared with isolated p53 deletion. More studies have to be realized to determine if trisomy 12 is a cell defence mechanism.

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Chronic Lymphocytic Leukemia, Detection of Five Significant Prognostic Genomic Aberrations by Interphase Two-Color Fluorescence in Situ Hybridization Analyses: a Study of 24 Patients with Clinical Follow-up Ranged From 7 to 120 Months.

Blood ◽

10.1182/blood.v114.22.4716.4716 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4716-4716

Author(s):

Carlos Sergio Barragan ◽

Silvia B. Hansson ◽

Silvina A Cicchini ◽

Monica Tamashiro ◽

Pablo G Dinardo ◽

...

Keyword(s):

In Situ Hybridization ◽

Chronic Lymphocytic Leukemia ◽

Fluorescence In Situ Hybridization ◽

Lymphocytic Leukemia ◽

The Other ◽

Prognostic Information ◽

Trisomy 12 ◽

Genomic Aberrations

Abstract Abstract 4716 Background Conventional cytogenetic studies by chromosome banding are difficult in chronic lymphocytic leukemia (CLL) because of the low in vitro proliferation or mitotic activity of CLL cells. Interphase Fluorescence in situ hybridization (FISH) has improved the detection of genomic aberrations in CLL. We used this method to identify chromosomal abnormalities in patients with CLL at diagnosis, progression disease, after relapse or treatment failure. Methods Mononuclear cells from the blood of 24 Caucasian patients, 12 men and 12 women, age ranged from 39 to 84 years (median, 64) with CLL were analyzed by FISH, for deletions in chromosome bands 11q22.3, 6q23.3, 13q14.3, 17p13.1, and trisomy of chromosome 12. The patients stages were 0A:12; IA:1; IIA: 2; IIB:4; IIIA:1, IIIB:1; IIIC:1; IV:2. The follow up ranged was from 7 to 124 months. Results Chromosomal aberrations were detected in 15 of 24 (58.33 percent). The most frequent changes were a 12 trisomy (37.5 percent), a deletion in 11q23.3, (12.5 percent), a deletion in 6q23.3 (8.33 percent), a deletion in 17p13.1 ( 8.33 percent), a deletion in 13q14.3 8.33%. A patient showed four aberrations tri(12), d(17p13.1), d(6q23.3), d(11q23.3), she was resistant to Fludarabine + Cyclophosfamide treatment and Rituximab CHOP and had a survival of 51 months. The other patients with trisomy 12 alone are still alive and the survival were ranged from 7 to 120 month. Trisomy 12 was correlated with enlarged lymph nodes. Two patients undergo Richter transformation one of them with 6q23.3 the other without the aberrations assessed. The patients with deletion 11q23.3 were resistant to standard regimens treatment. Ten patients have stable disease (0A), clinical follow up ranged from 7 to 124 months; three with trisomy 12 the others without the genetic aberrations assesses. Longest survivals (124 month) were found in patients without aberration or with trisomy 12. Patients without aberrations or with trisomy 12 had similar evolution. A female patient, 84 years old state in stage 0A along 13 month with d(17p13.1), and d(11q23.3). Patients with 11q23.3 deletions had the shortest median treatment-free interval (11months), and those with trisomy 12 or deletion 13q14.3 had the longest (124 and 40 months respectively). Patients with 11q23.3 and 6q23.3 deletion had more advanced disease. Two patients died, both of them with 6q23.3, overall survival 51 and 54 months respectively. ZAP 70 and CD38 do not have correlation with presence of the genomic aberration assessed .The present of 11q23.3, 6q23.3, 17p13.1, age, the white-cell count, Rai - Binet stage and the serum lactate dehydrogenase level gave significant prognostic information. Conclusions Genomic aberrations are independent prognosis factors of disease progression and survival in Chronic lymphocytic leukemia; establish them properly will be an important goal standard, therefore incorporate FISH assay routinely could give significant prognostic information. These genetic findings are predictors of outcome treatment regimens and could help to choose the appropriated strategic treatments. Disclosures: No relevant conflicts of interest to declare.

