Improved survival with rituximab-based chemoimmunotherapy in older patients with extranodal diffuse large B-cell lymphoma

Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database, we investigated the relative benefits of adding rituximab to CHOP chemotherapy in diffuse large B-cell lymphoma (DLBCL) of extranodal origin, and found similar advantage for nodal and extranodal lymphomas. Hazard ratio for overall survival was 0.64 for nodal, and 0.70 for extranodal DLBCL. Hazard ratios for lymphoma-related death were 0.62 and 0.57, respectively. The advantage was largest for DLBCL of the spleen, liver and lung. Conversely, it was not evident for thyroid or testicular lymphomas. Compared with nodal DLBCL, spleen was the only site with significantly better prognosis after R-CHOP.     

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).     

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).     

Venous thromboembolism in patients with diffuse large B-cell lymphoma

We conducted a retrospective record review to determine the frequency of venous thromboembolism (VTE) in patients with diffuse large B-cell lymphoma (DLBCL). All records from 1990 to 2001 of patients with the diagnosis of DLBCL at a tertiary care hospital were reviewed. Those with transformation from low-grade lymphoma, central nervous system lymphoma, HIV-related lymphoma or with incomplete records were excluded. All episodes of symptomatic VTE confirmed by imaging studies that were either present at diagnosis or occurred during initial treatment were identified. VTE occurred in 27 of 211 patients (12.8%). Stage I disease was associated with a low risk, whereas a high international prognostic index score increased risk. Of patients with VTE, thrombosis was present at diagnosis in 37% and occurred during the first chemotherapy cycle in 22% and during the first three cycles in 82%. The median survival of patients with VTE was 1.04 years [95% confidence interval (CI) = 0.75 - 1.33] compared to 5.2 years (95% CI 1.8 - 8.6) for those without VTE (P = 0.038). We conclude that VTE is a frequent complication of DLBCL that occurs particularly at diagnosis and during initial therapy, and it is associated with a worse prognosis.     

Conditional survival of patients with diffuse large B-cell lymphoma

BACKGROUND: Prognosis of lymphoma patients is usually estimated at the time of diagnosis and the estimates are guided by the International Prognostic Index (IPI). However, conditional survival estimates are more informative clinically, as they consider those patients only who have already survived a period of time after treatment. Conditional survival data have not been reported for lymphoma patients. METHODS: Conditional survival was estimated for 1209 patients with diffuse large B-cell lymphoma (DLBCL) from the population-based LYFO registry of the Danish Lymphoma Group. The Kaplan-Meier method was used to estimate conditional survival at 0-5 years after diagnosis. RESULTS: The probability of surviving 5 years increases with each year survived for the first 3 years after diagnosis, after which the increase is minimal. The median survival increases from 38 months for all patients to between 108 and 120 months, conditioned on survival for at least 3-5 years. The prognostic capacity of the IPI and the age-adjusted IPI was high at diagnosis, but the significance gradually declined in the first years after diagnosis. Furthermore, the prognostic impact of the individual clinical variables of the IPI was also significant at diagnosis, but 2 years after diagnosis only age had prognostic impact. Multivariate analysis of patients who survived > or = 3 years identified only age as a prognostic factor. CONCLUSION: For patients with DLBCL who have survived more than 1 year after diagnosis, the conditional survival probability provides more accurate prognostic information than the conventional survival rate estimated from the time of diagnosis.     

弥漫性大B细胞淋巴瘤的治疗选择

弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphpma,DLBCL）是非霍奇金淋巴瘤中最常见的类型,在分子遗传学、免疫表型等方面具有高度异质性,患者临床预后也截然不同。R-CHOP方案为DLBCL标准治疗方案,如何进一步提高DLBCL疗效是近年来的研究热点。2015年美国临床肿瘤学会（ASCO）提出基于细胞起源分型进行R-CHOP+X方案治疗的策略,但这些方案相继失败。基于更加精准的分层方法,筛选出不同DLBCL亚组并进行针对性治疗,是未来DLBCL治疗的方向。此外,抗体-药物偶联物、双特异性抗体和嵌合抗原受体T细胞（chimeric antigen receptor T-cell,CAR-T）等免疫治疗近年来取得突破性进展,为DLBCL患者带来新的希望。本文针对基于精准分层的DLBCL靶向治疗、免疫治疗的最新进展及遗传学检测方法予以综述。      

