Objective:To investigate the vaccination status, characteristics and prognosis of patients suffering from a combination of COVID-19 and chronic lymphocytic anemia (CLL) in China.Methods:Clinical data of 328 patients with chronic lymphocytic leukemia (CLL) who were first diagnosed with COVID-19 and treated in the Department of Hematology of Jiangsu Provincial People’s Hospital between November 2022 and February 2023 were retrospectively analyzed. Univariate and multivariate analysis of data of patients with severe/critical COVID-19 were conducted by applying the binary logistic regression model.Results:The median age of the CLL patients was 60 (24-87) years. 23.5% (77/328) of these patients suffered from severe/critical COVID-19 infection. Univariate analysis of the data demonstrated that a combination of factors including age >67 years ( OR=2.15, 95% CI 1.24- 3.73, P=0.006), diabetes ( OR=2.09, 95% CI 1.05-4.20, P=0.037), chronic hepatitis B ( OR=2.91, 95% CI 1.30-6.51, P=0.010), CLL progressive ( OR=3.79, 95% CI 1.57-9.15, P=0.003) and CD20 antibody-based treatments within three months prior to the COVID-19 infection ( OR=2.79, 95% CI 1.35-5.77, P=0.006) were the risk factors for severe/critical COVID-19. According to the multivariate analysis, CLL progressive ( OR=2.98, 95% CI 1.10-8.10, P=0.033) was an independent risk factor for severe/critical COVID-19 and administration of the BTK (Bruton tyrosine kinase) inhibitor monotherapy might exert a protective effect and influence a positive outcome of the COVID-19 infection ( OR=0.38, 95% CI 0.16-0.90, P=0.028). Among the 242 patients who were followed up until October 2023, 9.1% (22/242) had multiple subsequent COVID-19 infections (≥3), and 2.1% (5/242) had persistent COVID-19 infections (patients with persistent positive test for the SARS-CoV-2 antigen testing until missing follow-up for any reason). The peak value of the anti-SARS-CoV-2-IgG titres was observed between three and four months post symptom onset (median: 3.511 S/CO vs 1.047 S/CO, P<0.05). The levels of immunoglobulin A gradually decreased following infection with COVID-19, and its trough levels were attained between two to four weeks post infection (median: 0.30 g/L vs 0.74 g/L, P<0.05). According to this study the mortality of patients suffering from a combination of COVID-19 infection and CLL was 2.7% (9/328), and the main reason for their death was respiratory failure and heart failure. Conclusions:A low rate of COVID-19 vaccination and a high rate of severe/critical COVID-19 infection was observed in the CLL patients. CLL progressive was associated with severe/critical COVID-19. Anti-CD20-based treatments received within the past three months might be a risk factor for exacerbation of COVID-19 infection, whereas a monotherapy with BTK inhibitors exert a protective effect and improve outcome of COVID-19 infection.

Objective:To explore the clinical efficacy and safety of CCR (cyclophosphamide+clarithrobin+rituximab) regimen in the treatment of hairy cell leukemia (HCL).Methods:A retrospective case series study was performed. The clinical data of 4 HCL patients who received the treatment of single course CCR regimen in the First Affiliated Hospital of Nanjing Medical University from October 2015 to March 2023 were collected. The short-term efficacy and safety of CCR regimen were summarized, and the survival status of patients was evaluated by using Kaplan-Meier method.Results:All 4 patients were initial-treated classic HCL, including 3 males and 1 female, with a median age of 46 years old (range: 41-66 years old). The median follow-up time of 4 patients was 34.5 months (range: 4-92 months). Four months after the end of treatment, 3 patients achieved complete remission (CR), and 1 patient achieved partial remission (PR); none of 3 CR patients had minimal residual disease. The prognostication of Kaplan-Meier method showed that all 4 patients had progression-free survival and overall survival at 5 years. No serious drug-related adverse events occurred during the treatment process. No infusion response related to rituximab occurred. Two patients developed grade 1 fatigue, 1 patient developed grade 2 pneumonia; 1 patient developed grade 4 granulocytopenia, 3 patients developed grade 4 thrombocytopenia, and no bleeding event occurred; all adverse reactions were controllable.Conclusions:The single course CCR regimen has good efficacy and safety in treating HCL, and it can serve as a new attempt in clinical treatment of HCL.