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Near-Tetraploidy Is Strongly Associated with Development of Richter's Transformation in Chronic Lymphocytic Leukemia Patients Receiving Ibrutinib

Blood ◽

10.1182/blood.v128.22.3198.3198 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3198-3198

Author(s):

Cecelia R. Miller ◽

Amy S. Ruppert ◽

Nyla A. Heerema ◽

Kami J. Maddocks ◽

Jadwiga Labanowska ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Complex Karyotype ◽

Advisory Committees ◽

Data Set ◽

Richter’S Transformation ◽

Richter's Transformation

Abstract Ibrutinib is a promising targeted therapy for chronic lymphocytic leukemia (CLL). However, a small subset of patients progress on ibrutinib either through progressive CLL or Richter's transformation. Patients responding to ibrutinib and then progressing with Richter's transformation do so most commonly within the first 2 years of treatment and have an extremely poor prognosis. Identifying biomarkers associated with this transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas; however, its incidence in CLL has not been described. We investigated the prevalence of near-tetraploidy in CLL patients prior to starting ibrutinib and identified it as a pre-treatment biomarker for Richter's transformation. We examined near-tetraploidy in a large series of CLL patients enrolled across four ibrutinib clinical trials at the Ohio State University, for which extensive correlative studies and follow up data are available (previously described by Maddocks et al., JAMA Oncol, 2015). We identified this abnormality in 9 of 300 patients (3.0%, 95% CI: 1.4-5.6) in blood or bone marrow samples taken prior to starting therapy. Near-tetraploidy was detected by the presence of four signals with four or more fluorescence in situ hybridization (FISH) probes and confirmed in the metaphase karyotype of each patient in at least one cell. Near-tetraploidy was associated with aggressive disease characteristics including: Rai stage 3/4 (p=0.03), deletion 17p (p=0.03), and complex karyotype (p=0.01), as well as trisomy 12 (p=0.05). With a median follow-up time of 40.5 months, in patients positive with near-tetraploidy, one patient (11%) progressed with CLL on ibrutinib, six patients (67%) progressed with Richter's transformation, and two patients (22%) were still on treatment. Cumulative incidence of Richter's transformation was significantly higher in patients with near-tetraploidy (Figure; p<0.0001). Notably, near-tetraploidy was not associated with progression with CLL alone (p=0.53). In a multivariable model, both near-tetraploidy (HR 8.66, 95% CI 3.83-19.59, p<0.0001) and complex karyotype (HR 4.78, 95% CI 1.42-15.94, p=0.01) were independent risk factors for discontinuing ibrutinib due to Richter's transformation. Our results suggest that near-tetraploidy is a distinct biomarker to assess in patients initiating ibrutinib which would predict a high risk for Richter's transformation. As a biomarker it will be important to confirm this association in a second independent data set as well as interrogate the distinct pathophysiology of this genomic subset of CLL. Figure Figure. Disclosures Lozanski: Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding. Jones:Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Awan:Novartis Oncology: Consultancy; Pharmacyclics: Consultancy; Innate Pharma: Research Funding. Blum:Pharmacyclics: Research Funding. Woyach:Acerta: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding.

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Fluorescent in situ hybridization and cytogenetic studies of trisomy 12 in chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v81.10.2702.2702 ◽

1993 ◽

Vol 81 (10) ◽

pp. 2702-2707 ◽

Cited By ~ 68

Author(s):

SM Escudier ◽

JM Pereira-Leahy ◽

JW Drach ◽

HU Weier ◽

AM Goodacre ◽

...

Keyword(s):

In Situ Hybridization ◽

Chronic Lymphocytic Leukemia ◽

Median Survival ◽

Chromosomal Abnormalities ◽

Residual Disease ◽

Clonal Evolution ◽

Lymphocytic Leukemia ◽

Cytogenetic Studies ◽

Trisomy 12

Abstract Cytogenetic studies (CG) of 475 chronic lymphocytic leukemia (CLL) cases showed trisomy 12 in 6.1% or 26% of patients with abnormal karyotypes. Fluorescence in situ hybridization (FISH) detected trisomy 12 in 35% of 117 CLL patients. Only 34.6% of cases detected by FISH were detected by CG. Twelve patients had low levels of trisomic cells (4% to 11%) relative to clonal B cells (47.5% to 86%), suggestive of clonal evolution. Untreated patients with trisomy 12 were predominantly male (P < .05) and had an increased incidence of splenomegaly (P < .03). Patients with trisomy 12 were more likely to be previously treated and had advanced Binet stage compared with those without trisomy 12. The median survival was shorter in patients with trisomy 12 (7.8 years) and patients with other chromosomal abnormalities without trisomy 12 by FISH (5.5 years) than in patients with diploid karyotypes (14.4 years). The response to fludarabine was similar to that of patients with diploid karyotypes, but there was a trend for earlier disease progression. FISH detected residual disease in all patients with trisomy 12 in complete (n = 6) or partial remission (n = 4). As few as 1 trisomic cell in 5,000 was detected by performing FISH on fluorescence-activated cell sorter-sorted cells. Trisomy 12 was absent in T cells in patients with trisomy 12. We conclude that FISH identifies trisomy 12 approximately 2.6 times more often than CG, readily identifies minimal residual disease, and predicts for a shorter median survival.

