ABSTRACT
PURPOSE: The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies. PATIENTS AND METHODS: This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses. RESULTS: From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient. CONCLUSION: The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.
ABSTRACT
Several factors predict outcome for patients with non-Hodgkin's lymphoma (NHL) after chemotherapy. However, predictors of response to rituximab have not been identified. Baseline characteristics for 166 NHL patients (130 follicular) in a phase III trial of rituximab were analysed by univariate and multivariate methods to determine whether any of 27 factors predict response and/or response duration. In a univariate analysis, response to rituximab was associated with follicular histology, no prior fludarabine therapy, prior autologous bone marrow transplantation (ABMT), lack of bone marrow involvement or extranodal disease, positive bcl-2 in blood, and fewer relapses. By univariate analysis, longer median time to progression (TTP) and/or duration of response (DR) after rituximab therapy was associated with International Prognostic Index lower-risk group, multiagent chemotherapy, and low/normal serum lactate dehydrogenase (LDH) or beta2 microglobulin. In the multivariate analysis, response to rituximab correlated with follicular histology, prior ABMT, multiagent chemotherapy, and no bone marrow involvement; longer TTP and/or DR correlated with low/normal serum LDH or beta2 microglobulin, high CD3+ cells, and response to last chemotherapy. The follicular lymphoma international prognostic index (FLIPI) did not correlate consistently with response to rituximab or response duration. Several factors associated with prognosis following chemotherapy did not correlate with response to rituximab or response duration. NHL patients can respond to rituximab despite having factors associated with a poor outcome to chemotherapy.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/metabolism , Lymphoma, B-Cell/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Antibodies, Monoclonal, Murine-Derived , Disease Progression , Disease-Free Survival , Female , Humans , Lymphoma, B-Cell/metabolism , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/metabolism , Lymphoma, Non-Hodgkin/metabolism , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Prospective Studies , Rituximab , Survival Rate , Treatment OutcomeABSTRACT
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 microg/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.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Granulocyte Colony-Stimulating Factor/administration & dosage , Lymphoma, B-Cell/drug therapy , Adult , Aged , Antibodies, Monoclonal/toxicity , Antibodies, Monoclonal, Murine-Derived , Dose-Response Relationship, Drug , Granulocyte Colony-Stimulating Factor/toxicity , Humans , Lactoferrin/blood , Leukocyte Elastase/blood , Middle Aged , Neutrophil Activation/drug effects , Recurrence , Remission Induction , RituximabABSTRACT
Rituximab, a chimeric CD20 monoclonal antibody (mAb), is widely used in the treatment of patients with low-grade non-Hodgkin's lymphoma. Possible anti-tumour mechanisms involve complement-mediated lysis and/or antibody-dependent cellular cytotoxicity (ADCC). Because G-CSF greatly enhances the cytotoxicity of neutrophils (PMN) in ADCC, the clinical efficacy of rituximab might be enhanced by the addition of G-CSF. Therefore, we investigated the neutrophil-mediated CD20-dependent cellular cytotoxicity in B cell lines. In contrast to previous studies by others, we found that G-CSF-primed PMN are capable of functioning as effector cells in CD20-dependent cellular cytotoxicity. However, HLA class II mAbs were far more effective. The differences between HLA class II- and CD20-mediated PMN-ADCC were not due to: (1) the use of chimeric (hIgG1) mAbs vs mIgG2a mAbs; (2) HLA class II-induced apoptosis as an 'ADCC-sensitising' mechanism; (3) CD20-induced inhibition of ADCC; (4) inferior membrane mobility of CD20. Analysis of Fcgammareceptor (FcgammaR) involvement showed that although CD20-induced ADCC was mediated mainly via FcgammaRI, for optimal lysis FcgammaRI and FcgammaRII were both required. In contrast, in HLA class II-dependent ADCC both FcgammaRI and II were capable of independently inducing maximum lysis. The mechanism underlying these differences in FcgammaR-binding and activation remains to be elucidated.
