Jin-Hua Liang

Epstein-Barr virus positive diffuse large B-cell lymphoma predict poor outcome, regardless of the age

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined as patients older than 50 years alone. However, recent studies showed young patients with sound immune status could also be affected. In this study, we investigated the clinical features and outcomes of patients with EBV positive DLBCL in the different age groups using different EBER cut-off values. The prevalence of EBV positive DLBCL was 14.0% (35/250) and 10.4% (26/250) for EBER cut-off of 20% and 50%, respectively. With both EBER cut-off values, patients with EBV DLBCL shared many unfavorable prognostic characteristics, regardless of age. EBV positive patients, both in the elderly and young groups, showed significantly worse overall survival and progression-free survival than negative cases. Moreover, no significant differences of outcomes were identified between different age groups with EBV positive DLBCL. In conclusion, EBV positive DLBCL patients, regardless of age, shared similar poor prognostic features and showed worse outcome than negative cases. We suggest that the age criterion of EBV positive DLBCL of the elderly, and possibly the name itself, be modified in future.

Low T3 syndrome is a strong prognostic predictor in diffuse large B cell lymphoma.

The aim of this study was to evaluate the prognostic effect of low triiodothyronine (T3) syndrome on patients with diffuse large B cell lymphoma (DLBCL). A hundred and eighty‐eight patients with detailed thyroid hormone levels at diagnosis of DLBCL were enrolled. Low T3 syndrome was defined as a low serum free T3 (FT3) level with low or normal serum free tetraiodothyronine (FT4) and thyroid stimulating hormone levels. Multivariate Cox regression analysis was used to screen prognostic factors associated with progression‐free survival (PFS) and overall survival (OS). Receiver‐operator characteristic curves and the corresponding areas under the curve were calculated to assess the predictive accuracy of International Prognostic Index (IPI) and low T3 syndrome. Twenty‐four patients were diagnosed with low T3 syndrome, which was associated with worse PFS and OS in the rituximab era. It was an independent prognostic factor for PFS and OS, especially for those with IPI 0−2, extranodal sites ≤1 and stage III−IV. Synchronously low FT3 and FT4 had poorer survival outcome compared to only low FT3 and adding criterion of low T3 syndrome improved the prognostic capacity of IPI for predicting PFS and OS in DLBCL. Low T3 syndrome was found to be a strong prognostic predictor in DLBCL.

Prognostic impact of Epstein-Barr virus (EBV)-DNA copy number at diagnosis in chronic lymphocytic leukemia

Epstein-Barr virus (EBV)-DNA is detected in the blood of some persons with chronic lymphocytic leukemia (CLL) at diagnosis. Whether this is important in the development or progression of CLL is controversial. We interrogated associations between blood EBV-DNA copy number and biological and clinical variables in 243 new-diagnosed consecutive subjects with CLL. Quantification of EBV-DNA copies was done by real-time quantitative PCR (RQ-PCR). All subjects had serological evidence of prior EBV-infection. However, only 24 subjects (10%) had a EBV-DNA-positive test at diagnosis. EBV-DNA-positive subjects at diagnosis had lower hemoglobin concentrations and platelet levels, higher thymidine kinase-1 and serum ferritin levels, un-mutated IGHV genes and a greater risk of Richter transformation compared with EBV-DNA-negative subjects. Percent CD20-, CD148- and ZAP70-positive cells and mean fluorescence intensity (MFI) of each cluster designation were also increased in EBV-DNA-positive subjects at diagnosis. EBV-DNA test positivity was associated with a briefer time-to-treatment interval (HR 1.85; [95% confidence interval, 1.13, 3.03]; P=0.014) and worse survival (HR 2.77; [1.18, 6.49]; P=0.019). Reduction in EBV copies was significantly associated with therapy-response. A positive blood EBV-DNA test at diagnosis and sequential testing of EBV copies during therapy were significantly associated with biological and clinical variables, time-to-treatment, therapy-response and survival. If validated these data may be added to CLL prognostic scoring systems.

Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming

Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naïve CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL.

