The modified program NHL-BFM-90 in the treatment of patients with diffuse large B-cell lymphosarcoma

AIM: To investigate efficacy of the modified protocol NHL-BFM-90 in patients with diffuse large B-cell lymphosarcoma (DLBCLS). MATERIAL AND METHODS: A total of 13 DLBCLS patients with stage II-IV of the disease with affection of lymph nodes at the disease onset (nodal lesion) and stage II with tumor size more than 10 cm (bulky disease) received first-line treatment according to the modified program NHL-BFM-90 from 2002 to 2005. The diagnosis was made by WHO criteria. RESULTS: A complete remission was achieved in 76.9% patients. Resistance to therapy was observed in the patients with bone marrow affection. The 2.5-year overall survival was 74%, 2-year event-free survival was 75% (the events were recurrence and resistance). Follow-up continued from 5 to 47 months. CONCLUSION: The efficacy of the modified protocol NHL-BFM-90 in DLBCLS patients with stage III-IV of the "nodal" disease and stage II of the "bulky" disease was high.     

Primary diffuse large B-cell lymphosarcoma of the spleen

AIM: To investigate characteristics of the course and efficacy of treatment of diffuse large B-cell lymphosarcoma (DLBL) with primary lesion of the spleen. MATERIAL AND METHODS: From 1998 to 2006, primary splenic lesion was registered in 15 of 120 patients with DLBL and affected lymph nodes (LN), spleen and Waldeyer's ring. The diagnosis was made according to WHO criteria. Of them 14 patients had splenectomy as the first stage of therapy. The operation was followed with 6 to 8 courses of CHOP-21 (8 patients), 4 courses of R-CHOP-21 and radiotherapy (one patient). One patient received 7 courses of CHOP-21 followed by splenectomy. Because of the presence of several signs of unfavourable prognosis 5 patients under 60 years were given intensive therapy: 4-6 courses of the modified program NHL-BFM-90, 2 of 5 patients received radiotherapy. RESULTS: All the patients with primary DLBL of the spleen had two and more signs of unfavourable prognosis: elevated concentration of serum LDG, size of the tumor more than 10 cm, high proliferative activity of tumor cells, B-symptoms, severe condition. Seven patients had centroblastic, 8--anaplastic variants of DLBL. Tumor cells in primary DLBL of the spleen had no specific immunophenotype. Complete remission of the disease was achieved in 9 (90%) of 10 patients treated on programs CHOP-21, R-CHOP-21, in 4 of 4 patients on the modified program NHL-BFM-90. Mean follow-up was 39.3 months (from 7 to 103 months). CONCLUSION: For primary DLBL of the spleen characteristic are long-term remissions on first line therapy according to CHOP-21 program irrespective of morphology and immunophenotype.     

First experience with the modified program NHL-BFM-90 application in adult patients with primary diffuse large B-cell gastric lymphosarcoma with unfavourable prognosis

AIM: To assess efficacy of a modified program NHL-BFM-90 in adult patients with primary diffuse large B-cell gastric lymphosarcoms (PDLBGL) with unfavourable prognosis. MATERIAL AND METHODS: Modified courses of NHL-BFM-90 were conducted in 5 patients aged 27-67 years from January 2004 to September 2005. Four patients received chemotherapy of the first line, in one patient block therapy followed monotherapy with chlorambucil and a CHOEP course. All the patients were in a severe clinical condition and had several initial factors of unfavourable prognosis: size of the tumor more than 10 cm; stage IE and more advanced; B-symptoms; proliferative activity above 70%. The program NHL-BFM-90 was modified because of the patients' age. Chemotherapy was conducted according to the middle arm of the original program NHL-BFM-90, but methotrexate was introduced in a dose 1 g/m2 for 12 hours, while leukovorin was given 18 hours after the start of methotrexate injection. In two cases the blocks were enhanced with rituximab, 2 patients had doxorubicin in block A, in one case block C was enhanced with methotrexate. A total of 23 modified blocks NHL-BFM-90 were performed: one patient was given 6 blocks, two patients--5, one patient--4 blocks and one patient--3 blocks. RESULTS: Four patients after block 2 and one patient after block 3 of polychemotherapy NHL-BFM-90 achieved remission of the disease of 6 to 22 months duration which still continues. Infectious complications related to hematological toxicity arose more frequently at the latest courses of chemotherapy. CONCLUSION: Treatment according to the modified program NHL-BFM-90 in adult patients with PDLBGL and unfavourable prognosis is highly effective. For a mean follow-up of 10.2 months no recurrences occurred. The number of courses can be reduced to decrease accumulated hematological toxicity and in case of rapid achievement of remission.     

