scholarly journals Lipoprotein Lipase mRNA Expression in Whole Blood Is a Prognostic Marker in B Cell Chronic Lymphocytic Leukemia

2007 ◽  
Vol 53 (2) ◽  
pp. 204-212 ◽  
Author(s):  
Femke Van Bockstaele ◽  
Valerie Pede ◽  
Ann Janssens ◽  
Filip Callewaert ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mrna Expression ◽  
Lipoprotein Lipase ◽  
Prognostic Marker ◽  
Whole Blood ◽  
Predictive Value ◽  
Variable Region ◽  
Individual Variability ◽  
Lymphocytic Leukemia ◽  
Mutation Status

Abstract Background: Chronic lymphocytic leukemia (CLL) is characterized by high individual variability in clinical course and the need for therapy. Differentiation of prognostic subgroups is based primarily on the mutation status of the genes for the variable region of the immunoglobulin heavy chain (IGHV). The time- and labor-intensive nature of this analysis necessitates the use of easily applicable surrogate markers. Methods: We developed a quantitative PCR (qPCR) method for determining lipoprotein lipase (LPL) mRNA expression and analyzed samples of lysed whole blood and CD19-selected cells from 50 CLL patients. Associations of LPL and ZAP70 [ζ-chain (TCR) associated protein kinase 70 kDa] expression with IGHV mutation status, overall survival (OS), and treatment-free survival (TFS) were investigated. Results: Lysed samples of whole blood and CD19-selected cells were similar with respect to LPL expression (R = 0.88; P <0.0001). LPL expression was significantly associated with IGHV mutation status [χ2(1) = 15.3; P <0.0001] and showed an 89.3% specificity, a 68.2% sensitivity, an 83.3% positive predictive value, and a 78.1% negative predictive value for IGHV mutation status. LPL expression was significantly associated with both OS and TFS in log-rank tests (both P values = 0.002). LPL-positive patients had a significantly shorter median TFS time (23 months) than LPL-negative patients (88 months) (P = 0.002). Conclusions: LPL mRNA expression is a valuable prognostic marker in CLL. The method does not require cell purification, and its applicability with archived samples facilitates its use in the clinical routine and other studies.

Additional Genetic High-Risk Features Such As 11q Deletion, 17p Deletion, and V3-21 Usage Characterize Discordance of ZAP-70 and VH Mutation Status in Chronic Lymphocytic Leukemia

2006 ◽  
Vol 24 (6) ◽  
pp. 969-975 ◽  
Author(s):  
Alexander Kröber ◽  
Johannes Bloehdorn ◽  
Sebastian Hafner ◽  
Andreas Bühler ◽  
Till Seiler ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Variable Region ◽  
Multivariate Regression Analysis ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Characteristic Modes ◽  
Genomic Aberrations ◽  
Vh Gene

Purpose Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. Patients and Methods We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. Results ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. Conclusion There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

scholarly journals Karyotype-specific microRNA signature in chronic lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 114 (18) ◽  
pp. 3872-3879 ◽  
Author(s):  
Rosa Visone ◽  
Laura Z. Rassenti ◽  
Angelo Veronese ◽  
Cristian Taccioli ◽  
Stefan Costinean ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chromosomal Abnormalities ◽  
Variable Region ◽  
Normal Karyotype ◽  
Lymphocytic Leukemia ◽  
High Expression ◽  
Mutation Status ◽  
Ighv Gene ◽  
Trisomy 12 ◽  
Disease Initiation

Abstract Chromosomal abnormalities, immunoglobulin heavy chain variable–region (IGHV) gene mutation status, and ζ-associated protein 70 (ZAP-70) expression levels have independent prognostic relevance in chronic lymphocytic leukemia (CLL); however, their concordance is variable. Because deregulation of microRNAs has been linked to disease initiation and progression in CLL, we studied the value of the microRNAs as a signature for CLL patients with specific chromosomal abnormalities. We identified 32 microRNAs able to discriminate the 11q deletion, 17p deletion, trisomy 12, 13q deletion, and normal karyotype cytogenetic subgroups. The expression values of 9 among the 32 microRNAs (miR-151-3p, miR-34a, miR-29c, miR-29b, miR-155, miR-148a, miR-146a, miR-146b5p, and miR-640) were correlated with gene expression data from the same samples to assess their biologic impact on CLL. In this study we also found that IGHV unmutated, high expression of ZAP-70 protein, and low expression of the miR-223, miR-29c, miR-29b, and miR-181 family were strongly associated with disease progression in CLL cases harboring 17p deletion, whereas in those harboring trisomy 12 only high expression of the miR-181a, among the analyzed parameters, suggested more aggressive disease. Thus, the use of the microRNA-based classifications may yield clinically useful biomarkers of tumor behavior in CLL.

