Multi-center study of COVID-19 infection in elderly patients with lymphoma: on behalf of Jiangsu Cooperative Lymphoma Group (JCLG).

Elderly patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we retrospectively described the clinical features and outcomes of the first time infection of Omicron SARS-CoV-2 in 364 elderly patients with lymphoma enrolled in Jiangsu Cooperative Lymphoma Group (JCLG) between November 2022 and April 2023 in China. Median age was 69 years (range 60-92). 54.4% (198/364) of patients were confirmed as severe and critical COVID-19 infection. In univariable analysis, Age > 70 years (OR 1.88, p = 0.003), with multiple comorbidities (OR 1.41, p = 0.005), aggressive lymphoma (OR 2.33, p < 0.001), active disease (progressive or relapsed/refractory, OR 2.02, p < 0.001), and active anti-lymphoma therapy (OR 1.90, p < 0.001) were associated with severe COVID-19. Multiple (three or more) lines of previous anti-lymphoma therapy (OR 3.84, p = 0.021) remained an adverse factor for severe COVID-19 in multivariable analysis. Moreover, CD20 antibody (Rituximab or Obinutuzumab)-based treatments within the last 6 months was associated with severe COVID-19 in the entire cohort (OR 3.42, p < 0.001). Continuous BTK inhibitors might be protective effect on the outcome of COVID-19 infection (OR 0.44, p = 0.043) in the indolent lymphoma cohort. Overall, 7.7% (28/364) of the patients ceased, multiple lines of previous anti-lymphoma therapy (OR 3.46, p = 0.016) remained an adverse factor for mortality.

The clinical significance and prognostic value of serum beta-2 microglobulin in adult lymphoma-associated hemophagocytic lymphohistiocytosis: a multicenter analysis of 326 patients.

To investigate the prognostic impact of serum beta-2 microglobulin (B2M) in adult lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). The clinical and laboratory characteristics of 326 adult patients in a multicenter cohort with lymphoma-associated HLH with available baseline serum B2M levels were retrospectively analyzed. A total of 326 cases were included in this study, and the median serum B2M level was 5.19 mg/L. The optimal cut-off of serum B2M was 8.73 mg/L, and the cases with serum B2M level >8.73 mg/L were older and had a more advanced stage, lower levels of platelets, albumin, and fibrinogen, and higher creatinine level. The serum B2M >8.73 mg/L, creatinine ≥133 µmol/L, fibrinogen ≤1.5 g/L, agranulocytosis (<0.5 × 109/L), severe thrombocytopenia (<50 × 109/L), and high Epstein-Barr virus DNA copy number were found to have independent prognostic values in all patients, and the serum B2M >8.73 mg/L was also an independent prognostic factor in patients with creatinine <133 µmol/L. Finally, a prognostic scoring system was established based on independent prognostic factors of all patients and categorized the patients into three groups with significant prognostic differences. This study confirmed that the serum B2M level can be an independent prognostic factor in lymphoma-associated HLH and established a prognostic scoring system to predict patients' survival.

Gemcitabine, oxaliplatin and dexamethasone (GemDOx) as salvage therapy for relapsed or refractory diffuse large B-cell lymphoma and peripheral T-cell lymphoma.

Background Outcomes of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) remain poor. The objective of this study was to evaluate the efficacy and safety of gemcitabine, oxaliplatin and dexamethasone (GemDOx) with or without rituximab as salvage therapy in patients with relapsed or refractory DLBCL and PTCL. Materials and Methods: We retrospectively reviewed patients with relapsed or refractory DLBCL and PTCL receiving GemDOx as salvage therapy between Jul 1, 2011, and Aug 31, 2017. Results: Thirty-three (57.9%) patients with relapsed or refractory DLBCL and 24 (42.1%) with PTCL were included in this study. The median age was 57 years (inter-quartile range 46-67). The overall response rate (ORR) in DLBCL was 48.5% with 27.3% of complete remission (CR), and the 2-year progression-free survival (PFS) and 2-year overall survival (OS) was 21% and 44%. In patients with PTCL, ORR was 50.0% with CR rate of 29.2%; the 2-year PFS and 2-year OS was 28% and 49%, respectively. Common grade 3-4 hematological adverse events were thrombocytopenia (26.3%), anemia (15.7%) and neutropenia (15.7%). Conclusion: With acceptable efficacy and good tolerability, GemDOx might be a new therapeutic option for relapsed or refractory DLBCL and PTCL.