Subject(s)
Antibody-Dependent Cell Cytotoxicity/immunology , Antigens, CD20/immunology , Granulocyte Colony-Stimulating Factor/pharmacology , Neutrophils/immunology , Antibodies, Bispecific/immunology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Murine-Derived , Apoptosis/drug effects , B-Lymphocytes/immunology , Histocompatibility Antigens Class II/immunology , Humans , Immunoglobulin Fc Fragments/immunology , Monocytes/immunology , Neutrophil Activation/drug effects , Rituximab , Tumor Cells, Cultured/cytology , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/immunologyABSTRACT
PURPOSE: Rituximab has been reported to have little activity in small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) and to be associated with significant infusion-related toxicity. This study sought to decrease the initial toxicity and optimize the pharmacokinetics with an alternative treatment schedule. PATIENTS AND METHODS: Thirty three patients with SLL/CLL received dose 1 of rituximab (100 mg) over 4 hours. In cohort I (n = 3; 250 mg/m(2)) and cohort II (n = 7; 375 mg/m(2)) rituximab was administered on day 3 and thereafter three times weekly for 4 weeks using a standard administration schedule. Cohort III (n = 23; 375 mg/m(2)) administered rituximab similar to cohort II for the first two treatments and then over 1 hour thereafter. RESULTS: A total of 33 CLL/SLL patients were enrolled; only one patient discontinued therapy because of infusion-related toxicity. Thirteen patients developed transient hypoxemia, hypotension, or dyspnea that were associated with significant changes in baseline interleukin-6, interleukin-8, tumor necrosis factor alpha, and interferon gamma compared with those not experiencing such reactions. Infusion-related toxicity occurred more commonly in older (median age 73 v 62 years; P =.02) patients with no other pretreatment clinical or laboratory features predicting occurrence of these events. The overall response rate was 45% (3% CR, 42% PR; 95% CI 28% to 64%). Median response duration for these 15 patients was 10 months (95% CI, 6.8-13.2; range, 3 to 17+). CONCLUSION: Rituximab administered thrice weekly for 4 weeks demonstrates clinical efficacy and acceptable toxicity. Initial infusion-related events seem to be cytokine mediated and resolve by the third infusion making rapid administration possible. Future combination studies of rituximab with other therapies in CLL seem warranted.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Cytokines/pharmacology , Dose-Response Relationship, Drug , Drug Administration Schedule , Dyspnea/chemically induced , Female , Humans , Hypotension/chemically induced , Hypoxia/chemically induced , Infusions, Intravenous , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Rituximab , Treatment OutcomeABSTRACT
PURPOSE: Patients who were PCR-positive for B-cell leukemia-lymphoma 2 (bcl-2) gene rearrangement [t(14;18)] were evaluated for responses to rituximab alone or combined with CHOP. PATIENTS AND METHODS: Patients had relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (IWF: A-D). The single-agent trial used 375 mg/m2 weekly x 4; combination therapy included six cycles of CHOP and six 375 mg/m2 infusions of rituximab. Bcl-2 analyses of bone marrow (BM) and peripheral blood (PB) samples at base-line and following therapy were performed using a PCR assay. RESULTS: In the single-agent trial, of 70 patients whose peripheral blood (PB) was bcl-2 positive at baseline, 36 became bcl-2-negative, 13 remained positive, and 21 varied between positive and negative. The overall response rates (ORRs) were 72%, 31%, and 57%, respectively. Twelve of twenty-two patients with repeat bone marrow (BM) samples were bcl-2-negative three months post-treatment. Of 18 patients in the combination trial, 8 were bcl-2 positive in PB and/or BM. All of seven patients positive in PB at baseline and six of seven patients positive in BM were negative at the end of therapy; all patients responded to treatment (100% ORR). CONCLUSIONS: Rituximab, alone or combined with CHOP, eradicated bcl-2 positive cells from PB and BM in over half of the patients treated and was associated with a high overall clinical response rate. The impact on disease-free and overall survival awaits long-term follow up.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 18/genetics , Genes, bcl-2/genetics , Hodgkin Disease/drug therapy , Hodgkin Disease/genetics , Neoplastic Cells, Circulating , Translocation, Genetic/genetics , Adult , Aged , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bone Marrow Cells , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Prednisone/administration & dosage , Rituximab , Vincristine/administration & dosageABSTRACT