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ZAP-70 Expression, VH-Mutation Status, Genomic Aberrations and Prognosis in Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.1920.1920 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1920-1920 ◽

Cited By ~ 1

Author(s):

Alexander Kröber ◽

Dirk Kienle ◽

Dirk Winkler ◽

Andreas Bühler ◽

Till Seiler ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Gene Rearrangement ◽

Progressive Disease ◽

Clinical Course ◽

Surrogate Marker ◽

Lymphocytic Leukemia ◽

Mutation Status ◽

Free Survival ◽

Genomic Aberrations

Abstract The VH status is a strong prognostic marker in chronic lymphocytic leukemia (CLL). ZAP-70, a zeta associated tyrosine kinase physiologically expressed by T-cells, is overexpressed in VH unmutated CLL and could therefore serve as a surrogate marker for the VH status. We analyzed ZAP-70 expression (n=96), the VH status (n=75) and genomic aberrations (n=84) in a single center CLL cohort to study associations among these parameters and to assess their relative prognostic value. ZAP-70 expression was measured by 4-colour flow cytometry (CD5, CD19, CD3/56, ZAP-70) applying an unconjugated anti-ZAP-70-antibody (Upstate, clone 2F3.2) according to Crespo et al., NEJM 2003. ZAP-70 expression was positive (cut-off 20%) in 67% and negative in 33% of cases. VH was mutated in 33% and unmutated in 67% of cases. Unfavorable genomic aberrations (17p−, 11q−) were more frequently observed in cases with unmutated VH (46 vs. 9%) and in ZAP-70 positive cases (39 vs. 20%), while favorable genomic aberrations (13q− as single aberration) occurred more frequently in VH mutated (48 vs. 17%) and ZAP-70 negative subgroups (50 vs. 18%). ZAP-70 expression predicted the VH status in 84% of cases. At a median follow up time of 47 months (m), the median treatment free survival (TFS) of ZAP-70 positive and negative cases was 31 and 86 m (p=.057). The median TFS of the VH unmutated and VH mutated subgroups were 24 and 172 m (p<.001). Within the follow up time 10 deaths occurred. Of these, 8 cases exhibited high ZAP-70 expression and an unmutated VH, whereas 2 cases showed discordant results. Overall, discordant results for ZAP-70 expression and VH status were identified in 12 cases (ZAP-70 positive/VH mutated, 8 cases; ZAP-70 negative/VH unmutated, 4 cases). Of the 8 VH mutated cases with high ZAP-70 expression, only 1 case exhibited unfavorable genomic aberrations, 4 remained in stable disease, 4 developed progressive disease, 3 patients required therapy, and 1 of these 3 died within follow up time. Two of the 3 patients who required therapy, including the patient who died, showed a mutated V3-21 gene rearrangement, associated with an unfavorable outcome. Among the 4 cases with an unmutated VH and low ZAP-70 expression, 2 cases exhibited unfavorable genomic aberrations, 3 cases required therapy, 1 of these 3 died, and for one patient no clinical data were available. In summary, the imbalanced distribution of high risk genomic aberrations was similar when comparing the subgroups according to ZAP-70 expression and VH status. In our series an unmutated VH status predicted for shorter TFS, whereas high ZAP-70 expression did not reach significance. ZAP-70 expression was associated with unmutated VH, but a substantial number of cases showed discordant results for ZAP-70 expression and VH status. The pattern of genomic aberrations and the clinical course of the discordant cases were typical for their respective VH status. Compared to ZAP-70 expression the VH status appeared to be more informative in the prediction of the clinical course in our series of CLL patients.

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Mutations of NOTCH1 Are An Independent Predictor of Survival in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.283.283 ◽

2011 ◽

Vol 118 (21) ◽

pp. 283-283

Author(s):

Davide Rossi ◽

Silvia Rasi ◽

Giulia Fabbri ◽

Valeria Spina ◽

Marco Fangazio ◽

...

