Yi Xia

Angiogenic factors in chronic lymphocytic leukemia

Angiogenesis is a complex process controlled by the balance of a large number of regulating factors, the pro- and anti-angiogenic factors. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks for cancer. Recent emphasis on the microenvironments influence in chronic lymphocytic leukemia (CLL) progression and drug resistance nurtures the interest in angiogenesis. Researchers have already identified a variety of angiogenic factors involved in the CLL, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), angiopoietin-2(Ang-2), thrombospondin-1 (TSP-1), as well as extracellular proteinases such as matrix metalloproteinase-9 (MMP-9). Besides modulating neovascularization, angiogenic factors also participate in the regulation of pro-survival effects of CLL cells. However, the precise mechanism involved still needs to be elucidated further. At present, the levels of some angiogenic factors are regarded as prognostic markers of the progression of CLL, although it is not widely used. Several anti-VEGF agents are currently under clinical trial. Advances in the understanding of the bases of angiogenesis regulators will be benefit for the comprehension of CLL pathogenesis and help to conquer the disease.

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.

Low expression of CD200 predicts shorter time-to-treatment in chronic lymphocytic leukemia.

CD200, formerly known as OX-2, is a type I glycoprotein that is expressed on a variety of cell types. CD200 has been shown to be overexpressed in chronic lymphocytic leukemia (CLL). Although previous studies have confirmed the diagnostic value of CD200 in differentiating CLL from to other B-cell chronic lymphoproliferative disorders especially mantle cell lymphoma, whether CD200 has prognostic significance in CLL remains to be determined. We evaluated the mean fluorescence intensity (MFI) of CD200 in 307 consecutive, untreated patients with CLL in our center using flow cytometry. Using a CD200 MFI cutoff of 189.5, these cases could be divided into two groups. Patients with lower CD200 MFI (< 189.5) had a significantly shorter time-to-treatment (TTT) than those with higher CD200 MFI (≥ 189.5) (median TTT: 2 months vs 28 months, p = 0.0008). However, the effect of CD200 MFI on overall survival was not significant (CD200 MFI < 189.5: undefined vs CD200 MFI ≥ 189.5: undefined, P = 0.2379). In subgroup analysis, CD200 MFI retained its prognostic value in patients with favourable characteristics such as Binet stage A disease, mutated IGHV status, normal TP53 or negative CD38 expression. In conclusion, our study identified CD200 MFI as a potential prognostic factor in CLL.

Gemcitabine-oxaliplatin plus rituximab (R-GemOx) as first-line treatment in elderly patients with diffuse large B-cell lymphoma: a single-arm, open-label, phase 2 trial

BACKGROUND The combination of rituximab, gemcitabine, and oxaliplatin (R-GemOx) has shown high efficacy with a low toxicity profile in elderly patients with relapsed and refractory diffuse large B-cell lymphoma. We aimed to evaluate the efficacy, safety, and feasibility of the R-GemOx regimen as a first-line treatment in elderly patients with diffuse large B-cell lymphoma. METHODS In this single-arm, open-label, phase 2 clinical trial, we enrolled patients with previously untreated, histologically confirmed, CD20-positive diffuse large B-cell lymphoma, aged 70 years or older, or aged 60-69 years with an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or greater. Patients were recruited from Jiangsu Province Hospital (Jiangsu Sheng, China). The R-GemOx regimen was administered intravenously: rituximab 375 mg/m2 on day 0; gemcitabine 1 g/m2 on day 1; and oxaliplatin 100 mg/m2 on day 1. The cycle was repeated every 14 days. Six cycles were planned if the patient achieved at least partial remission after the interim assessment. The primary endpoint was the proportion of patients who achieved an overall response at the end of treatment (defined as complete response plus partial response). Analyses were done by intention to treat. The trial is ongoing but no longer recruiting patients. This study is registered with ClinicalTrials.gov, number NCT01670370. FINDINGS Between Aug 22, 2012, and Dec 31, 2015, 60 patients were enrolled and included in the study. The median age of the patients was 75 years (IQR 70-80) and 27 (45%) patients had a poor performance status with an ECOG score of 2 or greater. 45 (75%) patients achieved an overall response at the end of the treatment, with 28 (47%) achieving a complete response. Common grade 3-4 adverse events were haematological toxicities (thrombocytopenia in five [8%] patients, anaemia in four [7%], and neutropenia in nine [15%]) and gastrointestinal complications (nausea in five [8%] patients, vomiting in three [5%], and diarrhoea in one [2%]). No treatment-related deaths were reported. INTERPRETATIONS The R-GemOx regimen shows high efficacy and safety as a front-line treatment in an elderly patient subpopulation and might be a therapeutic option for management of diffuse large B-cell lymphoma in elderly patients. FUNDING National Natural Science Foundation of China, Jiangsu Provinces Medical Elite Programme, Project of National Key Clinical Specialty, National Science & Technology Pillar Program, Jiangsu Provincial Special Program of Medical, and National Science and Technology Major Project.

