滤泡性淋巴瘤新药研究进展

 滤泡性淋巴瘤（FL）是一种起源于B淋巴细胞的非霍奇金淋巴瘤（NHL）,临床自然病程较长,表现惰性,初始治疗后易复发,传统的治疗方案多难以治愈。因此选择合适的治疗方案是延长患者生存时间的关键。利妥昔单抗、放射免疫治疗、苯达莫司汀等已应用于FL的治疗。一些具有前景的新药如ofatumumab、epratuzumab、雷利度胺、硼替佐米、ABT-263等目前正在进行临床试验,这些新药将会为FL的治疗增加更多的选择。     

2011年欧洲血液学协会大会有关抗CD20单克隆抗体治疗淋巴瘤和慢性淋巴细胞白血病的热点报道

2011年6月9日至12日,第16届欧洲血液学协会（EHA）大会在英国伦敦召开。在此次年会上,抗CD20单克隆抗体（利妥昔单抗）及靶向治疗相关研究依然是大会的热点。继PRIMA研究证实利妥昔单抗诱导和维持治疗滤泡性淋巴瘤（FL）的疗效后,     

自体造血干细胞移植联合利妥昔单抗治疗CD+20B细胞淋巴瘤

 采用自体造血干细胞移植（AHSCT）治疗中,高危侵袭性淋巴瘤已获得了较好疗效,但仍有部分移植患者因复发而死亡。复发的根源主要为微小残留病变,包括体内残留的肿瘤细胞和移植物中的肿瘤细胞污染。利妥昔单抗可靶向性清除CD+20 B细胞,因此,对CD+20 B细胞淋巴瘤患者,移植前后应用利妥昔单抗可起到体内净化和清除残留病灶作用,AHSCT联合利妥昔单抗有望进一步提高CD+20 B细胞淋巴瘤的疗效。     

氟达拉滨联合异环磷酰胺治疗利妥昔单抗治疗后复发难治非霍奇金淋巴瘤21例

目的：探讨氟达拉滨联合异环磷酰胺方案对利妥昔单抗治疗后复发难治非霍奇金淋巴瘤（NHL）的治疗效果。方法21例利妥昔单抗治疗后复发难治NHL患者应用氟达拉滨联合异环磷酰胺方案联合化疗,2个月为1个周期,每个周期进行疗效及不良反应评价。结果21例患者中完全缓解4例,部分缓解9例,疾病稳定5例,疾病进展3例,临床总有效率为61.90%（13／21）。其中惰性淋巴瘤的总有效率为71.43%（5／7）,侵袭性淋巴瘤为57.14%（8／14）,两者差异无统计学意义（P＝0.656）。结论氟达拉滨联合异环磷酰胺方案治疗利妥昔单抗治疗后复发难治的NHL患者效果较好。     

利妥昔单抗在淋巴瘤维持治疗中的新进展

利妥昔单抗是第一个被批准用于淋巴瘤治疗的单克隆抗体。在弥漫大B细胞性淋巴瘤、滤泡淋巴瘤等B细胞非霍奇金淋巴瘤中取得了显著疗效。对于诱导治疗获得缓解后的滤泡淋巴瘤,利妥昔单抗维持治疗可进一步改善患者预后,为治疗指南所推荐。随着淋巴瘤治疗方案的不断改进,如何更好地把握维持治疗的适应症并进一步优化现有的治疗策略,成为研究的热点。本文通过总结分析近年来的相关文献,对利妥昔单抗用于淋巴瘤维持治疗的最新进展进行综述。      

利妥昔单抗在造血干细胞移植治疗淋巴瘤中应用的研究进展

由于毒性较低且具有抗淋巴瘤活性,利妥昔单抗被纳入淋巴瘤的移植治疗中.其不仅可提高疗效,减少移植后疾病复发,还可发挥免疫调节作用,有利于移植物抗宿主病的防治.文章对利妥昔单抗在自体和异基因造血干细胞移植治疗淋巴瘤中的应用作一综述.     

