Diffuse Large B-cell Lymphoma In China Research Articles

Simplified Geriatric Assessment-Albumin: The Modified Tool for Older Diffuse Large B-Cell Lymphoma in China

Introduction Geriatric assessment can aid in optimizing treatment strategies and supportive interventions for older adults with diffuse large B-cell lymphoma (DLBCL). Recently, Fondazione Italiana Linforni developed the simplified Geriatric Assessment (sGA) and Elderly Prognostic Index (EPI) to tailor treatment and predict the prognosis of DLBCL in older adults. Herein, we validated the prognostic value of sGA and EPI, and modified the sGA to make it more effective for older DLBCL patients in China. Methods A total of 257 patients with DLBCL aged ≥65 years from Beijing Hospital and Peking University Third Hospital were included in the study. The sGA, which was modified from original geriatric assessment (oGA), incorporates age, activities of daily living (ADL), instrumental ADL, and Cumulative Illness Rating Scale for Geriatrics (CIRS-G), identifying patients into fit, unfit, and frail group. EPI integrated sGA with the IPI score and hemoglobin, identifying patients into low-, intermediate-, and high-risk group. Early mortality was defined as any death occurring within three months from the date of diagnosis. Kaplan-Meier and receiver operating characteristic (ROC) curves were used to assess survival rates and the sensitivity and specificity of the geriatric assessment tools, respectively, whereas the log-rank test was used for comparison. Univariate and multivariate Cox regression analyses were used to identify the independent biomarkers for the patients. Logistics regression analyses were used to analyze the correlation between the geriatric assessment tools and early mortality. Results In the study, both sGA and EPI were related to the progression-free survival (PFS; Figure 1A and 1B), overall survival (OS; Figure 1C and 1D), and early mortality of older patients with DLBCL in China (All p < 0.05). Although they had no ability to predict PFS ( p > 0.05; Figure 1E), ROC curves showed that sGA could predict OS ( p = 0.006; AUC: 0.602; 95%CI: 0.530-0.674; Figure 1F), and early mortality ( p = 0.002; AUC: 0.744; 95%CI: 0.634-0.853; Figure 1G) in older patients with DLBCL in China. As for EPI, it also could predict OS ( p = 0.027; AUC: 0.584; 95%CI: 0.512-0.656; Figure 1F) and early mortality ( p = 0.009; AUC: 0.703; 95%CI: 0.590-0.815; Figure 1G). To make the geriatric tools more effective for older patients with DLBCL in China, albumin, the independent prognostic biomarker for OS of the cohorts, was added into sGA to establish the modified tool sGA-A (Table 1). According to sGA-A, patients were stratified into fit (36.7%), unfit (30.9%), and frail (32.4%) group. However, 1 patient was excluded due to the deficiency of albumin. The sGA-A was associated with age ( p < 0.001), Ann Arbor stage ( p = 0.002), ECOG-PS ( p < 0.001), lactic dehydrogenase (LDH; p = 0.001), IPI score ( p < 0.001), B symptom ( p < 0.001), hemoglobin ( p < 0.001), and albumin ( p < 0.001). Besides, sGA-A was related to PFS ( p < 0.001; Figure 1H), OS (( p < 0.001; Figure 1I), and early mortality ( p = 0.010) of older patients with DLBCL in China. Furthermore, ROC curves showed that sGA-A not only could predict OS ( p < 0.001; ACU: 0.647; 95%CI: 0.577-0.717; Figure 1F), and early mortality (p = < 0.001; AUC: 0.769; 95%CI: 0.679-0.859; Figure 1G), but also could predict PFS ( p = 0.046; AUC:0.577; 95%CI: 0.502-0.652; Figure 1E). In predicting OS, sGA-A was superior to sGA ( p = 0.010), EPI ( p = 0.006). As for early mortality, sGA-A was superior to the EPI ( p = 0.033), but not sGA ( p = 0.520). Conclusions In the study, we validated that sGA and EPI could predict OS and early mortality of older patients with DLBCL in China. Based on sGA, we propose sGA-A, which combined sGA and albumin, as an effective tool for geriatric assessment in DLBCL. The sGA-A compensated for the deficits of the sGA and EPI in predicting PFS, and was superior to sGA and EPI in predicting OS and early mortality. However, further investigations on whether sGA-A could guide the treatment may assist clinicians in improve the prognosis of older patients with DLBCL.

Diagnostic and Prognostic Value of Circulating Cell-Free DNA in Cerebrospinal Fluid and Plasma in Newly Diagnosed Diffuse Large B Cell Lymphoma

Background:Diffuse large B cell lymphoma (DLBCL) is a clinically and molecularly heterogeneous non-Hodgkin lymphoma. The clinical risk assessment for central nervous system (CNS) recurrence is still challenging in DLBCL due to the limited conventional biomarkers and techniques available. Circulating cell-free DNA (cfDNA), which reflects comprehensive tumor genetic profiles, has emerged as a potential novel strategy in the era of precision medicine. However, the clinical value of cfDNA detected in different samples in newly diagnosed DLBCL in China remains elusive. This study aims to explore the diagnostic and prognostic value of cfDNA detection in cerebrospinal fluid (CSF) and plasma in DLBCL. Methods:Next-generation sequencing (NGS) was performed on cfDNA derived from CSF, plasma, encompassing single nucleotide variants (SNV), insertion/deletions, copy number variants (CNV), IG related fusions, and clonotypic immunoglobulin gene rearrangements，alongside systemic tumor tissues in newly diagnosed DLBCL patients. Results:We recruited 30 patients, among whom CSF cfDNA was detected in 19 patients, with 6 (31.6%) being positive for SNV only. The positive rate of CSF cfDNA increased to 36.8% when considering both SNV, IG related fusion, and clonotypic immunoglobulin gene rearrangement. Notably, cfDNA was detected in 100% of CSF samples from 3 patients with known CNS involvement, and in 4 patients without known CNS involvement based on absent evidence of abnormal CSF cytology, flow cytometry, or radiography. The positive rates of SNV, IG related fusion, and clonotypic immunoglobulin gene rearrangement in CSF were 80%, 40%, and 40%, respectively, relatively confirmed by available paired tumor tissues or bone marrow samples. CfDNA was detected in 100% of plasma samples. When accounting for both SNV, IG related fusion, and clonotypic immunoglobulin gene rearrangement, the positive rate increased to 76.7% from 73.3%, which was much higher than paired peripheral blood genomic DNA (20%). The cfDNA detected in plasma exhibited high concordance rates with matched systemic tumor tissues or bone marrow samples, with concordance rates of 100%, 76.9%, and 76.5% for SNV, IG related fusion, and clonotypic immunoglobulin gene rearrangement, respectively. Interestingly, cfDNA was detected in plasma samples of 2 patients while tumor tissues' genomic DNA was negative. In total, 24 gene alterations were identified in CSF, 172 in plasma, and 160 in tumor tissue or bone marrow. Commonly mutated genes in plasma and CSF cfDNA included PIM1 (36.7% vs. 14.2%), MYD88 (33.3% vs. 28.6%), TET2 (30% vs. 28.6%), and CD79B (26.7% vs. 28.6%). The most common types of immunoglobulin gene rearrangement were IGK in different samples, and the common IG related fusions were IGH:: BCL6, IGH:: MYC, and IGH:: BCL2. Conclusion:Our study suggests that plasma cfDNA exhibits a high concordance rate with tumor tissues and can aid in the precise diagnosis and measurable residual disease monitoring. CSF cfDNA is more sensitive than conventional methods for diagnosing CNS invasion and could serve as a more accurate biomarker for predicting the risk of CNS recurrence among patients with newly diagnosed DLBCL, helping to select patients who may require enhanced CNS prophylaxis. Moreover, synchronous detection of SNV, CNV, IG related fusion, and clonotypic immunoglobulin gene rearrangement could be helpful in improving the positive rate of cfDNA.

Patients’ experience with chimeric antigen receptor T-cell therapy for DLBCL in China: a qualitative study

PurposeThe experiences of patients with diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor (CAR) T-cell therapy have received little attention. This study aimed to explore the treatment experiences of patients with relapsed or refractory (R/R) B-cell lymphoma during CAR T-cell therapy in China.MethodsThis descriptive qualitative study was conducted using face-to-face semi-structured interviews with 21 DLBCL patients 0–2 years after CAR-T infusion. Two researchers independently coded the interviews in MAXQDA 2022, and the original data were analyzed by conventional content analysis.ResultsFour themes emerged from the transcripts: (1) physiological distress, (2) functional impacts, (3) psychological experience, and (4) support requirement. Participants expressed 29 short-term or long-term symptoms related to their disease and treatment, influencing their daily life and function in a social setting. The participants expressed different negative emotions, polarized expectations about efficacy, and over-reliance on authoritative medical care. Their major concerns and hopes were achieving life goals, being treated with respect, obtaining more information about CAR T-cell therapy, and receiving government financial sponsorship.ConclusionsThe patients experienced short-term and long-term symptoms of physical distress. Patients who have experienced failure in CAR T-cell therapy also experience strong negative emotions, such as dependency and guilt. They also require authentic spiritual and financial information that is authentic. Our study may guide the development of standardized and comprehensive nursing care for R/R DLBCL patients undergoing CAR T-cell therapy in China.

Cost-effectiveness analysis of axicabtagene ciloleucel as a second-line treatment for diffuse large B-cell lymphoma in China and the United States.

Axicabtagene ciloleucel (Axi-cel) is the first Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) product approved in China for treating adult patients with relapsed or refractory large B-cell lymphoma after receiving second-line or above systemic therapy. However, it cannot be widely used in clinical practice due to its high price. To evaluate the economic value of Axi-cel fully in countries at different stages of economic development, this article, from the perspective of the medical and health system in China and the United States, evaluated the cost-effectiveness of Axi-cel in the second-line treatment of diffuse large B-cell lymphoma (DLBCL). Cost effectiveness analysis of Axi-cel in the treatment of relapsed or refractory large B-cell lymphoma (LBCL). Based on the clinical trial data of ZUMA-7, a short-term decision tree and a long-term semi-Markov partitioned survival model were constructed to evaluate the cost-effectiveness of the two strategies. This model was cycled for 40 years in 1-month cycles. In this article, only direct medical costs were considered. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to assess the robustness of the base-case results. In the baseline cost-effectiveness analysis, Axi-cel was associated with more quality-adjusted life year (QALY; 2.72 versus 1.46) and greater costs overall ($180,501.55 versus $123,221.34) than standard second-line chemotherapy in China. Moreover, the incremental cost-effectiveness ratio (ICER) of the Axi-cel group was $45,726.66/QALY, which was greater than the threshold of $37,654.5. To achieve cost-effectiveness, the price of Axi-cel must be reduced appropriately. In the United States, Axi-cel was associated with more QALYs (2.63 versus 1.74) and greater costs overall ($415,915.16 versus $289,564.34). The ICER for the Axi-cel was $142,326.94/QALY, below the set threshold of $150,000. Axi-cel is not a cost-effective option as second-line therapy for treating DLBCL in China. However, In the United States, Axi-cel has shown a cost-effectiveness advantage as a second-line treatment for DLBCL.

A Multicenter Study of 239 Patients Aged Over 70 Years With Diffuse Large B-Cell Lymphoma in China

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma subtype worldwide and occurs frequently in the elderly population. However, there are limited data on the clinical profiles of patients with DLBCL over 70 years of age. Our objective was to summarize the clinical characteristics, treatment strategies and survival outcomes of this population in China. Methods: This multicenter retrospective study was conducted in China from January 2012 to July 2020 to investigate the clinical characteristics and survival outcomes. A total of 239 patients with DLBCL aged over 70 years underwent pretreatment evaluations, treatment, and follow-up at local hospitals. The primary endpoints were the progression-free survival (PFS) and the overall survival (OS) rates at 2 years. Secondary endpoints included median PFS and OS, the estimated PFS and OS rates at 5 years, and adverse events during treatment. Results: With a median follow-up of 50 months (range, 1–102 months), the 2-year PFS and OS rates were 53.0% and 65.5%, respectively. The median PFS and OS were 42.1 and 96.4 months, respectively; and the estimated 5-year PFS and OS rates were 44.7% and 56.1%, respectively. Hematological toxicities were the most common adverse effects in this study, accounting for 90.4%; and leukopenia was the most frequently observed ≥ grade 3 event. Furthermore, we found that regimens without rituximab and chemotherapy cycles < 6 were significantly associated with worse survival. Additionally, in the 70–80-year group, reduction in chemotherapy dose was associated with a significantly shorter OS, with a 2-year OS rate of 74.4% in the full dose group, compared to 67.1% for the decreased-dose group (p = 0.044). Conclusion: Our study presents the clinical profiles and survival outcomes of elderly patients with DLBCL in China. Treatment of these patients requires careful evaluation of toxicities and benefits. To this end, a prognosis model, such as comprehensive geriatric assessment, is required in clinical practice to optimally manage elderly patients with DLBCL.

Impact of relative dose intensity of R-CCOP regimen in elderly patients with diffuse large B-cell lymphoma in China

BackgroundThe actual relative dose intensity (RDI) of the attenuated R-CCOP regimen (rituximab, cytoxan, pegylated liposomal doxorubicin [PLD], vincristine, and prednisone) has not been fully investigated in Chinese geriatric patients with diffuse large B-cell lymphoma (DLBCL). In particular, the optimum dose for PLD remains unclear. MethodsWe retrospectively collected clinical data from patients with untreated DLBCL aged 65–80 years subsequently treated with the R-CCOP. The restricted cubic spline model (RCS) was used to test the non-linear relationship between the predictors and outcomes. ResultsEighty-four patients were enrolled, with a median age of 73.5 years. More than half of the patients (54.8%) received at least 6 cycles. The median dose per cycle of cytoxan and PLD were 605.5 and 19.9 mg/m2. The 5-year progression-free survival (PFS), overall survival rate, and disease-specific survival rates were 38.7%, 44.8%, and 57.2%, respectively. The RDI of PLD (PLD-RDI, <70% vs ≥ 70%) was only significant in the univariate analysis (P = 0.002) but not in the multivariate analysis. The RCS model showed a decreasing trend of hazards with an increasing PLD dose per cycle after adjustment. No significant difference was observed between the low- and high-risk groups with PLD-RDI ≥ 70% (P = 0.548). However, patients in the high-risk group had unfavorable PFS with PLD-RDI < 70% (P = 0.006). ConclusionThe optimal dose of PLD for elderly patients with DLBCL in China remains to be determined. Evaluating the tolerance and identifying risk categories are critical for clinical decision-making in this population.

Outcomes in refractory diffuse large B‐cell lymphoma: results from a multicenter real‐world study in China

BackgroundDiffuse large B‐cell lymphoma (DLBCL) patients refractory to rituximab‐based immunochemotherapy have a dismal prognosis. However, the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries. To validate the definition and outcomes of refractory DLBCL in China, we conducted a multicenter, retrospective cohort study.MethodsThe REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL (REAL‐TREND) study was performed using real‐world data from 8 centers in China. DLBCL patients with curative intent were included in the REAL‐TREND dataset. Overall survival (OS) was estimated using the Kaplan‐Meier method and compared by the log‐rank test. Due to heterogeneity in response rates among different centers, the response rates of refractory patients were pooled using random‐effect models. Multivariate survival analysis was performed using the Cox regression model.ResultsA total of 2778 DLBCL patients diagnosed between January, 2010 and December, 2015 were enrolled to this study. After validating previous definitions, the SCHOLAR‐1 study was most suitable to define refractory DLBCL. The estimated 5‐year cumulative incidence of refractory patients was 20% (95% confidence Interval [CI] = 18%‐22%). After the determination of refractory disease, overall response rate and complete remission rate were 30% (95% CI = 22%‐38%) and 9% (95% CI = 4%‐15%), respectively. Patients with either no response to immunochemotherapy or relapse within 12 months after stem‐cell transplantation had inferior survival with a median OS of 5.9 months (95% CI = 5.5‐7.1 months) and 2‐year OS rate of 16% (95% CI = 12%‐20%). International prognostic index score 4‐5 (hazard ratio [HR] = 2.22; 95% CI = 1.47‐3.35), central nervous system relapse (HR = 1.43; 95% CI = 1.04‐1.97), and best response status (HR = 2.68; 95% CI = 1.42‐5.03 for partial remission. HR = 5.97, 95% CI = 3.21‐11.11 for stable disease/progressive disease) were independent unfavorable prognostic factors.ConclusionsThis is the first large‐scale Asian cohort study focusing on outcomes of refractory DLBCL. The definition of the SCHOLAR‐1 study identifies patients with homogenously inferior survival, thus is appropriate to select refractory DLBCL. Due to poor clinical outcomes in the rituximab era, patients with refractory DLBCL may be potential candidates for novel treatment modalities.