Low natural killer (NK) cell counts in peripheral blood adversely affect clinical outcome of patients with follicular lymphoma

Low natural killer (NK) cell counts in peripheral blood adversely affect clinical outcome of patients with follicular lymphoma

Elevated absolute NK cell counts in peripheral blood predict good prognosis in chronic lymphocytic leukemia

PurposeThe aim of this study was to investigate the prognostic significance of the absolute natural killer (NK) cell counts in peripheral blood in patients with chronic lymphocytic leukemia (CLL). MethodsA total of 273 previously untreated patients with CLL from April 2004 and October 2015 were enrolled into this retrospective study. We analysed the T cell subsets of all patients and figured out the number of NK cells. Comparisons of NK cell count as continuous parameter in different groups were described using Mann–Whitney U test and the Kruskal–Wallis test. Kaplan–Meier method was used to survival analysis, and the Cox proportional hazards models were used for the estimation of prognostic factors.ResultsNK cell counts were calculated in 273 therapy-naive CLL patients, and higher number of NK cell was observed in those with Binet stage A/B, ZAP-70 < 20%, normal serum albumin and β2-microglobulin levels. Using a NK cell count cut-off of 0.40 × 109/L, patients with lower NK cell count (< 0.40 × 109/L) had a significantly shorter overall survival (OS) than those with higher NK cell count (≥ 0.40 × 109/L) (P = 0.0014). Multivariate analysis showed that NK cell counts remained its prognostic value. However, the effect of NK cell count on time to treatment was not significant. ConclusionsOur results suggest that NK cell count is an independent prognostic marker for OS in patients with CLL and NK cell counts ≥ 0.40 × 109/L can routinely be used to identify patients with favorable survival.

Low T3 syndrome as a predictor of poor prognosis in chronic lymphocytic leukemia: Low T3 syndrome in CLL

Low triiodothyronine (T3) state is associated with poor prognosis in critical acute and prolonged illness. However, the information on thyroid dysfunction and cancer is limited. The aim of our study was to evaluate the prognostic value of low T3 syndrome in chronic lymphocytic leukemia (CLL). Two hundred and fifty‐eight patients with detailed thyroid hormone profile at CLL diagnosis were enrolled. Low T3 syndrome was defined by low free T3 (FT3) level accompanied by normal‐to‐low free tetraiodothyronine (FT4) and thyroid‐stimulating hormone (TSH) levels. A propensity score‐matched method was performed to balance the baseline characteristics. Multivariate Cox regression analyses screened the independent prognostic factors related to time‐to‐first‐treatment (TTFT) and cancer‐specific survival (CSS). Area under the curve (AUC) assessed the predictive accuracy of CLL‐International Prognostic Index (IPI) together with low T3 syndrome. The results showed that 37 (14.34%) patients had low T3 syndrome, which was significantly associated with unfavorable TTFT and CSS in the propensity‐matched cohort, and it was an independent prognostic indicator for both TTFT and CSS. Serum FT3 level was positively related to protein metabolism and anemia, and inversely related to inflammatory state. Patients with only low FT3 demonstrated better survival than those with synchronously low FT3 and FT4, while those with synchronously low FT3, FT4 and TSH had the worst clinical outcome. Low T3 syndrome together with CLL‐IPI had larger AUCs compared with CLL‐IPI alone in TTFT and CSS prediction. In conclusion, low T3 syndrome may be a good candidate for predicting prognosis in future clinical practice of CLL.

The percentage of cells with 17p deletion and the size of 17p deletion subclones show prognostic significance in chronic lymphocytic leukemia without treatment indication

TP53 disruption is considered to be the most important prognostic factor in chronic lymphocytic leukemia (CLL), but not all patients with TP53 disruption have similar dismal outcomes. We evaluated the prognostic value of TP53 disruption in CLL patients without treatment indications. Data of 305 CLL patients were analyzed. 41 of them (13%) had TP53 disruption. Patients with lower percentage of cells with del(17p) had significantly better survival. Patients with mutated IGHV, β2‐microglobulin ≤3.5 mg/L, wild‐type TP53, age ≤65 years or without complex karyotype (CK) had relatively favorable outcomes in the del(17p) group. Furthermore, patients with del(17p) as a minor clone showed survival advantage compared with those with del(17p) as a major clone. These data suggest that the percentage of cells with del(17p), the size of the del(17p) subclone, CLL International Prognostic Index, and CK should be considered to build refined prognostication models for patients with TP53 disruption.

Albumin-to-Fibrinogen Ratio as an Independent Prognostic Parameter in Untreated Chronic Lymphocytic Leukemia: A Retrospective Study of 191 Cases

Purpose Chronic lymphocytic leukemia (CLL) is one of the most frequent type of B-cell chronic lymphoproliferative disorders and chronic inflammation takes part in the development of CLL. However, there has been no valid immune biomarker to predict the prognosis of untreated CLL patients. Materials and Methods In this retrospective study, we analyzed the clinical correlations and prognostic value of albumin-to-fibrinogen ratio (AFR) detected at diagnosis in 191 CLL patients. Results The cut-off value of AFR was 9.7 calculated by X-tile. Patients who were more than 65 years old were often accompanied by low level of AFR (p < 0.001). Survival analysis showed that patients with low level of AFR had shorter overall survival (OS) than patients with high level of AFR (p < 0.001). Multivariate analysis illustrated that AFR had a negative impact on OS (p=0.003) and was independent of parameters involved in CLL international prognostic index and other prognostic markers such as CD38 and ZAP-70. Conclusion These data provide a comprehensive view of AFR and shows that AFR at diagnosis is an adverse prognostic factor in untreated CLL patients.