A pilot study of rituximab in patients with recurrent, classic Hodgkin disease (original) (raw)
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Annals of Hematology, 2006
To better define the role of rituximab in salvage and high-dose therapy (HDT) for relapsed or refractory non-Hodgkin's lymphoma (NHL), patients treated before the implementation of rituximab in salvage and HDT (n=57, control group) were compared with patients with rituximab included in this procedure (n=36, study group). All patients had been antibody-naive at this point, and analyses were performed separately for 22 and 31 patients with aggressive, and 14 and 26 patients with indolent NHL, respectively. All patients received two courses of salvage therapy, predominantly dexamethasone, BCNU, etoposide, cytosine arabinoside, melphalan. Conditioning regimens included BCNU, etoposide, cytosine arabinoside, melphalan; BCNU, etoposide, cytosine arabinoside, cyclophosphamide or total body irradiation and cyclophosphamide, with rituximab added for patients in the study group. Despite the absence of differences in stem cell collection, haematopoietic recovery was delayed in patients with aggressive NHL treated in the study group: median days to absolute neutrophil count more than 0.5×10 9 /l, 11 vs 10 (p=0.01), and platelets more than 20×10 9 /l, 14 vs 11 (p=0.0005), with an increased requirement for platelet transfusions. No similar observations were made in indolent lymphoma patients. Remission rates were superior for patients with aggressive NHL in the study group. With a median followup of 7.25 and 4.5 years, this resulted in an improvement in OS at 4.5 years: 67 vs 45% (95% confidence interval, 47-87% vs 28-64%; p=0.0468). For patients with indolent lymphoma, no comparable benefit was detectable. Our data support the use of rituximab in HDT for patients with aggressive NHL. For patients with indolent NHL, only longer follow-up and/or randomized trials may help to fully determine the impact of rituximab on the outcome after HDT.
Re-Treatment of Relapsed Indolent B-Cell Lymphoma With Rituximab
International Journal of Hematology, 2001
Recently, a new chimeric mouse human monoclonal antibody, rituximab (IDEC-C2B8), has been incorporated into the therapy of B-cell non-Hodgkin's lymphoma (B-NHL) that expresses CD20 . Use of rituximab has given rise to a good response rate and a relatively long progression-free survival (PFS) in patients with recurrent indolent B-NHL ; however, the toxicity and the efficacy of re-treatment with rituximab are unknown. Also, it remains to be determined if either an extended (more than 4 weeks) or a repeated dosing regimen of rituximab is effective in decreasing relapse or in prolonging PFS. Recently, we conducted multicenter phase I and phase II studies of rituximab for the treatment of recurrent indolent B-NHL . In the phase II study, more than half of the relapsed patients with indolent B-NHL responded to rituximab with an acceptable level of toxicity profiles . Here we report the results of re-treatment with rituximab in 13 patients whose B-NHL relapsed after they showed an initial response to rituximab.
Blood, 2008
Since nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) express CD20, rituximab may be used as a non-mutagenic treatment option to avoid late toxicities in this rather indolent entity. Between 1999-2004 the German Hodgkin Study Group investigated the activity of rituximab (375mg/m² x 4) in a phase-II trial in 21 relapsed or refractory NLPHL patients. The initial diagnosis of NLPHL was confirmed in 15/21 enrolled patients by reference pathology. The remaining cases were reclassified as Hodgkin lymphoma transformed to T-cell rich B-cell lymphoma (TCRBCL) (n=2) or CD20+ classical Hodgkin lymphoma (cHL) (n=4). In NLPHL patients the overall response rate was 94%, including 8 CR and 6 PR. With a median follow-up of 63 months (range 3-84), the median time to progression was 33 months, with the median OS not reached. Thus, rituximab is highly effective in relapsed and refractory NLPHL. This study is registered at http://www.klinisches-studienzentrum.de/trial/285.
