The role of complement in the mechanism of action of rituximab for B-cell lymphoma: implications for therapy

Rituximab, a genetically engineered chimeric monoclonal antibody specifically binding to CD20, was the first antibody approved by the U.S. Food and Drug Administration for the treatment of cancer. Rituximab significantly improves treatment outcome in relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL). However, there are also some challenges for us to overcome: why approximately 50% of patients are unresponsive to rituximab in spite of the expression of CD20, and why some responsive patients develop resistance to further treatment. Although the antitumor mechanisms of rituximab are not completely understood, several distinct antitumor activities of rituximab have been suspected, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), apoptosis, and direct growth arrest. To counteract resistance to rituximab therapy, several strategies have been developed to: (a) augment the CDC effect by increasing CD20 expression, heteroconjugating rituximab to cobra venom factor and C3b, and inhibiting membrane complement regulatory protein, especially CD59, function; (b) enhance the ADCC effect through some immunomodulatory cytokines and CR3-binding beta-glucan; and (c) reduce the apoptotic threshold or induce apoptotic signaling on the tumor. Extensive studies indicate that rituximab combined with these approaches is more effective than a single rituximab approach. Herein, the mechanism of action of and resistance to rituximab therapy in B-cell NHL, in particular, the involvement of the complement system, are extensively reviewed.     

Intravascular large b-cell lymphoma: case report

Intravascular lymphoma has an aggressive course. Its clinical manifestations may vary and most often include fever, skin lesions and mental disorders. Diagnosis can be made by biopsy of an affected organ. In 30-50% of cases, intravascular lymphoma is diagnosed post mortem. Poor diagnosis is mostly due to a variety of clinical manifestations and an aggressive course. Yet, in cases of timely diagnosis, complete remission can be achieved by combination chemotherapy in approximately 55%. We report a clinical cases of intravascular B-cell lymphoma which was verified in a post mortem immunochemical investigation.     

血管内大B细胞淋巴瘤临床病理观察

目的:探讨血管内大B细胞淋巴瘤的临床病理学特点、诊断及其预后。方法:报道2例血管内大B细胞淋巴瘤,对其临床资料、组织学形态及免疫标记结果进行分析,并复习相关文献。结果:2例患者年龄分别为73岁、54岁,临床表现为反复发热。组织学所见,受累组织小血管扩张,管腔内充满异型肿瘤细胞。免疫组化标记,肿瘤细胞CD20(+),CD3(-)。随访1例于发病后2个月死亡,1例于发病后7个月死亡。结论:血管内大B细胞淋巴瘤是一种罕见的非霍奇金淋巴瘤,临床表现缺乏特异性,诊断依靠病理学检查。该肿瘤恶性度极高,患者预后极差。     

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma

Rituximab is the first monoclonal antibody to have been registered for the treatment of B-cell lymphomas. Randomized studies have demonstrated its activity in follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma in untreated or relapsing patients. Rituximab has transformed the outcome of these patients because of its high activity and low toxicity. A combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, has the highest efficacy ever described with any chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma.     

Intravascular large B-Cell lymphoma with bone marrow involvement and superior sagittal sinus thrombosis: report of a case successfully treated with a CHOP/rituximab combination regimen

Intravascular large B-cell lymphoma (ILBCL) is a rare subtype of diffuse large B-cell lymphoma (as currently recognized by the World Health Organization classification) and is characterized by proliferation of mature B-cells within the lumina of small and medium vessels. We report on a 66-year-old man who presented with a fever of undetermined origin, a splenomegaly, and an elevated lactate dehydrogenase level. The diagnosis of ILBCL was established by a bone marrow biopsy that showed CD20+ tumor cells confined within the lumina of sinuses. A karyotypic analysis obtained from the bone marrow aspirate showed a hypotetraploid clone. Magnetic resonance imaging of the brain revealed multiple high-signal areas in the periventricular white matter above the tentorium. Focal dural enhancement (pachymeningitis) close to the medium third of the superior sagittal sinus was also observed and was related to a partial superior sagittal sinus thrombosis as confirmed by venous magnetic resonance angiography. After 8 courses of a CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) plus rituximab regimen, normalization of the superior sagittal sinus and of the bone marrow was obtained. With a follow-up of 15 months, the patient is still considered in complete remission. This observation highlights an unusual vascular aspect of ILBCL and the efficacy of the current standard treatment for this age group (CHOP/rituximab) in this particularly aggressive lymphoma subtype.     

