An Anomaly with Potential as a New Prognostic Marker in CLL with del(13q): Gain of 16p13.3

2021 ◽  
pp. 1-9
Author(s):  
Sevgi Isik ◽  
Gulcin Gunden ◽  
Eren Gunduz ◽  
Olga Meltem Akay ◽  
Abdulvahap Aslan ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Copy Number Variations ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Array Analysis ◽  
Disease Prognosis ◽  
Snp Microarrays ◽  
Advanced Disease Stage ◽  
Time To First Treatment ◽  
Short Time

Deletion 13q [del(13q)] is a favorable prognostic marker if it is detected as a sole abnormality in chronic lymphocytic leukemia (CLL). However the clinical courses of cases with isolated del(13q) are quite heterogeneous. In our study, we investigated copy number variations (CNVs), loss of heterozygosity (LOH), and the size of del(13q) in 30 CLL patients with isolated del(13q). We used CGH+SNP microarrays in order to understand the cause of this clinical heterogeneity. We detected del(13q) in 28/30 CLL cases. The size of the deletion varied from 0.34 to 28.81 Mb, and there was no clinical effect of the deletion size. We found new prognostic markers, especially the gain of 16p13.3. These markers have statistically significant associations with short time to first treatment and advanced disease stage. Detecting both CNVs and LOH at the same time is an advantageous feature of aCGH+SNP. However, it is very challenging for the array analysis to detect mosaic anomalies. Therefore, it is very important to confirm the results by FISH. In our study, we detected approximately 9% mosaic del(13q) by microarray. In addition, the gain of 16p13.3 may affect the disease prognosis in CLL. However, additional studies with more patients are needed to confirm these results.

Association of a novel regulatory polymorphism (−938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 290-297 ◽  
Author(s):  
Holger Nückel ◽  
Ulrich H. Frey ◽  
Maja Bau ◽  
Ludger Sellmann ◽  
Jens Stanelle ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cox Regression ◽  
Gene Promoter ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Genotype Distribution ◽  
Single Nucleotide ◽  
Regulatory Polymorphism ◽  
Time To First Treatment

Abstract Bcl-2 plays a key role in the regulation of apoptosis. We investigated the role of a novel regulatory single-nucleotide polymorphism (−938C>A) in the inhibitory P2 BCL2 promoter in B-cell chronic lymphocytic leukemia (B-CLL). The −938C allele displayed significantly increased BCL2 promoter activity and binding of nuclear proteins compared with the A allele. Concomitantly, Bcl-2 protein expression in B cells from CLL patients carrying the −938 AA genotype was significantly increased compared with CC genotypes. Genotype distribution between 123 CLL patients (42 AA, 55 AC, 26 CC) and 120 genotyped healthy controls (36 AA, 63 AC, 21 CC) was not significantly different, suggesting that genotypes of this polymorphism do not increase the susceptibility for B-CLL. However, median time from first diagnosis to initiation of chemotherapy and median overall survival were significantly shorter in patients with −938AA genotype (38 and 199 months, respectively) compared with AC/CC genotypes (120 and 321 months, respectively; P = .008 and P = .003, respectively). Multivariable Cox regression identified the BCL2−938AA genotype as an independent prognostic factor for the time to first treatment (hazard ratio [HR] 1.9; P = .034) together with disease stage at diagnosis (HR 2.5; P = .004) and ZAP-70 status (HR 3.0; P = .001). The BCL2−938AA genotype is associated with increased Bcl-2 expression and a novel unfavorable genetic marker in patients with B-CLL.

Circulating CXCL13 could be served as a biomarker for chronic lymphocytic leukemia severity

2021 ◽  
pp. 1-7
Author(s):  
Salah Aref ◽  
Doaa Atia ◽  
Ahmed Ramez ◽  
Tarek Abou Zeid ◽  
Enas Gouda
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cox Regression ◽  
Independent Predictor ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Cox Regression Analysis ◽  
Lymphoid Malignancies ◽  
Patient’S Outcome ◽  
Time To First Treatment ◽  
Short Time