Improving outcomes for patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring form of non-Hodgkin lymphoma in the western world. Until the mid 1990s the incidence of DLBCL increased in both sexes, across racial categories, and across all age groups except the very young, the etiology of most cases remains unknown. DLBCL is associated with an aggressive natural history, but it can be cured with combination chemotherapy regimens like cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which has been the mainstay of therapy for several decades. Remarkable progress has been made in understanding the biological heterogeneity of DLBCL and in improving survival for DLBCL patients with novel combinations of chemotherapy and immunotherapy. Gene expression profiling (GEP) has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses, and the addition of the monoclonal antibody, rituximab, to CHOP has markedly improved outcomes. Future approaches to DLBCL management will use molecular signatures identified through GEP to provide prognostic information and to isolate therapeutic targets that are being evaluated for DLBCL patients who relapse or those with high risk disease.     

Treatment of elderly patients with diffuse large B-cell lymphoma

With the implementation of rituximab, tremendous progress has been achieved in the treatment of diffuse large B-cell lymphoma (DLBCL). Nevertheless, the majority of patients with DLBCL are over the age of 65 years and the management of these patients is often suboptimal. Standard chemo-immunotherapy with curative approach should be appropriate for all elderly patients who can tolerate it. Therefore, a careful evaluation of each patient is mandatory prior to treatment allocation. R- CHOP regimen (rituximab, cyclophosphamide doxorubicin, vincristine, prednisolone) remains the standard of care, but special attention has to be paid to rigorous supportive care. Patients not fit enough for R-CHOP are candidates for dose-reduced therapy or other palliative strategies.     

Debulking surgery for patients with diffuse large B-cell non-Hodgkin's lymphoma

Chemotherapy and radiotherapy have been the principal modalities of treatment for diffuse large B-cell non-Hodgkin's lymphoma (B-NHL) for over 30 years. Various treatment regimens have been designed over the years to try to increase response and cure rates. The role of surgery has been generally restricted to defined and limited situations including diagnostic tissue biopsies and treating abdominal emergencies such as organ rupture or perforation. We present two cases of refractory B-NHL, where surgery was used as a part of stepwise and multi-modal treatment with curative intent. In both cases, the treatment approach included standard dose chemotherapy, eradication of residual mass by surgery, high dose chemotherapy (HDC) with stem cell support and posttransplantant immunotherapy. Currently, 2 years after completing the therapy, both patients are well with no evidence of active disease. Based on our experience with 2 patients we believe that in specific cases of residual chemo-resistant lymphomatous mass, surgery should be considered as a part of a multimodal approach.     

Statin-independent prognosis of patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy

BackgroundA recent laboratory study indicated that statins impaired the antitumor effects of rituximab by inducing conformational changes in CD20. Although these findings raised significant concerns about statin use during rituximab treatment, their clinical significance is unclear.Patients and methodsWe conducted a retrospective study investigating the effects of statins on the prognosis of diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). Newly diagnosed DLBCL patients were analyzed (n = 256), including 35 patients taking statins.ResultsThe 3-year progression-free survival rates were 84% and 73% (P = 0.38), while the overall survival rates were 89% and 78% (P = 0.28) for those patients treated with and without statins, respectively. After adjusting for the International Prognostic Index and serum cholesterol level, statin use was not associated with prognosis.ConclusionsThese results indicate that statins do not influence the clinical prognosis of DLBCL treated with RCHOP. Further studies with larger numbers of patients are warranted to confirm the prognostic significance of statins for patients with DLBCL receiving rituximab-containing chemotherapy.     