Prognostic models for diffuse large B-cell lymphoma in the rituximab era: a never-ending story

BackgroundImproved treatment have modified survival outcome in patients with diffuse large B-cell lymphoma (DLBCL) and altered the importance of previously recognized prognostic markers.Design and methodsTo evaluate International Prognostic Index (IPI) score before and after rituximab introduction and to validate the absolute lymphocyte count (ALC)/revised International Prognostic Index (R-IPI) model, we carried out a retrospective analysis on a total of 831 patients with DLBCL.ResultsOur results show that IPI lost its discriminating power with the introduction of rituximab. The analysis of our second set allowed us to validate the ALC/R-IPI model. The R-IPI and ALC/R-IPI could still be used for designing clinical trials, but both have difficulty recognizing a high percentage of poor prognosis patients, though it remains an important goal of a good prognostic model considering the modest impact of salvage treatments on survival.ConclusionsA new model on the basis of significant variables in the rituximab era and built on a large database of patients treated with rituximab is urgently needed. As prognostic models are changing with the efficacy and mechanisms of action of treatment utilized, looking for a new prognostic score is a never-ending story in which researchers are trying to hit a continuously moving target.     

Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK).

PURPOSE: To evaluate the effect of single-agent rituximab given at the standard or a prolonged schedule in patients with newly diagnosed, or refractory or relapsed mantle cell lymphoma (MCL). PATIENTS AND METHODS: After induction treatment with the standard schedule (375 mg/m2 weekly x 4), patients who were responding or who had stable disease at week 12 from the start of treatment were randomly assigned to no further treatment (arm A) or prolonged rituximab administration (375 mg/m2) every 8 weeks for four times (arm B). RESULTS: The trial enrolled 104 patients. After induction, clinical response was 27% with 2% complete responses. Among patients with detectable t(11;14)-positive cells in blood and bone marrow at baseline, four of 20, and one of 14, respectively, became polymerase chain-reaction-negative after induction. Anemia was the only adverse predictor of response in the multivariate analysis. After a median follow-up of 29 months, response rate and duration of response were not significantly different between the two schedules in 61 randomly assigned patients. Median event-free survival (EFS) was 6 months in arm A versus 12 months in arm B; the difference was not significant (P = .1). Prolonged treatment seemed to improve EFS in the subgroup of pretreated patients (5 months in arm A v 11 months in arm B; P = .04). Thirteen percent of patients in arm A and 9% in arm B presented with grade 3 to 4 hematologic toxicity. CONCLUSION: Single-agent rituximab is active in MCL, but the addition of four single doses at 8-week intervals does not seem to significantly improve response rate, duration of response, or EFS after treatment with the standard schedule.     

Rapid-infusion rituximab in lymphoma treatment.

Rituximab® (MabThera; Rituxan Roche) is a chimeric human/murineimmunoglobulin G1 monoclonal antibody that binds specificallyto the B-cell-surface antigen, CD20. Using the combination ofCHOP-R leads to significant improvement in the outcome of elderlypatients with diffuse large B-cell lymphoma, with significantsurvival benefits maintained during a 5-year follow-up [1]. Other studies have been conducted in patients with follicularlymphoma or mantle-cell lymphoma and have shown the same benefitsfor the combination of rituximab plus chemotherapy [2]. In general, rituximab is a well-tolerated medicine, althougha specific infusion rate     

Pegylated liposomal doxorubicin as single-agent treatment of low-grade non-Hodgkin's lymphoma: a phase II multicenter study