BACKGROUND: Recent reports indicated the importance of chemotractants CXCL-13 in solid tumors and lymphoid malignancies. However, the prognostic value of the mentioned cytokines as biomarkers in chronic lymphocytic leukemia patient’s remains to be identified. Therefore; this study was designed in order to address the relation between CXCL-13 concentrations levels and markers of severity in CLL patients. METHODS: Our study included 150 CLL patients and 20 controls. Serum CXCL-13 was determined by ELISA for CLL patients at diagnosis as well as controls. RESULTS: The serum CXCL-13 levels were significantly higher in CLL patients as compared to controls. The high CXCL-13 concentration levels was significantly associated with high number of smudge cells; high LDH; high grade of Rai stage, short time to first treatment (TTT). Cox regression analysis was conducted for prediction of TTT, using age, gender, WBCs, smudge cells, CXCL-13, LDH, ZAP70, CD38, β2-microglobulin, Rai staging as covariates. High LDH, CXCL-13 and CD38% were significantly independent predictor for shorter TTT. CONCLUSION: High CXCL-13 serum levels at CLL diagnosis is correlated with other markers of disease activity; and could be served as biomarkers that predict CLL patient’s outcome.

scholarly journals DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Tsagiopoulou ◽  
Nikos Papakonstantinou ◽  
Theodoros Moysiadis ◽  
Larry Mansouri ◽  
Viktor Ljungström ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Epigenetic Alterations ◽  
Healthy Donors ◽  
Pre Treatment ◽  
Time To First Treatment ◽  
Genomic Regions ◽  
Time To Relapse ◽  
Short Time

Abstract Background In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen. Results The extent of identified changes in CLL cells versus memory B cells from healthy donors was termed “epigenetic burden” (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed “relapse changes” (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology. Conclusions Overall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.

scholarly journals Serum Soluble TACI, a BLyS Receptor, Is a Powerful Prognostic Marker of Outcome in Chronic Lymphocytic Leukemia

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Marie-Christine Kyrtsonis ◽  
Katerina Sarris ◽  
Efstathios Koulieris ◽  
Dimitrios Maltezas ◽  
Eftychia Nikolaou ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Prognostic Significance ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Soluble Form ◽  
Free Light Chains ◽  
Binet Stage ◽  
Time To First Treatment ◽  
The Impact ◽  
First Time

BLyS is involved in CLL biology and its low soluble serum levels related to a shorter time to first treatment (TFT). TACI is a BLyS receptor and can be shed from cells’ surface and circulate in soluble form (sTACI). We investigated the impact of serum BLyS and sTACI levels at diagnosis in CLL patients and their relationship with disease parameters and patients’ outcome. Serum BLyS was determined in 73 patients, while sTACI in 60. Frozen sera drawn at diagnosis were tested by ELISA. sTACI concentrations correlated with BLyS (P=-0.000021), b2-microglobulin (P=0.005), anemia (P=-0.03), thrombocytopenia (P=0.04), Binet stage (P=0.02), and free light chains ratio (P=0.0003). Soluble BLyS levels below median and sTACI values above median were related to shorter TFT (P=0.0003and 0.007). During a ten-year followup, sTACI levels, but not BLyS, correlated with survival (P=0.048). In conclusion, we confirmed the prognostic significance of soluble BLyS levels with regard to TFT in CLL patients, and, more importantly, we showed for the first time that sTACI is a powerful prognostic marker, related to parameters of disease activity and staging and, more importantly, to TFT and OS.

Multiple Metamorphoses of CD38 from Prognostic Marker to Disease Modifier to Therapeutic Target in Chronic Lymphocytic Leukemia

2013 ◽  
Vol 13 (23) ◽  
pp. 2955-2964 ◽  
Author(s):  
Tiziana Vaisitti ◽  
Valentina Audrito ◽  
Sara Serra ◽  
Cinzia Bologna ◽  
Francesca Arruga ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Marker ◽  
Therapeutic Target ◽  
Lymphocytic Leukemia ◽  
Disease Modifier

scholarly journals Loss of cIAP1 in Endothelial Cells Limits Metastatic Extravasation through Tumor-Derived Lymphotoxin Alpha

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 599
Author(s):  
Lazaros Vasilikos ◽  
Kay Hänggi ◽  
Lisanne M. Spilgies ◽  
Samanta Kisele ◽  
Stefanie Rufli ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Advanced Disease ◽  
Disease Stage ◽  
Stromal Compartment ◽  
Tumor Load ◽  
Smac Mimetics ◽  
Advanced Disease Stage ◽  
Lymphotoxin Alpha ◽  
Open Question