Elevated absolute monocyte count predicts unfavorable outcomes in patients with angioimmunoblastic T-cell lymphoma

This study was aimed at investigating the prognostic significance of the absolute monocyte count (AMC) in peripheral blood in patients with newly diagnosed angioimmunoblastic T cell lymphoma (AITL). AMC was performed in 73 therapy-naive patients with AITL in 2 institutions during 2008-2015, and higher AMC was observed in those with extranodal sites >1, bone marrow involvement, high lactate dehydrogenase level, the EBV infection, no response to treatment and high IPI, PIT, PIAI score group. The best AMC cut-off level at diagnosis was 0.8 × 10(9)/L and the 3-year overall survival (OS) was 64% for patients with low AMC group (≤ 0.8 × 10(9)/L) compared to 10% in high AMC group (>0.8 × 10(9)/L) (P<0.001). Multivariate analysis showed that elevated AMC remained an adverse prognostic parameter. Our results suggest that AMC is an independent prognostic parameter for OS in patients with AITL, and AMC >0.8 × 10(9)/L can routinely be used to identify high-risk patients with unfavorable survival.

Investigating Factors Associated with Thymic Regeneration after Chemotherapy in Patients with Lymphoma

The factors involved in thymus regeneration after chemotherapy has not been sufficiently explored. This study was aimed to identify the clinical characteristics and single-nucleotide polymorphisms in the gene (IL7R) encoding IL-7Rα associated with thymus renewal after chemotherapy in Chinese Han individuals with lymphoma. The dynamics of thymic activity in 134 adults with Hodgkin lymphoma (HL) and B cell lymphoma from baseline to 12 months post-chemotherapy were analyzed by assessing thymic structural changes using serial computed tomography scans and correlating these with measurements of thymic output by concurrent analysis of single-joint T-cell receptor excision circles (sjTREC) and CD31+ recent thymic emigrants (RTE) in peripheral blood. The association of clinical variables and IL7R polymorphisms with the occurrence of rebound thymic hyperplasia (TH) and the recovery of thymic output following chemotherapy were evaluated. Thymic regeneration was observed, with the evidence that TH occurred in 38/134 (28.4%) cases, and thymic output, assessed by CD31+ RTE numbers and sjTREC content, recovered to baseline levels within 1 year after the end of therapy. The frequencies of the T allele and TT + GT genotype of rs7718919 located in the promoter of IL7R were significantly higher in patients with TH compared with those without TH (P = 0.031 and 0.027, respectively). In contrast, no significant difference was found between two groups with respect to the distribution of allele and genotype frequencies of rs6897932. By general linear models repeated-measure analysis, rs7718919 and rs6897932 were determined to exert no significant effects on the recovery of thymic output after therapy. Univariate analysis revealed host age under 30, the diagnosis of HL, baseline thymic index and CD31+ RTE counts, and rs7718919 genotype as potential predictors for TH after chemotherapy (P < 0.05); after multivariate adjustment, only host age was independently associated with the occurrence of TH (odds ratios = 4.710, 95% confidence intervals: 1.727–12.845, P = 0.002). These findings indicate that patient age is an independent predictor for thymic regrowth after chemotherapy, which should promote awareness among physicians to make a timely diagnosis of TH in young adults and help physicians to prioritize intervention strategies for thymus rejuvenation in this population.

Thymic hyperplasia following chemotherapy in adults with lymphoma: (18)F-fluorodeoxyglucose positron emission tomography/computed tomography findings and correlation with T cell repopulation.

Thymic hyperplasia (TH) after chemotherapy is an infrequent phenomenon in adults. This study analyzed the incidence and metabolic activity of TH on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in this population. By reviewing 471 PET/CT recordings of 211 adults with lymphoma, increased FDG uptake within an enlarged thymus regarded as TH was observed in 27 patients aged 18–53 years. FDG uptake in hyperplastic thymus was mild and diffuse, with a maximum standard uptake value (SUVmax) of 2.6 ± 0.9. Its intensity varied with different occurrence times following chemotherapy. In addition, by comparing the recovery of T cell subsets in patients with TH (n = 20) and without TH (n = 28), no impact of the presence of TH was found on the repopulation of total CD4 + and CD8 + T cells within the first year after treatment. These data may be helpful to avoid misinterpretation of increased thymic uptake in adults.