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 Province's 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.

[Lipoprotein lipase and serum thymidine kinase level in chronic lymphocytic leukemia and their correlations with other prognostic factors].

OBJECTIVE: To investigate lipoprotein lipase (LPL) and serum thymidine kinase (TK) levels in chronic lymphocytic leukemia (CLL) and their correlations with other prognostic factors. METHODS: LPL expression level in peripheral blood samples of 58 CLL patients was detected by semi-quantitative reverse transcription PCR (RT-PCR). Serum TK1 level in 39 CLL patients was detected by enhanced chemiluminescence (ECL) and TK monoclonal antibody (Anti-TK mAb). IgVH mutation status was detected by multiplex PCR and sequencing of purified PCR products. The expression of ZAP-70 protein and CD38 were determined by flow cytometry . Panel probes and fluorescence in situ hybridization (FISH) were used to detect cytogenetic aberrations. RESULTS: The median LPL expression level in CLL was 0.26 (0 -6.29), while undetectable in normal controls. LPL expression level was significantly correlated with IgVH mutation status, Binet stages, CD38 and cytogenetic aberrations. Patients with unmutated IgVH genes had higher LPL than those with IgVH mutations (P = 0.010). Patients in Binet stage B and C had higher LPL than those in stage A (P = 0.011). LPL level was higher in patients with CD38 > or = 30% (P = 0.001). Higher LPL level was found in patients with unfavorable cytogenetic aberrations (deletion in 17p13 or 11q22) than those with favorable cytogenetics (deletion in 13q as the sole abnormality) (P = 0.002). LPL level was not significantly correlated with sex, age, and ZAP-70 protein (P > 0.05). The level of TK1 was higher in CLL patients than that in normal control (P < 0.05). Patients with higher level of absolute lymphocyte count (ALC), lactate dehydrogenase (LDH), unmutated IgVH genes and ZAP-70 had higher levels of TK1 than those with lower level of ALC, LDH, mutated IgVH genes and ZAP-70 (P = 0.018, P = 0.018, P = 0.030 and P = 0.038, respectively). TK1 level had no correlation with sex, age, Binet stages, CD38, and cytogenetic aberrations (P > 0.05). CONCLUSIONS: LPL expression and serum TK1 levels significantly correlate with other CLL prognostic factors and could be predictive markers for IgVH mutation status. LPL and serum TK1 might be applied to the assessment of prognosis in CLL patients.

[Expressions of bcl-6, lpp and miR-28 genes in diffuse large B cell lymphoma cell lines].

This study was purposed to explore the expressions of bcl-6, lpp and miR-28 genes in diffuse large B cell lymphoma (DLBCL) cell lines at the levels of gene and protein, and the relationship between them. Northern blot was used to detect bcl-6 and lpp mRNA expression in 8 DLBCL cell lines. Solution hybridization was used to measure miR-28 expression, and Western blot was performed for BCL-6 and LPP protein determinations. The results showed that the expression of bcl-6 mRNA was higher in the cell lines with Ig/BCL-6 translocation (Oc1-ly8, MD903, CTB-1, and MD901), and negative in those without Ig/BCL-6 translocation (HRC57 and K231). The expression of lpp mRNA in CTB-1 cell line was negative. MiR-28 was positive in all cell lines, and the expression levels from high to low were in line as follows: K231, CTB-1, MD903, HRC57, MD901, RCK8, OC1-LY8 and BEVA. BCL-6 protein was also positive in all of cell lines, and the expression levels from high to low were as follows: RCK8, BEVA, MD901, CTB-1, MD903, OC1-LY8, HRC57 and K231. LPP protein was negative in K231 cells, and the expression levels in other cells from high to low were line up as follows: HRC57, OC1-LY8, BEVA, RCK8, CTB-1, MD901 and MD903. The expression levels of bcl-6 and lpp mRNA were not consistent with expression levels of protein. It is concluded that the gene expression levels of bcl-6, lpp and miR-28 are different in various DLBCL cell lines. The expression levels of bcl-6 and lpp mRNA are not parallel with expression levels of protein. The roles of bcl-6, lpp and miR-28 in initiation and development of DLBCL need further investigation.