In this study, we determined whether Smac mimetics play a role in metastasis, specifically in circulation, tumor extravasation and growth in a metastatic site. Reports suggest inducing the degradation of IAPs through use of Smac mimetics, alters the ability of the tumor cell to metastasize. However, a role for the immune or stromal compartment in affecting the ability of tumor cells to metastasize upon loss of IAPs has not been defined. To address this open question, we utilized syngeneic tumor models in a late-stage model of metastasis. Loss of cIAP1 in the endothelial compartment, rather than depletion of cIAP2 or absence of cIAP1 in the hematopoietic compartment, caused reduction of tumor load in the lung. Our results underline the involvement of the endothelium in hindering tumor cell extravasation upon loss of cIAP1, in contrast to the immune compartment. Endothelial specific depletion of cIAP1 did not lead to cell death but resulted in an unresponsive endothelium barrier to permeability factors causing a decrease in tumor cell extravasation. Surprisingly, lymphotoxin alpha (LTA), and not TNF, secreted by the tumor cells, was critical for the extravasation. Using TCGA, we found high LTA mRNA expression correlated with decreased survival in kidney carcinoma and associated with advanced disease stage. Our data suggest that Smac mimetics, targeting cIAP1/2, reduce metastasis to the lung by inhibiting tumor cell extravasation.

scholarly journals Aberrant Expression of TLR2, TLR7, TLR9, Splicing Variants of TLR4 and MYD88 in Chronic Lymphocytic Leukemia Patients

2021 ◽  
Vol 10 (4) ◽  
pp. 867
Author(s):  
Katarzyna Skorka ◽  
Paulina Wlasiuk ◽  
Agnieszka Karczmarczyk ◽  
Krzysztof Giannopoulos
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Cytotoxic T Cells ◽  
Lymphocytic Leukemia ◽  
Aberrant Expression ◽  
Downstream Signaling ◽  
Splicing Variants ◽  
High Level ◽  
Time To First Treatment ◽  
First Time

Functional toll-like receptors (TLRs) could modulate anti-tumor effects by activating inflammatory cytokines and the cytotoxic T-cells response. However, excessive TLR expression could promote tumor progression, since TLR-induced inflammation might stimulate cancer cells expansion into the microenvironment. Myd88 is involved in activation NF-κB through TLRs downstream signaling, hence in the current study we provided, for the first time, a complex characterization of expression of TLR2, TLR4, TLR7, TLR9, and MYD88 as well as their splicing forms in two distinct compartments of the microenvironment of chronic lymphocytic leukemia (CLL): peripheral blood and bone marrow. We found correlations between MYD88 and TLRs expressions in both compartments, indicating their relevant cooperation in CLL. The MYD88 expression was higher in CLL patients compared to healthy volunteers (HVs) (0.1780 vs. 0.128, p < 0.0001). The TLRs expression was aberrant in CLL compared to HVs. Analysis of survival curves revealed a shorter time to first treatment in the group of patients with low level of TLR4(3) expression compared to high level of TLR4(3) expression in bone marrow (13 months vs. 48 months, p = 0.0207). We suggest that TLRs expression is differentially regulated in CLL but is similarly shared between two distinct compartments of the microenvironment.

Ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1/CD39) as a new prognostic marker in chronic lymphocytic leukemia

2014 ◽  
Vol 56 (1) ◽  
pp. 113-119 ◽  
Author(s):  
Nashwa Khairat Abousamra ◽  
Manal Salah El-Din ◽  
Eman Hamza Elzahaf ◽  
Mohammed Ebrahim Esmael
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Marker ◽  
Lymphocytic Leukemia

scholarly journals Multivariable Model for Time to First Treatment in Patients With Chronic Lymphocytic Leukemia

2011 ◽  
Vol 29 (31) ◽  
pp. 4088-4095 ◽  
Author(s):  
William G. Wierda ◽  
Susan O'Brien ◽  
Xuemei Wang ◽  
Stefan Faderl ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Multivariable Analysis ◽  
Lymphocytic Leukemia ◽  
Cancer Center ◽  
Serum Lactate Dehydrogenase ◽  
Multivariable Model ◽  
Cervical Lymph Nodes ◽  
Mutation Status ◽  
Time To First Treatment

