Management of relapsed diffuse large B-cell lymphoma

Despite more effective front-line regimens, a substantial portion of patients with diffuse large B-cell lymphoma relapse and require further therapy. Several trials have established the efficacy of autologous stem cell transplantation for relapsed diffuse large B-cell lymphomas, but the benefit has been largely restricted to patients with chemosensitive disease and low-risk features at the time of relapse. In an effort to improve outcomes following an autologous transplant, researchers are exploring several avenues, including improvement of salvage regimens, addition of radioimmunotherapy to preparative regimens, and application of posttransplant treatments to eliminate minimal residual disease. Allogeneic stem cell transplantation also appears promising, but there is much to learn about optimal patient selection and timing. This review outlines the current approach to the management of relapsed diffuse large B-cell lymphoma, with an emphasis on newer peritransplant therapies.     

难治性/复发性弥漫大B细胞淋巴瘤的生物治疗

尽管弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)患者的总体预后有所改善,但仍有大约三分之一患者属于难治性/复发性DLBCL,这是导致其发病率和病死率增加的主要原因。临床上治疗难治性/复发性DLBCL的方法仍以大剂量化疗以及对无并发症的患者进行大剂量化疗-自体干细胞移植(high-dose chemotherapy-autologous stem cell trans-plant,HD-ASCT)为主。但对于给予利妥昔单抗联合CHOP化疗(rituximab-CHOP,R-CHOP)治疗后无反应的难治性DLBCL患者进行HD-ASCT,预后极差。因此,如何提高难治性/复发性DLBCL患者总生存期成了新的研究热点。本文主要从治疗方面对难治性/复发性DLBCL进行综述。     

异基因造血干细胞移植治疗复发难治性淋巴瘤的临床研究

目的 探讨异基因造血干细胞移植(allo-HSCT)治疗复发难治性淋巴瘤的疗效和安全性.方法 北京军区总医院血液科2007年1月至2012年1月应用allo-HSCT共治疗7例复发难治性淋巴瘤患者,其中男4例,女3例,年龄18～ 48岁,平均年龄33.7岁.原发病为非霍奇金淋巴瘤6例,其中弥漫大B细胞淋巴瘤(DLBCL)2例,T淋巴母细胞淋巴瘤(T-LL)1例,皮肤结外鼻型NK/T细胞淋巴瘤(ENKTCL-N)1例,肝脾T细胞淋巴瘤(HSTCL)1例,伯基特淋巴瘤(BL)1例;霍奇金淋巴瘤1例,为混合细胞型.首次复发4例,2次及以上复发2例,原发难治1例;自体移植后复发2例(均为2次及以上复发者);移植时有3例缓解,4例未取得缓解.供受者HLA全相合3例,HLA不全相合4例,采用骨髓加外周血干细胞联合移植,预处理均采用氟达拉滨替代环磷酰胺(Cy)的改良白消安(Bu)+Cy方案,移植物抗宿主病(GVHD)的预防采用经典环孢素(CsA)和甲氨蝶呤(MTX),移植后观察患者并发症和无病生存等情况.结果 6例患者能较好耐受预处理方案,均获造血重建,植入证据检测证实100％为完全供者造血,1例预处理后死亡.全部患者中位随访29.6个月(1～70个月).共5例发生急性GVHD,4例发生慢性GVHD;死亡2例(因感染死亡1例、复发死亡1例),其余5例患者无病生存,无病生存率为71.4％,最长无病生存时间已达70个月.结论 allo-HSCT治疗复发难治性淋巴瘤安全有效,可作为挽救治疗的关键技术,可在临床广泛开展.     

