Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial

BackgroundCentral nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial.Patients and methodsThe R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I–IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated.Results177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX)n = 163, intravenous (IV) MTXn = 2, prophylaxis type unknownn = 11 and IT MTX and cytarabinen = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolatedn = 11, with systemic relapsen = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a ‘high-risk’ extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively.ConclusionDespite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence.ClinicalTrials.govISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.     

利妥昔单抗联合CHOP方案治疗弥漫性大B细胞淋巴瘤的临床病理学研究

 目的　探讨利妥昔单抗（商品名：美罗华）联合CHOP方案对弥漫性大B细胞淋巴瘤（DLBCL）患者预后的影响。方法　收集北京大学基础医学院血液病理研究室确诊的DLBCL患者156例,免疫组织化学方法检测bcl-2、CD10、bcl-6和MUM-1表达情况。根据Hans模型将患者区分为生发中心B细胞样细胞起源组（GCB）和非生发中心B细胞样细胞起源组（non-GCB）;利用Muris分型将DLBCL患者分为低临床风险组（1组）和高临床风险组（2组）;将使用利妥昔单抗联合CHOP方案治疗的患者设为研究组,未使用利妥昔单抗治疗的患者设为对照组。随访全部病例的治疗过程和预后情况。采用SAS8.2统计软件对所得资料进行χ2 检验、对数线性模型及Life Table 生存分析。结果　研究组的30例患者,3年总体生存率78.3 %,对照组的126例患者3年总体生存率53.4 %,研究组患者整体预后情况明显好于对照组,二者之间差异有统计学意义（P＜0.05）。研究组和对照组中,Hans模型所区分的不同起源组之间预后差异无统计学意义（P＞0.05）。研究组中Muris模型所区分的1组预后与2组之间差异无统计学意义（P＞0.05）;而对照组中,Muris模型所区分的1组预后明显较2组好,差异有统计学意义（P＜0.05）。bcl-2蛋白表达与对照组患者的预后不良具有较强相关性,而与研究组预后无明显相关。结论　使用利妥昔单抗联合CHOP方案化疗能够显著提高DLBCL患者的生存率。利妥昔单抗使用后,bcl-2蛋白表达及Muris模型分组对DLBCL的预后提示作用明显减弱。     

The Hans algorithm is not prognostic in patients with diffuse large B-cell lymphoma treated with R-CHOP

Our objective was to evaluate the non-germinal center (GC) profile as a marker for response and survival in DLBCL and to compare the characteristics of patients with GC and non-GC DLBCL treated with rituximab-containing regimens. In this patient-level meta-analysis, retrospective data from 712 newly diagnosed DLBCL patients treated with chemoimmunotherapy from 7 centers were analyzed. GC and non-GC profiles were defined according to the Hans algorithm. Although the non-GC profile showed a trend towards worse overall survival (HR 1.24, 95% CI 0.92-1.66; p=0.15) and progression-free survival (HR 1.29, 95% CI 0.96-1.73; p=0.09), it did not retain its value in the multivariate survival analysis. Additionally, the non-GC profile was independently associated with worse complete response rates (OR 0.55, 95% CI 0.37-0.83; p<0.01) in the multivariate logistic regression analysis. Interestingly, Asian patients had higher proportion of GC DLBCL (p=0.01).     

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).     