Objective To construct a Nomogram prediction model based on body position exercise training for patients with chronic constipation. Methods A total of 327 patients with chronic constipation from March 2021 to March 2023 were divided into qualified group (n=279) and unqualified group (n=48) according to their performance in body position exercises. General clinical materials of the patients were collected, and univariate and multivariate Logistic regression analyses were performed to identify risk factors for unqualified body position exercises in patients with chronic constipation; the R software was used to construct a Nomogram model for predicting unqualified body position exercises in patients with chronic constipation, and the receiver operating characteristic (ROC) curve and calibration curve were applied to verify the discrimination and consistency of the Nomogram model. Results There were no significant differences in gender, education level, history of smoking, history of alcohol abuse, history of hypertension, history of abdominal surgery, history of colonoscopy, and correct medication administration ratio between the two groups (P>0.05); the unqualified group had higher age, longer duration of chronic constipation, and a higher proportion of diabetes history compared to the qualified group (P < 0.05); age, duration of chronic constipation, and diabetes history were independent risk factors for unqualified body position exercises in patients with chronic constipation (P < 0.05). The constructed Nomogram prediction model demonstrated excellent discrimination (area under the curve was 0.923, 95%CI, 0.888 to 0.949, with sensitivity and specificity of 87.50% and 81.00% respectively) and consistency (H-L goodness-of-fit test χ²=2.246, P=0.973). The clinical value of this Nomogram model in predicting unqualified body position exercises for patients with chronic constipation was high when the high-risk threshold probability ranged from 0.06 to 0.80. Conclusion Age, duration of chronic constipation, and diabetes history are independent risk factors for unqualified body position exercises in patients with chronic constipation, and the Nomogram model constructed based on these multi-factor results has high discrimination and consistency in predicting unqualified body position exercises for patients with chronic constipation.

OBJECTIVE: To analyze the correlation between the mutational status of immunoglobulin heavy chain variable (IGHV) gene with the prognosis of patients with Waldenström macroglobulinemia (WM). METHODS: Immunoglobulin heavy chain gene (IGH) clonotypic sequence analysis was carried out to assess the mutational status of IGHV in the blood and/or bone marrow samples from 44 WM patients. The usage characteristics of IGHV-IGHD-IGHJ gene was explored. RESULTS: The most common IGHV subgroup was IGHV3, which was similar to the data from the Institute of Hematology of Chinese Academy of Medical Science. IGHV3-23 (20.45% vs. 15.44%) and IGHV3-74 (11.36% vs. 7.35%) were the main fragments used, which was followed by IGHV4 gene family (15.91% vs. 24.26%). However, no significant correlation was found between the IGHV4 usage and the prognosis of the patients. Should 98% be taken as the cut-off value for the IGHV mutation status, only 5 patients had no IGHV variant, and there was no correlation with the prognosis. Based on the X-tile analysis, 92.6% was re-selected as the cut-off value for the IGHV variant status in such patients. LDH was increased in 26 patients (59.1%) without IGHV variant (P < 0.05), whilst progression-free survival (P < 0.05) and overall survival (P < 0.05) were significantly shorter compared with those with IGHV variants. CONCLUSION The usage characteristics of IGHV-IGHD-IGHJ in our patients was similar to reported by the Institute of Hematology of Chinese Academy of Medical Science, albeit that no correlation was found between the IGHV4 usage and the prognosis of the patients. Furthermore, 98% may not be appropriate for distinguishing the IGHV variant status in WM patients.
Humans ; Immunoglobulin Heavy Chains/genetics* ; Multigene Family ; Mutation ; Waldenstrom Macroglobulinemia/genetics*