ABVD方案治疗复发/难治弥漫大B细胞淋巴瘤的临床分析

目的研究吡柔比星+博来霉素+长春新碱+氮烯咪胺(ABVD)方案挽救化疗复发/难治弥漫大B细胞淋巴瘤(DLBCL)的疗效和安全性。方法回顾性分析2011年1月至2017年3月收治的无法接受强烈化疗或自体造血干细胞移植(ASCT),接受ABVD方案挽救化疗的复发/难治DLBCL患者35例。ABVD方案如下:吡柔比星25 mg/m^2静滴d_1、d₁₅,博来霉素10 mg/m^2静滴d_1、d₁₅,长春新碱1.4 mg/m^2静滴d_1、d₁₅,氮烯咪胺375 mg/m^2静滴d_1、d₁₅。28天为1个周期,化疗6个周期。观察近期疗效、1年生存率、总生存时间(OS)和不良反应。结果随访截止于2019年3月,中位随访14.4个月。全组患者经ABVD方案挽救化疗后,获CR 8例、PR 17例、SD 6例、PD 4例;有效率(RR)为71.5%,疾病控制率(DCR)为88.6%。中位缓解持续时间为3.5个月(95%CI:3.13~3.87个月),1年生存率为45.7%,中位OS为13.0个月(95%CI:11.90~14.10个月)。25例国际预后指数(IPI)评分低中危组患者(0~2分)的RR、DCR、1年生存率、中位OS分别为84.0%、100.0%、60.0%和14.0个月(95%CI:12.71~15.30个月),均高于10例中高危组患者(3~4分)的40.0%、60.0%、10.0%和6.0个月(95%CI:3.65~8.35个月),差异均有统计学意义(P<0.05);而不同CD5表达情况以及ABVD方案不同治疗线程的患者上述指标的差异均无统计学意义(P>0.05)。全组主要不良反应为骨髓抑制和消化道反应,发生率分别为61.8%(24/35)和14.3%(5/35),以1~2级为主。结论 ABVD方案对多次化疗、无法接受强烈化疗或ASCT的低中危型复发/难治DLBCL疗效可靠、耐受性好,值得进一步临床研究。     

复发难治性弥漫大B细胞淋巴瘤的生物靶向治疗

含有利妥昔单抗的化疗方案能改善弥漫大B细胞淋巴瘤(DLBCL)患者的预后,然而仍有部分患者在一线应用R-CHOP方案后转为复发难治性DLBCL(RR-DLBCL),且预后不良.对DLBCL及其相关肿瘤基因表达研究证实基因水平的生物靶向治疗能改善RR-DLBCL患者的预后.目前,一些新的靶向治疗成为研究热点.文章就RR-DLBCL的生物靶向治疗进展进行综述.     

Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma

BackgroundThis study compared the induction regimens doxorubicin, cyclophosphamide and etoposide (ACE) with doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone (ACVBP) before high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) for patients with poor-risk diffuse large B-cell lymphoma (DLBCL). A second randomisation compared rituximab with observation post-ASCT.Materials and methodsFour hundred and seventy-six patients <60 years old with newly diagnosed CD20+ DLBCL were randomised to induction with ACE or ACVBP. Three hundred and thirty responders received HDT followed by ASCT. After ASCT, 269 patients were re-randomised to receive either maintenance rituximab or observation alone. Randomisation was stratified by the quality of response to ASCT. The primary end point of this study was event-free survival (EFS).ResultsAt a median of 4 years’ follow-up from the second randomisation, there was a trend (P = 0.1) towards increased EFS for patients who received rituximab compared with observation.ConclusionThe type of induction therapy (ACVBP or ACE) did not significantly affect overall survival at a median 51 months’ follow-up.     

减低强度预处理异基因造血干细胞移植治疗复发难治性淋巴瘤的临床研究

目的 探讨减低强度预处理异基因造血干细胞移植（allo-HSCT）治疗复发难治性淋巴瘤的疗效和安全性.方法 北京军区总医院2012年1月至2013年12月应用减低强度预处理allo-HSCT治疗5例复发难治性淋巴瘤,其中男4例,女1例,平均年龄28.7岁（20～ 39岁）.3例为HLA配型全相合,2例为HLA配型不全相合.供者接受粒细胞集落刺激因子动员,采用骨髓加外周血干细胞联合移植,预处理方案为减低强度的氟达拉滨、白消安及抗人淋巴细胞免疫球蛋白,采用联合免疫抑制剂预防移植物抗宿主病（GVHD）,包括环孢素A、甲氨蝶呤、霉酚酸酯等,移植后观察患者不良反应、GVHD和无病生存等情况.结果 5例患者均获造血重建,中性粒细胞数≥0.5＆#215;109/L及血小板数≥20＆#215; 109/L的平均时间分别为18.8 d及24.5d,植入证据检测为100％完全供者造血.随访至2014年12月,中位随访时间19.2个月（6～35个月）,2例患者死于复发,其余患者处于完全缓解状态,最长无病生存时间达35个月.结论 减低强度预处理allo-HSCT治疗复发难治性淋巴瘤的方案安全、可行,疗效确切,可作为挽救性治疗的关键技术在临床广泛开展.     