Clinical characteristics and outcomes in HIV-associated diffuse large B-cell lymphoma in China: A retrospective single-center study.

Human immunodeficiency virus (HIV) infection is associated with an increased risk of aggressive lymphoma, especially diffuse large B cell lymphoma (DLBCL). There are few data regarding HIV-associated DLBCL in China. Therefore, we analyzed the characteristics and outcomes of patients with HIV-associated DLBCL from our center. We retrospectively studied HIV-infected patients with DLBCL from 2011 to 2019. Data on HIV infection and lymphoma characteristics, treatments and outcomes were retrieved and analyzed. In 78 patients with HIV-associated DLBCL, most had poor performance status (PS) (74%), elevated lactate dehydrogenase (LDH) levels (95%), B symptoms (74%), advanced Ann Arbor stages (81%), bulky diseases (64%) and extranodal involvement (70%) at diagnosis. The median CD4+ T cell count was 162/µl, and 26 patients were already on combination antiretroviral therapy (cART) treatment at diagnosis of DLBCL. Elevated whole blood EBV DNA copy number was detected in 38 patients (66%, 38/58). Of the 45 patients evaluated at the end of treatment, 26 (58%) achieved CR, 6 (13%) achieved PR and 6 (13%) experienced progressive disease. The 2-year progression-free survival (PFS) and overall survival (OS) rates were 56.4% and 62.7%, respectively. Factors associated with decreased PFS and OS in univariate analysis were unfavorable PS and high international prognostic index. Elevated EBV DNA copy number was inclined to be associated with worse outcome. We did not observe a significant difference in survival between R-EPOCH and R-CHOP regimens. In our population, patients with HIV-associated DLBCL presented with aggressive characteristics and exhibited poor survival outcomes, even in the modern cART era.

Exploratory Study on the Relationship Between FcγRIIIa Gene Polymorphisms and the Efficacy and Toxicity of Rituximab in the Treatment of Stage I/II Diffuse Large B-Cell Lymphoma

Rituximab is an IgG1 monoclonal antibody approved for the treatment of diffuse large B-cell lymphoma (DLBCL); however, its efficacy is poor in some patients. Previous studies indicate that the difference in efficacy may be due to antibody-dependent cell-mediated cytotoxicity (ADCC). The effect of ADCC is closely related to Fcγ receptor IIIA (FcγRIIIa) receptor gene polymorphisms, but no study has investigated this gene in patients with DLBCL in China. In this study, we explored FcγRIIIa gene polymorphisms in patients with DLBCL in China and the ethnic differences in the FcγRIIIa gene. Moreover, we determined the relationship between FcγRIIIa gene polymorphisms and the effect and toxicity of rituximab treatment. Peripheral blood samples of 60 patients with newly diagnosed stage I/II DLBCL who received standard treatment with rituximab were collected, and DNA samples were extracted and normalized. Among the FcγRIIIa gene polymorphisms, there was a homozygous mutation, a heterozygous mutation, and a wild-type genotype at the site of 161514542 (rs396991). The proportion of these genotypes was significantly different from those found in previous studies for European and American populations and healthy Chinese populations. Moreover, we found that individuals with the homozygous (158-V/V) or heterozygous (V/F) mutation possessed better near-term effectiveness of the standard chemotherapeutic treatment, although there was no significant difference in long-term survival. However, patients with one of these genotypes usually suffer from a more severe hematological toxicity in response to the rituximab treatment. In conclusion, knowledge of a patient's FcγRIIIa gene polymorphism may be of value for the individualized treatment of DLBCL, which is worthy of follow-up research.