Keyword(s):

Multivariate Analysis ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Prognostic Role ◽

Trisomy 12 ◽

Notch1 Mutations

Abstract Abstract 283 The clinical course of chronic lymphocytic leukemia (CLL) ranges from very indolent, with a nearly normal life expectancy, to rapidly progressive leading to death and occasionally undergoing transformation to Richter syndrome (RS). TP53 disruption identifies a fraction of high risk CLL destined to experience a very short survival. High risk CLL, however, cannot be fully recapitulated by TP53 disruption and other lesions of cancer genes may be implicated in this aggressive phenotype. Analysis of the CLL coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of previously untreated CLL were utilized as training (n=309, median follow-up 6 years) and validation (n=230, median follow-up 7 years) cohorts. NOTCH1 mutations were analyzed by DNA Sanger sequencing in blind with respect to clinical data. In the training series, NOTCH1 mutations occurred in 34/309 (11.0%) patients, being mostly represented (26/34, 76.5%) by a recurrent two bp frameshift deletion (c.7544_7545delCT). The remaining NOTCH1 mutations (8/34, 23.5%) were frameshift deletions other than c.7544_7545delCT (n=7) and frameshift insertions (n=1). All mutations were predicted to disrupt the NOTCH1 PEST domain. CLL with NOTCH1 mutations preferentially carried unmutated IGHV genes (76.5%, p<.001). Other characteristics at presentation associated with NOTCH1 mutations were advanced Rai stage (26.5%, p=.006) and trisomy 12 (44.1%, p<.001). By univariate analysis, NOTCH1 mutations associated with an increase in the hazard of death (HR: 3.77; 95% CI: 2.14–6.66) and a significant overall survival OS shortening (p<.001) (Fig. 1A). Multivariate analysis selected NOTCH1 mutations as an independent risk factor of OS (HR: 4.22; 95% CI: 2.15–8.28; p<.001), after adjusting for age (p<.001), Rai stage (p=.005), IGHV mutation status (p=.465), 11q22-q23 deletion (p=.128), trisomy 12 (p=.183) and TP53 disruption (p<.001). The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to a shorter time to progression requiring treatment (p<.001), and a higher cumulative probability of RS development (p=.026). Although NOTCH1 mutated patients were devoid of TP53 disruption in 31/34 (91.2%) cases, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL (Fig. 1C). Analysis of the validation series confirmed: i) the prevalence of NOTCH1 mutations at CLL presentation (26/230, 11.3%); ii) the spectrum of NOTCH1 mutations at CLL presentation (c.7544_7545delCT: 21/26, 80.7%; other mutations: 5/26, 19.3%) iii) the adverse prognostic impact of NOTCH1 mutations in CLL both by univariate analysis (Fig. 1B) and by multivariate analysis (HR: 2.08; 95% CI: 1.10–3.93; p=.023); iv) the preferential mutually exclusive distribution of NOTCH1 mutations and TP53 disruption (25/26, 96.2%); v) that OS of NOTCH1 mutated CLL is similarly poor as that of TP53 disrupted CLL (Fig. 1D). The current study on 539 CLL documents that NOTCH1 mutations: i) represent one of the most frequent cancer gene mutations known to be involved at CLL presentation; ii) identify a subgroup of patients showing poor OS similar to that of TP53 disrupted cases; iii) exert a prognostic role independent of widely accepted clinical and genetic risk factors; iv) predict OS in series from different institutions, as documented by the training-validation approach chosen for the design of this study. Disclosures: No relevant conflicts of interest to declare.

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The complex karyotype landscape in chronic lymphocytic leukemia allows to refine the risk of Richter syndrome transformation

Haematologica ◽

10.3324/haematol.2021.278304 ◽

2021 ◽

pp. 0-0

Author(s):

Andrea Visentin ◽

Laura Bonaldi ◽

Gian Matteo Rigolin ◽

Francesca Romana Mauro ◽

Annalisa Martines ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Complex Karyotype ◽

Biological Variables ◽

Richter Syndrome ◽

Binet Stage ◽

The Impact

Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural abnormalities) or high-CK (CK with C5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter reallife retrospective study to test its prognostic impact. Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q-/TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; while mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (p<0.0001). We herein demonstrated that CK landscape at CLL diagnosis allows to refine the risk of RS transformation and we recapitulated clinico-biological variables into a prognostic model.