Despite testing since the mid-1900s, only in the past three years have some monoclonal antibodies provided sufficient efficacy and safety data to support regulatory approval as cancer therapy. Adjuvant-edrecolomab monoclonal antibody was approved in Germany after demonstration of a statistically significant 32% improvement over observation alone in the seven-year mortality rate for patients with colorectal cancer. Similarly, trastuzumab monoclonal antibody combined with chemotherapy prolonged the median time to the progression of breast cancer compared to chemotherapy alone. Unconjugated monoclonal antibodies investigated for the treatment of hematologic malignancies include anti-idiotype, CAMPATH-1, and rituximab. Rituximab was the first such therapy approved in the United States for relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma after demonstration of an overall response rate of 48% and a duration of response of 11.7 months. The radioisotope-conjugated monoclonal antibodies tested as therapy include anti-B1, LYM-1, LL2, anti-CD33, and ibritumomab tiuxetan. Clearly, the full potential of immunotherapy still lies ahead.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Immunotherapy/methods , Neoplasms/therapy , Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal, Murine-Derived , Combined Modality Therapy , Disease Progression , Humans , Neoplasms/immunology , Rituximab , Trastuzumab , Treatment OutcomeABSTRACT
Monoclonal antibodies (MAbs) have been used as therapeutic agents for many years. In 1997, Rituxan (IDEC-C2B8, rituximab, MabThera) became the first MAb to be approved by the FDA for a cancer indication. Rituxan served to heighten interest in the therapeutic applications of MAbs. Herceptin (for patients with breast cancer) and Mylotarg (for patients with acute myeloid leukemia) were approved shortly thereafter. Literally dozens of antibodies are currently under investigation for a variety of malignant and non-neoplastic indications. Rituxan is effective in patients with low-grade or follicular, relapsed or refractory non-Hodgkin's lymphoma (NHL). The response rate and time to progression (responders) are in the 50% and 13 months range, respectively. It is also active in intermediate-grade NHL where a large randomized study, in combination with CHOP chemotherapy, has shown a statistically significant increase in complete response (CR) rate (75% vs. 60%), prolongation of 1 year event-free survival (69% vs. 49%) and of overall survival (83% vs. 68%) as compared to CHOP alone. This marks the first time that any agent has shown results superior to CHOP, the curative gold standard for this type of NHL. Other promising antibodies under clinical investigation include: Hu1D10; Anti CD19, 22, 52, and anti-Id antibodies. The safety profile, clinical activity, and mechanism of action of these MAbs make them ideal candidates for combination with chemotherapy or biologicals. Over the next few years, we will see very significant therapeutic advances emerge as this important research yields additional clinical results.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Lymphoma, Non-Hodgkin/therapy , Antigens, Neoplasm/immunology , Clinical Trials as Topic , Humans , Lymphoma, Non-Hodgkin/immunology , MaleABSTRACT
Treatment with rituximab, a chimaeric anti-CD20 monoclonal antibody, can be associated with moderate to severe first-dose side-effects, notably in patients with high numbers of circulating tumour cells. The aim of this study was to elucidate the mechanism of these side-effects. At multiple early time points during the first infusion of rituximab, complement activation products (C3b/c and C4b/c) and cytokines [tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and IL-8] were measured in five relapsed low-grade non-Hodgkin's lymphoma (NHL) patients. Infusion of rituximab induced rapid complement activation, preceding the release of TNF-alpha, IL-6 and IL-8. Although the study group was small, the level of complement activation appeared to be correlated both with the number of circulating B cells prior to the infusion (r = 0.85; P = 0.07) and with the severity of the side-effects. We conclude that complement plays a pivotal role in the pathogenesis of side-effects of rituximab treatment. As complement activation can not be prevented by corticosteroids, it might be relevant to study the possible role of complement inhibitors during the first administration of rituximab.
Subject(s)
Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Complement Activation , Cytokines/blood , Lymphoma, Non-Hodgkin/immunology , Adult , Aged , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Agents/therapeutic use , Complement C3b/analysis , Complement C3c/analysis , Complement C4/analysis , Complement C4b/analysis , Female , Humans , Interleukin-6/blood , Interleukin-8/blood , Lymphocyte Count , Lymphoma, Non-Hodgkin/drug therapy , Male , Middle Aged , Peptide Fragments , Rituximab , Stimulation, Chemical , Tumor Necrosis Factor-alpha/analysisABSTRACT