滤泡淋巴瘤治疗进展:第56届美国血液学会年会报道

滤泡淋巴瘤(FL)是一种起源于滤泡生发中心的惰性非霍奇金淋巴瘤(NHL).在2014年12月召开的第56届美国血液学会年会上,多篇研究报道了FL治疗的最新进展.放疗在早期FL的疗效依旧被肯定,GA101联合化疗治疗中晚期FL的临床试验结果亦鼓舞人心;利妥昔单抗年代造血干细胞移植仍给复发难治的FL患者带来更优的缓解,BTK、PI3K抑制剂等新药随着相应临床试验的进展也树立了治疗复发难治FL的新路标.     

来那度胺单药及联合利妥昔单抗维持治疗滤泡性淋巴瘤的回顾性研究

目的:观察来那度胺单药及联合利妥昔单抗维持治疗滤泡性淋巴瘤(follicular lymphoma,FL)的疗效及安全性.方法:24例FL患者接受R-CHOP方案足程化疗后获得完全缓解(complete response,CR),于2018年1月-2021年1月继续接受维持治疗.按维持治疗方案,分为仅接受来那度胺单药维...     

利妥昔单抗体内净化造血干细胞移植治疗非霍奇金淋巴瘤

 目的 探讨利妥昔单抗（商品名：美罗华）体内净化造血干细胞移植治疗非霍奇金淋巴瘤（NHL）的疗效。方法 自体造血干细胞移植（AHSCT）-1、+8天运用利妥昔单抗375 mg／m2的体内净化。结果 7例患者移植后造血功能恢复,未观察到利妥昔单抗的严重毒副反应,移植后随访1～28个月（中位随访时间15个月）,均未见疾病进展或复发。结论 利妥昔单抗净化造血干细胞移植能提高CD+20 NHL的疗效,有助于清除微小残留病灶,延长NHL的生存期。     

滤泡型淋巴瘤患者临床特征及预后因素分析

目的:分析滤泡型淋巴瘤（follicular lymphoma,FL）患者的临床特征及预后因素。方法:对2006年至2016年115例经我院病理科确诊为FL患者进行回顾性病理及临床特征分析,其中62例住院诊治的患者中,30例接受含有利妥昔单抗方案的治疗,22例患者进行普通化疗,10例患者未行任何治疗,并随访观察。结果:62例患者中,利妥昔单抗联合化疗组和单用化疗组,2年OS率均为100%,5年OS率分别为90%和70%,OS间无显著性差异（P=0.332 5）。2年PFS率分别为94%和84%,5年PFS率分别为84%和49%,PFS间有显著性差异（P=0.025 3）。FLIPI-2预后分析,中危组中利妥昔单抗联合化疗与单用化疗组间2年PFS分别为100%、80%,有显著性差异（P=0.021 9）,低危组中利妥昔单抗联合化疗与单用化疗组间2年PFS分别为100%、95%,高危组中利妥昔单抗联合化疗与单用化疗组间2年PFS分别为92%、76%,低危组和高危组中利妥昔单抗联合化疗与单用化疗组相比PFS均无显著性差异。CD10表达阳性组的总反应率（37.14%）明显高于阴性组（22.86%）。结论:FL好发于60岁以下男性,结外病变少见,预后分层多为低危组。规律利妥昔单抗联合化疗可以进一步提高缓解率,延长生存期。     

滤泡性淋巴瘤的靶向药物研究进展

滤泡性淋巴瘤(follicular lymphoma,FL)是最常见的惰性淋巴瘤,在非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)中发病率仅次于弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL),具有易向DLBCL转化、缓解后复发率高等特点.美罗华的问世明显改善了滤泡淋巴瘤患者的预后,但并没有改变FL患者易复发的结局.随着针对FL的治疗新靶点包括Bcl-2、PI3K、PD-1等发现及其机制的进一步阐明,针对相应靶点的新药也开始进入临床试验,为改善FL患者的预后提供了新的可能.     