沙利度胺联合R-CHOP方案一线治疗年轻人高危弥漫大B细胞淋巴瘤

目的 探讨沙利度胺联合R-CHOP方案一线治疗年轻高危弥漫大B细胞淋巴瘤(DLBCL)患者的疗效及安全性.方法 经病理学确诊的CD20+的DLBCL患者60例,男性34例,女性26例,中位年龄48岁(18～60岁),年龄调整国际预后指数(aaIPI)≥2分,随机分为2组,每组30例.A组采用沙利度胺联合R-CHOP方案治疗,标准R-CHOP:利妥昔单抗375 mg／m2第0天,长春新碱1.4 mg/m2第1天,多柔比星50 mg/m2第1天,环磷酰胺75 mg/m2第1天,泼尼松60 mg/d第1天至第5天,21 d为1个周期,共6个周期,并给予阿司匹林预防血栓形成,高凝血状态患者给予低分子肝素钙预防血栓.沙利度胺150 mg,1次/d,口服,持续6个月;B组采用标准剂量R-CHOP方案治疗,21d为1个周期,共6个周期.结果 A、B两组完全缓解(CR)率分别为77 ％(23/30)与57％(17/30),无事件生存(EFS)率分别为81％与67％,无进展生存(PFS)率分别为87％与73％,差异均有统计学意义(均P＜0.05),两组Ⅲ级以上粒细胞减少分别为12例与8例,均无毒性相关死亡.结论 沙利度胺联合R-CHOP一线治疗年轻DLBCL可明显提高患者CR率,且安全性好,可改善患者生命质量,值得临床研究.     

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.     

Refractory or relapsed aggressive B-cell lymphoma failing (R)-CHOP: an analysis of patients treated on the RICOVER-60 trial

BackgroundThe prognosis of elderly patients with aggressive B-non-Hodgkin’s lymphoma after first lymphoma-related treatment failure (TF-L) is not well described.MethodsWe analysed patient characteristics including the presence of MYC rearrangements and MYC-expression immunohistochemistry (IHC) at diagnosis and modalities of salvage therapy and their impact on the prognosis of patients between 61 and 80 years who had been treated on the RICOVER-60 trial.ResultsTF-L occurred in 301 of the 1222 (24.6%) patients; 297 patients could be analysed. Prognosis was extremely poor in patients with primary progressive disease or early relapse (≤12 months) with median survivals of 3.3 and 6.4 months. Survival after TF-L was significantly lower in patients pretreated with R-CHOP compared with CHOP (23.0% versus 36.4% at 2 years, P = 0.016). In patients with MYC translocation at diagnosis Rituximab reduced the risk of TF-L from 58.8% to 26.3%. Survival after TF-L was significant longer for patients after CHOP without MYC translocations (31.8% versus 0% at 2 years, P < 0.001) or negative MYC-IHC (41.0% versus 16.8% at 2 years, P = 0.017) but not after R-CHOP. 224 patients (75.4%) received salvage therapy. Rituximab was part of salvage therapy in 57.4% and improved 2-year survival rate from 20.7% to 46.8% (P < 0.001). The benefit of R was significant after first-line CHOP [2-year overall survival (OS) 49.6% versus 19.1%, P < 0.001] as well as after R-CHOP (2-year OS 33.1% and 22.5%, P = 0.034). For patients pretreated with R-CHOP long-term survival was below 15% regardless of the treatment chosen.ConclusionMYC rearrangement and IHC are adverse prognostic factors after TF-L for CHOP treated patients, rituximab as part of first-line therapy reduced the effects of MYC-break. Rituximab improves results of any type of salvage therapy; however, survival after progression/relapse of aggressive B-cell lymphoma in elderly patients pretreated with (R)-CHOP is poor regardless of treatment chosen.     

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.     