Relative Value of CD38 and ZAP-70 Versus Immunoglobulin Mutation Status in Predicting Early Disease Progression in Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2778-2778 ◽  
Author(s):  
Laura Z. Rassenti ◽  
Donna S. Neuberg ◽  
Lang Huynh ◽  
William G. Wierda ◽  
John G. Gribben ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Added Value ◽  
Logrank Test ◽  
Region Gene ◽  
Mutation Status ◽  
Mutational Status ◽  
Relative Value ◽  
Median Level

Abstract We assessed the relative value of CD38 in predicting the need for early treatment in 307 patients with chronic lymphocytic leukemia (CLL) previously characterized for ZAP-70 and immunoglobulin heavy-chain-variable region gene (IgVH) mutational status (NEJM2004, 351;9;893–901). Recursive partitioning by maximally selected chi-square analyses of flow cytometry and clinical data identified the optimal cut-off for designating a CLL sample as CD38+ was at 34%, which was highly similar to the conventional cut-off of 30%. Since these cut-offs identified highly similar cohorts of CD38+ CLL patients (e.g. 32.2% (99/307) vs. 35.5% (109/307)) we chose to use 30% as the cut-off for this analysis. We used the logrank test to compare CD38 expression-status to the time from diagnosis to therapy (TTT), initiated per established NCI-Working Group guidelines. Patients with CLL cells that were CD38-negative by this criterion had a median TTT of 7.8 years; whereas, patients with CD38+ CLL cells had a median TTT of 3.7 years (p<0.0001). There was a significant association between expression of CD38 and ZAP-70 or use of unmutated IgVH genes (p < 0.0001). The median level of CD38 among cases that used mutated IgVH was 4.0%, compared to 27.4% among cases that used unmutated IgVH (p < 0.0001). The median level of CD38 among ZAP-70-negative cases was 5.3% (range from 0.1% to 99.5%), compared to 27.2% among ZAP-70-positive cases (range from 0.1% to 99.4%) (p < 0.0001). We explored the TTT based only on flow cytometric parameters (CD38 and ZAP-70) and investigated whether addition of mutation status significantly altered our predictions. For most patients, the knowledge of CD38 and ZAP-70 provided a reliable means for predicting the TTT and the knowledge of the IgVH mutation status did not substantially alter the prediction. Only in 41 cases (14% of the total), where the CLL cells were CD38+ but negative for ZAP-70, was the prediction significantly improved by inclusion of IgVH mutation status. The median TTT of this group of 41 patients was 7.8 years. Addition of mutation status identified a subgroup of 20 patients with unmutated IgVH genes for whom median TTT was estimated at 4.6 years; 21 patients with mutated IgVH genes had a median TTT of 8.4 years. For patients with CLL cells that were CD38-negative and either negative or positive ZAP-70, stratification via IgVH mutation status did not identify subgroups within each of these categories that had significantly different median TTT. We conclude that knowledge of CD38 and ZAP-70, as assessed by the CRC, can reliably predict TTT in most patients with CLL. For the 14% of cases that are CD38+ but negative for ZAP-70, determining the IgVH mutation status may provide added value in predicting the time from diagnosis to initial therapy.

scholarly journals LDOC1 mRNA is differentially expressed in chronic lymphocytic leukemia and predicts overall survival in untreated patients

Blood ◽  
2011 ◽  
Vol 117 (15) ◽  
pp. 4076-4084 ◽  
Author(s):  
Hatice Duzkale ◽  
Carmen D. Schweighofer ◽  
Kevin R. Coombes ◽  
Lynn L. Barron ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mrna Expression ◽  
Somatic Mutation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Differentially Expressed ◽  
Mutation Status

Abstract We previously identified LDOC1 as one of the most significantly differentially expressed genes in untreated chronic lymphocytic leukemia (CLL) patients with respect to the somatic mutation status of the immunoglobulin heavy-chain variable region genes. However, little is known about the normal function of LDOC1, its contribution to the pathophysiology of CLL, or its prognostic significance. In this study, we have investigated LDOC1 mRNA expression in a large cohort of untreated CLL patients, as well as in normal peripheral blood B-cell (NBC) subsets and primary B-cell lymphoma samples. We have confirmed that LDOC1 is dramatically down-regulated in mutated CLL cases compared with unmutated cases, and have identified a new splice variant, LDOC1S. We show that LDOC1 is expressed in NBC subsets (naive > memory), suggesting that it may play a role in normal B-cell development. It is also expressed in primary B-cell lymphoma samples, in which its expression is associated with somatic mutation status. In CLL, we show that high levels of LDOC1 correlate with biomarkers of poor prognosis, including cytogenetic markers, unmutated somatic mutation status, and ZAP70 expression. Finally, we demonstrate that LDOC1 mRNA expression is an excellent predictor of overall survival in untreated CLL patients.