Comparison of CD20 expression in B-cell lymphoma between newly diagnosed, untreated cases and those after rituximab treatment

Few studies have statistically investigated reduced CD20 expression in B-cell lymphoma after rituximab therapy and genomic mutation of CD20 associated with reduction. We examined CD20-positive rate in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) by flow cytometry (FCM) and immunohistochemical staining (IHS), comparing 138 cases after rituximab therapy with 360 initial, not yet treated cases. Sequence analysis of exons 3 to 8 of CD20 was performed on 22 cases with low CD20-positive rate after rituximab treatment. The results showed a statistical correlation between CD20-positive rate in FCM and IHS. By FCM, the CD20-positive rate among post-rituximab cases was significantly lower than among initial cases in DLBCL, non-germinal center origin B-cell type (average values [avg] 57.8 and 87.9, respectively) (P < 0.0001), FL2 (avg, 93.9; 103.2) (P = 0.0083), and FL3A (avg, 90.6; 100.7) (P = 0.033). Stratified analyses of post-rituximab cases showed significantly lower CD20-positive rate in cases that were resistant at the start of the treatment and cases with progressive disease during rituximab therapy before biopsy. Sequence analysis showed silent mutation of exon 4 (632 C/T) in seven cases, although this number was not statistically significant. These results suggest the influence of B-lymphoma subtype and a therapeutic effect before biopsy on CD20 expression at relapse and contribute to a better therapeutic approach for relapse cases after rituximab therapy.     

滤泡性淋巴瘤的临床特点、预后及治疗

 滤泡性淋巴瘤的发生率居非霍奇金淋巴瘤发病率的第二位,临床上疾病发展呈惰性,主要表现为无痛性淋巴结肿大。预后因素包括滤泡淋巴瘤国际预后指数（FL IPI）、肿瘤组织免疫微环境。免疫化疗已成为滤泡淋巴瘤的一线治疗方法,滤泡淋巴瘤一经诊断即应开始治疗,观察等待策略仅限于少数选择病例。造血干细胞移植适用于复发、难治的病例。     

Recent progress in the treatment of malignant lymphoma

The present state of the art and developments in the treatment for Hodgkin's disease (HD), follicular lymphoma (FL), MALT lymphoma, and aggressive non-Hodgkin's lymphoma are reviewed. Four courses of ABVD therapy (ABVd therapy in Japan) followed by involved-field irradiation (IFRT), and 6 to 8 courses of ABVD (ABVd in Japan) are the current state art of the therapy for early stage HD and advanced stage HD, respectively. High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) is also the state of the art for refractory or relapsed HD within 1 year after complete remission (CR) produced by polychemotherapy. The prognosis of the patients with 3 or more International Prognostic Scores (IPS) is poor. New intensified polychemotherapy or auto-HSCT as up-front setting is under randomized phase III clinical trial in Europe and the USA. There is no state of the art therapy for indolent lymphoma including FL, or MALT. Promising results were reported from clinical studies using new anti-lymphoma drugs such as rituximab, iibritumomab, or purine analogs (cladribine and fludarabine), and auto-HSCT with effectively purged stem cells or allogeneic HSCT. These therapeutic strategies hold a possibility of cure for indolent lymphomas. Antibiotic treatment for Helicobacter pylori-positive localized gastric MALT lymphoma is the state of the art therapy. However, there is no standard therapy for advanced stage MALT lymphoma. Risk adapted therapy using the International Prognostic Index is essential for the treatment of aggressive NHL. Three courses of CHOP followed by IFRT for localized aggressive NHL and 8 courses of CHOP for the low-risk group of advanced stage aggressive NHL are the state of the art therapies, respectively. High-dose chemotherapy with auto-HSCT is also the state of the art for sensitive relapse patients with aggressive NHL. Although some clinical studies suggested that high-dose chemotherapy with auto-HSCT as up-front setting for high-intermediate or high-risk group aggressive NHL is more effective than conventional chemotherapy, the efficacy remains to be determined. The development of new therapeutic strategies with combined use of molecular targeting drugs such as rituximab, or new anti-lymphoma drugs such as purine analogs, and HSCT is desired for more effective therapy for refractory lymphomas.     