My treatment approach to patients with diffuse large B-cell lymphoma

My favored treatment approach for patients with diffuse large B-cell lymphoma continues to evolve. Diffuse large B-cell lymphoma can now be cured in more than 50% of patients. This is a result of improved definitions of the disease, improved diagnostic capabilities, better staging and restaging techniques, a useful prognostic index to guide therapeutic decisions, and the development of increasingly effective therapies. Positron emission tomographic scans have improved the accuracy of both staging and restaging. Findings on a positron emission tomographic scan at the end of therapy are the best predictors of a good treatment outcome. Numerous subtypes of diffuse large B-cell lymphoma have been identified that require specific treatment approaches. For example, plasmablastic lymphoma typically lacks CD20 and does not benefit from treatment with rituximab. Diffuse large B-cell lymphoma originating in specific extranodal sites such as the central nervous system, testes, and skin presents special problems and requires specific treatment approaches. A subgroup of diffuse large B-cell lymphoma with a very high proliferative rate seems to have a poor outcome when treated with CHOP-R and does better with regimens used for patients with Burkitt lymphoma. New insights into the biology of these disorders are likely to further change treatment approaches. Recognition that diffuse large B-cell lymphoma is not one disease, but a variety of clinicopathologic syndromes provides the opportunity to further improve our ability to benefit patients.     

A CHOP-21 course efficacy in therapy of diffuse large B-cell lymphosarcoma

AIM: To examine efficacy of polychemotherapy (PCT) CHOP-21 in patients with diffuse large B-cell lymphosarcoma (DLBCL). MATERIAL AND METHODS: Fifty-five DLBCL patients received first-line therapy according to CHOP-21 program in 1996-2004. The diagnosis was made by WHO criteria. RESULTS: Initially, 37 patients had lymph node lesions, 18--nonlymphatic lesions. Complete remissions were achieved in 49% (56.7% in nodal lesions, 33.3% in extranodal ones). Overall 5-year survival was 35%, event-free--25%, for patients with nodal lesions--36 and 32%, respectively, extranodal lesions--35 and 22%, respectively. Overall 5-year and event-free survival in patients with local lesions was 85 and 75%, generalized--25 and 20%, respectively. In patients with involvement of the gastrointestinal tract 3-year overall and event-free survival reached 50 and 45%. Event-free survival was not seen in patients with extranodal lesions of other locations in overall 3-year survival 45%. CONCLUSION: PCT program CHOP-21 was effective in DLBCL patients with local nodular lesions except cases with large-size tumors, invasion in the adjacent organs and tissues and isolated gastric lesion.     

Prognostic value of a focal bone marrow lesion in diffuse large B-cell lymphosarcoma

AIM: To study prognostic implications of a focal mature cell lesion of the bone marrow (BM) in patients with diffuse large B cell lymphosarcoma (DBLCL). MATERIAL AND METHODS: 54 patients with histologically confirmed DBLCL were given first-line CHOP and CHOP-like courses from 1996 to 2003. B-cell nature of the tumor was confirmed immunohistochemically, immunophenotypically and with flow fluorimetry. RESULTS: In debute of the disease 16 patients had local involvement of the lymph organs (stage I-II by Enn-Arbor), 21 patients--generalized disease (stage III-IV) and 17 patients--involvement of non-lymphatic organs. Overall 3-year survival in first-line therapy in mature cell lesion of BM was 23%, without it--0%. One-year event-free survival was 34 and 0%, respectively. CONCLUSION: The presence of a focal mature cell lesion of BM in DBLCL patients influences the prognosis. Regarding high frequency of transformation of mature cell lymphoproliferative diseases in DBLCL, focal lesion of BM is an indirect sign of a secondary nature of the disease.     