The purpose of this study was to determine the objective response rate, median duration of response, time to disease progression, and survival time and to evaluate the safety of pegylated liposomal doxorubicin in previously treated patients with low-grade non-Hodgkin's lymphoma. Thirty-two patients with low-grade non-Hodgkin's lymphoma were treated and analyzed. Pegylated liposomal doxorubicin 30 mg/m2 was administered intravenously as a single dose on day 1 of each 3-week cycle. Patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had stage II-IV disease. The median baseline left ventricular ejection fraction was 60%, and the median age was 68 years. In 29 evaluable patients, there were 3 (10%) complete responses, 6 (21%) partial responses, 11 (38%) patients with stable disease, and 9 (31%) with progressive disease. The median number of cycles was 4 (range, 1-22 cycles). The median duration of response (complete response plus partial response) was 11.0 months (range, 2.3-37.0 months). The estimated median time to progression was 5.6 months (range, 1.1-40.5 months) and the estimated median survival was 29.6 months (range, 3.9-41.6 months). Treatment-related toxicities grade = 3 included neutropenia (25%) and palmoplantar erythrodysesthesia (9%). Only 1 clinically significant cardiac toxicity was observed. There were 17 deaths; none were treatment related. Single-agent pegylated liposomal doxorubicin 30 mg/m2 every 3 weeks, is associated with antitumor activity in the treatment of low-grade non-Hodgkin's lymphoma, as shown by an objective response of 31%, and produced no significant cardiac or hematologic toxicity. Based on these results, pegylated liposomal doxorubicin should be further evaluated in combination with other agents in low-grade non-Hodgkin's lymphoma.     

Intravascular lymphoma: the oncologist's "great imitator"

Intravascular lymphoma (IVL) is a rare subtype of extranodal diffuse large B-cell lymphoma with a distinct presentation. Anatomically the disease is characterized by the proliferation of clonal lymphocytes within small vessels with relative sparing of the surrounding tissue. The clinical symptoms of the disease are dependent on the specific organ involvement, which most often includes the central nervous system and skin. Because of the various modes of presentation and the rarity of IVL, the diagnosis is often made postmortem. The diagnosis is almost exclusively made by surgical biopsy of a suspected site of involvement. Advances in imaging and immunohistochemistry have led to increasing antemortem diagnosis of this lymphoma. Although some patients with this disease may be curable with aggressive therapy, further research into novel treatment strategies is needed to improve outcome. Some potential insights into future therapies may be drawn from the small amount of basic science literature relevant to this entity. This review provides a concise, up-to-date summary of IVL.     

Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a retrospective analysis

For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy because of comorbidities, advanced age, or relapse after heavy salvage regimens, treatment options are very limited and prognosis is poor. We retrospectively analyzed 29 patients with relapsed/refractory DLBCL treated with combination bendamustine plus rituximab (BR) between July 2010 and January 2014 to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and treatment safety. Twenty-eight patients were available for this analysis. ORR was 50% (14 patients), with 39.3% CR (11 patients), and 10.7% PR (3 patients). SD was reported in 2 patients (7.2%) and PD in 12 patients (42.8%). At the median follow up of 8 months (range 1–37.4 months), the median PFS was 8 months for all patients (95% CI 5.5–26.6). The median DOR was 24.7 months (95% CI 3.2–24.7). Grade 3/4 toxicity observed included hematologic events: lymphopenia (42.8%), neutropenia (32.1%), anemia (17.2%), and thrombocytopenia (14.2%). BR can be considered to have a role in the treatment of patients with relapsed/refractory DLBCL with limited therapeutic options, in that it can induce long-term remission in some patients with an acceptable toxicity profile.     

Treatment of Burkitt's lymphoma: Randomized clinical trial of single-agent versus combination chemotherapy

A randomized clinical trial designed to compare the effectiveness of cytoxan (CTX) alone versus a combination consisting of CTX, vincristine (Oncovin) and methotrexate (COM) in the treatment of Burkitt's lymphoma (BL) was carried out. Nineteen patients were selected at random to receive CTX alone while 21 received COM. The two treatment regimens were equally effective in inducing remissions, and complete response rates of 83.3% and 84.3% were observed for CTX- and COM-treated patients, respectively. The relapse frequencies were also equal but the pattern of relapse was clearly different. Seven out of 8 (87.5%) in the CTX group relapsed with systemic and central nervous system (CNS) tumor, while 8 out of 10 (80%) in the COM group relapsed with CNS disease only. This difference is highly significant p = 0.008. The remission durations and survival to date are the same.