Clinical characteristics and outcomes of relapsed follicular lymphoma after autologous stem cell transplantation in the rituximab era

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed follicular lymphoma (FL). The clinical characteristics and outcomes of FL relapse after ASCT in the rituximab era have not yet been fully elucidated. We retrospectively reviewed 414 FL patients treated with ASCT between 2000 and 2014 in four hematology departments. All patients received rituximab as a first-line treatment. We specifically analyzed the clinical characteristics, treatment strategies at relapse, and outcomes of 95 patients (23%) who relapsed after ASCT. The patients (median age, 57 y) received a median of two lines of therapy (range, 2-6) prior to ASCT, with 92% in complete response (CR) or partial response (PR) before ASCT. Histological transformation at relapse after ASCT was observed in 20% of the patients. Treatment at relapse after ASCT consisted of chemotherapy with or without rituximab (n = 45/90, 50%), targeted agents (18%), rituximab monotherapy (14%), or consolidation allogeneic transplantation after induction chemotherapy (12%) and radiotherapy (6%). After relapse, the median progression-free survival (PFS) and overall survival (OS) were 1 year (95% CI, 0.541-1.579) and 5.5 years (95% CI, 1.910-9.099), respectively. In the multivariate analysis, histological transformation (HT) was associated with OS (P = .044; HR 2.439; 95% CI, 1.025-5.806), and a high FLIPI score at relapse was associated with PFS (P = .028; HR 2.469; 95% CI, 1.104-5.521). This retrospective study showed that the period of PFS of patients who relapsed after ASCT is short. A biopsy should be performed for these patients to document the HT. Our results indicate that new treatment strategies will need to be developed for these patients.     

Histological and immunophenotypic changes in 59 cases of B-cell non-Hodgkin's lymphoma after rituximab therapy

Rituximab is a chimeric monoclonal antibody that recognizes the CD20 antigen. It has been used to treat B-cell non-Hodgkin lymphoma (B-NHL), but recently rituximab resistance has been a cause for concern. We examined histological and immunohistochemical changes in 59 patients with B-NHL after rituximab therapy. The patients comprised 32 men and 27 women with a median age of 59 years. Pre-rituximab specimens comprised 34 follicular lymphomas (FL), 11 diffuse large B-cell lymphomas (DLBCL), 10 mantle cell lymphomas, two marginal zone B-cell lymphomas (MZBCL), and two chronic lymphocytic leukemias (CLL). CD20 expression in lymphoma cells was evaluated by immunohistochemistry or flow cytometry. Post-rituximab materials were taken a median of 6 months (4 days to 59 months) after rituximab therapy. Sixteen cases (27%) showed loss of CD20 expression with four histological patterns: pattern 1, no remarkable histological change (FL, 5; DLBCL, 3; and CLL, 2); pattern 2, proliferation of plasmacytoid cells (FL, 2; DLBCL, 1; and MZBCL, 1); pattern 3, transformation to classical Hodgkin's lymphoma (FL, 1); and pattern 4, transformation to anaplastic large cell lymphoma-like undifferentiated lymphoma (FL, 1). Loss of CD20 was unrelated to the interval of biopsies, treatment regimen, clinical response, and frequency of rituximab administration. Loss of CD20 within 1 month of rituximab therapy (3/14, 21%) and regain of CD20 (2/7, 29%) were not frequent. CD20-positive relapse with transformation occurred most frequently in cases of early relapse. In conclusion, B-NHL showed various histological and immunophenotypic changes after rituximab therapy, including not only CD20 loss but also proliferation of plasmacytoid cells or transformation to special subtypes of lymphoma. ( Cancer Sci 2009; 100: 54–61)     

Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study.

BACKGROUND: Patients with follicular (FL) or mantle cell lymphoma (MCL) are incurable with conventional therapy. We investigated the safety and efficacy of rituximab consolidation after autologous stem cell transplantation (ASCT) in order to prevent relapse by clearance of minimal residual disease (MRD). METHODS: Rituximab was given approximately 8 weeks after CD34+ cell enriched ASCT at 375 mg/m2, weekly for 4 weeks. Monitoring of MRD was performed by repetitive PCR analyses. RESULTS: Thirty-one patients were included; one died early after ASCT before rituximab administration. Thirty patients (20 FL, 10 MCL) were evaluable after rituximab consolidation, and 27 of these were assessable for MRD detection. Rituximab consolidation post-ASCT was safe, the most common toxicity being infection. At a median follow-up of 42 months (range 13-96) after ASCT, 25 patients were censored with an actuarial event-free survival (EFS) of 81% at 4 and 5 years. Four patients (two FL, two MCL) relapsed, and one additional MCL patient died unexpectedly in complete remission. PCR-negativity was observed in 22% of the patients before ASCT, 53% post-ASCT (P=0.0547), 72% after rituximab (P=0.0018) and 100% at 6 months post-transplant (P < 0.001). CONCLUSIONS: One single course of rituximab consolidation given after ASCT is safe, may help to eliminate MRD and may translate into improved EFS in both FL and MCL patients.     

