Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma

BACKGROUND: The current study was conducted to asses the safety profile and clinical activity of rituximab in combination with fludarabine and cyclophosphamide in patients with recurrent follicular lymphoma (FL). METHODS: This study was a noncomparative, multicenter, phase II study. Between March 2000 and December 2002, 54 patients with recurrent FL were enrolled in the FC+R trial. Patients received fludarabine at a dose of 25 mg/m(2) and cyclophosphamide at a dose of 300 mg/m(2) daily for 3 consecutive days, every 3 weeks for 4 cycles. Rituximab was administered at a dose of 375 mg/m(2) beginning 2 weeks after the first course of fludarabine and cyclophosphamide and then on Day 1 of each cycle thereafter. The planned treatment duration was 10 weeks. RESULTS: Overall, 92% of patients completed the planned therapy in 10 to 14 weeks and 74% achieved a complete response (CR). Among patients with BCL2-positive bone marrow, 86% obtained a molecular disease remission (MR). The median survival from treatment (SFT), the duration of disease remission (DR), and time to disease progression (TTP) had not been reached after a median follow-up of 45 months. Of the baseline characteristics, >2 previous treatments, BCL2-positive bone marrow, and low Follicular Lymphoma International Prognostic Index (FLIPI) score were found to be associated with better DR and/or TTP. Hematologic toxicity was transient and reversible, with the exception of 3 patients with severe and prolonged neutropenia. Three patients presented with infections, 1 of whom died of bronchopneumonia. CONCLUSIONS: The FC+R scheme, a nonanthracycline-containing regimen lasting up to 10 weeks, was found to be relatively well-tolerated and demonstrated significant antilymphoma activity with excellent clinical CR and molecular response rates.     

Failure of combination chemotherapy of advanced follicular (low-grade) non-Hodgkin's lymphoma

Twenty-two patients with Stage III and IV follicular non-Hodgkin's lymphoma were treated for 8 months by a chemotherapy regimen alternating between two different four-drug combinations (doxorubicin, teniposide, cyclophosphamide, prednisone; vincristine, cyclophosphamide, CCNU, prednisone). The overall response rate (complete and partial remission) was 68%. The complete remission rate was 23%. Twenty patients are alive, 50% of them are free of disease progression (median follow-up 76 months). It is concluded that our chemotherapy regimen is not satisfactory and that new therapeutic approaches are needed.     

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma

Background: Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen which has been utilized for therapy of B-cell non-Hodgkin's lymphoma. A previous clinical trial demonstrated that treatment with four weekly doses of 375 mg/m² of Rituximab in patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) was well tolerated and had significant clinical activity.Patients and methods: To assess the safety and efficacy of Rituximab treatment, an open-label, single-arm, multi-center, phase II study of eight consecutive weekly infusions of 375 mg/m² Rituximab in patients with low-grade or follicular B-cell NHL who had relapsed or had failed primary therapy was conducted. Thirty-seven patients with a median age of 55 years were treated.Results: Grade 1 or 2 adverse events were the majority of reported toxicities and occurred most frequently with the first infusion, decreasing with subsequent infusions. No patients developed a host antibody response (HACA) to Rituximab. The mean serum immunoglobulin levels for IgG, IgA, and IgM stayed within the normal range throughout the study. The majority of patients who were bcl-2 positive at baseline in peripheral blood became bcl-2 negative during treatment and remained negative at the time of B-cell recovery. In the 37 intent-to-treat patients, 5 (14%) had a complete response and 16 (43%) had a partial response for an overall response rate of 57%. Of 35 evaluable patients, 21 (60%) responded to treatment (14% CR and 46% PR). In responders, the median time to progression (TTP) and the median response duration have not been reached after 19.4+ months and 13.4+ months, respectively.Conclusions: The safety profile and efficacy achieved in this pilot study of extended treatment with Rituximab compares favorably with that seen with four weekly doses. Further studies are warranted to investigate whether this or other extended Rituximab schedules will result in increased efficacy in all or in certain subgroups of patients with low-grade or follicular NHL.     

Rituximab in combination with platinum-containing chemotherapy in patients with relapsed or primary refractory diffuse large B-cell lymphoma

The aim of the study was to evaluate the efficacy of a regimen consisting of rituximab and a platinum-containing chemotherapy with either Ifosfamide, Carboplatin and Etoposide (ICE) or Cisplatin, high-dose Ara-C and Dexamethasone (DHAP) in patients with relapsed or primary refractory diffuse large B-cell lymphoma. Ten patients with relapsed or primary refractory diffuse large B-cell lymphoma were treated from June 2000 until May 2001 with a platinum-containing chemotherapy regimen according to the ICE- or DHAP-protocol in combination with rituximab at the University of Muenster. Two cycles of ICE or DHAP and rituximab were given. In case of at least a minor response after 2 cycles, 2 additional cycles of the same combination were applied. Response rate, remission duration and duration of survival were evaluated. All 10 patients could be analysed with respect to these endpoints. No treatment related mortality was observed. The response rate (CR/PR) was 60% (10/50%). Twenty percent of the patients had progressive disease. The median duration of remission and survival was 3 and 3.5 months, respectively (range: 1-6 and 1-7 months, respectively), the survival rate was 10%. Eight of 10 patients died because of their underlying disease with short remission duration, 1 patient died of complications of allogeneic transplantation in CR. In conclusion, the combination of platinum-containing chemotherapy (ICE or DHAP) with rituximab demonstrates significant activity in intensively pretreated patients with relapsed or primary refractory diffuse large B-cell lymphoma. Considering the short duration of remission and survival, respectively, other experimental therapeutic approaches (e.g. allogeneic stem cell transplantation, radioimmunotherapy) should be pursued following this treatment in order to induce long-term remission.     

