Rituximab and chemotherapy in diffuse large B-cell lymphoma

Rituximab is an anti-CD20 chimeric monoclonal antibody with activity in nearly all subtypes of B-cell lymphomas. Association of rituximab with chemotherapy (mostly the cyclophosphamide, doxorubicin, vincristine and prednisolone [CHOP] regimen) in diffuse large B-cell lymphoma (DLBCL) represents an extraordinary revolution in the prognosis of DLBCL, and is the new standard of therapy in elderly and young, low-risk patients. Despite the lack of randomized, clinical trials in younger patients with high risk, rituximab is also a standard of care in these patients in clinical practice, at least in North America. The practice is based on observational trials (e.g., the British Columbia Registry) and the missing logic in classifying patients as ‘younger’ or ‘older’: 60 years old or 65 years old. In Europe, trials are ongoing to establish the best treatment for young, high-risk patients. Association of rituximab and chemotherapy deeply modifies prognostic factors defined before the rituximab era.     

利妥昔单抗联合二线化疗药物治疗老年人复发或难治性淋巴瘤

目的 研究利妥昔单抗联合二线化疗药物对老年人复发和难治性非霍奇金淋巴瘤(NHL)的治疗效果及安全性.方法 采用利妥昔单抗联合二线化疗药物治疗复发和难治性NHL患者12例.结果 12例共治疗38个周期,总有效(CR+PR)8例,有效率66.7%,临床收益(CR+PR+SD)11例,收益率91.3%.1年无进展生存率和总生存率分别为41.0%和50.0%.不良反应以自细胞和血小板减少最为常见,但均可耐受.结论利妥昔单抗联合二线化疗方案治疗老年人复发和难治性NHL安全有效,且能耐受.     

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。     

Aclarubicin-combined combination chemotherapy in patients with refractory or relapsed non-Hodgkin's lymphoma

Patients with lymphoma who became refractory or resistant to standard chemotherapy including anthracyclines were treated with aclarubicin-combined chemotherapy including VP-16, ifosfamide, and carboquone in a multicenter study. Twenty-one patients were entered in this study, and 18 of them were evaluable. The median age was 52 years old (range 27-74), and there were 17 male and 3 female patients. The vast majority of patients were diagnosed as having diffuse lymphoma, of which 10 cases had large cell type. Surface markers were measured in 8 patients, of whom 4 had T-cell lymphoma. Remission was attained in 3 of 18 patients (17%) with one complete and lasting remission with T-cell lymphoma. In conclusion, the response rate in this study was poor, but this type of combination chemotherapy might be considered in patients with T-cell lymphoma.     

Rituximab in treatment of primary gastric diffuse large B-cell lymphoma

Abstract In the rituximab era, the optimal treatment modality for primary gastric diffuse large B-cell lymphoma (PG-DLBCL) still remains unclear. We performed a retrospective, multicenter analysis of 65 patients with PG-DLBCL to assess the efficacy and toxicity of the addition of rituximab to conventional chemotherapy. When compared with conventional chemotherapy, there was a trend that rituximab plus chemotherapy yielded a higher complete response rate, 5-year event-free survival (EFS) rate and 5-year overall survival (OS) rate, but this was not statistically significant. In subgroup analysis, better OS was observed only for patients with advanced-stage disease when rituximab was added. When involved-field radiotherapy (IFRT) was included, EFS and OS were significantly prolonged in the conventional chemotherapy group, but not in the immunochemotherapy group. If focusing on patients with localized-stage disease receiving immunochemotherapy, the efficacies of short-course rituximab (R)-chemotherapy plus IFRT and 6-8 courses of R-chemotherapy without IFRT were comparable. In conclusion, it is necessary to carry out prospective randomized trials to help further illuminate the role of rituximab in the PG-DLBCL treatment landscape. If a patient has been treated with a non-rituximab-containing regimen, additional IFRT should be considered, and for patients with advanced-stage disease, rituximab should be considered.     