Pros and cons of rituximab maintenance in follicular lymphoma

Follicular lymphoma (FL) is the most prevalent indolent non-Hodgkin lymphoma. Most patients present with advanced disease and are incurable with current therapy. The approval of rituximab has revolutionized the treatment of follicular lymphoma when administered in the induction setting for high-tumor burden disease, but the use of rituximab as a maintenance therapy (MR) continues to be a point of controversy. In this article, we review the main data and arguments in favor and against MR in FL. In summary, most studies have demonstrated a significant benefit in progression-free or event-free survival in this notoriously recurrent disease; however, long-term outcomes could not consistently demonstrate to be improved with this intervention. In a meta-analysis of randomized trials overall survival (OS) showed a tendency to improvement when given to patients in relapse, but no single study reached a significant OS advantage. The risk of high-grade transformation does not seem to be reduced in prospective trials. On the other hand, MR clearly increases toxicity without an improvement in quality of life. Finally, MR is expensive, and it is not proven that the delayed relapse time can compensate for these costs. In conclusion, despite the proven increase in progression-free survival, MR can’t be recommended as a standard for the treatment of FL.     

Treatment of secondary central nervous system lymphoma with intrathecal rituximab,high‐dose methotrexate,and R‐DHAP followed by autologous stem cell transplantation: results of the HOVON 80 phase 2 study

The prognosis of central nervous system (CNS) relapse of systemic non‐Hodgkin lymphoma is poor with 1‐year survival historically at 0% to 20%. Aiming to improve these results, we performed a multicenter phase 2 study in patients with a CNS relapse, with or without concurrent systemic relapse. Treatment consisted of 2 cycles of R‐DHAP alternating with high‐dose methotrexate (MTX) and was combined with intrathecal rituximab. Responding patients received a third R‐DHAP‐MTX cycle followed by busulfan and cyclophosphamide myeloablative therapy and autologous stem cell transplantation. In patients with persistent cerebrospinal fluid lymphoma after cycle 1, the intrathecal rituximab was replaced by intrathecal triple therapy, with MTX, cytarabine, and dexamethasone. Thirty‐six patients were included. Eighteen had evidence of cerebrospinal fluid lymphoma, 24 had brain parenchymal disease, and 20 (56%) had concurrent systemic disease. The overall response rate after 2 R‐DHAP‐MTX was 53% (19/36), with 22% (8/36) complete remission. Fifteen patients (42%) underwent a transplant. One‐year progression‐free survival was 19% (95% confidence interval, 9‐34): 25% in patients without and 15% in patients with systemic disease. One‐year overall survival was 25% (95% confidence interval, 12‐40). This treatment regimen did not result in a major improvement of outcome of secondary CNS lymphoma, especially when concurrent systemic disease was present. Registered in the Dutch trial register www.trialregister.nl , NTR1757; EudraCT number 2006‐002141‐37.     

Loss of CD20 antigen expression after rituximab therapy of CD20 positive B cell lymphoma (diffuse large B cell extranodal marginal zone lymphoma combination): A case report and review of the literature

Rituximab (the chimeric anti-CD20 antibody) is widely used in the treatment of CD20 positive non-Hodgkin’s lymphoma (NHL). The response rate at relapse after repeated use in prior CD20 positive responders is lower than 50%. Several mechanisms can be responsible for rituximab resistance. CD20 negative relapses which transformed from CD20 positive aggressive and indolent forms of lymphoma can be the one of the reason of secondary resistance to rituximab. The authors report a case with combination of aggressive and indolent form of lymphoma who relapsed after 7 months from the last dose of rituximab therapy. CD20 transformed negative from positive in her relapsed disease. Patients with CD20 positive B cell NHL must rebiopsy after first line rituximab therapy if their disease relapsed or progressed.