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Clinical Characteristics and Outcome of a Large Series of Patients with Chronic Lymphocytic Leukemia (CLL) According to ZAP-70 Expression.

Blood ◽

10.1182/blood.v104.11.14.14 ◽

2004 ◽

Vol 104 (11) ◽

pp. 14-14 ◽

Cited By ~ 1

Author(s):

Francesc Bosch ◽

Marta Crespo ◽

Neus Villamor ◽

Ana Muntañola ◽

Ana Ferrer ◽

...

Keyword(s):

Median Survival ◽

Biological Diversity ◽

Lymphocytic Leukemia ◽

Prognostic Parameters ◽

Time To Progression ◽

Cd38 Expression ◽

Richter Syndrome ◽

Clinical Stages ◽

Binet Stage

Abstract The prognosis of patients with CLL has been traditionally assessed by using clinical stages. Clinical stages, however, are a mere reflection of the biological diversity of CLL. In this regard, we and others have recently shown that ZAP-70 expression separates CLL into two clinical forms with different outcome. The aim of this study was to analyze the distribution of age, gender, and different prognostic parameters according to ZAP-70 expression in 222 pts with CLL (median age, 62 yrs; female/male: 89/133). ZAP-70 was determined by flow cytometry, a high expression being defined as >20% ZAP-70 positive CLL cells. Median follow-up of the series was 7.1 years. Clinical stages at diagnosis were: Binet stage A, 187 pts; B, 21 pts; and C, 14 pts. Rai Stage 0, 123 pts; I, 53 pts; II, 28 pts; III, 7 pts; and IV, 11 pts. Overall median survival was 13 years. Parameters associated with a high ZAP-70 expression were lymphocyte doubling time >12 mos., atypical morphology, bone marrow infiltration > 60%, increased serum LDH and timidin kinase, CD38 expression >20%, del(13q14), unmutated status of IgVH, and development of Richer syndrome. Interestingly, ZAP-70 expression distribution correlated with Rai’s stage (0 vs. 1 to 4). Also, CD38 expression was able to separate two subpopulations with different survival among CLL cases with low ZAP-70 expression (median survival 18 yrs vs. 13 yrs), but not in pts. with ZAP-70>20%. About 50% of pts in Binet A progressed during the follow-up. Median time to progression for patients with high ZAP-70 expression was 3.3 years whereas it was not reached for patients with low ZAP-70 expression. Median survival of pts with low ZAP-70 expression was 16.3 years, whereas it was of 8.5 years in those with high ZAP-70 expression. In conclusion, ZAP-70 expression identifies a subgroup of patients with CLL with unfavorable prognostic factors related to the proliferation and progression of the disease. Prognostic Parameters according to ZAP-70 expression Variable ZAP-70 >20% ZAP-70 < 20% p= Median age 60 yrs 63 yrs Gender (female) 39% 41% LDT < 12 mos 42% 23% 0.009 Atypical morphology 54% 12% 0.000 BM infiltration >60% 50% 33% 0.03 Increased LDH 13% 4% 0.028 Increased TK 66% 28% 0.000 CD38 > 20% 67% 32% 0.000 Del(13q14) 38% 55% 0.027 Unmutated IgVH 88% 11% 0.000 Richter Syndrome 8% 2% 0.039 Rai Stage > 0 53% 37% 0.039 TTP (Binet A) 3.3 yrs NR 0.000 Median Survival 16.3 yrs 8.5 yrs 0.000

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Cellular Expression of CD23, CD71, and CD38 Are Independent Prognostic Variables in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.2801.2801 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2801-2801

Author(s):

Howard J. Meyerson ◽

Samir M. Dalia ◽

Omer N. Koc ◽

Pingfu Fu ◽

Amy E. Cocco

Keyword(s):