弥漫性大B细胞淋巴瘤的临床特征及预后影响因素分析

目的　探讨弥漫性大B细胞淋巴瘤 (DLBCL)的临床特征及其预后的影响因素。方法回顾性分析 138例DLBCL患者的临床特征 ,结合随访资料 ,对DLBCL的预后影响因素进行单因素和多因素分析。结果　 87.7%侵犯淋巴结 ,6 0 .1%有结外侵犯 ,全组 5年生存率为 4 1.3%。多因素分析表明 ,患者年龄、临床分期和近期疗效是DLBCL预后的独立影响因素。国际预后指数 (IPI)计分低危组 5年生存率为 6 1.9% ,低中危组为 4 4 .3% ,高中危组为 2 0 .2 % ,高危组为 9.2 % ,差异有统计学意义(P <0 .0 1)。伴结外侵犯者 ,化疗联合手术治疗 5年生存率为 5 5 .6 % ,明显高于单纯化疗组。结论患者年龄、临床分期和近期疗效是DLBCL预后的独立影响因素 ,结外侵犯病例应采取手术和化疗联合治疗。     

原发性胃弥漫大B细胞淋巴瘤的临床分析

目的 分析原发性胃弥漫大B细胞淋巴瘤(PG-DLBCL)患者的临床特征和预后影响因素,探讨PC-DLBCL的分期系统和治疗模式.方法 回顾性分析69例PG-DLBCL患者的临床资料,以无事件生存期(EFS)和总生存期(OS)为主要研究终点.结果 全组患者的1、3和5年无事件生存率分别为83.8%、71.1%和69.0%,平均EFS为91.3个月;1、3和5年总生存率分别为91.3%、80.3%和72.4%,平均OS为98.8个月.单因素分析结果显示,改良Ann Arbor分期为ⅠE或ⅡE1期、血清乳酸脱氢酶(LDH)水平正常、血红蛋白水平正常、血清白蛋白水平正常、国际预后指数(IPI)评分为0～1分、肿瘤长径＜5 cm、浸润深度浅的患者EFS和OS显著延长(均P＜0.05),而患者的性别、年龄、有无B症状、ECOG体力评分结果以及治疗方法与患者的预后无关(均P＞0.05).Cox多因素回归分析结果显示,改良Ann Arbor分期、血清白蛋白水平是影响PG-DLBCL患者EFS和OS的独立因素.结论 PG-DLBCL的分期系统和各种治疗措施所处的地位仍存有争议,需进一步大样本的前瞻性研究以优化PG-DLBCL的治疗方案.     

复发难治性弥漫大B细胞淋巴瘤研究进展

近年来非霍奇金淋巴瘤(NHL)的发病率呈上升趋势,弥漫大B细胞淋巴瘤(DLBCL)是其中的主要类型.利妥昔单抗联合化疗虽获得了明显疗效,但目前仅有10%复发难治性DLBCL患者有治愈机会,且治疗方法有限.文章从复发难治性DLBCL的发病与耐药机制、二线治疗中的个体化选择、新药及新药联合的疗效、针对不同亚型与耐药机制的靶向药物、免疫检查点抑制剂及嵌合抗原受体T细胞免疫疗法的应用及复发难治性DLBCL复发监测等方面作一综述.     