Dosimetry studies in patients with non-Hodgkin's lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of 90Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received (111)In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of 90Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of (111)In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n=56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2-7.8 Gy), 2.6 Gy to lungs (range 0.72-4.4 Gy), and 0.38 Gy to kidneys (range 0.07-0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8-67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T(1/2), blood AUC, plasma T(1/2), and plasma AUC. It is concluded that 90Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T(1/2), reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Lymphoma, B-Cell/radiotherapy , Radioimmunotherapy , Yttrium Radioisotopes/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , Bone Marrow/radiation effects , Humans , Lymphoma, Follicular/radiotherapy , Lymphoma, Non-Hodgkin/radiotherapy , Radiometry , RituximabABSTRACT
PURPOSE: This phase II trial investigated the safety and efficacy of re-treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with low-grade or follicular non-Hodgkin's lymphoma who relapsed after a response to rituximab therapy. PATIENTS AND METHODS: Fifty-eight patients were enrolled onto this study, and two were re-treated within the study. Patients received an intravenous infusion of 375 mg/m(2) of rituximab weekly for 4 weeks. All patients had at least two prior therapies and had received at least one prior course of rituximab, with a median interval of 14.5 months between rituximab courses. RESULTS: Most adverse experiences (AEs) were transient grade 1 or 2 events occurring during the treatment period. Clinically significant myelosuppression was not observed; hematologic toxicity was generally mild and reversible. No patient developed human antichimeric antibodies after treatment. The type, frequency, and severity of AEs in this study were not apparently different from those reported in the phase III trial of rituximab. The overall response rate in 57 assessable patients was 40% (11% complete response and 30% partial responses). Median time to progression (TTP) in responders and median duration of response (DR) have not been reached, but Kaplan-Meier estimated medians are 17.8 months (range, 5.4+ to 26.6 months) and 16.3 months (range, 3.7+ to 25.1 months), respectively. These estimated medians are longer than the medians achieved in the patients' prior course of rituximab (TTP and DR of 12.4 and 9.8 months, respectively, P: >.1) and in a previously reported phase III trial (TTP in responders and DR of 13.2 and 11.6 months, respectively). Responses are ongoing in seven of 23 responders. CONCLUSION: In this re-treatment population, safety and efficacy were not apparently different from those after initial rituximab exposure.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antigens, CD20/immunology , Antineoplastic Agents/therapeutic use , Lymphoma, B-Cell/drug therapy , Lymphoma, Follicular/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/blood , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Leukopenia/chemically induced , Lymphoma, B-Cell/blood , Lymphoma, Follicular/blood , Lymphoma, Non-Hodgkin/blood , Male , Middle Aged , Neoplasm Recurrence, Local/blood , Neutropenia/chemically induced , RituximabABSTRACT
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.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Interferon-alpha/therapeutic use , Lymphoma, B-Cell/drug therapy , Lymphoma, Follicular/drug therapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease Progression , Disease-Free Survival , Female , Humans , Immunotherapy/adverse effects , Infusions, Intravenous , Interferon alpha-2 , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Lymphoma, B-Cell/pathology , Lymphoma, Follicular/pathology , Male , Middle Aged , Neoplasm Staging , Recombinant Proteins , Rituximab , Time FactorsABSTRACT
BACKGROUND: Oncologic literature cites many different definitions of critical response measurements. PATIENTS AND METHODS: Response criteria (RC) for non-Hodgkin's lymphoma (NHL) were developed by lymphoma experts, endorsed by international lymphoma clinicians, and applied to a 166-patient rituximab (Rituxan, MabThera) trial by a third-party, blinded panel of NHL experts (LEXCOR). Retrospectively, we analyzed this data using variations of the original RC and comparing with recently published RC. RESULTS: The definition of a 'normal' lymph node affected the complete response (CR) rate (< or = 1.0 x 1.0 cm, 6%; < or = 1.5 x 1.5 cm, 18%; < or = 2.0 x 2.0 cm, 28%); overall response rate (ORR) was not affected. CR rates increased progressively without > or = 28 days response confirmation: 12% vs. 6% (< or = 1.0 x 1.0 cm), 26% vs. 18% (< or = 1.5 x 1.5 cm), and 36% vs. 28% (< or = 2.0 x 2.0 cm). CR rate and duration of response (DR) were unaffected when only the six largest, rather than all lesions, were measured. When the new RC were applied, CR rate (32%) was higher and DR (13.9 months) and time to progression (15.6 months) were shorter in complete responders. CONCLUSIONS: Standard RC must be consistently and rigorously applied for accurate comparisons between studies.