Risk Factors ◽

Flow Cytometry ◽

Overall Survival ◽

Relative Risk ◽

Chronic Lymphocytic Leukemia ◽

Antigen Expression ◽

Lymphocytic Leukemia ◽

Cellular Expression ◽

Cell Chronic Lymphocytic Leukemia

Abstract Prognostic factors available to help predict the outcome of patients with B-cell chronic lymphocytic leukemia (B-CLL) include clinical stage, lymphocyte doubling time, cytogenetic abnormalities, immunoglobulin heavy chain variable region (IgVH) mutation status, serum factors such as soluble CD23 and, in particular, cellular phenotyping. For instance, several studies have shown that cellular expression of CD38 or zap-70, as assessed by flow cytometry, is associated with a more aggressive course of disease. However, previous phenotyping studies have not addressed the significance of more subtle findings such as whether bimodal expression (the identification of two discrete cell populations within the neoplasm) or the level of antigen expression impacts patient outcome. Therefore, a retrospective analysis of flow cytometry data from 246 patients diagnosed with B-CLL at University Hospitals of Cleveland and Case Western Reserve University was performed. Twenty-five different antigens were assessed for bimodality and the level of expression of all antigens was determined on a 0–3 scale. CD38 and CD71 expression level was further analyzed as percent positive over control. The optimal threshold values of CD38 and CD71 was estimated by the tree-structure survival method. Bimodality was identified by visual inspection of the flow cytometry histograms. The overall survival was measured from the date of analysis to date of death and censored at the date of last follow-up for survivors. Survival distribution was estimated using Kaplan-Meier methods and difference between/among groups was examined using log rank test. The mean follow-up was an average of 2.7 years. Bimodal antigen expression was found in 107 (43%) of all analyzed cases. However, neither the presence of bimodality by itself, nor the number of bimodal antigens per case was associated with worse overall survival. Bimodality of CD38, identified in 14.5% of cases, was not correlated with a worse overall survival in this study and bimodality of individual antigens CD13 (12.9%), CD11c (7.9%), CD20 (7.3%), CD5 (7.3%), FMC-7 (6.4%), and surface immunoglobulin (4.5%) also did not impact survival. Antigens bimodal in less than 4.5% of cases were not analyzed. In multivariate analysis, the expression level of CD38, CD23 and CD71 were found to be independent prognostic risk factors. The effect of CD38, CD23, and CD71 on overall survival, controlling for the effect of age, was further estimated using the Cox proportional hazards model. The relative risk of dying for patients with CD71 expression on B-CLL cells less than 9.5% was 6.37 (p = 0.0001, CI 2.56–15.87) compared to patients expressing higher levels of CD71. Patients with low level B-CLL cellular CD23 expression had a relative risk of dying of 4.22 (p= 0.007, CI 1.49–11.9) compared to those patients expressing higher levels of CD23 and those patients with B-CLL cells expressing CD38 greater than 24.5% had a relative risk of dying of 2.85 (p = 0.016, CI 1.22 – 6.65) compared to those patients expressing lower levels of CD38. Taken together, our findings show for the first time that cellular expression of CD23 and CD71 impact survival in B-CLL and indicate that the level of expression of CD38, CD23, and CD71 are independent risk factors while bimodal antigen expression appears not to influence outcome in B-CLL patients.

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Comparison of Genomic Aberrations and Expression of ZAP-70 and CD38.

Blood ◽

10.1182/blood.v106.11.5004.5004 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5004-5004

Author(s):

Lucrecia Yañez ◽

Maria Angeles Cuadrado ◽

Andres Insunza ◽

Arancha Bermudez ◽

Belen Gonzalez Mesones ◽

...

Keyword(s):