CD38 as a prognostic factor in Chinese patients with chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western countries, however, infrequent in the Eastern. It shows a remarkable heterogeneity, with some patients having an almost normal lifespan, others surviving only several years after diagnosis despite intensive therapy. To explore the prognostic significance of CD38 expression in Chinese patients with CLL, multi-parameter flow cytometry was used to detect the expression of CD38 on CD5(+)CD19(+) cells of 147 patients. CD38 expression and its association with some other prognostic factors such as Binet stage, lymphocyte count in peripheral blood, serum lactate dehydrogenase (LDH), beta2-microglobulin (beta2-MG), ZAP-70 expression and cytogenetic abnormalities were analyzed. The Kaplan-Meier method was used to construct survival curves, and results were compared using the log-rank test. Univariate and multivariate Cox regression analyses were used to assess associations between survival time and potential risk factors. Out of the 147 CLL patients, positive expression of CD38 was found in 45 (30.6%) cases. CD38-positivity identified a subgroup of CLL patients with aggressive disease of Binet stage at the time of the test (P=0.036). Furthermore, the presence of higher serum LDH and beta2-MG levels at diagnosis was strongly correlated with CD38-positive (P=0.016 and 0.025, respectively). Prognostically unfavorable cytogenetic abnormalities, including 17p13 and 11q22 deletions, were significantly more frequent in CD38-positive patients than in CD38-negative ones (P=0.047 and 0.001, respectively). There was no significant difference between CD38-positive and CD38-negative groups in molecular cytogenetic aberrations of del(6q23), del(13q14), 14q32 translocation, or trisomy 12. In addition, in CD38-positive patients, the percentage of leukemic cells expressing ZAP-70 protein was not significantly higher than in CD38-negative ones (P=0.120). CD38 expression was associated with poor outcome. Patients with positive expression of CD38 had significantly shorter overall survival (mean, 81 months) than patients without CD38 expression (mean, 179 months) (P=0.015). Univariate analysis showed that serum levels of LDH and beta2-MG, del(17p13) and CD38 expression were the significant factors in determining overall survival (OS). Del(17p13) and CD38 expression were the variables strongly associated with OS by multivariate Cox regression analysis. It was showed that the patients with high level of CD38 expression had poorer outcome; CD38 was a good predictor of OS in Chinese patients with CLL.

[Serum levels of soluble CD(23) and thrombopoietin in chronic lymphocytic leukemia].

OBJECTIVE: To investigate the serum levels of soluble CD(23) (sCD(23)) and thrombopoietin (TPO) in chronic lymphocytic leukemia (CLL) and their correlation with other prognostic factors. METHODS: The serum levels of sCD(23) and TPO of 25 CLL patients were detected with enzyme linked immunosorbent assay. Flow cytometry was employed to determine the expression of CD(38) and ZAP-70 protein. RESULTS: TPO level in CLL patients was significantly higher than that in normal controls 67.22 - 1881.77 ng/L and 70.29 - 147.98 ng/L respectively, P = 0.003. sCD(23) level in CLL patients was significantly higher than that in normal controls 129.80 - 405.31 U/ml and 0.65 - 32.99 U/ml respectively, P = 0.000. TPO level was significantly correlated with Binet stage and CD(38) expression. Patients in stage B and C had higher level of TPO than those in stage A 140.57 - 457.48 ng/L and 121.92 - 163.83 ng/L respectively, P = 0.014, while TPO level was higher in patients with higher CD(38) expression than in patients lower CD(38) expression 113.23 - 199.10 ng/L and 141.34 - 454.92 ng/L respectively, P = 0.033. No significant correlation of sCD(23) and TPO levels with ZAP-70 protein, sex, age, peripheral lymphocyte count and lactate dehydrogenase were observed. CONCLUSION: Serum TPO level might be a prognostic factor in CLL.