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.     

Bortezomib in combination with rituximab, dexamethasone, ifosfamide, cisplatin and etoposide chemoimmunotherapy in patients with relapsed and primary refractory diffuse large B-cell lymphoma

Patients with relapsed or refractory diffuse large B-cell lymphoma may experience extended survival with second-line chemotherapy and autologous stem cell transplant (ASCT). Since a major determinant of outcome after ASCT is responsiveness to second-line therapy, the development of more effective second-line treatments is desirable. We investigated the addition of bortezomib to rituximab, dexamethasone, ifosfamide, cisplatin and etoposide (VIPER). Fifteen patients were enrolled, of whom seven were refractory to first-line chemotherapy and only three had maintained first response for 1 year. Nine (60%) patients achieved objective responses, of which three (20%) were IWC-PET (International Workshop Criteria positron emission tomography) complete responses. Median progression-free survival was 3 months, and median overall survival was 10 months. At a median follow-up of 26 months, five patients (33%) remained alive. Treatment was well tolerated with no unexpected toxicity. Although response rates did not meet predefined criteria, activity was at least comparable to other second-line approaches despite a poor-prognosis patient population.     

Rituximab, gemcitabine, cisplatin, and dexamethasone in patients with refractory or relapsed aggressive B-cell lymphoma

This study was conducted to evaluate the efficacy and safety of Rituximab, Gemcitabine, Cisplatin, and Dexamethasone (R-GDP) in relapsed or refractory aggressive B-Cell Non-Hodgkin's Lymphoma (NHL). Treatments consisted of rituximab 375?mg/m(2), i.v. on day 1; gemcitabine 1,000?mg/m(2), i.v. on days 1 and 8, dexamethasone 40?mg i.v. on days 1-4, and cisplatin 25?mg/m(2) i.v. on days 1-3, every 21?days. The primary end-points were the overall survival (OS) and progression-free survival (PFS). Secondary endpoints included response rate (ORR; CR) and toxicities. Eligible patients could then proceed to high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or receive up to six treatment cycles. From January 2005 to December 2010, 50 successive patients at Tianjin cancer hospital lymphoma department were enrolled in this study. All patients were recurrent or refractory aggressive B-cell NHL, including diffuse large B-cell lymphoma (n?=?30) and follicular lymphoma grade 3b (n?=?20). The median follow-up time was 42?months (range, 12-70). After two cycles, the overall response rate was 72.0?%, with a CR/CRu rate of 56?%. The 2-year OS and PFS of all patients were 70.0 and 48.0?%, respectively. Grade III-IV neutropenia and thrombocytopenia occurred in 34 and 40?% of patients, respectively. Twenty-one patients (42?%) proceeded to ASCT. Higher International Prognostic Index and refractory disease were independently associated with worse survival and progression-free survival. R-GDP chemotherapy in patients with refractory or relapsed aggressive B-Cell NHL was effective as a salvage therapy and helpful for HDC/ASCT.     

DHAP in combination with rituximab vs DHAP alone as salvage treatment for patients with relapsed or refractory diffuse large B-cell lymphoma: a matched-pair analysis

The addition of rituximab to chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) has been shown to improve outcome in first-line therapy. However, in patients with relapsed or refractory disease, the value of adding rituximab to salvage chemotherapy is less clearly defined. This study performed a matched-pair analysis of patients with relapsed or refractory DLBCL by comparing the combination of dexamethasone, high-dose cytarabine and cisplatin (DHAP) with rituximab to DHAP alone. Sixty-seven patients with relapsed or refractory DLBCL were collected from two prospective phase II trials from Germany and Italy. Twenty-three patient pairs treated with either DHAP in combination with rituximab or DHAP alone could be analysed after matching for important prognostic factors. The addition of rituximab to the DHAP regimen led to higher complete and similar overall remission rates. However, differences with regard to complete remission rates failed to reach statistical significance, thereby necessitating further evaluation of the role of combined immunochemotherapy in this patient population.     

