Polymorphisms Of Human Leukocyte Antigen-G Gene and Clinical Outcome Of Patients With Chronic Lymphocytic Leukemia

Abstract Introduction The human leucocyte antigen-G (HLA-G) is a nonclassical class Ib molecule that suppresses various immune cell functions and may contribute to immune escape and cancer development. HLA-G polymorphisms, especially HLA-G-725(C/G/T) 5’URR and HLA-G 14bp del/ins 3’UTR, might influence the expression of HLA-G transcript and protein, and in consequence, affect the biological features of HLA-G. Therefore, we investigated whether these two polymorphisms, which seem to be functionally relevant, may play a role in susceptibility to chronic lymphocytic leukemia (CLL) and a clinical course of the disease. So far, no studies have reported any potentially impact of HLA-G polymorphisms on lymphoid neoplasms. Methods HLA-G725(C/G/T) 5’URR and HLA-G 14bp del/ins 3’UTR polymorphisms were genotyped in 167 previously untreated patients with CLL. The control group consisted of 98 randomly selected blood donors. Results Strong linkage disequilibrium between HLA-G-725(C/G/T) and HLA-G 14 bp del/ins was observed (D’=1.0 and r2=0.2). Six distinct haplotypes, including G/del, C/del, T/del, G/ins, C/ins, T/ins were found in the CLL patients. Among the controls only five haplotypes were found due to the T/ins haplotype not being observed. The probability of the occurrence of G/ins and T/ins haplotypes was higher in the CLL than in the controls (p= 0.01). The analysis of the prognostic significance of diplotypes, as well as the previously reported correlations between HLA-G genotypes and HLA-G expression in vitro and in vivo, allowed us to identify the HLA-G diplotype-based risk groups. The low-risk (LR) group comprised CC/del-del, CC/del-ins and CC/ins-ins diplotypes, and the high risk (HR) group included GG/del-del, GG/del-ins, GG/ins-ins, GC/del-del, GC/del-ins, GC/ins-ins, TT/del-del, TT/del-ins, TT/ins-ins and CT/del-ins diplotypes. The patients carrying LR diplotypes presented a higher 3-year treatment-free survival (TFS) (56.7%, 95% CI 47-66) than those with HR diplotypes (38.6%, 95% CI 27-52; p= 0.005). Additionally in the group of mutated IGHV patients, subjects carrying LR diplotypes presented a higher probability of 3-year TFS than those with HR diplotypes (68.5% vs 43.2%; p= 0.04). In regard to overall survival (OS), the estimated 5-year OS rates were 95.6% (95% CI 89-98) and 74.2% (95% CI 57-86) in the LR and HR group respectively (p= 0.005). Moreover, among the unmutated IGHV patients, those carrying LR diplotypes had a better 5-year OS compared to the patients with HR diplotypes (87.1% vs 71%; p= 0.02). Multivariate analysis demonstrated the IGHV mutation status (p= 0.005) and HLA-G diplotype-based risk groups (p= 0.01) to be independent factors predicting OS. Conclusions The results suggest the potential role of HLA-G and its polymorphisms in CLL. The inherited ability of the host to increase expression of the HLA-G antigen might contribute to the escape of CLL cells of the immuno-surveillance of the host and in turn to disease progression and the worse outcome for patients with CLL. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Abnormal Free Light Chain Ratios in Chronic Lymphocytic Leukemia: A New Prognostic Factor?.

Blood ◽

10.1182/blood.v114.22.1237.1237 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1237-1237 ◽

Cited By ~ 2

Author(s):

Johannes Matschke ◽

Lewin Eisele ◽

Ludger Sellmann ◽

Ulrich Duehrsen ◽

Jan Duerig ◽

...