[Fluorescent in situ hybridization with a panel of probes detects molecular cytogenetic abnormalities in patients with chronic lymphocytic leukemia].

OBJECTIVE: To explore the characteristics and prognostic significance of molecular cytogenetic aberrations in Chinese patients with chronic lymphocytic leukemia (CLL) and the significance thereof in diagnosis of CLL. METHODS: A panel of probes (LSI D13S319, LSI p53, LSI ATM, CEP 12, LSI MYB, and LSI IGHC/IGHV) and interphase fluorescence in situ hybridization (FISH) were used to prospectively detect the cytogenetic abnormalities in 106 CLL patients, 82 males and 24 females, aged 62 (34 - 86). RESULTS: Molecular cytogenetic aberrations were found in 79 of the 106 CLL patients (74.5%) and 35 patients (33.0%) showed more than two kinds of abnormalities. The most frequent abnormality detected was del (13q14) in 48 cases (45.3%), followed by trisomy of chromosome 12 in 27 patients (25.5%), IgH translocation in 25 patients (23.6%), del (17p13) in 17 patients (16.0%), del (11q22) in 11 patients (10.5%) and del (6q23) in 5 patients (4.7%). The Del (13q14) rate of the group younger than 60 was 56.5%, significantly higher than that of the group aged > or = 60 (36.7%, P = 0.033). There was no significant relationship between molecular cytogenetic aberrations and sex and Binet stages (both P > 0.05). Kaplan-Meier survival analysis showed that the survival time was shorter in the patients with p53 or ATM gene deletion. Patients with sole Del (13q14) had longer survival time than those with other abnormalities. CONCLUSION: The frequencies of the chromosomal abnormalities in Chinese CLL patients are similar to those in Western countries. Panel FISH has greatly increased the sensitivity of cytogenetic analyses. Del (13q14) is the most frequent abnormality in CLL. Molecular cytogenetic aberrations detected with FISH have important prognostic significance in CLL.

[Prognostic significance of p53 and ATM gene deletion in patients with chronic lymphocytic leukemia].

OBJECTIVE: To explore the prognostic significance of p53 and ATM gene deletion in patients with chronic lymphocytic leukemia (CLL). METHODS: Interphase fluorescence in situ hybridization (FISH) and probes of LSI p53 and LSI ATM were used to detect p53 and ATM gene deletion in 80 patients with CLL. p53 and ATM gene deletion and their association with some prognostic factors were analyzed. The Kaplan-Meier method was used to calculate survivals, and results were compared using the Log-rank test. Multivariate COX regression analysis was used to assess associations between survival and potential risk factors. RESULTS: Out of the 80 CLL patients, p53 gene deletion was found in 14 (17.5%) cases, ATM gene deletion in 9 (11.3% ) cases, and both the two genes deletion in 3 (3.8%) cases. There was no significant differences of p53 and ATM gene deletion rates in sex, age, Binet stages, peripheral lymphocyte count, and the levels of LDH, beta2-MG, and ZAP-70. The p53 and ATM gene deletion rates were higher in the group of CD38 high expression than that in the group of low expression (P=0.025 and P=0.001). Among 41 patients who received fludarabine containing protocol, none of the nine cases with p53 and/or ATM gene deletion achieved complete response (CR), while 12 of 32 (37.5%) cases without the gene deletion achieved CR. The survival time was shorter in patients with p53 gene deletion (P<0.01). There was no association between outcome and ATM gene deletion (P=0.556). On multivariate analysis by COX regression, p53 gene deletion and CD38 expression (P=0.014 and P=0.017, respectively) were found to be independent factors in predicting survival. CONCLUSION: CLL patients with p53 and/or ATM gene deletion had poor therapeutic effect, and hence poor prognosis.