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.     

Rituximab in combination with vinorelbine/gemcitabine chemotherapy in patients with primary refractory or early relapsed T cell rich B cell lymphoma. A pilot study

Rituximab is a chimeric monoclonal antibody that binds specifically to the CD20 antigen expressed in most B cell lymphomas. As single agent or in combination with chemotherapy rituximab has shown significant activity in patients with relapsing or refractory aggressive lymphomas. Because T cell rich B cell lymphomas (TCRBCL) also express the CD20 antigen, we decided to evaluate the efficacy and tolerability of the anti-CD20 monoclonal antibody rituximab combined with chemotherapy in four patients with either primary refractory or early relapsed TCRBCL. The chemotherapy regiment consisted of vinorelbin and gemcitabine, a combination with known efficacy in patients with refractory aggressive lymphomas. The patients received 6 cycles of rituximab at the dose of 375 mg/m², combined with vinorelbine 25 mg/m² and gemcitabine 800 mg/m² at 3-week intervals. Three complete responses and one partial response were observed among our four patients with refractory or early relapsed TCRBCL without significant adverse effects, indicating considerable efficacy of this combination. Therefore, rituximab should be tested in combination with chemotherapy in the front line treatment of patients with TCRBCL.     

Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma and despite recent chemotherapeutic advances up to half of all patients relapse. Here we report the results from a phase 2, single-arm, single-center trial evaluating the safety and efficacy of lenalidomide plus rituximab in elderly patients with relapsed or refractory DLBCL.Patients and MethodsBetween March and June 2009, elderly patients (65 years of age or older) with relapsed/refractory DLBCL who had been heavily pretreated were recruited. Oral lenalidomide (20 mg/d for 21 days of each 28-day cycle) was initiated for four cycles and rituximab (375 mg/m²) was administered on day 1 and day 21 of each 28-day cycle for four cycles. After this induction phase, patients achieving a complete response (CR), partial response (PR), or stable disease (SD) were given lenalidomide maintenance therapy at the same schedule for another 8 months.ResultsA total of 23 patients with a median of three prior treatments (range, 2 to 8) were included. The overall response rate (CR + PR) at the end of the induction phase was 35% (n = 8). Ten patients (7 CR, 1 PR, and 2 SD patients) were eligible for lenalidomide maintenance and 8 of these patients achieved a CR. Adverse events were manageable and the most common included neutropenia and thrombocytopenia.ConclusionOral lenalidomide in combination with rituximab is active in elderly patients with relapsed/refractory DLBCL with a high percentage of patients achieving a continuous CR after lenalidomide maintenance.     

Rituximab provides durable remission in a patient with refractory aggressive diffuse B-cell lymphoma failing salvage chemotherapy

The outcome of patients with aggressive refractory diffuse large B-cell lymphoma (DLCL) is generally poor. A 43-year-old female with DLCL, who relapsed after first line chemotherapy (CHOP--cyclophosphamide, doxorubicin, vincristine, and prednisone) and progressed despite salvage chemotherapy (EPOCH-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), was treated effectively with 8 cycles of Rituximab. She is without evidence of disease with a follow-up of 32 months. We report this case to bring to attention the possibility of sustained durable remission with single agent Rituximab in refractory DLCL.     

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.     

Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma

Background

Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor T-cell based anti-CD19 therapy. The ZUMA-1 study, multicenter, single-arm, registrational Phase 1/2 study of axi-cel demonstrated high objective response rate in patients with relapsed/refractory large B-cell lymphoma. Here, we present the results of the bridging study to evaluate the efficacy and safety of axi-cel in Japanese patients (JapicCTI-183914).

Methods

This study was the phase 2, multicenter, open-label, single-arm trial. Following leukapheresis, axi-cel manufacturing and lymphodepleting chemotherapy, patients received a single infusion of axi-cel (2.0 × 10⁶ cells/kg). Bridging therapy between leukapheresis and conditioning chemotherapy was not allowed. The primary endpoint was objective response rate.