Subject(s)
Lymph Nodes/pathology , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/pathology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Agents/therapeutic use , Disease Progression , Humans , Lymphoma, Non-Hodgkin/classification , Reference Values , Retrospective Studies , Rituximab , Treatment OutcomeSubject(s)
Antibodies, Monoclonal/therapeutic use , Antigens, CD20/immunology , Antineoplastic Agents/therapeutic use , Lymphoma, B-Cell/therapy , Antibodies, Monoclonal, Murine-Derived , Antigens, CD20/genetics , B-Lymphocytes/immunology , Gene Expression Regulation/immunology , Humans , Lymphocyte Depletion , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/immunology , RituximabABSTRACT
The scientific development of immunotherapies and radioimmunotherapies of cancer began more than four decades ago. Over time, it has become apparent that the choice of target antigen, immunogenicity of antibodies, length of antibody half-life, ability of antibodies to recruit immune effector functions, decision on conjugation of antibodies to toxins or radionuclides and antibody manufacturing are critical components of successful development of an immunotherapeutic regimen. Anti-idiotype antibodies were some of the first successful monoclonal antibody treatments developed for non-Hodgkin's lymphoma. In 1997, the chimeric antibody, Rituximab, was approved by the United States Food and Drug Administration for treatment of patients with relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. In an effort to enhance the efficacy of immunotherapy, toxins and radionuclides have been conjugated to monoclonal antibodies. Ibritumomab, the parent murine antibody of Rituximab, is conjugated to the radioisotope 90Y to create 90Y Ibritumomab tiuxetan, (90Y Zevalin, IDEC-Y2B8). Promising Phase I/II trials have been completed. Phase III experimental trials of 9Y Ibritumomab tiuxetan as treatment for relapsed or refractory NHL are in progress.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neoplasm/therapeutic use , Immunotherapy/methods , Lymphoma, Non-Hodgkin/therapy , Animals , HumansABSTRACT
Rituximab, a genetically engineered monoclonal chimeric antibody, targets the CD20 antigen expressed on B cells. It was approved by the US Food and Drug Administration on November 26, 1997, for the indication of relapsed or refractory, CD20-positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma (LG/F NHL), and by the European Agency for the Evaluation of Medicinal Products on June 2, 1998, for therapy of patients with Stage III/IV, follicular, chemoresistant or relapsed NHL. Eight Phase II or II clinical trials in LG/F NHL patients have been completed: five single-agent studies and three combination studies. Rituximab has a favorable safety profile: most adverse events (AEs) are Grade 1 or 2, and the frequency of AEs decrease with subsequent infusions. AEs in the combination studies are consistent with those seen with individual agents. For evaluable patients in the single-agent studies, overall response rates (ORR) ranged from 40% to 60%, median duration of response (DR) ranged from 5.9 to 15.0+ months, and median time to progression (TTP) ranged from 8.1 to 19.4+ months. For evaluable patients in the combination studies, the ORR ranged from 45% to 100%, median DR ranged from 11.7+ to 39.1+ months, and median TTP ranged from 12.9+ to 40.5+ months. Studies in intermediate- and high-grade NHL are ongoing. Long-term development plans include evaluating the safety and efficacy of rituximab in various types of lymphoma and in combination with other lymphoma regimens. Future studies may explore ways to increase rituximab efficacy by upregulating CD20 or increasing effector function with different cytokines.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Lymphoma/therapy , Animals , Antibodies, Monoclonal, Murine-Derived , Humans , RituximabABSTRACT
Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a unique monoclonal antibody for the treatment of non-Hodgkin's lymphoma. This chimeric mouse/human antibody was discovered in 1991 at IDEC Pharmaceuticals' laboratories, where the antibody was genetically engineered and produced utilizing high-yield expression systems. It is a human IgG1 kappa antibody with mouse variable regions isolated from a murine anti-CD20 antibody, IDEC-2B8, that binds with high affinity to cells expressing the CD20 antigen found on the surface of malignant and normal B cells, but not on other normal tissues. It mediates complement-dependent cell lysis in the presence of human complement, and antibody-dependent cellular cytotoxicity with human effector cells. Also, it has been shown to induce apoptosis and to sensitize chemoresistant human lymphoma cell lines in vitro. Clinical development was expedited (3 years) with the first patient entered in phase I trials in March 1993 and the last patient entered in the phase III study in March 1996. IDEC Pharmaceuticals began a collaboration with Genentech, Inc in March 1995 and with F. Hoffman-LaRoche (Nutley, NJ) shortly thereafter. Marketing approval was granted by the US Food and Drug Administration on November 26, 1997 (and by the European Union on June 2, 1998) for the indication of relapsed or refractory, CD20-positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma. Rituximab is the first therapeutic monoclonal antibody approved for the treatment of cancer and the first single agent approved specifically for therapy for a lymphoma. Substantial research has been performed over the past 8 years to further the understanding of this novel therapeutic. Nevertheless, much remains to be accomplished in key areas such as mechanism of action and resistance, combinations with chemotherapy, biologics and radiotherapy/radioimmunotherapy, role within multimodality regimens, and nonmalignant applications. Research conducted in the coming years should be targeted toward resolving these important issues.
Subject(s)
Antibodies, Monoclonal/history , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/history , Antineoplastic Agents/therapeutic use , Lymphoma, Non-Hodgkin/history , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Murine-Derived , Antigens, CD20/immunology , