Prognostic value of BCL2 and TP53 genetic alterations for diffuse large B-cell lymphoma patients treated with R-CHOP

Objective:Limited data about the prognostic significance of BCL2 mutations and BCL2 copy number variations in diffuse large B-cell lymphoma (DLBCL) are available. This study aimed to comprehensively describe BCL2 genetic alterations in DLBCL patients, and examine correlation of BCL2, TP53 and other genetic alterations with outcomes in patients treated with R-CHOP.Methods:Probe capture-based high-resolution sequencing was performed on 191 patients diagnosed with de novo DLBCL. MYC, BCL2, and BCL6 protein expressions were detected by immunohistochemistry.Results:The presence of BCL2 alterations significantly correlated with poor progression-free survival (PFS) (5-year PFS: 13.7% vs. 40.8%; P = 0.003) and overall survival (OS) (5-year OS: 34.0% vs. 70.9%; P = 0.036). Importantly, patients who harbored BCL2 gain/amplifications (BCL2^GA/AMP) also had a remarkably inferior 5-year PFS (11.1% vs. 38.3%; P < 0.001) and OS (22.1% vs. 69.6%; P = 0.009). In contrast, neither BCL2 mutations nor BCL2 translocations were significantly prognostic for survival. Multivariable analyses showed that the presence of BCL2 alterations, especially BCL2^GA/AMP, TP53 mutations, and International Prognostic Index (IPI) were significantly associated with inferior PFS and OS. Novel prognostic models for OS were constructed based on 3 risk factors, including BCL2 alterations (Model 1) or BCL2^GA/AMP (Model 2), TP53 mutations, and IPI, to stratify patients into 4 risk groups with different survival outcomes.Conclusions:This study showed that DLBCL patients treated with R-CHOP, BCL2 alterations, especially BCL2^GA/AMP and TP53 mutations were significantly associated with inferior outcomes, which were independent of the IPI. The novel prognostic models we proposed predicted outcomes for DLBCL patients treated with R-CHOP, but further validation of the prognostic models is still warranted.     

来那度胺联合R-CHOP治疗DLBCL改善ALC/AMC比值的研究进展

弥漫大B细胞淋巴瘤(diffuse large B-cell lymphomas, DLBCL)是非霍奇金淋巴瘤的主要亚型。DLBCL在临床表现、基因表达、治疗反应及预后方面均存在差异,外周血绝对淋巴细胞(ALC)/单核细胞(AMC)比值(ALC/AMC)作为宿主免疫和肿瘤微环境的替代指标,是预测DLBCL患者临床疗效的生物标志物。来那度胺是一种免疫调节药物,对DLBCL患者有效,对肿瘤微环境及宿主免疫反应有多种作用机制。来那度胺联合标准R-CHOP治疗以前未经治疗的DLBCL患者,似乎克服了单用R-CHOP治疗患者ALC/AMC比值的不良预后价值,本文对这一观点进行综述。     

Evolution of R-CHOP therapy for older patients with diffuse large B-cell lymphoma

Non-Hodgkin’s lymphoma is the fifth most common malignancy in adults in the USA. This disorder is especially relevant in the elderly patient population, as the median age of patients with this disorder is 65 years. Almost half of these disorders in older patients are of a diffuse large B-cell (DLBCL) subtype. The therapy of DLBCL has undergone a renaissance in the past decade, with the addition of rituximab to standard regimens, such as cyclophosphamide– doxorubicin–vincristine–prednisone (CHOP). Over this time, there have been several large Phase III treatment trials in which the CHOP and rituximab-CHOP (R-CHOP) regimens have been prospectively compared, including three trials confined to the elderly patient population. In these trials, it has been demonstrated repeatedly that the addition of rituximab results in an improved outcome, with higher response rates and prolongation in parameters including progression-free, event-free, disease-free and overall survival. In addition, this regimen has been well tolerated, even in older patients. Based upon these data, the R-CHOP regimen has now been established as the standard for initial therapy of DLBCL in older patients with DLBCL. However, issues still remain with regard to the ideal schedule of R-CHOP administration, specifically the optimal number of cycles of therapy (six vs eight), as well as cycle length (14 vs 21 days).     

Body Composition as a Predictor of Toxicity and Prognosis in Patients with Diffuse Large B-Cell Lymphoma Receiving R-CHOP Immunochemotherapy

Background: Our study measured the body composition of Diffuse large B-cell lymphoma (DLBCL) patients receiving rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimen by computed tomographic (CT) and assessed their correlation with treatment-related toxicity and other adverse outcomes. Methods: We retrospectively analyzed 201 DLBCL patients who underwent pre-treatment abdominal CT examination. CT images were used to assess body composition metrics at the third lumbar vertebrae including fat tissues and muscle. Based on the skeletal muscle area (SMA) and density (SMD), skeletal muscle index (SMI), skeletal muscle gauge (SMG = SMI × SMD) and lean body mass (LBM) were calculated. Also analyzed were the toxicity, adverse events and survival. Results: We found that SMG, SMD, SMI and LBM were correlated with any grade 3–4 toxicity, dose reduction, hospitalization or termination of the treatment due to immunochemotherapy and worse survival. However, multivariate analysis demonstrated SMG [progression-free survival (PFS): hazard ratio (HR), 2.889; 95% CI, 1.401–5.959; p = 0.004; overall survival (OS): HR, 2.655; 95% CI, 1.218–5.787; p = 0.014] was the best predictor of poor prognosis. Conclusions: SMG, SMD, SMI and LBM were identified as predictors of adverse reactions and poor survival. SMG was an innovative and valuable indicator of immunochemotherapy toxicity and other adverse outcomes. Additionally, it can be used to individualize antineoplastic drug dosing.     

Long-term update of a phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma

The present study aimed to determine the long-term safety and efficacy of chimeric anti-CD 20 antibody rituxan (rituximab, Biogen IDEC, San Diego, CA, USA; Genentech, South San Francisco, CA, USA) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in previously untreated patients with aggressive non-Hodgkin's lymphoma (NHL). Thirty-three patients with previously untreated aggressive B-cell NHL received six infusions of rituximab (375 mg/m² per dose) on day 1 of each cycle of CHOP chemotherapy, given on day 3 of each cycle of therapy. Currently, the patients now have a median follow-up of 63 months (range 34 - 82 months). The overall response (OR) rate was 94% and the complete response (CR) rate was 61% at the end of therapy. Of the 33 patients, 2 patients experienced disease progression and subsequently died of their disease, 2 patients experienced disease progression but were alive at last follow-up following additional therapy, and 2 patients died without experiencing disease progression: one due to a cerebral vascular accident at 9 months after therapy and a second patient due to small cell lung carcinoma at 55 months. The 5-year survival rate was 88% (95% confidence interval (CI) 72 - 97) and the 5-year progression-free survival was 82% (95% CI 64 - 93). There were no long-term adverse events noted directly related to the rituximab. The long-term follow-up of patients in this phase II trial of rituximab with CHOP chemotherapy for previously untreated aggressive NHL demonstrates a high response rate, which remains very durable with high 5-year overall and progression-free survivals.     

p53和MYC在弥漫性大B细胞淋巴瘤组织中的表达及与患者预后的相关性

目的:分析弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma,DLBCL)组织中p53和MYC的表达及与DLBCL患者预后的相关性。方法:分析我院收诊确认的149例DLBCL患者，应用Kaplan-Meier法计算生存率；并通过免疫组化法分析瘤组织中p53和MYC表达量，并采用单因素和Cox多因素分析MYC、p53表达与患者预后的相关性。结果:MYC基因的表达和患者年龄、性别以及BCL2/BCL6表达没有统计学差异；但MYC重组导致患者IPI指数较高、疾病分期较晚、乳酸脱氢酶（LDH）水平升高、p53表达升高（均P＜0.05)。生存率分析和Cox回归分析发现，MYC高表达患者中p53表达升高具有较差的预后（IPI指数较高）:生存期（OS）和无进展生存期（PFS）较差。 结论:p53和MYC高表达的协同作用导致DLBCL患者的预后较差。     

CD10,Bcl-6,CD138,Bcl-2,MUM1在136例弥漫大B细胞淋巴瘤中的表达及预后意义

Objective  

We evaluated the value of using a panel of GC B-cell (CD10 and Bcl-6) and activation (MUM1, CD138 and Bcl-2) markers by immunohistochemistry to define prognosis in patients with diffuse large B-cell lymphoma (DLBCL).     