Prognostic value of whole-body SUVmax of nodal and extra-nodal lesions detected by 18 F-FDG PET/CT in extra-nodal NK/T-cell lymphoma

We analyzed data from 54 newly-diagnosed persons with extra-nodal natural killer/T-cell (NK/T) lymphoma, who had a pretreatment 18F-FDG PET/CT study, to determine whether the sum of SUVmax of all the nodal and extra-nodal lesions predicted progression-free survival (PFS) and/or overall survival (OS). Three models (WB1SUVmax, WB2SUVmax, WB3SUVmax) based on the basis of the sum of SUVmax of the whole-body SUVmax of 11 nodal and 10 extra-nodal lesions were tested. The discrimination value of these models was evaluated using time-dependent receiver-operator characteristic (ROC) curves and corresponding areas under the curve (AUC) in training and validation cohorts. Findings were validated in an independent cohort of 15 subjects. ROC curve analysis showed the optimal cut-off values for WB1SUVmax, WB2SUVmax and WB3SUVmax were 15.8 (sensitivity 92%, specificity 67%, AUC 0.811; P<0.001), 12.7 (sensitivity 96%; specificity 57%; AUC 0.785; P<0.001) and 15.8 (sensitivity 88%; specificity 70%; AUC 0.793; P<0.001). Multivariate analyses indicated WB3SUVmax was independently associated with PFS (hazard ratio [HR]=3.67, 95% confidence interval [95% CI]=1.19, 11.29; P=0.023) and OS (HR= 4.51 [1.02, 19.91]; P=0.047). WB3SUVmax calculated based of the sum of the SUVmax of 3 nodal and 10 extra-nodal lesions was significantly associated with PFS and OS.

The distinct clinical features and prognosis of the CD10+MUM1+ and CD10−Bcl6−MUM1− diffuse large B-cell lymphoma

Using an immunohistochemistry (IHC) based method, diffuse large B-cell lymphoma (DLBCL) can be classified into germinal center B-cell (GCB) and non-GCB subtypes. However, the prognostic value of Hans algorithm was contradictory in the literature. Using IHC and fluorescence in situ hybridization, we analyzed the antibodies applied in Hans algorithm and other genetic factors in 601 DLBCL patients and prognostic value of Hans algorithm in 306 cases who were treated with chemoimmunotherapy. The results showed that patients with GCB subtype have better overall survival (OS) and progression-free survival (PFS) than non-GCB cases. However, to some extent, double positive (CD10+MUM1+, DP) and triple negative (CD10−Bcl6−MUM−, TN) showed different clinical characteristics and prognosis to others that were assigned to the same cell-of-origin group. The DP group showed similar OS (median OS: both not reached, P = 0.3650) and PFS (median PFS: 47.0 vs. 32.7 months, P = 0.0878) with the non-GCB group while the TN group showed similar OS (median OS: both not reached, P = 0.9278) and PFS (median PFS: both not reached, P = 0.9420) with the GCB group. In conclusion, Recognition of specific entities in Hans algorithm could help us to accurately predict outcome of the patients and choose the best clinical management for them.

Prognostic significance of bone marrow infiltration detected by PET-CT in newly diagnosed diffuse large B cell lymphoma

The aim of this study was to examine the prognostic value of bone marrow involvement (BMI) assessed by baseline PET-CT (PET(0)-BMI) in treatment-naïve patients with diffuse large B-cell lymphoma (DLBCL). All patients from a single centre diagnosed as DLBCL between 2005 and 2014 had data extracted from staging PET-CT (PET(0)-CT), bone marrow biopsy (BMB), and treatment records. The PET(3)-CT (PET-CT scan after cycle 3 of immunochemotherapy) was performed on all the patients with PET(0)-BMI positivity (PET(0)-BMI(+)). Of 169 patients, 20 (11.8%) had BMI on BMB, whereas 35 (20.7%) were PET(0)-BMI positive. Among PET(0)-BMI(+) patients, patients with maximum of standard uptake value (SUVmax) of bone marrow (SUVmax(BM)) more than 8.6 were significantly associated with high IPI score (3–5) (P=0.002), worse progression-free survival (PFS) and overall survival (OS) (P=0.025 and P=0.002, respectively). In the 68 stage IV cases, 3-year OS was higher in the patients with negative PET(0)-BMI (PET(0)-BMI(−)) than that with PET(0)-BMI(+) (84.2%±6.5% vs. 44.1%±8.6%; P=0.003), while 3-year PFS only shown a trend of statistic significance (P=0.077) between the two groups. Among the 69 patients of inter-risk of IPI (2–3), patients with PET(0)-BMI(+) had significantly inferior PFS and OS than that with PET(0)-BMI(−) (P=0.009 and P<0.001, respectively). The cut-off value of the decreased percentage of SUVmax(BM) between PET(0)-CT and PET(3)-CT (ΔSUVmax(BM)) was 70.0%, which can predict PFS (P=0.003) and OS (P=0.023). These data confirmed that along with the increased sensitivity and accuracy of identifying bone marrow by PET-CT, novel prognostic values of marrow involvement were found in patients with DLBCL.