Results

Among 17 enrolled patients, 16 received axi-cel infusion. In the 15 efficacy evaluable patients, objective response rate was 86.7% (95% confidence interval: 59.5–98.3%); complete response/partial response were observed in 4 (26.7%)/9 (60.0%) patients, respectively. No dose-limiting toxicities were observed. Grade ≥ 3 treatment-emergent adverse events occurred in 16 (100%) patients—most commonly neutropenia (81.3%), lymphopenia (81.3%) and thrombocytopenia (62.5%). Cytokine release syndrome occurred in 13 (81.3%) patients (12 cases of grade 1 or 2 and 1 case of grade 4). No neurologic events occurred. Two patients died due to disease progression, but no treatment-related death was observed by the data-cutoff date (October 23, 2019).

Conclusion

The efficacy and safety of axi-cel was confirmed in Japanese patients with relapsed/refractory large B-cell lymphoma who have otherwise limited treatment options.

Trial registration

JapicCTI-183914.

     

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。     

Irinotecan plus cisplatin and dexamethasone (ICD) combination chemotherapy for patients with diffuse large B-cell lymphoma previously treated with Rituximab plus CHOP

PURPOSE: The therapeutic strategy for relapsed or refractory patients with diffuse large B-cell lymphoma (DLBL) remains challenging yet. Salvage therapy has been tried for these patients according to their clinical status. We studied ICD (irinotecan, cisplatin and dexamethasone) regimen as salvage chemotherapy for DLBL patients previously treated with RCHOP. METHODS: Between February 2005 and May 2006, 15 patients were treated prospectively with ICD chemotherapy; irinotecan 65 mg/m(2)/day on days 1 and 8, cisplatin 30 mg/m(2)/day on days 1 and 8, and dexamethasone 40 mg/day on days 1-2 and 8-9. This schedule was planned to repeat every 3 weeks until disease progression, severe toxicity or stem cell transplantation. RESULTS: Of the 14 patients evaluable for response, 3 patients achieved CR, 7 patients PR, with 1 SD and 3 PD; overall response rate 71% (10/14; 95% confidence interval, 47-95%). The median progression free survival (PFS) and event free survival (EFS) were 113 (range 21-493+) and 77 (range 21-324+) days, respectively. The median overall survival was 267 (range 31-493+) days. Grade 3/4 neutropenia and grade 3 neutropenic fever were observed in 67% (22/33) and 18% (6/33) of cycles, respectively. There were 20% of grade 3/4 nausea and diarrhea observed. CONCLUSIONS: The ICD regimen with current schedule showed high response rate for DLBL patients previously treated with RCHOP. But the high incidence of neutropenia led to delay of subsequent cycles causing dose intensity reduced, which seems to be related with short PFS and EFS.     

R-GEMOX方案补救治疗复发或难治性弥漫大B细胞淋巴瘤

目的:观察利妥昔单抗联合盐酸吉西他滨和奥沙利铂(R-GEMOX)治疗复发或难治性弥漫大B细胞淋巴瘤的疗效和毒副反应。方法:利妥昔单抗375mg/m2化疗前1天静脉滴入,吉西他滨1000mg/m2,静脉滴入d1,d8,奥沙利铂130mg/m2,静脉滴入d2,以3周为1个化疗周期,3周期后评价临床疗效。结果:11例患者中,完全缓解(CR)3例,部分缓解(PR)4例。1例稳定(SD),3例进展(PD)。总缓解率为63.6%。化疗毒副反应主要为轻度的胃肠道反应,少数患者出现轻度的骨髓抑制,如白细胞及血小板减少。结论:利妥昔单抗联合盐酸吉西他滨和奥沙利铂(R-GEMOX)对复发或难治性进展型弥漫大B细胞淋巴瘤有较好的近期疗效,大部分患者可以承受其毒性,是一个值得进一步验证的补救性化疗方案。