Primary Diffuse Large B-Cell Lymphoma of the Urinary Bladder: Update on a Rare Disease and Potential Diagnostic Pitfalls

Diffuse large B-cell lymphoma (DLBCL) represents the most frequent type of non-Hodgkin lymphoma. Globally, DLBCL is an aggressive disease, requiring an accurate diagnosis and prompt treatment. The diagnosis is often made on biopsy samples of a nodal mass, however, approximately 40% of DLBCL cases arise at extranodal sites. The most common extranodal site is the gastrointestinal tract, however any extranodal area may be primarily involved. Primary urinary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas, whereas secondary involvement of the urinary bladder by a systemic lymphoma is a more common event. Despite being rare, DLBCL is considered to represent the predominant primary urinary bladder lymphoma. The majority of cases reported in the bladder belong to the DLBCL, NOS group, and there are only rare cases of EBV-positive DLBCL, NOS. In this review, we summarize the current knowledge on DLBCL primarily occurring in the urinary bladder, with the aim of increasing clinician and pathologist awareness on this aggressive lymphoma rarely arising in the urinary bladder. Additionally, we focus on those entities which should be taken into consideration in the differential diagnosis, highlighting potential diagnostic pitfalls.     

Chemotherapy for management of localised high-grade gastric B-cell lymphoma: how much is necessary?

BACKGROUND: Recent data suggest that chemotherapy with the cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen is a highly effective treatment for localised primary gastric lymphoma of diffuse large B-cell histology (DLBCL). We have reported that the large majority of patients achieve complete remission (CR) following three cycles of treatment, and now provide an updated series with special emphasis on patients receiving only short-term chemotherapy. PATIENTS AND METHODS: All patients with a histologically verified diagnosis of gastric DLBCL in stages EI and EII(1) undergoing chemotherapy with the CHOP regimen were evaluated. Data analysed included clinical stage, histology [presence of an additional mucosa-associated lymphoid tissue (MALT) component], evidence of Helicobacter pylori infection, H. pylori eradication, time to CR, survival and regular restaging (i.e. after three and six cycles, respectively). RESULTS: A total of 37 patients with DLBCL of the stomach with localised disease were identified, five of whom also had a MALT component. Twenty-two patients presented with stage EI and 15 with stage EII(1) disease. All patients were given chemotherapy as sole management of their lymphoma; 36 patients received CHOP, while one patient was given CHOP along with rituximab. Thirty-two (86%) achieved a CR after a maximum of three cycles, while only four patients had to be given six cycles for CR. In total, nine of 37 patients (24%) discontinued therapy earlier than scheduled: one patient received one cycle, two received two, six received three and one patient received four cycles. Two of these patients stopped treatment due to toxicity, i.e. protracted thrombocytopenia or chemotherapy extravasation. One additional patient died after one cycle of treatment; autopsy disclosed no signs of remaining lymphoma. Three patients have died after a median follow-up of 39 months (including the one patient who discontinued therapy after one cycle of treatment), while the remaining 34 patients are alive without evidence of disease. Twenty-four out of 37 patients (65%) had also undergone H. pylori eradication (including six of nine patients receiving only short-term treatment). CONCLUSIONS: DLBCL of the stomach appears to be a highly chemosensitive disease. Our data question the need for full-term CHOP treatment in patients achieving CR upon first follow-up. However, recent data suggest that additional H. pylori eradication might have contributed to the excellent results achieved in our series.     

Germinal-center type B-cell classification and clinical characteristics of Chinese pediatric diffuse large B-cell lymphoma:a report of 76 cases

Pediatric diffuse large B-cell lymphoma （DLBCL） is a highly aggressive disease with unique clinical characteristics. This study analyzed the germinal-center type B-cell （GCB） classification and clinical characteristics of Chinese pediatric DLBCL. A total of 76 patients with DLBCL newly diagnosed in Sun Yat- sen University Cancer Center between February 2000 and May 2011, with an age younger than 18 years, were included in the analysis. The male/female ratio was 3.47：1. The median age was 12 years （range, 2 to 18 years）, and 47 （61.8%） patients were at least 10 years old. Of the 76 patients, 48 （63.2%） had stage Ill/IV disease, 9 （11.8%） had bone marrow involvement, 1 （1.3%） had central nervous system （CNS） involvement, and 5 （6.6%） had bone involvement. The GCB classification was assessed in 45 patients： 26 （57.8%） were classified as GCB subtype, and 19 （42.2%） were classified as non-GCB subtype. The modified B-NHL-BFM-90/95 regimen was administered to 50 patients, and the 4-year event-free survival （EFS） rate was 85.8%. Among these 50 patients, 31 were assessed for the GCB classification： 17 （54.8%） were classified as GCB subtype, with a 4-year EFS rate of 88.2%; 14 （45.2%） were classified as non-GCB subtype, with a 4-year EFS rate of 92.9%. Our data indicate that bone marrow involvement and stage III/ IV disease are common in Chinese pediatric DLBCL patients, whereas the percentage of patients with the GCB subtype is similar to that of patients with the non-GCB subtype. The modified B-NHL-BFM-90/95 protocol is an active and effective treatment protocol for Chinese pediatric patients with DLBCL.     

一线序贯含铂方案治疗年轻弥漫大B 细胞淋巴瘤的临床研究

目的：回顾性分析一线序贯含铂方案治疗年轻弥漫大B 细胞淋巴瘤（diffuse large B-cell Lymphoma,DLBCL ）的疗效和安全性。方法：选择郑州大学附属肿瘤医院2005年1 月至2012年6 月收治的、符合入组标准的年轻初治DLBCL 患者,分为标准方案和序贯含铂方案组,χ2检验比较两组的缓解率,Kaplan-Meier 生存分析比较两组的5 年生存率,Cox 回归多因素分析生存相关影响因素,亚组分析序贯含铂方案最佳获益人群。结果：入组331 例患者,包括序贯含铂方案129 例和标准方案202 例。序贯含铂方案较标准方案获得较高的完全缓解率（complete remission rate,CRR ）（80%vs.63% ,P = 0.001）,较高的5 年无进展生存（progression free survival,PFS）（60% vs. 50% ,P = 0.014）和总生存（over all survival,OS）（70% vs . 58% ,P = 0.016）。 多因素生存分析显示序贯含铂方案治疗是PFS（HR= 0.635,P = 0.012）和总OS（HR= 0.625,P = 0.021）独立的影响因素。亚组分析显示预后良好和未联合应用利妥昔单抗的患者是序贯含铂方案的最佳获益人群。两组不良反应发生无显著性差异。结论：一线序贯含铂方案能够改善年轻DLBCL 患者的疗效,且安全性好;预后良好和未联合应用利妥昔单抗的患者是最佳获益人群。     

Hypercalcemia at diagnosis of diffuse large B-cell lymphoma is not uncommon and is associated with high-risk features and a short diagnosis-to-treatment interval

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma. The prevalence of hypercalcemia in this neoplasm and its prognostic significance is unclear. We retrospectively evaluated the prevalence of hypercalcemia at diagnosis of DLBCL and explored associations of hypercalcemia with clinical factors and outcome. Outcome was assessed using event-free survival at 24 months (EFS24). A total of 305 patients (248 de novo DLBCL and 57 transformed indolent lymphomas) diagnosed between 2006 and 2018 in Reims were analyzed. The prevalence of calcemia >10.5 mg/dL at diagnosis of de novo DLBCL and transformed indolent lymphomas was 23% and 26%, respectively. Hypercalcemia in de novo DLBCL was strongly associated with high-risk features, especially with International Prognostic Index (IPI) components, but also with B symptoms, β2-microglobulin, hemoglobin, and albumin levels. The diagnosis-to-treatment interval was significantly shorter for hypercalcemic patients (P = .001). These associations with adverse prognostic factors translated into lower rates of EFS24 (HR = 1.66; 95% CI, 1.08-2.54) and shorter PFS (P = .0059) and OS (P = .0003) for patients with lymphoma-related hypercalcemia but not independently of IPI parameters. These data suggest that hypercalcemia is rather a biomarker of the underlying biological aggressiveness of DLBCL.     

弥漫性大B细胞淋巴瘤诊治进展

弥漫性大B细胞淋巴瘤(DLBCL)是目前最常见的成人非霍奇金淋巴瘤,不同亚型在临床表现、遗传学以及分子生物学等特征方面存在明显差异,所观察到的遗传学改变主要集中在BCL6,BCL2,cMYC,FAS(CD95)的突变和体细胞超突变的异常上。虽然CHOP方案化疗能够治愈部分DLBCL,但完全缓解率仅为45%~55%。强化化疗方案或干细胞移植可改善某些患者的长期生存,最突出和一致改善弥漫性大B细胞淋巴瘤的长期生存效果则是随着抗CD20单克隆抗体药物与化疗的联合应用。     

A modified prognostic model in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

In the era of immunochemotherapy, the traditional international prognostic index (IPI) has partially lost its predictive value in diffuse large B-cell lymphoma (DLBCL) and the National Comprehensive Cancer Network-IPI (NCCN-IPI) is unable to effectively identify high-risk patients. Thus, the present study aimed to develop a modified prognostic model (M-PM) to identify high-risk patients that require aggressive treatment. The present study included 169 patients with newly diagnosed DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) or RCHOP-like regimens, between 2011–2017. The results demonstrated that the risk discrimination was improved in the NCCN-IPI compared with the IPI, and patients were divided into four risk groups with a 5-year overall survival rate of 93.8, 76.5, 54.3 and 39.4%, respectively. However, the NCCN-IPI failed to identify the high-risk DLBCL population. The newly developed M-PM presented here included four parameters: Age (≥65 years), an elevated lactate dehydrogenase level, Eastern Cooperative Oncology Group score ≥2 and total metabolic tumor volume ≥300 cm³. The M-PM also divided patients into four risk groups that comprised 40.8, 23.1, 26.0 and 10.1% of the patients, and the 5-year survival rates of these groups were 92.4, 70.6, 52.3 and 24.5%, respectively. Taken together, the results of the present study demonstrated that the M-PM was more accurate compared with the IPI and the NCCN-IPI, which served as an effective tool for identifying patients with DLBCL at high risk of an adverse prognosis.     

Predictive value of baseline 18F-FDG PET/CT and interim treatment response for the prognosis of patients with diffuse large B-cell lymphoma receiving R-CHOP chemotherapy

The present study aimed to investigate the prognostic value of baseline ¹⁸F-FDG PET/CT quantitative parameters and interim treatment response, and to assess whether the combination of these could improve the predictive efficacy in patients with diffuse large B-cell lymphoma (DLBCL) receiving R-CHOP chemotherapy. PET/CT images and clinical data of 64 patients with DLBCL who had undergone ¹⁸F-FDG PET/CT scan before and after 3 or 4 cycles of R-CHOP chemotherapy were retrospectively reviewed. The quantitative parameters including standardized uptake value (SUV), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum diameter of the maximum lesion (Dmax) were measured on baseline PET/CT images. Cox proportional hazards model was used to evaluate the influence of baseline PET/CT parameters, clinical indicators and interim treatment response on prognosis. Survival analysis was performed using Kaplan-Meier method. Receiver operating characteristic (ROC) curve analysis was performed to estimate the predictive efficacy of the combination of baseline PET/CT parameters and interim treatment response. Ann Arbor stage, International Prognostic Index (IPI), lactate dehydrogenase (LDH), necrosis, MTVmax, TLGmax, Dmax and interim treatment response showed association with 2-year progression-free survival (PFS, P<0.05). LDH, necrosis, MTVmax, MTVsum, TLGmax, TLGsum, Dmax and interim treatment response showed association with 2-year overall survival (OS, P<0.05). Ann Arbor stage, Dmax and interim treatment response were found to be independent predictors of 2-year PFS (P<0.05), while Dmax and interim treatment response were found to be independent predictors of 2-year OS (P<0.05). The PFS and OS curves of Dmax <5.7 cm group and Dmax ≥5.7 cm group, complete response (CR) group and non-CR group were significantly different, respectively (P<0.05). The baseline ¹⁸F-FDG PET/CT parameters and interim treatment response have important prognostic values in DLBCL patients who received R-CHOP chemotherapy. Combined application of Dmax and interim treatment response improved the predictive efficacy of 2-year PFS. It may be helpful to identify patients who are at high-risk of relapse and to guide early clinical intervention of these patients.     

Hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus-positive diffuse large B-cell lymphoma,NOS of bone marrow-liver-spleen type: an autopsy case report

Lymphoma-associated hemophagocytic lymphohistiocytosis (HLH) has a significantly poor prognosis among secondary HLH. We describe the rare case of a 74-year-old female with secondary HLH presenting with a rapidly fatal course. Post-mortem examination revealed Epstein-Barr virus (EBV) -positive diffuse large B-cell lymphoma (DLBCL). We were unable to make a definite antemortem diagnosis because the patient did not exhibit lymphadenopathy and bone marrow biopsy demonstrated hemophagocytosis without evidence of lymphoma. She died of multiple organ failure on the twelfth day of hospitalization despite a temporary response to steroids. Autopsy revealed diffuse lymphoma cell infiltration of the bone marrow, liver and spleen, suggesting “bone marrow-liver-spleen” (BLS)-type large B-cell lymphoma (LBCL). BLS-type LBCL is a rare and clinically aggressive lymphoma, usually associated with fever, cytopenia and HLH. The disease has a high mortality rate due to the delay in diagnosis and a highly aggressive clinical course. Further studies are required to improve our understanding of this rare extranodal DLBCL.