Keyword(s):

Prognostic Factor ◽

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Risk Groups ◽

Typical Feature ◽

Lymphocytic Leukemia ◽

Al Amyloidosis ◽

Abnormal Ratio

Abstract Abstract 1237 Poster Board I-259 Introduction Free light chains (FLC) have prognostic significance in monoclonal gammopathy of undetermined significance, solitary plasmocytoma of bone, smouldering myeloma, multiple myeloma, Waldenstroms macroglobulinaemia and AL amyloidosis. Although monoclonal protein secretion is a typical feature of plasma cell dyscrasias, it can also be detected in other B cell malignancies including chronic lymphocytic leukemia (CLL). Recent data suggest a significant correlation between abnormal ratio of FLC and outcome. Therefore, we investigated FLC in a large cohort of 120 patients in order to assess the role of FLC in CLL. Methods and Results Plasma samples which had been previously cryopreserved and collected at the time before the initiation of therapy or six months after finishing therapy were used. The levels of FLC were assessed using nephelometric immunoassays (The Binding Site) and quantified nephelometrically with the BNII analyser. A normal FLC range (κlγ) was defined as 0.26-1.65. Moreover, in all cases we evaluated the M band on immunofixation (IF). Abnormal FLC ratios were found in 71 patients (59%) whereas the IF was positive in only 32 cases (27%). In 48 cases the FLC ratio was positive while IF was negative and in only 9 cases the IF was positive while the FLC ratio was normal. In total, 23 patients had both a positive IF and an abnormal FLC ratio. Patients with an abnormal FLC ratio for γ had a significantly shorter treatment-free survival (TFS) than patients with an abnormal ratio for κ or with a normal FLC ratio (median TFS: 34 versus 78 versus 109 months, p=0.042). Evaluation of several disease characteristics in association with FLC of the patients' B-CLL cells showed no significant differences for FLC in the different risk groups (ZAP-70 status, CD38 status, cytogenetics and Binet stage) suggesting no correlation of the FLC with these already established adverse prognostic factors. Conclusion FLC can be detected in a substantial fraction of patients with CLL and the FLC technique improves detection of M-proteins. Moreover, an abnormal FLC ratio is associated with worse outcome, particularly those with a low abnormal FLC ratio. Evaluation of the prognostic significance of abnormal FLC in a larger cohort is currently under way. This data will be presented at the meeting. Future studies are warranted to elucidate the role of FLC as biomarkers of disease and as a prognostic factor for response. Disclosures No relevant conflicts of interest to declare.

Download Full-text

CD23 Receptor Positivity Has No Prognostic Implication in Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.4397.4397 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4397-4397

Author(s):

Jahan Aghalar ◽

Charles Chu ◽

Rajendra N Damle ◽

Che-Kai Tsao ◽

Nina Kohn ◽

...

Keyword(s):

Flow Cytometry ◽

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Prognostic Markers ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Lymphocytic Leukemia ◽

Mutation Status ◽

Percent Positivity ◽

Cd23 Expression

Abstract Abstract 4397 BACKGROUND Chronic Lymphocytic Leukemia (CLL) phenotypically expresses CD23, although the percentage of positive cells measured by flow cytometry is variable. We sought to analyze whether the percent of CD23 positive cells in the CLL clone correlates with time to treat (TTT), overall survival (OS) and prognostic markers CD38, ZAP-70, and IGHV mutation status. METHODS We retrospectively analyzed the flow cytometry data of 332 CLL patients on the gated population of cells that were CD5 and CD19 positive. Percentage positivity for CD23, CD38, and ZAP-70 was noted. CD38 and ZAP-70 were considered positive at cut-offs of >= 30% and >=20%, respectively. CD23 was considered negative at <30% and positive at >= 30%. IGHV sequence was determined from cDNA and then compared to germline to assess mutation status using IMGT/V-QUEST. The distributions of time from diagnosis until start of treatment and overall survival were stratified by CD23 positivity, estimated using the product limit method, and compared using the log rank test. Those who had expired without treatment or were alive and not treated at this time point were censored in the TTT analysis. Those who were still alive were censored in the OS analysis. Associations of CD23 positivity with IGHV mutation status, ZAP-70, and CD38 positivity were examined using the chi-square test. RESULTS Out of 332 patients, 25 had diminished CD23 expression (<30%) whereas 307 had normal CD23 expression (>30%). There was no difference in time until start of treatment or overall survival based on CD23 %positivity. CD23 %positivity showed no associations with IGHV mutation status, ZAP-70 or CD38 positivity. CONCLUSION CD23 percent positivity has no prognostic significance in CLL. There is no correlation between CD23 percent positivity and poor prognostic markers such as CD38, ZAP-70, or IGHV mutation status. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Increased CD39 Expression on CD4+ T-Lymphocytes Has Clinical and Prognostic Significance in Chronic Lymphocytic Leukemia,

Blood ◽

10.1182/blood.v118.21.3895.3895 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3895-3895

Author(s):

Yair Herishanu ◽

Inbal Hazan-Hallevi ◽

Sigi Kay ◽

Varda Deutsch ◽

Aaron Polliack ◽

...

Keyword(s):

T Cells ◽

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

Peripheral Blood ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Anti Inflammatory

Abstract Abstract 3895 Chronic lymphocytic leukemia (CLL) cells depend on their microenvironment for proliferation and survival. Ectonucleotidase CD39 has anti-inflammatory properties as it hydrolyzes pro-inflammatory extra-cellular ATP, generates anti-inflammatory adenosine and also protects regulatory T cells from ATP-induced cell death. In this study we investigated the clinical significance of CD39 expression on CD4+T-cells in 45 patients with CLL as well as its compartmental regulation and explored the possible mechanisms for its induction. Compared to healthy individuals, CD4+CD39+ lymphocytes were increased in the peripheral blood of patients with CLL (4.6%±2.28 vs. 17.3%±12.49, respectively, p=0.004), and correlated with advanced stage of disease (9.72%±5.76, 18.15%±12.03 and 25.90%±16.34, of CD4+ lymphocytes, in patients with Rai stages 0, 1+2 and 3+4, respectively, p=0.019). CD4+CD39+ cells were also higher in patients with CLL who needed therapeutic intervention (untreated; 12.99%±10.63 vs treated; 22.21%±12.88, p=0.01) and in those who were ZAP70+ or had b2-microglobulin levels>3g/L. There were more CD4+CD39+ lymphocytes in the bone marrow compartment (22.25%±16.16) than in the peripheral blood (16.60%±15.84, p=0.009). In-vitro studies showed that CD39 can be induced on CD4+cells by exposure to ATP or indirectly, following B-cell receptor (BCR) engagement (CD4+CD39+ lymphocytes increased by 1.56 fold, in the BCR engaged samples compared to their paired controls; 20.27%±11.3 vs. 13%±9.42, respectively, p=0.0006). Conclusions: Increased CD39 expression on CD4+ T-lymphocytes in CLL associates with an aggressive disease. This may reflect the ability of the leukemic cells to suppress the surrounding immune environment, and contribute to a poorer prognosis. CD39+ may also serve as a future target for the development of novel therapies with immune modulating anti–tumor agents in CLL. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Tyro3, Axl Ve Mer (TAM) Receptors On Surfaces of Mononuclear Cells in Patients with B-Cell Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v120.21.4588.4588 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4588-4588

Author(s):

Dilvin Guney ◽

Aysin Tulunay ◽

Funda Pepedil ◽

Isik Kaygusuz ◽

Cafer Adiguzel ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Mononuclear Cells ◽