感染HBV的弥漫大B细胞淋巴瘤患者临床特征与预后分析

目的 探讨HBV感染与弥漫大B细胞淋巴瘤(DLBCL)的关系.方法 回顾性分析308例有乙肝两对半检测记录的初治DLBCL患者,分为HBV携带者(HBsAg+)31例、HBV既往感染者(HBsAg-/HbcAb+)90例、无HBV感染者(HBsAg-/HbcAb-)118例,接受CHOP样或R-CHOP样方案化疗.对三组患者的临床特征、生存及化疗期间与化疗结束12个月内肝功能损害情况进行比较分析.结果 三组患者3年总体生存时间(OS)分别为80.9%、74.3%和84.1%,无统计学差异(P=0.946);无进展生存时间(PFS)亦无统计学差异(P=0.405).采用COX回归多因素分析生存的不良预后因素包括男性、年龄大于60岁、IPI评分高、晚期、未联合利妥昔单抗.三组化疗期间肝功能损害发生率分别为36.8%、27.3%、62.1%,HBsAg+组在化疗期间及结束后1～3个月内肝功损害严重度明显高于其他两组,具有统计学差异,P值分别为0.00039和0.008.结论 HBsAg-/HBcAb-、HBsAg-/HBcAb+、HBsAg+三组临床特征生存时间相似,采用联合利妥昔单抗的方案化疗能提高全组患者生存.本研究推荐对HBsAg+的DLBCL患者化疗或免疫治疗时进行预防性抗病毒治疗,同时建议抗病毒治疗至少须延续至化疗结束后3个月,化疗中与化疗后均须密切监测肝功能、HBV-DNA水平.     

含聚乙二醇脂质体多柔比星的R-CHOP方案治疗老年初治弥漫大B细胞淋巴瘤的疗效及安全性

目的:探讨应用含聚乙二醇脂质体多柔比星（PLD）的R-CHOP方案治疗老年初治弥漫大B细胞淋巴瘤（DLBCL）的疗效及安全性。方法:收集我院2011年1月至2014年5月收治的64例老年DLBCL患者的临床资料,34例应用含PLD的R-CHOP方案化疗,30例应用传统R-CHOP方案化疗,对比分析两组患者的治疗有效率、生存率、一般不良反应及心脏毒性。 结果:34例应用含PLD的R-CHOP方案化疗患者,CR 18例(52.9%),总有效率（OR）为82.4%。1、2、3年的总生存率(OS)分别为91.2%、79.4%及67.6%。30例应用传统R-CHOP方案化疗患者,CR 14例(46.7%),OR为73.3%。1、2、3年的OS分别为86.7%、66.7%及43.3%。两组CR率及OR率相比较,差异无统计学意义（P>0.05）。含PLD的R-CHOP方案化疗组患者3年生存率明显高于传统R-CHOP方案化疗组患者,且差异有统计学意义（P<0.05）。两组患者出现的一般不良反应最常见的为胃肠道反应及中性粒细胞减少。含PLD的R-CHOP方案化疗组患者心脏毒性反应,如心肌梗死、心功能不全及新发心电图异常与传统R-CHOP方案化疗组患者相比明显降低。结论:与多柔比星相比,含PLD的R-CHOP方案能明显减轻老年DLBCL患者化疗所致的心脏毒性,安全性较好,并可改善患者的长期生存。     

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。     

老年人EB病毒阳性弥漫大B细胞淋巴瘤临床病理学特点及预后分析

目的 探讨老年人EB病毒阳性（EBV＋）弥漫大B细胞淋巴瘤（DLBCL）的临床病理学特点及预后.方法 采用回顾性研究的方法 ,收集24例老年EBV＋DLBCL患者,以同期EBV-非特指型DLBCL患者为对照,分析老年EBV＋ DLBCL患者的临床病理学特点及预后.结果 24例老年EBV＋DLBCL患者肿瘤细胞形态上主要表现为单一性或多形性肿瘤细胞增生;多形性病例中常可见有地图状坏死.细胞起源免疫分型主要为非生发中心亚型,分别占91.3％（Hans分型）和100.0％（Choi分型）.CD30阳性率为55.0％,高于非特指型EBV-DLBCL（P＜ 0.001）.在总体生存时间方面,R-CHOP方案治疗的老年EBV＋DLBCL患者和＞50岁EBV-DLBCL患者的中位生存时间分别为44.2个月和29.2个月,两者差异无统计学意义（P=0.587）.结论 老年人EBV＋DLBCL肿瘤细胞形态上主要表现为单一性或多形性肿瘤性增生;多形性病例中常可见不规则坏死.CD30阳性率较高,并且主要为非生发中心B细胞亚型.R-CHOP方案治疗的老年EBV＋ DLBCL患者的总体生存时间与同年龄段非特指型EBV-DLBCL患者相近.     

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.