Bronchial infiltration with diffuse large B-cell lymphoma

Non-Hodgkin's lymphoma (NHL) refers to a heterogeneous group of lymphoproliferative diseases with a diversity of clinical courses, including involvement in another organs. NHL frequently involves the thoracic structures, and particularly the mediastinum and lung parenchyma. Several clinical reports have described bronchial-associated lymphoid tissue (BALT) lymphoma as an endobronchial lesion, but endobronchial infiltration with diffuse large B-cell lymphoma is extremely rare. Here, we provide the first report of this condition confirmed by a histopathological study and the presence of an immunoglobulin heavy chain (IgH) gene rearrangement detected by a polymerase chain reaction (PCR).     

Use of subsequent PET/CT in diffuse large B-cell lymphoma patients in complete remission following primary therapy

Interim 18F-fluorodeoxyglucose(FDG) positron emission tomography/computed tomography(I-PET/CT) is a powerful tool for monitoring the response to therapy in diffuse large B-cell lymphoma(DLBCL). This retrospective study aimed to determine when and how to use I-PET/CT in DLBCL. A total of 197 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone(R-CHOP) were enrolled between October 2005 and July 2011; PET/CT was performed at the time of diagnosis(PET/CT0), after 2 and 4 cycles of chemotherapy(PET/CT2 and PET/CT4, respectively), and at the end of treatment(F-PET/CT). According to the International Harmonization Project for Response Criteria in Lymphoma, 110 patients had negative PET/CT2 scans, and 87 had positive PET/CT2 scans. The PET/CT2-negative patients had significantly higher 3-year progression-free survival rate(75.8% vs. 38.2%) and 3-year overall survival rate(93.5% vs. 55.6%) than PET/CT2-positive patients. All PET/CT2-negative patients remained negative at PET/CT4, but 3 were positive at F-PET/CT. Among the 87 PET/CT2-positive patients, 57 remained positive at F-PET/CT, and 32 progressed during chemotherapy(15 at PET/CT4 and 17 at F-PET/CT). Comparing PET/CT4 with PET/CT0, 7 patients exhibited progression, and 8 achieved partial remission. Comparing F-PET/CT with PET/CT0, 10 patients exhibited progression, and 7 achieved partial remission. In conclusion, our results indicate that I-PET/CT should be performed after 2 rather than 4 cycles of immunochemotherapy in DLBCL patients. There is a limited role for subsequent PET/CT in the detection of relapse in PET/CT2-negative patients, but repeat PET/CT is required if the PET/CT2 findings are positive.     

Evolution of therapy for limited stage diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), with limited-stage DLBCL defined as stage I or II disease. Risk stratification, initial treatment options, and relapse patterns are distinct from advanced-stage DLBCL, but there is limited data on the impact of biologic features on outcome. Patients have excellent outcomes, with ~90% survival at 2 years. Over the past several years, sequential prospective trials and large registry studies have evaluated the optimal number of chemotherapy cycles and implemented PET-adapted approaches to reduce the need for radiotherapy. Special consideration must still be given to cases of bulky disease, extranodal disease, fully resected scenarios, and adverse biologic features such as high-grade B-cell lymphoma with double/triple hit rearrangements. This review presents the evolution of a modern management approach, with a discussion of recent treatment-defining studies.Subject terms: Cancer immunotherapy, Radiotherapy     

年轻高危弥漫大B细胞淋巴瘤患者治疗研究进展

弥漫大B细胞淋巴瘤(DLBCL)是成年人淋巴瘤中最常见的一种类型,约占非霍奇金淋巴瘤(NHL)的30％～ 40％.年轻高危DLBCL患者是临床预后不良的一组特殊人群,目前在临床实践中尚无标准治疗方案,常规化疗、联合利妥昔单抗的R-CHOP、R-CHOP样方案、大剂量化疗及自体造血干细胞移植并未完全扭转其预后不良的现实.文章就年轻高危DLBCL患者的治疗现状及未来的治疗方向进行综述.     