Blood, 2003
This phase 2 trial was performed to evaluate the safety and efficacy of the chimeric monoclonal anti-CD20 antibody rituximab in patients with relapsed lymphocyte-predominant Hodgkin lymphoma or other CD20(+) subtypes of Hodgkin disease (HD). Eligibility criteria required expression of the CD20 antigen on more than 30% of malignant cells. Fourteen patients were treated with 4 weekly intravenous infusions of rituximab (375 mg/m(2)). All patients had at least one prior chemotherapy (median, 2). The median time from first diagnosis was 9 years. Adverse events, such as rhinitis, fever, chills, and nausea, were usually transient and of mild to moderate grade, allowing outpatient treatment in most cases. All patients completed treatment and were eligible for a response. The overall response in 14 assessable patients was 86%, with 8 complete remissions and 4 partial remissions, and 2 patients with progressive disease. At a median follow-up of 12 months, 9 of 12 responders were in remission....
Leukemia, 2003
Antibody-dependent cellular cytotoxicity (ADCC) is one of the possible mechanisms of action of the chimeric CD20 monoclonal antibody IDEC-C2B8 (rituximab). As granulocyte-colony stimulating factor (G-CSF) greatly enhances the cytotoxicity of neutrophils in ADCC, the efficacy of rituximab might be enhanced by the addition of G-CSF. In a phase I/II clinical trial, we investigated the safety and efficacy of the combination of rituximab and G-CSF (5 lg/kg/day, administered for 3 days, starting 2 days before each infusion) in 26 relapsed low-grade lymphoma patients. Adverse events occurred in 25/26 patients and mainly consisted of (grade I/II) fever (29%) and allergic reactions (19%). In phases I and II (375 mg/m 2 rituximab+G-CSF), 19 patients were evaluable for efficacy. The response rate was 42% (8/19; 95% CI 20-67%), with 16% (3/19) complete remissions and 26% (5/19) partial remissions. The median duration of response was 18 months, the median time to progression was 24 months. We conclude that the combination of rituximab and G-CSF is well tolerated. Although the overall response rate seems comparable to that reported for rituximab monotherapy, remission duration in this pilot phase II study is remarkably long. Randomized comparison with rituximab monotherapy should substantiate this promising finding.
Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial
2003
with complete response (CR) in 9 (41%), unconfirmed complete response in 1 (5%), and partial response in 12 (54%). Acute treatment-related adverse events were minimal. With a median follow-up of 13 months, 9 patients had relapsed, and estimated median freedom from progres- sion was 10.2 months. Progressive dis- ease was biopsied in 5 patients: 3 had recurrent LPHD, while 2
Rituximab in Hodgkin lymphoma: Is the target always a hit
Cancer Treatment Reviews, 2011
In 1997, the anti-CD20 monoclonal antibody (MAb) rituximab became the first MAb approved for clinical use in oncology, and ushered in a new era of rationally designed targeted agents in cancer therapeutics. It is currently approved for use in non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and rheumatoid arthritis (RA). Rituximab is non-mutagenic, associated with low treatment-related toxicity, and few, if any, long term adverse events, making it an attractive agent to be tried in off-label settings like Hodgkin lymphoma (HL). HL consists of two distinct subtypes -classic HL (cHL) and lymphocyte predominant HL (LPHL). CD20 is present in virtually all patients with LPHL, and in a significant minority of patients with cHL. In this CD20 positive sub-population, the use of rituximab is a rational intervention strategy. Rituximab has been used in patients with cHL as well as LPHL with good efficacy. In this article, we provide a clinically-oriented overview of the use of rituximab in the different sub-types of HL, and report updated results of our series of 8 LPHL patients treated with rituximab. A systematic review of the literature is also presented.