Humans ; Hematopoietic Stem Cell Transplantation ; Transplantation, Autologous ; Lymphoma, Non-Hodgkin/drug therapy* ; Aminopyridines/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive efficacy in treating B-cell malignancies. A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR, a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule, for the treatment of patients with refractory diffuse large B-cell lymphoma (DLBCL). Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell (C-CAR011) treatment. The overall response rate was 20% and 50% at 4 and 12 weeks after the infusion of C-CAR011, respectively, and the disease control rate was 60% at 12 weeks after infusion. Treatment-emergent adverse events occurred in all patients. The incidence of cytokine release syndrome in all grades and grade ⩾ 3 was 90% and 0, respectively, which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel. Neurotoxicity or other dose-limiting toxicities was not observed in any dose cohort of C-CAR011 therapy. Antitumor efficacy was apparent across dose cohorts. Therefore, C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL, and further large-scale clinical trials are warranted.
Antigens, CD19/adverse effects* ; China ; Humans ; Lymphoma, Large B-Cell, Diffuse/therapy* ; Receptors, Chimeric Antigen ; T-Lymphocytes

Background::NOTCH1 mutation is an essential molecular biologic aberration in chronic lymphocytic leukemia (CLL). CLL patients with NOTCH1 mutation have shown an unfavorable survival and a poor response to chemoimmunotherapy. This study aims to present the mechanisms of adverse prognosis caused by NOTCH1 mutation from the perspective of the splicing factor heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Methods::The microarray data in Gene Expression Omnibus datasets were analyzed by bioinformatics and the function of hnRNPA1 was checked by testing the proliferation and apoptosis of CLL-like cell lines. Afterward, quantitative reverse transcription-polymerase chain reaction and Western blotting were applied to explore the relationship among NOTCH1, c-Myc, and hnRNPA1.Results::RNA splicing was found to play a vital part in NOTCH1-mutated CLL cells; hence, hnRNPA1 was selected as the focus of this study. Higher expression of hnRNPA1 validated in primary NOTCH1-mutated CLL samples could promote proliferation and inhibit apoptosis in CLL. The expression of hnRNPA1 increased when NOTCH1 signaling was activated by transfection with NOTCH1 intracellular domain (NICD)-overexpressed adenovirus vector and declined after NOTCH1 signaling was inhibited by NOTCH1-shRNA. Higher expression of c-Myc was observed in NICD-overexpressed cells and hnRNPA1 expression was downregulated after applying c-Myc inhibitor 10058-F4. Moreover, in NICD-overexpressed cells, hnRNPA1 expression decreased through c-Myc inhibition. Conclusion::Overexpression of c-Myc-dependent hnRNPA1 could promote proliferation and inhibit apoptosis in NOTCH1- mutated CLL cells, which might partly account for the poor prognosis of patients with NOTCH1 mutation.

Objective:To investigate the clinical, genetic, and clonality related aspects of individuals with Richter transformation (RT) .Methods:From January 2019 to December 2021, 18 RT patients with diagnoses at the First Affiliated Hospital of Nanjing Medical University (Pukou CLL center) were retrospectively examined. The immunoglobin heavy variable (IGHV) gene usage and IGHV-D-J rearrangement pattern of diagnosed CLL/SLL and transformed diffuse large B-cell lymphoma (DLBCL) were compared to determine the clonality relatedness. To investigate the risk factors of RT, Clinical and laboratory data from patients with newly diagnosed CLL/SLL and transformed DLBCL were gathered.Results:The median age of RT was 56.5 (41-75) years old. 17 patients transformed to DLBCL and 1 transformed to Hodgkin lymphoma (HL) . Of 17 individuals who had DLBCL transformation, 15 had CLL/SLL-related clonality and 2 had unrelated clonality. Next-generation sequencing (NGS) analysis of 11 paired initially diagnosed treatment-naive CLL/SLL and RT DLBCL found that EGR2、TP53 and NOTCH1 were among the most frequently mutated genes both in treatment-naive CLL/SLL and in RT DLBCL. In several cases, specific mutations were gained or lost throughout RT, indicating clonal evolution. Among 10 patients before exposure to BTK inhibitors before RT, four patients acquired BTK mutation. The aforementioned mutations should be considered high-risk variables for transformation; in addition, TP53 and EGR2 mutations could be linked to a poor prognosis following RT in patients receiving a cocktail of new medicines.Conclusion:Most RT DLBCL patients in our center are clonality related (15/17, 88.2% ) and we recommend all qualified centers to evaluate clonality relatedness of RT DLBCL patients. There was some variability in the mutational landscape between DLBCL that had undergone a transformation and initially diagnosed, treatment-naive CLL/SLL. The underlying molecular mechanism of RT needs more research.