Conflicts Of Interest ◽

Gradient Centrifugation ◽

Lymphocytic Leukemia ◽

Control Group ◽

Ligand Molecule ◽

Tam Receptors ◽

Cell Chronic Lymphocytic Leukemia

Abstract Abstract 4588 Background: Tyro 3 (Sky), Axl, and Mer receptors are members of the family of tyrosine kinases and Gas6 is their ligand molecule. In some types of cancer, upregulation of Axl/Gas6 indicated a worse prognosis, but an opposite situation was observed in renal “cell” carcinoma. This contradiction may suggest that Axl/Gas6 pathway varies depending on the type of cancer. The objective of this study is to investigate TAM receptors on surfaces of mononuclear cells in patients with B-Cell chronic lymphocytic leukemia (B-Cell-CLL). Material & Methods: B-Cell-CLL patients (grade 0–1, according to the classification of RAI), who were not on a drug treatment, were recruited in this study (n= 20; 9 female, 11 male). Their ages were 44 to 74 (mean: 63), and the control group consisted of 13 healthy volunteers (5 female, 8 male), whose age range is 20–89 (mean: 36). Mononuclear cells were isolated by density gradient centrifugation, and then surface TAM receptors were detected by flow cytometry. Mononuclear cell were stained with the primary antibodies against Tyro3, Axl and Mer. Results: The percentage of the surface TAM receptors on mononuclear cells from the patient group (25–75% interquartile range): Tyro 3= 25.50 (4.2– 45.62); Axl= 17/55 (5.57– 36.32), and Mer= 19.90 (1.92– 37.55). In the control group the following values were obtained: Tyro 3= 2.60 (1.35–3.25); Axl= 0.9 (0.4–2.6), and Mer= 2.50 (0.35–3.65). The percentage of three of them was significantly higher in the B-Cell-CLL group than those in the control group (P<0.01). Conclusion: In conclusion, this preliminary study showed that TAM receptors on surfaces of mononuclear cells are higher in patients with B-Cell-CLL patients than the control group. Gas6/TAM signaling may play a potential role in the pathogenesis of B Cell-CLL. Further studies are required to elucidate the actual role of Gas6/TAM signaling in B-Cell-CLL. Gas6/TAM signaling might be a new strategic goal for the treatment of B-Cell-CLL. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Mutations in the NOTCH1 PEST Domain Enhance the Expression of CCL17 By Displacing the Transcription Factor HDAC1 in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-116388 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4408-4408

Author(s):

Zhenshu Xu ◽

Shifen Wang ◽

Xiuli Chen ◽

Xueting Liang ◽

Huixin Liang ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Transcription Factor ◽

Chronic Lymphocytic Leukemia ◽

Cd4 T Cells ◽

Conflicts Of Interest ◽

Premature Stop Codon ◽

Lymphocytic Leukemia ◽

Control Group ◽

Multiple Point

Abstract The NOTCH1 is a ligand dependent transcription factor that plays an important role in lymphocyte differentiation and apoptosis . NOTCH1 dysfunction is closely related to the proliferation, differentiation, and apoptosis of tumor cells in chronic lymphocytic leukemia (CLL). With the popularization of next-generation sequencing technology the relationship between NOTCH1 mutations and disease progression in CLL, has attracted increasing attention. Here, we investigated whether the loss of a 2 bp frame shift deletion mutation influences the NOTCH1 pathway and whether this mutation alters the NOTCH1 nuclear mechanism in CLL. The ICN plasmid was engineered by cloning the ICN coding sequence into a pmax-Clover vector. The c.7541-7542delCT mutation (CTdel) was generated by site-specific mutagenesis. The BaF3 cells were transfected with Amaxa Nucleofector technology then sorted. The NOTCH1 protein expression was evaluated by Western blotting using an anti-NOTCH1 antibody, which showed compatible with the ICN. The CTdel mutation resulted in a lower molecular weight band, consistent with the presence of a premature STOP codon. Results from qRT-PCR showed elevated mRNA expression of NOTCH1 in the groups transfected with ICN and CTdel genes. An immunofluorescence assay showed that NOTCH1 was distributed in both the nuclei and cytoplasm in the control cells, while it was located in the nucleus of the cells of the ICN and CTdel groups. Compared with the control group, the activity of the reporter genes in both the ICN and CTdel groups increased, with the highest increase in the CTdel group, as reported by the two-fluorescent enzyme reporting system assay. These results determine the presence or absence of a NOTCH1 mutation, the ICN protein is located in the nucleus, and show that the NOTCH1 pathway is enhanced and the function is more stable in the presence of a NOTCH1 mutation. From the RNA-seq results we found that RT-PCR showed transcription levels of CCL17 in the ICN and CTdel groups were higher than those in the control group, and that CCL17 in the CTdel group was significantly higher than in the ICN group. We collected the culture supernatant of CLL cells for an ELISA assay and found that CCL17 was significantly elevated in the CTdel group, but CCL17 was not detected in the control group and the ICN group. In order to verify the CCL17 function of in CLL with the NOTCH1 mutation, we performed a transwell experiment to detect the ability of mediating activated CD4+ T cell migration by CCL17. The results showed that the number of CD4+ T-cells in the CTdel group that migrated in response to CCL17 was more than in the ICN group. In order to verify that the NOTCH1 mutation changed the ICN binding function, we performed a CO-IP experiment. The results showed that ICN had an interaction with MTA2/HDAC1, but this interaction was weakened with CTdel. Mass spectrometry (MS) analysis suggested that ICN was combined with MTA2 while CTdel peptides were not detected in MTA2 samples. In order to verify the negative regulatory effect of MTA2 and HDAC1 on the NOTCH1 mutation induced by C-terminal truncation in CCL17 transcription, we conducted a CHIP experiment on the nuclear pyrolysis of ICN/CTdel.The results showed that the combination of MTA2/HDAC1 and the promoter of CCL17 and ICN/CTdel was weaker than that of the control group. Because of the multiple-point binding characteristics of transcription factors on gene expression regulation, it can be concluded that CTdel DNA binding is weaker than the binding of ICN. As a result, in the presence of the NOTCH1 protein C-terminal truncation, which has lost MTA2/HDAC1 binding, its inhibition is reduced and the CCL17 expression becomes significantly elevated. In conclusion, it is suggested that the NOTCH1 mutation found in CLL stimulates the NOTCH1 pathway, and is related to the high expression of CCL17. The chemokine CCL17 can cause the migration of CD4+ T-cells and change the microenvironment to favor tumor cell survival. ICN in the nucleus combines with CSL to form activating complexes or recruits transcription factor MTA2/HDAC1 to form inhibiting complexes, and constitutes the balance between the promotion and the inhibition for the downstream gene expression. The NOTCH1 mutation with CTdel could result in loss of this balance, and activate the expression of downstream genes, such as CCL17. Key words: chronic lymphocytic leukemia; NOTCH1; mutation; HDAC1; CCL17; chemokine Disclosures No relevant conflicts of interest to declare.