Prognostic significance of ATM and TP53 deletions in Chinese patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common adult form of leukemia in the Western world, however, infrequent in the Eastern. It shows a remarkable heterogeneity, with some patients having an almost normal lifespan, others surviving only several years after diagnosis despite intensive therapy. To prospectively explore the prognostic significance of ATM and TP53 deletions in Chinese patients with CLL, interphase fluorescence in situ hybridization (FISH) and probes of LSI ATM and LSI p53 were used to detect ATM and TP53 deletions in 95 patients with CLL. ATM and TP53 deletions and their association with some other prognostic factors such as Binet stage, lymphocyte count in peripheral blood, serum lactate dehydrogenase (LDH), beta2-microglobulin (beta2-MG), CD38 and ZAP-70 expressions were analyzed. The Kaplan-Meier method was used to construct survival curves, and results were compared using the log-rank test. Univariate and multivariate Cox regression analyses were used to assess associations between survival time and potential risk factors. Out of the 95 patients with CLL, ATM gene deletion was found in 9 (9.5%) patients, TP53 gene deletion in 16 (16.8%) cases. There were no significant differences between ATM or TP53 deletion and clinical parameters of sex, age, Binet stage, lymphocyte count, LDH, beta2-MG or ZAP-70 expression. However, the frequency of ATM and TP53 deletions were obviously higher in CD38-positive group than in CD38-negative group (P=0.001 and P=0.047, respectively). Among 41 patients received treatment with fludarabine and cyclophosphamide, there were nine patients with TP53 or ATM deletion, and no patient with these cytogenetic abnormalities achieved complete response (CR). Survival analysis showed that the patients with TP53 deletion had significantly shorter survival times than the patients without TP53 deletion. There was no evidence of important association between outcome and ATM gene deletion. Serum levels of LDH and beta2-MG, CD38 expression, and TP53 deletion were the significant factors in determining overall survival (OS). TP53 deletion and CD38 expression were the variables strongly associated with OS by multivariate Cox regression analysis. It was showed that ATM or TP53 deletion is associated with high expression level of CD38 and TP53 deletion as a possible prognostic factor in Chinese patients with CLL.

[Prognostic significance of lactate dehydrogenase and beta2-microglobulin in chronic lymphocytic leukemia].

To evaluate the prognostic value of lactate dehydrogenase (LDH) and beta2-microglobulin (beta2-MG) in chronic lymphocytic leukemia (CLL), a total of 141 cases of CLL had been investigated retrospectively. The Kaplan-Meier method was used to estimate the overall and failure-free survival distributions. Cox regression was used in univariate and multivariate analysis of potential predictors for overall survival. In multivariate analysis, the expression levels of LDH and beta2-MG were divided into 3 groups: (1) elevation of both LDH and beta2-MG levels; (2) elevation of LDH or beta2-MG levels alone; (3) normal levels of both LDH and beta2-MG. The results showed that serum LDH and beta2-MG levels of patients in Binet C were significantly higher than those in Binet A (p=0.034 and p=0.035). The level of serum beta2-MG was not correlated with lymphocyte count (p=0.756). Binet C and high LDH level were associated with significantly shorter overall survival. beta2-MG was not proved to have any association with overall survival. The overall survival time in group of elevation of both LDH and beta2-MG levels was shorter than that in group of normal levels of both LDH and beta2-MG. It is concluded that serum LDH level and Binet stage are important prognostic factors for CLL.

[DNA sequencing of miR-17-92 cluster at chromosome 13q31-q32 in mantel cell lymphoma cell lines].

This study was aimed to explore the characteristics of miR-17-92 cluster at chromosome 13q31-q32 in B cell malignant lymphoma and to investigate the changes of miR-17-92 cluster in B cell lymphoma at genome DNA level and its influence on expression of miR-17-92 cluster and relation with lymphoma occurrence. PCR and DNA sequencing were used to detect miR-17-92 cluster at chromosome 13q31-q32 in mantel cell lymphoma (MCL) cell lines Rec1, G519 and Z138. The results showed that DNA sequence of miR-17-92 cluster at chromosome 13q31-q32 in MCL cell lines were normal. It is concluded that there is no abnormal change in DNA sequence of miR-17-92 cluster which is not the mechanism for miR-17-92 cluster overexpression in mantel cell lymphoma cell lines.