Objective:This study aims to explore the clinical characteristics of T-cell large granular lymphocyte leukemia (T-LGLL) patients with STAT3 mutation status and provide a reference for clinical management of such patients.Methods:The clinical data of T-LGLL patients between 2009 and 2019 in Jiangsu Province Hospital were retrospectively analyzed. Differences in baseline clinical data, treatment responses, and survival outcomes in patients with STAT3 mutations or with no mutations were compared.Results:A total of 80 patients were included, including 66 patients without STAT3 mutation and 14 patients (17.5%) with STAT3 mutation. The frequency of Y640F mutation was the highest (42.9%) . Compared with non STAT3 mutation group, STAT3 mutation group had lower HGB (67.5 g/L vs 82.5 g/L, P=0.018) , lower neutrophil count (0.665×10 9/L vs 1.465×10 9/L, P<0.001) , higher LDH (229 U/L vs 198 U/L, P=0.041) , higher ferritin (402.5 g/L vs 236.0 g/L, P=0.029) , higher expression rate of TCR Vβ subfamily (89.2% vs 65.4%, P=0.014) and higher proportion of patients with treatment indications (100% vs 74%, P=0.033) . The complete remission rates of STAT3 mutation group and non mutation group were 38.5% and 32.7%, respectively, with no significant difference ( P=0.748) . The overall response rate of first-line immunosuppressive therapy in STAT3 mutation group and non mutation group were 69.2% and 69.4%, respectively, with no significant difference ( P=1.000) . The median follow-up time was 63 (2-121) months. There was no significant difference in the overall survival time between the two groups ( P=0.170) . Conclusions:T-LGLL patients with STAT3 mutations seems to be correlated with an increased tumor burden and high treatment demand, and had a good response to first-line immunotherapies. The prognostic significance of STAT3 mutation in T-LGLL patients requires further validation.

Objective:The study aimed to analyze the clinical features and prognosis of chronic lymphocytic leukemia (CLL) with t (14;18) (q32;q21) and conduct a literature review.Methods:The clinical data of 8 patients with CLL carrying t (14;18) (q32;q21) seen in Jiangsu Province Hospital from November 2009 to November 2019 were collected and analyzed.Results:Among the 8 cases, 7 were male and 1 was female. The median age at diagnosis was 70 years old. The immunophenotype score was 5 in 3 patients. 4 patients were scored 4 and the remaining one scored 3. The bone marrow histopathology showed the typical manifestation of CLL. Karyotype analysis showed that all the cases carried t (14;18) (q32;q21) in the stemline. The t (14;18) (q32;q21) showed as the sole abnormality in 3 cases, with +12 in 4, and with 13q- in 1 case. 13q- was found in another 3 patients by FISH. Immunoglobulin heavy chain gene (IGHV) mutation status was detected in 6 cases and all of them were mutated. None of them used IGHV3-21. Only 1 case harbored TP53 mutation and no TP53, SF3B1, NOTCH1, or MYD88 mutations were found in the remaining cases who underwent the relevant tests. At a median follow-up of 30.9 months, 1 case died. The remaining 7 cases survived and 3 of them have not reached the treatment indication. 4 patients who received chemotherapy or immunotherapy were stable.Conclusions:The t (14;18) (q32;q21) is rare in CLL and often accompanied by +12 and mutated IGHV. CLL with t (14; 18) (q32; q21) tends to have a good prognosis.