Download Full-text

Presenting features and prognosis of chronic lymphocytic leukemia in younger adults [see comments]

Blood ◽

10.1182/blood.v78.6.1545.bloodjournal7861545 ◽

1991 ◽

Vol 78 (6) ◽

pp. 1545-1551 ◽

Cited By ~ 1

Author(s):

E Montserrat ◽

F Gomis ◽

T Vallespi ◽

A Rios ◽

A Romero ◽

...

Keyword(s):

Prognostic Factors ◽

Chronic Lymphocytic Leukemia ◽

Median Survival ◽

Risk Groups ◽

Lymphocytic Leukemia ◽

Control Group ◽

Younger Adults ◽

Female Ratio ◽

Prognostic Features ◽

The Impact

We have analyzed 117 younger patients with chronic lymphocytic leukemia (CLL) (mean age, 44.5 years; SD, 4.8; range, 19 to 49; male/female ratio, 2.08) with three main objectives: (1) to see whether these patients have distinctive presenting clinical features; (2) to investigate the impact of the disease on survival; and (3) to analyze whether already well-known prognostic factors are also useful when applied to these patients. As compared with an older age population (greater than or equal to 50 years), there were no major differences in presenting features except for an increased proportion of males (2.08 v 1.21; P less than .025) and a higher hemoglobin level (13.47 +/- 2.70 g/dL v 12.84 +/- 2.77 g/dL; P less than .05) in the younger group. Median survival is 12.3 years (expected median from a control group, 31.2 years). Clinical stages, bone marrow patterns, blood lymphocyte counts, and its doubling time are all useful to separate different risk groups of patients. Whereas patients with favorable prognostic factors have a survival probability of about 80% 14 years after diagnosis, those with poor prognostic features have a median survival of less than 3 years. It is concluded that CLL in younger adults has no major distinctive presenting features and that known prognostic factors are useful to separate different risk groups of patients. These results should be of help in planning therapy for younger persons with CLL.