异基因造血干细胞移植在复发难治淋巴瘤中的应用

复发难治淋巴瘤的治疗仍然是临床上的一大难题,目前主要以大剂量化疗联合自体造血干细胞移植及新药、细胞免疫治疗为主。近年减低强度预处理方案异基因造血干细胞移植（allo-HSCT）及替代供者的应用,使allo-HSCT成为复发难治淋巴瘤有价值的治疗选择。疾病特征、患者临床特点、替代供者的选择、预处理强度及移植相关并发症的管理等因素均影响着患者移植后的生存。allo-HSCT治疗复发难治淋巴瘤的数据主要来源于各移植中心的回顾性报道,前瞻性试验仍缺乏,移植患者的选择及移植时机的把握、移植物来源、预处理强度的选择等仍无统一的标准。文章将围绕这些方面对allo-HSCT在复发难治淋巴瘤中的应用进展进行介绍。     

Effect of addition of rituximab to salvage chemotherapy on outcome of patients with diffuse large B-cell lymphoma relapsing after an autologous stem-cell transplantation

BackgroundWe have investigated if rituximab-based salvage regimens improve response rates and survival of patients with diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous stem-cell transplantation (ASCT).Patients and methodsWe have retrospectively analyzed 82 patients with DLBCL who received salvage therapy for relapse or progression after ASCT. Patients were divided into two groups, according to whether rituximab-based salvage regimens were given (n = 42, ‘R-’ group) or not (n = 40, ‘R+’ group) after ASCT.ResultsPatients in the R+ group had better complete remission (CR) (55% versus 21.4%, P = 0.006) and overall response (OR) (75% versus 40.4%, P = 0.001) rates, and better 3-year event-free survival (EFS) (37% versus 9%, P = 0.002) and overall survival (OS) (50% versus 20%, P = 0.005) than patients in the R- group. Patients retreated with rituximab had better CR (42.9% versus 21.4%, P = 0.032) and OR (66.7% versus 40.4%, P = 0.019) rates, and better OS (36.2% versus 20% at 3 years, P = 0.05) and EFS (36.2% versus 9% at 3 years, P = 0.05) than patients who received chemotherapy alone at relapse after ASCT.ConclusionsThe addition of rituximab to salvage chemotherapy improves response rates and EFS in patients with relapsed DLBCL after ASCT. These patients may benefit from rituximab retreatment, although larger prospective studies are needed to confirm these results.     

Donor-derived diffuse large B-cell lymphoma after haploidentical stem cell transplantation for acute myeloid leukemia

We report a case of donor-derived diffuse large B-cell lymphoma (DLBCL), which developed 5 years after stem cell transplantation from a human leukocyte antigen (HLA)-haploidentical donor for acute myeloid leukemia (AML). A 51-year-old male was diagnosed with AML with variant KMT2A translocation involving t(6;11)(q13;q23). After 12 cycles of azacitidine treatment, fluorescence in situ hybridization (FISH) for KMT2A split signal indicated that 94% of his bone marrow (BM) cells were positive. He underwent peripheral blood stem cell transplantation (PBSCT) from his HLA-haploidentical son. The preconditioning regimen consisted of fludarabine, busulfan, melphalan, and antithymocyte globulin (ATG). The graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and short-term methotrexate. On day 28, KMT2A FISH analysis indicated that he had achieved a complete response (CR). He continued to receive tacrolimus for the limited type of cutaneous chronic GVHD. Five years after the transplantation, positron emission tomography/computed tomography (PET/CT) showed an abdominal tumor. The tumor was diagnosed as DLBCL without Epstein-Barr virus. BM aspiration revealed the infiltration of lymphoma cells with t(8;14)(q24;q32). Chimerism analysis showed that both the peripheral blood (PB) and abdominal lymphoma cells were of donor origin. After 4 cycles of salvage chemotherapy, PET/CT showed that a CR had been achieved. He underwent a second PBSCT from an HLA-identical unrelated donor. The preconditioning regimen and GVHD prophylaxis were the same as those for the first PBSCT without ATG. The patient’s PB revealed complete second donor-type chimerism, and the patient has maintained a CR since the second transplantation.     

弥漫大B细胞淋巴瘤研究最新进展

弥漫大B细胞淋巴瘤(DLBCL)是成年人发生率最高的淋巴瘤亚型,是一组高度异质性的肿瘤,不同亚型有不同的生物学特征、临床表现及治疗反应,患者预后差别很大,尽管目前的标准治疗R-CHOP方案为基础的免疫化疗使DLBCL治愈率提高,但仍有约40％的患者治疗早期即出现耐药或达到缓解后复发,预后差.本文结合第59届美国血液学会(ASH)年会有关报道,对DLBCL的新分子分型、新靶点药物研发、复发难治患者治疗等的研究进展进行总结.     