Pidilizumab in the treatment of diffuse large B-cell lymphoma

Introduction: The programmed death-1 (PD-1) immune checkpoint pathway is an emerging target in the treatment of hematologic malignancies. Pidilizumab is an mAb that binds to PD-1 and is a safe and well-tolerated therapy. Recent data have shown clinical activity utilizing this strategy in diffuse large B-cell lymphoma (DLBCL).

Areas covered: The role of PD-1 expression in hematologic malignancies is explored. Recent clinical trials including the results of a Phase I trial in hematologic malignancies and a Phase II trial of pidilizumab following autologous hematopoietic stem-cell transplant (AHSCT) are reviewed.

Expert opinion: We review data that suggest that PD-1 is a promising target in the treatment and management of DLBCL. Changes in immune subsets following administration of pidilizumab are felt to represent on-target responses. The improvement in progression-free survival (PFS) following AHSCT supports a response to therapy. Importantly, the improvement in PFS for patients with positive FDG-PET/CT following AHSCT indicating residual disease further supports direct activity of pidilizumab in DLBCL.     

弥漫大B细胞淋巴瘤治疗进展

非霍奇金淋巴瘤(non-Hodgkin lymphoma NHL)是恶性淋巴瘤的一大类型,在中国所占比例明显高于霍奇金淋巴瘤.弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)是非霍奇金淋巴瘤中最为常见的一种类型,在临床、免疫表型及分子遗传学等方面具有高度异质性,其治疗方案也呈多样化.近10年来,DLBCL的诊断及治疗取得了重要进展,现就其规范化治疗方案及最新治疗研究进行阐述.     

Pembrolizumab for the treatment of diffuse large B-cell lymphoma

ABSTRACT

Introduction: Pembrolizumab is a novel monoclonal antibody that targets the interaction between programmed cell death protein 1 (PD-1) and its ligand (PD-L1). Pembrolizumab has shown significant clinical efficacy in Hodgkin Lymphoma (HL), but results in non Hodgkin Lymphoma (NHL) are mixed. Some NHL subtypes, which share certain genetic features with HL, such as alterations in chromosome 9p24.1 and expression of PD-L1, have shown promising responses in early phase trials.

Areas covered: In this review, we provide an overview of pembrolizumab as a compound, and present the available clinical efficacy and safety data in the treatment of diffuse large B cell lymphomas.

Expert opinion: Current early phase data suggest that single agent pembrolizumab in NHL demonstrates both efficacy and a favorable safety profile. However, it is anticipated that future treatment strategies will be biomarker-driven and incorporate pembrolizumab into combination therapies with chemotherapy and/or immunotherapy agents.     

弥漫性大B细胞淋巴瘤的治疗最新进展

弥漫性大B细胞淋巴瘤(DLBCL)是一组具有生物学异质性的B细胞恶性肿瘤.CD20单克隆抗体(如利妥昔单抗)的应用使得DLBCL患者的预后得到明显改善,但是仍有部分患者应用联合利妥昔单抗的化疗方案后疗效不佳.因此,根据DLBCL的不同亚型及细胞起源,选择不同的治疗方案,成为目前DLBCL治疗关注的重点.本文就DLBCL的亚型及细胞起源等方面,总结DLBCL治疗方法及其预后研究的最新进展.     