Download Full-text

Risk of Serious Adverse Events, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Idelalisib

Blood ◽

10.1182/blood-2019-123179 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5489-5489

Author(s):

Jonathan Kopel ◽

Sriman Swarup ◽

Anita Sultan ◽

Lukman Tijani ◽

Ei Moe Phyu ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Adverse Events ◽

Conflicts Of Interest ◽

Group Versus ◽

Lymphocytic Leukemia ◽

Control Group ◽

Study Group ◽

Small Lymphocytic Lymphoma ◽

Phase 3 ◽

Serious Adverse Events

Introduction: Idelalisib is a first-in-class potent, oral, selective small-molecule inhibitor of δ isoform of phosphatidylinositol 3-kinase (PI3Kδ), which involves in the signaling of B-cell receptor pathways via activation of downstream serine threonine kinases AKT and mammalian target of rapamycin (mTOR), and has been implicated in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL). Yet, there are considerable safety concerns. We undertook a systematic review and combined analysis of phase 3 randomized controlled trials to determine the risk of serious adverse events, infection and sepsis in patients with relapsed/ refractory CLL/SLL treated with idelalisib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing idelalisib in patients with relapsed and refractory CLL/SLL that mention serious adverse events, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Three phase 3 RCTs with a total of 892 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 83, suggesting moderate heterogeneity among RCTs. The incidence of serious adverse events was 341 (69.59%) in study group vs 177 (44.03%) in control group with RR of 1.50 (95% CI: 1.28-1.75; p < 0.0001). Pneumonitis was noted in 14 (2.86%) vs 1 (0.25%) in control group (RR, 5.42; 95% CI: 1.22-24.13; p = 0.03). The incidence of any-grade pneumonia was 78 (15.92%) in study group vs 45 (11.19%) in control group (RR, 1.38; 95% CI: 0.98 - 1.96; P = 0.07). High-grade pneumonia was reported in 59 (12.04%) in idelalisib arm versus 33 (8.21%) in control group with RR of 1.36 (95% CI: 0.82 - 2.27; P = 0.23). Pneumocystis jiroveci (PJP) pneumonia rate was 2.56% higher in study group compared to control arm (RR, 4.25; 95% CI: 1.10 - 16.34; P = 0.04). Febrile neutropenia was noted in 13.47% in study group versus 4.73% in control arm (RR, 2.39; 95% CI: 0.90-6.34; p = 0.08). Sepsis rate was 3.36% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.64 (95% CI 1.10-6.30; p = 0.03). Treatment-related deaths were 45 (6.92%) in idelalisib arm vs 21 (3.74%) in control arm according to analysis of 2 trials. The pooled RR was not statistically significant at 1.64 (95% CI: 0.99 -2.71; P = 0.06). Conclusion: Patients on idelalisib experienced higher risk of serious adverse events, pneumonitis, PJP pneumonia, and sepsis, with RR of 1.50 for serious adverse events, RR of 5.42 for pneumonitis, RR of 4.25 for PJP pneumonia and RR of 2.64 for sepsis respectively. Nevertheless, there was no significant increase in treatment-related deaths due to TRAE in the idelalisib group, compared to control arm. Preemptive measures with proper supportive care are required to reduce those toxicities which can ultimately improve patients' quality of life and may probably affect patients' compliance. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Presenting features and prognosis of chronic lymphocytic leukemia in younger adults [see comments]

Blood ◽

10.1182/blood.v78.6.1545.1545 ◽

1991 ◽

Vol 78 (6) ◽

pp. 1545-1551 ◽

Cited By ~ 81

Author(s):

E Montserrat ◽

F Gomis ◽

T Vallespi ◽

A Rios ◽

A Romero ◽

...

Keyword(s):