Cytogenetic Study ◽

Normal Karyotype ◽

Lymphocytic Leukemia ◽

Cell Surface Expression ◽

Biological Study ◽

P Value ◽

Complex Karyotype ◽

Genomic Aberration ◽

Trisomy 12 ◽

Genomic Aberrations

Abstract Expression of CD38 and /or ZAP 70 and chromosome abnormalities such as deletions of 11q23 and 17p13 have been previously identified by several groups as predictors of disease progression and decrease overall survival in Chronic Lymphocytic Leukemia (CLL). Moreover, few are described about the relationship between ZAP70/CD38 status and their genomic aberrations associated. We analysed 86 patients (median age: 70 yrs; female/male: 28/58) diagnosed of CLL between 1980 and 2005. Cytoplasmic ZAP-70 expression and cell surface expression of CD38, was determined by flow cytometry in CD19+ CD5+ B-CLL cells. Trisomy 12 and deletions in 13q14, 11q22–23 and 17p13, were detected by the interphase cytogenetic fluorescence in situ hybridization (FISH). Biological study in patients diagnosed before 2001 was done on cryopreserved blood cells. Concordant expression of ZAP-70 and CD38 was seen in 66 of 86 patients (76%). Fifty-one patients were ZAP-70- and CD38-, and 15 patients were ZAP-70+ and CD38+. Discordant ZAP70/CD38 status was present in 20 patients. Cytogenetic study identified chromosome aberrations in 85% of patients. Deletions in band 13q14 (43%), followed by trisomy 12 (21%), deletions in 11q22–23 (11%) and in 17p13 (10%) were the most frequent abnormalities. Normal karyotype was presented in 28% of patients and complex karyotype in 11%. In the concordant ZAP70-CD38- cases and ZAP70+ CD38+, 13q14 aberration (47, 9%) and normal karyotype (42%) respectively, were more frequent than in the other groups but in our study this differences were not statistically significant. Moreover deletion in 11q22–23 (25%) was seen statistically significant, p = 0, 05, in patients with concordant expression of ZAP70+ and CD38+. Patients with discordant status in the expression of ZAP70 and CD38, were statistically associated with trisomy 12 (38%) p = 0,002. In conclusion, in our study we find that expression in ZAP70 and CD38 is associated with a different genomic aberration. Deletion in 13q14 appears more frequent in patients with concordant ZAP70- and CD38- expression. Trisomy 12 is associated with discordant status expression. Finally, the worse prognostic group ZAP70+ and CD38+ is associated with a normal karyotype or deletions in 11q22–23. Expression of ZAP 70 and CD38 and genomic aberrations ZAP70+ CD38+ ZAP70- CD38- Discordant status p-value Del 11q22-23 25% 4,2% 12,5% 0,05 Del 17p13 8,3% 4,2% ---- 0,52 Trisomy12 8,3% 10,4% 37,5% 0,002 Del 13q14 16,7% 47,9% 31,3% 0,10 Normal 41,7% 33,3% 18,8% 0,39 Complex Karyotype 20% 5,9% 20% 0,13

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Clinical characteristics and course of chronic lymphocytic leukemia patients with the combination favorable and unfavorable cytogenetics

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.8086 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 8086-8086

Author(s):

R. R. Harting ◽

P. Venugopal ◽

W. Hsu ◽

R. Catchatourian ◽

O. Ogundipe

Keyword(s):

Median Survival ◽

Chart Review ◽

Historical Data ◽

Clinical Course ◽

Retrospective Chart Review ◽

Lymphocytic Leukemia ◽

Stage Disease ◽

Genetic Abnormalities ◽

Genomic Aberrations

8086 Background: Patients with CLL have a highly variable clinical course. Genomic aberrations detected by FISH have been shown to correlate with survival and treatment free interval (TFI). Patients with the presence of 17p or 11q deletions (del) either alone or in combination with other cytogenetic abnormalities have the worst prognosis while patients with 13q del as a sole abnormality have the best prognosis. Our objective was to further investigate poor prognosis CLL patients with either del 17p or 11q to determine if the addition of the favorable 13q del influences the predicted clinical course and survival. Methods: We performed a retrospective chart review on 22 patients (pts) who had been identified by FISH as having either the combination of del 17p and 13q or del 11q and 13q. Results: 128 CLL FISH panels were performed from April of 2003 through October of 2006. Twenty-two pts (17%) had either del 17p and 13q (9%) or del 11q and 13q (9%). Historical data notes a frequency of 7% and 8% for deletions 17p and 11q, respectively, and 55% for 13q as a sole aberration. The median age was 66 yrs, the majority of whom were male (73%). Two of 22 pts (9%) presented with advanced stage disease. Splenomegaly was seen more often in the 17p/13q pts (36%) vs 11q/13q pts (9%). With a median follow up of 46 months since diagnosis, the median TFI for all patients (20 known) was 56 months. TFI was 13 months for patients with 17p/13q del; whereas TFI was not reached for patients with 11q/13q. Historical data noted a TFI for patients with deletions 17p, 11q, and 13q (as a sole aberration) as 9, 13, and 92 months respectively. The median survival from diagnosis was not reached for the group overall or for either combination of genetic abnormalities. Historical data noted, with 70 months follow up, a median survival of 108 months overall and 32, 79, and 133 months for 17p, 11q, and 13q (as a sole aberration) respectively. Conclusions: The addition of favorable cytogenetics, del 13q, in a CLL patient with an unfavorable cytogenetic pattern (either del 17p or del 11q) appears to improve the predicted clinical outcome and survival. Additional follow up and prospective studies are needed to further define which genetic subgroups help to prognosticate CLL patients. No significant financial relationships to disclose.

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