Coexistence of Mutated and Unmutated IgVH Forms in Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4984-4984
Author(s):  
M. Sheikholeslami ◽  
W. Ma ◽  
J. Uyeji ◽  
K. Tornyos ◽  
L. Cone ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Family ◽  
Pcr Amplification ◽  
Variable Region ◽  
Gene Families ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Mutation Status ◽  
Aggressive Disease

Abstract The mutation status of the immunoglobulin heavy chain variable region (IgVH) gene is an independent prognostic indicator in patients with chronic lymphocytic leukemia (CLL). Unmutated IgVH is associated with rapid disease progression and shorter survival. The assay for determining IgVH mutation status depends on specific amplification of the mRNA of the expressed clonal IgVH. The presence of more than 1 clone in patients with CLL has been speculated and can be documented when the 2 clones express different light chains. Determining the IgVH gene family that is expressed in subclones also allows the confirmation of the presence of two clones in some cases. We describe 3 patients with two clones of CLL discovered in the process of determining the IgVH mutation status. PCR amplification of the expressed IgVH mRNA yielded 2 distinct bands. Sequencing each band separately revealed 2 different clones in each patient. Interestingly, each clone had a different mutation profile. In 2 of the 3 patients, the 2 clones were from completely different IgVH gene families (VH1-2 with VH2-5 and VH4-34 with VH5-51); both of these patients showed kappa light chain restriction. In the third patient the expressed IgVH gene family was VH3-21 in both clones, but 1 was mutated (6.8%) and the second was unmutated. Two of the 3 patients had evidence of aggressive disease with hepatosplenomegaly and lymphadenopathy; 1 of these patients expressed the VH3-21 gene family, which is known to be associated with aggressive disease irrespective of its mutation status. The other patient had a 9-year history of indolent disease without therapy. The intensity of the expressed IgVH clones as determined by PCR indicated that the mutated clones were dominant in 2 patients (approximately 80%). In the patient with VH3-21 expression, the unmutated clone accounted for 80% of total expressed IgVH. These data suggest that the presence of more than 1 clone should be considered when testing for IgVH mutation status and, more importantly, that evolution of a more aggressive second clone should be suspected. The presence of 2 clones—1 arising in naïve cells and the second in memory cells—suggests the possibility that the first hit occurred very early in the ontogeny of lymphocytes and that a second hit occurred at a later stage. However, the presence of naïve and memory clones in the same family raises the possibility that the naïve leukemic cells might still go through the germinal center programming process.

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&lt;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.

The Repertoire of Heavy Chain Immunoglobulin Genes in B-Cell Chronic Lymphocytic Leukemia in Russia and Belarus