Prognostic Factors ◽

Chronic Lymphocytic Leukemia ◽

Median Survival ◽

Risk Groups ◽

Lymphocytic Leukemia ◽

Control Group ◽

Younger Adults ◽

Female Ratio ◽

Prognostic Features ◽

The Impact

Abstract We have analyzed 117 younger patients with chronic lymphocytic leukemia (CLL) (mean age, 44.5 years; SD, 4.8; range, 19 to 49; male/female ratio, 2.08) with three main objectives: (1) to see whether these patients have distinctive presenting clinical features; (2) to investigate the impact of the disease on survival; and (3) to analyze whether already well-known prognostic factors are also useful when applied to these patients. As compared with an older age population (greater than or equal to 50 years), there were no major differences in presenting features except for an increased proportion of males (2.08 v 1.21; P less than .025) and a higher hemoglobin level (13.47 +/- 2.70 g/dL v 12.84 +/- 2.77 g/dL; P less than .05) in the younger group. Median survival is 12.3 years (expected median from a control group, 31.2 years). Clinical stages, bone marrow patterns, blood lymphocyte counts, and its doubling time are all useful to separate different risk groups of patients. Whereas patients with favorable prognostic factors have a survival probability of about 80% 14 years after diagnosis, those with poor prognostic features have a median survival of less than 3 years. It is concluded that CLL in younger adults has no major distinctive presenting features and that known prognostic factors are useful to separate different risk groups of patients. These results should be of help in planning therapy for younger persons with CLL.

Download Full-text

Prognostic Significance of Telomere Length in Chronic Lymphocytic Leukemia Patients in Early Stage Disease,

Blood ◽

10.1182/blood.v118.21.3890.3890 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3890-3890

Author(s):

Sonia Fabris ◽

Mirjam Hoxha ◽

Luca Agnelli ◽

Laura Dioni ◽

Valentina Bollati ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Telomere Length ◽

Conflicts Of Interest ◽

Early Stage ◽

Prognostic Significance ◽

Normal Karyotype ◽

Lymphocytic Leukemia ◽

Limited Information ◽

Early Stage Disease ◽

Variable Regions

Abstract Abstract 3890 Chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease with a variable outcome. The identification of factors that could predict the clinical course of early-stage CLL represents a crucial objective. Although previous studies indicated that telomere length may be a useful independent prognostic factor in the risk stratification of CLL, limited information has been reported in asymptomatic early stage patients (Binet stage A). We investigate the association of telomere length with the major biological and cytogenetic markers known to predict clinical outcome in CLL. The global DNA methylation levels of Alu and LINE sequences, was also investigated. Correlation with disease progression, measured as the time elapsed from diagnosis to first treatment, was evaluated. We measured relative telomere length (RTL) by real-time PCR in a panel of highly purified (>90%) peripheral mononuclear CD19+ cells from 7 healthy donors and 77 untreated CLLs. All the cases were characterized by FISH for the most frequent chromosomal aberrations (Fabris et al. GCC, 2008). Molecular markers including mutation status of the heavy chain variable regions of immunoglobulin genes (IGVH), the expression of the 70-kd zeta-chain T-cell receptor-associated protein kinase (ZAP-70) and CD38 cell surface antigen protocols were previously reported (Cutrona et al., Haematologica, 2008). A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu and LINE-1. We found a significantly lower RTL values in CLLs (median RTL=0.4 IQR 0.3–0.6) as compared with controls (median RTL=1.0 IQR 0.9–1.3) (P <0.001). A progressive and significant RTL decrease in low (13q- and normal karyotype), intermediate (+12) and high (11q- and 17p-) cytogenetic risk categories (P for trend =0.008) was observed. Patients with IGVH mutated genes had longer telomeres than patients with unmutated genes (P <0.001). No significant association between telomere length and either CD38 or ZAP-70 expression was found. Telomere shortening was significantly correlated with hypomethylation of Alu (P =0.048) and LINE-1 (P =0.001), indicating a contribution to chromosome instability. Finally, follow-up analysis showed a significantly higher risk of starting treatment for patients with shorter telomeres (P =0.0037). Our results extended previous evidence that telomere length could be used as marker for the identification of CLLs with a different prognostic risk. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

IDO1-Targeted Therapy Does Not Control Disease Development in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia

Cancers ◽

10.3390/cancers13081899 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1899

Author(s):

Selcen Öztürk ◽

Verena Kalter ◽

Philipp M. Roessner ◽

Murat Sunbul ◽

Martina Seiffert

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Mouse Model ◽

Adoptive Transfer ◽

Immune Cell ◽

Immune Escape ◽

Cell Activity ◽

Lymphocytic Leukemia ◽

Transfer Model ◽

Leukemia Development

Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.

Download Full-text