Rituximab maintenance therapy in follicular lymphoma

Follicular lymphomas are considered incurable, but most patients survive for many years. The introduction of rituximab into the treatment of malignant lymphomas of the B-cell lineage has had a major impact on the management of these diseases. Numerous studies confirm the benefit of rituximab, in monotherapy and in combination with chemotherapy, in regard to remission rate, remission duration, and overall survival. To further improve the treatment results, rituximab has been applied as maintenance therapy after induction with rituximab alone or with immunochemotherapy including rituximab. This article reviews the trials that have incorporated rituximab maintenance in the treatment of patients with follicular lymphoma.     

Rituximab maintenance in follicular lymphoma patients

Rituximab maintenance (RM) therapy following successful induction has recently emerged as a highly effective treatment for follicular lymphoma (FL). Randomized trials analyzing the impact of RM compared to observation alone have demonstrated a significantly better outcome in terms of progression-free survival (but not overall survival) in patients (pts) who received as first-line treatment single-agent rituximab, standard chemotherapy (CVP) and recently also immunochemotherapy (R-CHOP, R-CVP or R-FND), as shown by preliminary results of the PRIMA trial. Also in the setting of relapsed disease, RM has shown significant benefit either after chemotherapy or immunochemotherapy. RM has been generally well tolerated, and treated pts developed only mild toxicity, mainly a small increased rate of neutropenia, hypogammaglobulinaemia and self-limiting upper-respiratory tract infections. Moreover, no cumulative or unexpected toxicities were observed and quality of life was not affected. These data have established RM therapy as an important part of multi-modal therapeutic strategies in patients affected by FL.     

Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma.

PURPOSE: To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab. RESULTS: After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT. CONCLUSION: Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.     

Successful treatment of gastrointestinal follicular lymphoma with rituxan and combination chemotherapy

The clinical course of follicular lymphoma (FL) is well known. Although it is a chemosensitive disease, thereby allowing substantial palliation, recurrence is the rule; only a small subset who presents with limited stage disease is cured. Multiple attempts have been made over the past two decades to improve the survival of patients with FL, and a large number of phase III trials have been reported. These have included a variety of different therapeutic interventions, such as combination chemotherapy, recombinant interferons, new cytotoxic drugs, and immunologic agents. Most studies have not demonstrated that the use of a particular therapy convincingly prolongs survival. Follicular lymphoma cells express CD20 and are associated in most cases with the t(14:18) chromosomal translocation. Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen, which has been utilized for the therapy of B-cell non-Hodgkin's lymphoma. Rituximab was shown to be active in FL, and studies of its effectiveness in combination with cytotoxic chemotherapy to increase the response rate are forthcoming.     

Rituximab maintenance versus retreatment in follicular lymphoma

Follicular lymphoma (FL) is the most common type of indolent non‐Hodgkin lymphoma. Although the introduction of the anti‐CD20 monoclonal antibody rituximab has represented a major breakthrough, FL remains incurable with standard chemoimmunotherapies. The goals of therapy in symptomatic FL patients include the following: obtaining high response rates, extending the duration of remission, prolongation of survival and improving quality of life, while minimizing adverse events. To extend remission duration and possibly survival outcomes, maintenance therapy with rituximab has been shown to be effective in both frontline and relapsed/refractory settings. However, the optimal timing, schedule and length of maintenance therapy are controversial. Herein, we review the current data for maintenance rituximab in FL, discuss the current controversies for this modality, attempt to define its role relative to the more conservative retreatment approach and provide practical recommendations for its clinical use. Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up.

PURPOSE: Long-term follow-up with updated time to disease progression (TTP) and duration of response (DR) data are presented from a multicenter, phase II trial of rituximab/cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) combination therapy in 40 patients with CD20+, B-cell, non-Hodgkin's lymphoma (NHL). Revised response rates based on International Workshop Response Criteria are also provided. PATIENTS AND METHODS: Enrollment began in April 1994 and consisted of patients with histologically confirmed, low-grade, B-cell lymphoma who had received no prior chemotherapy or who had no more than four prior standard therapies. Patients received six cycles of CHOP and six infusions of rituximab. RESULTS: Eight (21%) of the 38 treated patients were classified as International Working Formulation (IWF) A, 16 (42%) were IWF B, 13 (34%) were IWF C, and one (3%) was IWF D. Nine (24%) of 38 patients had received prior chemotherapy. Nine (24%) of 38 were considered poor risk according to the Follicular Lymphoma International Prognostic Index. Overall response rate was 100%; 87% of patients achieved a complete response or unconfirmed complete response. The median TTP and DR were 82.3 months and 83.5 months, respectively. Seven of eight patients who were bcl-2 positive at baseline converted to negative, and three of the seven patients have sustained the molecular remission. CONCLUSION: Although a cure has not been found yet for follicular NHL, the R-CHOP combination provides a lengthy response duration in patients with relapsed or newly diagnosed indolent NHL.     

Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a.

Rituximab and IFN have each demonstrated single-agent activity in patients with low-grade non-Hodgkin's lymphoma (NHL). A single-arm, multicenter, Phase II trial was conducted to assess the safety and efficacy of combination therapy with rituximab and IFN-alpha-2a in 38 patients with relapsed or refractory, low-grade or follicular, B-cell NHL. IFN-alpha-2a [2.5 or 5 million units (MIU)] was administered s.c., three times weekly for 12 weeks. Starting on the fifth week of treatment, rituximab was administered by i.v. infusion (375 mg/m2) weekly for 4 doses. All 38 patients received four complete infusions of rituximab and were evaluable for efficacy, although 11 patients (29%) did not-receive all 36 injections of IFN. The mean number of IFN-alpha-2a injections was 31 doses; the mean total units received were 141 MIU (maximum, 180 MIU). The study treatment was reasonably well tolerated with no unexpected toxicities stemming from the combination therapy. No grade 4 events were reported. Frequent adverse events during the treatment period included asthenia (35 of 38 patients), chills (31 of 38), fever (30 of 38), headache (28 of 38), nausea (23 of 38), and myalgia (22 of 38). The overall response rate was 45% (17 of 38 patients); 11% had a complete response, and 34% had a partial response. The Kaplan-Meier estimates for the median response duration and the median time to progression in responders are 22.3 and 25.2 months, respectively. Further follow-up is needed to determine whether this treatment combination leads to a significantly longer time to progression than single-agent treatment with rituximab.     

Treatment of low-grade and intermediate-grade lymphoma with intensive combination chemotherapy results in long-term, disease-free survival.

To define the role of intensive combination chemotherapy in the treatment of low-grade or intermediate-grade lymphomas, the authors report results in 49 patients treated with intermediate-dose or high-dose methotrexate, bleomycin, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cytoxan (cyclophosphamide), vincristine, and dexamethasone (m/M-BACOD) with long-term follow-up. The complete response rate was 59% (29 of 49), including 67% (eight of 12) with low-grade and 57% (21 of 37) with intermediate-grade disease. The median survival for the entire group was 81 months. The 29 complete responders had a long median survival of 131 months. Forty-five percent (13 of 29) of the complete responders, 27% of the entire group, continue in remission with a median disease-free survival of 76 months. This includes five of 19 patients with diffuse poorly differentiated lymphoma, a disease generally characterized by early relapse. Twelve patients achieved a partial response and had a shorter median survival of 53 months, whereas nonresponders survived a median of less than 5 months. Late relapse was noted in patients with low-grade and intermediate-grade disease. Age (younger than or older than 60 years) was the only predictor of long-term survival. These data indicate very long disease-free survival can be achieved in low-grade and intermediate-grade lymphomas after attaining a complete remission. Intensive doxorubicin containing chemotherapy can be considered as an option for patients with advanced low-grade lymphoma but can only be proven to be superior to single-agent chemotherapy or no initial therapy by controlled randomized trails.     

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 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.     

Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma.

PURPOSE: In a phase II trial we investigated fludarabine phosphate (FAMP) as therapy for patients with relapsed lymphoma to determine its effectiveness and toxicity in this disease. PATIENTS AND METHODS: The 67 assessable patients had a median age of 56 years and had received a median of three chemotherapy regimens before treatment with FAMP. The starting dose was 25 mg/m2 administered intravenously over 30 minutes daily for 5 days every 3 to 4 weeks. RESULTS: High response rates were observed for follicular small cleaved-cell lymphoma (FSCCL) (62%), follicular mixed small- and large-cell lymphoma (80%), and follicular large-cell lymphoma (FLCL) (100%). Responses also occurred in small lymphocytic lymphoma (SLL) (33%), transformed lymphoma (33%), mycosis fungoides (40%), and Hodgkin's disease (25%). No responses were observed in other intermediate- or high-grade lymphomas (N = 20). Overall, there were five patients with a complete response, 23 patients with a partial response, and an overall response rate of 37%. Toxicity was primarily hematologic and infectious. No significant gastrointestinal, hepatic, renal, or neurologic toxicity occurred. CONCLUSIONS: We conclude that FAMP has major activity in follicular lymphoma. Fundamental research is needed to understand this differential efficacy in low-grade lymphoma yet lack of efficacy in intermediate- and high-grade lymphoma. Clinical investigations should be done using FAMP in varying dose schedules and in combination regimens.