Impact of Rituximab (Rituxan) on the Treatment of B-Cell Non-Hodgkin's Lymphoma
illness, new treatments are needed to prolong survival, with the ultimate goal to provide cure. For patients with aggressive lymphoma, unmet needs include higher initial cure rates, improved salvage chemotherapy options, and less toxic therapies for old and frail patients. Conventional methods of treatment, including chemother-apy and radiation, are associated with toxicity and lack specific antitumor-targeted activity. Cell–surface proteins, such as CD19, CD20, and CD22, are highly expressed on B-cell lym-phomas and represent key potential targets for treatment. Antibody therapy directed against CD20 has had the most important clinical impact to date. CD20 is thought to be involved in the regulation of intracellular calcium, cell cycle, and apoptosis. CD20 is not shed, modulated, or in ternalized significantly upon antibody binding, thus making it an ideal target for passive immunotherapy. 5 Over the past two decades, significant progress has been made in the development of new therapies for B-cell lym-phoma. Perhaps the most important advance is the addition of rituximab (Rituxan, Genentech/Biogen Idec), which the FDA approved for use in the U.S. in 1997. Rituximab is a chimeric (mouse and human) monoclonal antibody directed against the B-cell antigen CD20. It depletes B cells by several mechanisms , including direct antibody-dependent cellular cytotoxi-city (ADCC), complement-mediated cell death, and signaling apoptosis. 6–11 Phase 1 trials of two doses of rituximab (500 mg/m 2 and 375 mg/m 2 for four weeks) showed clinical responses with no dose-limiting toxicity. 12 The weekly 375-mg/m 2 dose, given for four weeks, was selected for further phase 2 evaluation and is currently the standard single-agent dose and schedule. Since this first reported activity, the role of rituximab has expanded to include both indolent and aggressive lymphomas. This article addresses the effect of rituximab on survival and long-term outcomes in patients with NHL. TREATMENT Indolent, Low-Grade Lymphomas Unlike aggressive lymphomas, indolent B-cell lymphomas are not considered curable with conventional therapies. Many patients are observed for prolonged periods without requiring treatment. 13 In one study, more than 50% of the patients remained untreated for a median period of almost six years after diagnosis. 14 Treatment goals focus on maintaining good quality of life with minimal symptoms. The indications for treatment include the presence of B symptoms (fevers, night sweats, and weight loss), compromise of normal organ func-ABSTRACT Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy in adults, with B-cell lymphomas accounting for 85% of all NHLs. The most substantial advancement in the treatment of B-cell malignancies, since the advent of combination chemotherapy, has been the addition of the monoclonal anti-CD20 antibody rituximab (Rituxan). Since its initially reported single-agent activity in indolent lymphomas in 1997, the role of rituximab has expanded to cover both indolent and aggressive lymphomas. This article focuses on the impact of rituximab on the treatment , survival, and long-term outcomes of patients with indolent and aggressive lymphomas over the past two decades.
British Journal of Haematology, 2002
Re-treatment with rituximab for B-cell non-Hodgkin's lymphoma (NHL) relapsing after previous rituximab therapy has recently been shown to be clinically efficacious. Although the mechanism of resistance to rituximab re-treatment in non-responding patients is unknown, it is possible that loss of CD20 expression in the relapsed NHL could be important in some patients. We examined the incidence and nature of CD20 negative relapses following rituximab therapy in aggressive B-cell NHL treated at our institution. Of a total of 18 patients who received rituximab, 13 have relapsed, with 10 patients subsequently undergoing repeat tissue biopsy. Six of these 10 patients (60%) were shown to have lost CD20 expression by either immunohistochemistry and/or flow cytometry. Furthermore, three of the six patients who relapsed with CD20-negative NHL also suffered relapses at unusual anatomical sites. We conclude that loss of CD20 expression in aggressive B-cell NHL relapsing post-rituximab therapy is common. As such, repeat tissue biopsy should be undertaken to document CD20 expression by both flow cytometry and immunohistochemistry prior to considering repeated courses of rituximab in relapsed aggressive lymphomas.
Clinical Cancer Research, 2006
The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)-bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m(2) (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcgammaR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.