The Glasgow Prognostic Score as a significant predictor of diffuse large B cell lymphoma treated with R-CHOP in China.

The Glasgow Prognostic Score (GPS) incorporates C-reactive protein and albumin as clinically useful markers of tumor behavior and shows significant prognostic value in several types of solid tumors. The accuracy of the GPS in predicting outcomes in diffuse large B cell lymphoma (DLBCL) remains unknown. We performed this study to evaluate the prognostic significance of the GPS in DLBCL in China. We retrospectively analyzed 160 patients with newly diagnosed DLBCL at the Shanghai Ruijin Hospital (China). The prognostic value of the GPS was evaluated and compared with that of the International Prognostic Index (IPI) and immunohistochemical subtyping. The GPS was defined as follows: GPS-0, C-reactive protein (CRP) ≤10mg/L and albumin ≥35g/L; GPS-1, CRP >10mg/L or albumin <35g/L; and GPS-2, CRP >10mg/L and albumin <35g/L. Patients with lower GPS tended to have better outcomes including progression-free survival (PFS, P < 0.001) and overall survival (OS, P < 0.001). Multivariate analysis demonstrated that high GPS and high IPI score were independent adverse predictors of OS. Similar to several other tumors, GPS is a reliable predictor of survival outcomes in DLBCL patients treated with R-CHOP therapy. Inflammatory responses are implicated in the progression and survival of patients with DLBCL.

Clinical significance of bcl-2 protein expression and classification algorithm in diffuse large B-cell lymphoma

To investigate the clinical significance of bcl-2 protein expression and three classification algorithms including Hans model, Chan model and Muris model in patients with diffuse large B-cell lymphoma (DLBCL). Two-hundred and thirty-seven cases were collected. Standard two-step EnVision method of immunohistochemical staining was used to assess the expression of Ki-67, CD3, CD45RO, CD20, CD79a, bcl-2, bcl-6, CD10, MUM-1, GCET-1, and FOXP-1. The phenotypic classifications were assessed according to the standard of the three models. The male (131 cases) to female (106 cases) ratio was about 1.24:1, the average age was 52.6 years. Seventy-five cases (31.6%, 75/237) showed primarily lymph node involvement. Gastrointestinal tract (71 cases) was the most commonly involved extra-nodal organ. All cases expressed one or more pan B cell markers such as CD20 (99.1%, 231/233). All patients with complete clinical follow-up data survived from 1 - 120 months. The expression of bcl-2 protein indicated an adverse prognosis (P = 0.019). Two-hundred and thirty cases were classified according to Hans model, with ninety five GCB cases and one-hundred and thirty five non-GCB cases. Survival analysis showed no difference between GCB and non-GCB subtypes (P = 0.102). According to the Chan's algorithm, sixty eight case of one-hundred and eighty one were belong to GCB group, with one-hundred and thirteen non-GCB cases. GCB subtype showed much better prognosis than non-GCB subtype according to survival analysis (P = 0.031). Additionally, bcl-2 protein expression in non-GCB subtype showed the worst survival. In Muris' model, 154 of 218 cases were classified as Group 1, while 64 cases were classified as Group 2. Group 1 showed better prognosis than Group 2 (P < 0.05). Non-GCB group is the more common type of DLBCL in China. High expression of bcl-2 protein is detected in the non-GCB group. Not all subgroups classified with different classification models indicate different prognosis. Bcl-2 expression combined with Chan's algorithm may be the best tool to predict outcome.