Purpose The clinical course for patients with chronic lymphocytic leukemia (CLL) is diverse; some patients have indolent disease, never needing treatment, whereas others have aggressive disease requiring early treatment. We continue to use criteria for active disease to initiate therapy. Multivariable analysis was performed to identify prognostic factors independently associated with time to first treatment for patients with CLL. Patients and Methods Traditional laboratory, clinical prognostic, and newer prognostic factors such as fluorescent in situ hybridization (FISH), IGHV mutation status, and ZAP-70 expression evaluated at first patient visit to MD Anderson Cancer Center were correlated by multivariable analysis with time to first treatment. This multivariable model was used to develop a nomogram—a weighted tool to calculate 2- and 4-year probability of treatment and estimate median time to first treatment. Results There were 930 previously untreated patients who had traditional and new prognostic factors evaluated; they did not have active CLL requiring initiation of treatment within 3 months of first visit and were observed for time to first treatment. The following were independently associated with shorter time to first treatment: three involved lymph node sites, increased size of cervical lymph nodes, presence of 17p deletion or 11q deletion by FISH, increased serum lactate dehydrogenase, and unmutated IGHV mutation status. Conclusion We developed a multivariable model that incorporates traditional and newer prognostic factors to identify patients at high risk for progression to treatment. This model may be useful to identify patients for early interventional trials.

Survival trends in chronic lymphocytic leukemia in the era of oral targeted therapies in the United States: SEER database analyses (1985 to 2017).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7524-7524
Author(s):  
Neda Alrawashdh ◽  
Ali McBride ◽  
Daniel O. Persky ◽  
Joann Sweasy ◽  
Brian Erstad ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Survival Rates ◽  
Relative Survival ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Seer Database ◽  
Cure Model ◽  
Gender And Age ◽  
Long Term Survivors

7524 Background: The survival of chronic lymphocytic leukemia (CLL) patients has progressively improved after the approval of new targeted therapy for first-line treatment and relapsed disease. We performed a corresponding analysis from the U.S. population-based SEER database (1973–2017) to explore the trend of survival and the effect of advanced CLL treatment on overall survival in CLL patients. Methods: Data were extracted from SEER*Stat for all patients 15 years or older with a primary diagnosis of CLL with or without subsequent cancers. A period analysis was performed to estimate the 5- and 10-year relative survival rates for patients diagnosed (dx) during different calendar periods from 1985 to 2017, based on gender and age at time of diagnosis (15–44, 45–54, 55–64, 65–74, 75–84, 85 years or older). A mixture cure model was used to examine the proportion of long-term survivors per gender and age category among CLL patients diagnosed between 1985 and 2015. Cox proportional hazard modeling was used to calculate the hazard ratios (HRs) of death adjusted for gender and age at diagnosis for two cohorts: (a) diagnosed in 2000–2003 and followed to 2012; (b) 2004–2007 and followed to 2015. Results: For males, the 5-year age-adjusted relative survival rate improved progressively from 72.0% (dx 1985-1989) to 88.2% (dx 2010-2014); for females, from 76.8% (dx 1985-1989) to 90.8% (dx 2010-2014). The corresponding 10-year age-adjusted relative survival rates were 47.3% (dx 1985-1989) and 72.5% (dx 2005-2009) for males; and 58.2% (dx 1985-1989) and 78.7% (dx 2005-2009) for females. The table below shows the proportions of long-term survivors for the 1985–2017 cohort as estimated in the mixed cure model. The HRs (95%CI) of death for cohort (b) in comparison to cohort (a) were 0.58 (0.43–0.78), 0.58 (0.48–0.70), 0.57 (0.49–0.67), 0.68 (0.54–0.85); and 0.83 (0.68–1.02) for age categories of 45–54, 55–64, 65–74, 75–84, and 85 years or old. Conclusions: Survival is significantly improved by calendar period among patients diagnosed after 2004 and treated in the era of advanced therapies. Females and younger patients had a higher probability of long term survival. Future studies should consider such covariates as treatment type, disease stage and genetics.[Table: see text]

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