影响弥漫大B细胞淋巴瘤预后的主要危险因素分析

目的 探讨弥漫大B细胞淋巴瘤(DLBCL)的临床特点、实验室检查、治疗措施以及肿瘤细胞来源与预后的关系.方法 对106例DLBCL患者进行国际标准化预后指数(IPI)评分、Ann Arbor分期、ECOG评分、肿瘤细胞来源以及采用不同治疗策略的疗效进行回顾性分析,并对影响预后的独立危险因素进行分析.结果 按IPI评分,低中危者61例(57.5％),中高危者45例(42.5％);按AnnArbor分期,Ⅰ期8例(7.6％),Ⅱ期16例(15.1％),Ⅲ期54例(50.9％),Ⅳ期28例(26.4％);25例(23.6％)患者伴骨髓受侵,其中16例诊断为淋巴肉瘤细胞白血病;38例ECOG评分≥2分、67例(63.2％)乳酸脱氢酶(LDH)值升高;伴B症状者59例(55.7％).106例DLBCL患者完全反应(CR)63例(59.4％),部分反应13例(12.3％),病情稳定3例(2.8％),死亡29例(27.4％),治疗总有效率为71.7％,4年总生存率为72.6％;单因素分析显示:IPI评分、临床分期、ECOG分级、肿瘤细胞来源、LDH水平、有无骨髓侵犯、治疗策略的选择、是否获得CR均与预后有关.COX核型回归多因素分析发现非生发中心来源(HR=4.24,P=0.001)、骨髓侵犯(HR=2.08,P=0.012)、是否获得CR(HR=2.72,P=0.006)以及治疗策略的选择(HR =2.58,P=0.009)是影响DLBCL预后的独立危险因素.结论 骨髓侵犯、不同肿瘤细胞来源是DLBCL的独立预后影响因素,用免疫组化方法检测不同肿瘤细胞的来源类型,对预后有一定的提示作用,同时利妥昔单抗联合化疗可显著提高DLBCL患者的疗效,造血干细胞移植是DLBCL的最佳治疗策略.     

弥漫大B淋巴瘤C反应蛋白的表达特点及临床意义

目的探讨C-反应蛋白（C-reactive protein,CRP）在弥漫大B淋巴瘤（diffuse large B-cell lymphoma,DLBCL）患者中表达规律。方法采用免疫比浊法检测87例DLBCL患者及健康体检者血浆CRP浓度。结果 DLBCL患者CRP（23.9±7.1mg/L）明显高于健康成年人,P〈0.05;不同分期的DLBCL患者CRP浓度各不相同,差异均有统计学意义,P〈0.05;不同危险度分组的DLBCL患者CRP浓度亦各不相同,差异均有统计学意义,P〈0.05。CRP与分期及危险度级别之间存在正相关。CRP低表达组近期疗效（有效率77.7%）明显优于高表达组（有效率42.8%）。结论 CRP可能成为反应DLBCL患者疾病变化的指标,并且有可能有助于判断不同DLBCL患者的预后。     

T淋巴细胞亚群检测在弥漫大B细胞淋巴瘤患者诊疗中的意义

目的 探讨T淋巴细胞亚群检测在弥漫大B细胞淋巴瘤(DLBCL)患者诊疗中的意义.方法 选取2017年6月至2020年8月该院DLBCL患者71例作为DLBCL组,并选取同期健康体检者71例作为健康对照组.比较两组T淋巴细胞亚群水平(CD3+、CD4+、CD8+、CD4+/CD8+);比较不同DLBCL分期、化疗前后和不同化疗效果患者的T淋巴细胞亚群水平;分析T淋巴细胞亚群水平与DLBCL分期、化疗效果的相关性.结果 DLBCL组CD3+、CD4+、CD4+/CD8+水平均明显低于健康对照组,CD8+水平明显高于健康对照组,差异有统计学意义(P<0.05).DLBCLⅣ期患者CD3+、CD4+、CD4+/CD8+水平均明显低于Ⅰ、Ⅱ、Ⅲ期,CD8+水平明显高于Ⅰ、Ⅱ、Ⅲ期,差异有统计学意义(P<0.05).DLBCL患者化疗后CD3+、CD4+、CD4+/CD8+水平明显高于化疗前,CD8+水平明显低于化疗前,差异有统计学意义(P<0.05).化疗有效的DLBCL患者CD3+、CD4+、CD4+/CD8+水平明显高于化疗无效患者,CD8+水平明显低于化疗无效患者,差异有统计学意义(P<0.05).Spearman相关分析结果显示,CD3+、CD4+、CD4+/CD8+水平与DLBCL分期呈负相关(P<0.05),CD8+水平与DLBCL分期呈正相关(P<0.05);CD3+、CD4+、CD4+/CD8+水平与化疗效果呈正相关(P<0.05),CD8+水平与化疗效果呈负相关(P<0.05).结论 T淋巴细胞亚群在DLBCL患者中异常表达,和疾病分期、化疗效果具有一定相关性.     