Autologous stem-cell transplantation in diffuse large B-cell non-Hodgkin's lymphoma not achieving complete response after induction chemotherapy: the GEL/TAMO experience.

BACKGROUND: Here we evaluate the results of high-dose chemotherapy and autologous stem-cell transplantation (HDC/ASCT) in 114 patients included in the GEL/TAMO registry between January 1990 and December 1999 with diffuse large B-cell lymphoma who failed to achieve complete remission (CR) with front-line conventional chemotherapy. PATIENTS AND METHODS: Sixty-eight per cent had a partial response (PR) and 32% failed to respond to front-line therapy. At transplant, 35% were chemoresistant and 29% had two to three adjusted International Prognostic Index (a-IPI) risk factors. RESULTS: After HDC/ASCT, 57 (54%) of 105 patients evaluable for response achieved a CR, 16 (15%) a PR and 32 (30%) failed. Nine patients were not assessed for response because of early death due to toxicity. With a median follow-up of 29 months for alive patients, the survival at 5 years is 43%, with a disease-free survival for complete responders of 63%. The lethal toxicity was 8%. Multivariate analysis revealed a-IPI and chemoresistance to be predicting factors. CONCLUSIONS: Our results show that one-third of patients who do not obtain a CR to front-line chemotherapy may be cured of their disease with HDC/ASCT. However, most chemoresistant patients pretransplant failed this therapy. For this population, as well as for those who presented with adverse factors of the a-IPI, pretransplant novel therapeutic modalities need to be tested.     

Outcome of relapsed non-Hodgkin's lymphoma patients after allogeneic and autologous transplantation

A retrospective review of 58 patients with non-Hodgkin's lymphoma (NHL) relapse or progression after autologous bone marrow transplantation (auto BMT), peripheral stem cell transplantation (PSCT), or allogeneic bone marrow transplantation (allo BMT) between November 1988 and December 1997 was performed. Forty-six (79%) patients had autologous transplant and 12 (21%) patients had allogeneic transplant. Median time to relapse post-transplant was 4.8 months with 49 relapses within 12 months after transplant. Overall 5-year survival was 22% (auto BMT or PSCT 25%, allo BMT 18%, p=0.38) with a median survival of 10 months (auto BMT or PSCT 10.2 months, allo BMT 7 months, p=0.38). Thirty-five patients received salvage therapy and, of these, 13 demonstrated objective response. The 3-year survival of responders and non-responders was 55 and 14% and median survivals were 27.8 and 8 months, respectively (p=0.02). Interval between BMT and relapse (p=0.0001), and response to salvage therapy (p=0.02) were the only significant predictors of survival.     

High-dose therapy followed by autologous stem-cell transplantation with and without rituximab for primary treatment of high-risk diffuse large B-cell lymphoma

BackgroundWe aimed to determine safety and efficacy of rituximab (R) in combination with repetitive high-dose therapy (HDT) as primary treatment for diffuse large B-cell lymphoma (DLBCL).Patients and methodsPatients aged 18–60 years and elevated lactate dehydrogenase were treated with four cycles of MegaCHOEP and transplantation of autologous stem cells after cycles 2, 3 and 4. Rituximab (375 mg/m²) was given before each cycle and 12 and 33 days after start of the last cycle of chemotherapy. Sixty-four patients given R-MegaCHOEP were compared with 29 patients who had received identical treatment without rituximab.ResultsOverall survival (OS) and event-free survival (EFS) after 3 years were significantly improved in patients treated with R-MegaCHOEP (OS: 78.7% versus 55.0%, P = 0.045; EFS: 72.7% versus 47.2%, P = 0.013). In a Cox regression model adjusted for performance status and stage, relative risk of treatment failure was lower (relative risk 0.5, P = 0.041) and OS was better (relative risk 0.4, P = 0.054) for patients given R-MegaCHOEP. Grade 3/4 infections were more frequent in the R-MegaCHOEP group (18.5% versus 6.0%, P = 0.003).ConclusionsThe addition of rituximab to MegaCHOEP significantly improved outcome in young patients with high-risk DLBCL. The higher incidence of grade 3/4 infections needs consideration when rituximab and HDT regimens are combined.