性腺弥漫大B细胞淋巴瘤十例临床病理分析

目的 观察性腺弥漫大B细胞淋巴瘤(DLBCL)的临床病理及免疫表型特点,探讨其病理诊断方法及预后.方法 回顾性分析10例性腺DLBCL患者临床病理资料,包括形态学、免疫组织化学,并复习相关文献.结果10例患者中9例为睾丸DLBCL,患者年龄40~85岁,中位年龄67岁;1例为卵巢DLBCL,年龄46岁.光学显微镜下可见肿瘤细胞中等大小或偏大,弥漫一致浸润性分布,睾丸肿瘤组织可见残留的曲细精管.Hans分型以非生发中心B细胞型(non-GCB型)为主(70%,7/10).随访6~103个月,失访2例,患者1、3、5年生存例数分别为4、2、2 例.结论 原发性性腺DLBCL少见,多为non-GCB型,预后不佳,可采用手术及化疗等综合治疗,预后需多因素综合评价.     

弥漫大B细胞淋巴瘤125例临床病理分析

目的:分析弥漫性大B细胞淋巴瘤(DLBCL)临床特点及CHOP方案治疗结果,探讨DLBCL的临床预后因素。方法:回顾性分析125例CHOP类方案初次化疗的DLBCL患者的临床特征,结合随访资料,采用Kaplan-Meier法对生存率进行评估,进一步采用Cox回归模型对单因素分析中有统计学意义的参数进行多因素分析。结果:125例DLBCL患者中,男女比例1.3∶1,中位年龄49岁,Ann ArborⅢ~Ⅳ期患者占52.0%,LDH升高占42.1%,IPI中高危组(3~5分)占22.6%。首发为浅表淋巴结肿大60.0%,结外器官受侵72.8%。中位化疗5个周期,CR38.4%,PR 44.8%。中位随访28.2个月,中位生存期(MST)46.5个月,3和5年生存率分别为51.9%和48.9%。单因素分析显示,≤60岁、Ann ArborⅠ~Ⅱ、LDH正常、体能评分好(ECOG 0~1)I、PI评分低、未侵及骨髓、肝未受侵、接受放疗、无B症状以及缓解者是DL-BCL的良好预后因素。Cox多因素分析显示,IPI评分高(P=0.000)、未行放疗(P=0.045)和未能缓解者(P=0.049)是DLBCL的独立不良预后因素。结论:DLBCL结外侵犯发生率高,IPI评分高、未行放疗和一线治疗未能缓解者预后不良。     

Prognosis of localized diffuse large B-cell lymphoma in younger patients

BACKGROUND: The International Prognostic Index (IPI) is widely used as a predictive model in diffuse large B-cell lymphoma (DLBCL) patients of all ages and stages. To determine the optimal IPI-based prognostic system at the time of diagnosis in younger patients with limited-stage DLBCL, the authors evaluated the age-adjusted IPI and the recently proposed stage-adjusted IPI, and constructed an IPI-based model adjusted for both age and stage. METHODS: From the population-based LYFO registry of the Danish Lymphoma Group, 233 patients not older than 60 years with Stage I-II DLBCL treated with anthracycline-based chemotherapy with or without involved-field irradiation were identified. The primary endpoint of analysis was overall survival. RESULTS: At the end of the observation period, 151 patients were alive with a median follow-up time of 8.3 years. All the variables in the age-adjusted and the stage-adjusted IPI had major prognostic significance (P < or = 0.0001). Log-rank analyses of survival showed highly significant differences between the subgroups in each model (P < 0.0001); however, the stage-adjusted IPI was more powerful (chi-square test = 44.99) than the age-adjusted IPI (chi-square test = 36.27). By using the median age of the cohort (50 years) as a cutoff point, age was found to be a strong prognostic factor (P = 0.0036). An age-/stage-adjusted IPI was constructed, the predictive power of which was equal to the stage-adjusted IPI (chi-square test = 44.16) but with different distribution of patients between the risk groups, making the proposed model better suited to identify poor-risk patients. CONCLUSIONS: The data from the current study suggest that the proposed age-/stage-adjusted IPI is the superior IPI-based model in predicting outcome in younger patients with localized DLBCL.