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4579-4579
Author(s):  
Bella Biderman ◽  
Eugene Nikitin ◽  
Tatiana Sergienko ◽  
Alexandra Bakun ◽  
Irina Taras ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Conflicts Of Interest ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Antigen Receptors ◽  
Mutation Status ◽  
The Uk ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abstract 4579 Introduction. Mutation status of the heavy chain variable region genes is known as an important factor in long-term prognosis in B-cell chronic lymphocytic leukemia (B-CLL). A more detailed study of the gene sequences of immunoglobulin heavy chain (IgVH) led to the discovery of stereotyped antigen receptors (SAR) - receptors that have the same set of VH-, D- and JH- genes used. SARs have been found almost in a quarter of all B-CLL cases. Since this study there have been no data available concerning VH-gene usage and SARs in Russian and Belarusian B-CLL patients. Patients and methods. DNA or cDNA was amplified in 6 separated reactions using primers specific for VH-families, and a consensus JH primer [Campbell et al. 1992] or primer sets recommended by the BIOMED-2 [van Dongen et al. 2003]. PCR products were sequenced using family-specific primers and Big Dye Terminator v3.1 kit (Applied Biosystems). Sequences were analyzed with IgBlast (http://www.ncbi.nlm.nih.gov/igblast). 98% homology cutoff was used to discriminate between mutated and unmutated cases. Results. Total of 547 patients with B-CLL where analyzed; 192 patients with mutated IgVH-genes (35%) and 355 patients with unmutated ones (65%). We have identified 65 stereotyped receptors (SARs) in 198 of 491 Russian patients (40%). Twenty one SARs (confirmed) appeared in more than 3 patients (110 out of 198, 55%), 44 SARs (potential) found in 2 patients (88 out of 198 cases, 45%). The vast majority of confirmed SARs were found in the subgroup of patients without mutations in IgVH genes (95%). Among the potential SARs 15 pairs were from patients with and without mutations (34%), seven pairs from patients with mutations (16%) and 22 pairs from patients without IgVH mutations (50%). The most common SARs were: VH1–69/D3-3/JH6 (24 patients, 5%); VH1–69/D3–16/JH3 (8 patients); VH1–69/D2-2/JH6 (8 patients); VH1–69/D3–10/JH6 (6 patients). Among 56 Belarusian patients we have identified only 4 SARs, one confirmed SAR (4 cases) and 3 potential ones. Confirmed (VH1–69/D3-3/JH6) and one potential (VH1–69/D3–16/JH3) were also found in Russia while other two potential (VH1–69/D2–15/JH6 and VH2–5/D2-2/JH6) were not observed in Russia. Discussion. In Russia and Belarus, VH1–69 gene is found in 20% of all cases of B-CLL, and almost always (95%) in unmutated cases. This finding well correlates to the data obtained by [Kryachok et al. 2012] concerning high VH1–69 usage in Ukrainian patients. In other European countries, this gene is less common: about 14% of cases in Sweden, France and Spain, 11% in the UK and about 6–7% in Greece and Italy [Ghia et al. 2005; Tobin et al. 2004; Duke et al. 2003]. In all these countries, this gene is also prevalent in patients with unmutated VH-genes. Nordic countries are characterized by very frequent use of gene VH3–21 - 9%, while in Russia and the countries of central and southern Europe, it occurs at least 3 times less (about 3%), and was not found in Belarusian samples. This gene is also associated with poor prognosis of B-CLL, regardless of mutation status of IgVH genes. Interestingly, in Asia (China, Japan, Iraq) VH1–69 and VH3–21 genes are almost not observed [Nakamura et al. 1999; Farsangi et al. 2007; Lijuan Chen et al. 2008]. Narrowing of the repertoire of IgVH genes - specific feature of B-CLL indicatites that influence of antigen (at least in some cases) occurs during the development of the disease. Also, factors of genetic background as well as geographical environment could be important. It is possible that future treatment decisions will be based not only on the IgVH mutation status, but also on the characteristics of certain antigen receptor. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results

Blood ◽  
2020 ◽  
Vol 135 (15) ◽  
pp. 1204-1213 ◽  
Author(s):  
John C. Byrd ◽  
William G. Wierda ◽  
Anna Schuh ◽  
Stephen Devereux ◽  
Jorge M. Chaves ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Variable Region ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
Duration Of Response ◽  
Phase 1B ◽  
Btk Inhibitor ◽  
Grade 3

Abstract Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Plasma thrombopoietin compared with immunoglobulin heavy-chain mutation status as a predictor of survival in chronic lymphocytic leukemia

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 1001-1006 ◽  
Author(s):  
Charles Koller ◽  
B. Nebiyou Bekele ◽  
Xian Zhou ◽  
Charles Park ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Proportional Hazards ◽  
Variable Region ◽  
Immunoglobulin Heavy Chain ◽  
Cox Proportional Hazards ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
Previously Treated

Abstract We investigated the association of plasma thrombopoietin (TPO) and overall survival in 127 patients with previously treated and previously untreated chronic lymphocytic leukemia (CLL). Higher levels of TPO were associated with advanced Rai stage (P < .001), higher levels of β2-microglobulin (β2-M) (P < .001), and the absence of mutation in the immunoglobulin heavy chain variable region (IgVH) (P < .001), and were inversely correlated with platelet count (P = .002). We found that TPO correlated strongly in a continuous manner with overall survival in both previously treated and untreated patients. The univariate Cox proportional hazard model demonstrated that high TPO levels were associated with shorter survival (P < .001), and multiple variable Cox proportional hazards regression analysis demonstrated that this was independent of the IgVH mutation status, β2-M, and Rai stage. Recursive partitioning showed that a cutoff point of 639 pg/mL separated the CLL patients into 2 major survival groups (P < .001). The effects of β2-M were masked by the effects of TPO in the patients with TPO levels higher than 639 pg/mL, but in the remainder, patients with β2-M level higher than 4.95 mg/L had significantly shorter survival than those with lower values. Plasma TPO and β2-M may be useful for the prediction of clinical behavior in CLL and may replace the need for the determination of IgVH mutation status.

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