International prognostic index in diffuse B large cell lymphosarcoma

AIM: To evaluate efficacy of the International Prognostic Index (IPI) in relation to diffuse B-large cell lymphosarcoma (BLCLS), to identify significant prognostic factors. MATERIAL AND METHODS: The trial enrolled 121 patients (67 males and 54 females, mean age 54 years) suffering from BLCLS with involvement of the lymph nodes, spleen, tonsils. The diagnosis was made according to WHO criteria. 83 patients (29 with local lesion of lymph nodes, 10 with primary lesion of the tonsils, 9 with primary lesion of the spleen and 35 with generalized lesion) received polychemotherapy (PCT): CHOP-21, R-CHOP-21. Patients with primary splenic lesion have undergone splenectomy followed by CHOP-21 PCT, radiotherapy on the splenic region and that of regional lymph nodes. Radiation therapy was also given to patients with stage I-II, 38 patients received NHL-BFM-90 PCT. RESULTS: In distribution of patients into prognosis groups according to IPI 5-year event-free survival on CHOP-21 and R-CHOP-21 therapy was 83% in the group of low risk, 79% in the group of low/intermediate risk, 52% in the group of high/intermediate risk, 34% in the group of a high risk. However, there were poor outcomes in the group of low risk (recurrence, resistance) and long-term persistent remissions in high risk groups. Frequency and duration of complete remissions depended on location of the primary lesion. Five-year event-free survival in patients with solitary lesion of the peripheral lymph nodes on CHOP-21, R-CHOP-21 in spite of their size (bulky) and high concentration of lactate dehydrogenase) was 97% while in tonsillar lesion (according to IPI all the patients entered groups of low and low/intermediate risk) - 50%. All the patients with primary splenic lesion according to IPI had high risk but after splenectomy and PCT (CHOP-21, R-CHOP-21) followed by radiotherapy they demonstrated 100% 5-year event-free survival (follow-up since 1998). CONCLUSION: Determination of prognosis groups in BLCLS is not valid as such distribution gives no grounds for choice of adequate therapy. A decisive prognostic factor is now site of the lesion.     

原发性胃弥漫大B细胞淋巴瘤诊疗进展

原发性胃肠道淋巴瘤(PGIL)最常见的发生部位是胃,以非霍奇金淋巴瘤中的弥漫大B细胞淋巴瘤(DLBCL)为主,近年来其发病率呈明显上升的趋势。随着超声胃镜、多层螺旋CT(MDCT)、PET-CT等检查的应用,以及利妥昔单抗等靶向治疗的推广,胃DLBCL的诊断和治疗也取得了很大的进展。     

EZH2对弥漫大B细胞淋巴瘤RCHOP方案治疗效果的预测价值

目的:探讨Zeste基因增强子(enhancer of zeste homolog 2,EZH2)对弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)RCHOP方案治疗的效果的预测价值。方法:纳入2017年1月至2018年5月南华大学附属第二医院80例接受RCHOP方案治疗的DLBCL患者,分析患者EZH2表达情况与治疗效果的关系,绘制EZH2预测治疗效果的ROC曲线,并对患者pCR与病理特征的关系进行讨论。结果:80例患者中EZH2高表达者49例,EZH2低表达者31例,DLBCL患者RCHOP治疗的pCR率为51.25%,其中EZH2高表达患者完全缓解(complete response,CR)、客观缓解率(objective response rate,ORR)均明显低于EZH2低表达患者(P<0.05);EZH2预测治疗效果的曲线下面积为0.874(P<0.05);pCR与性别、年龄、美国东部肿瘤协作组(Eastern Cooperative Oncology Group,ECOG)得分、淋巴瘤国际预后指数(International Prognostic Index,IPI)得分、乳酸脱氢酶(lactate dehydrogenase,LDH)因素无相关关系(P>0.05);与Hans分型、EZH2表达水平存在一定的相关性(P<0.05)。结论:DLBCL患者EZH2低表达是RCHOP治疗后高pCR率的预测因子,在临床上有助于为DLBCL患者临床治疗提供更好的指导。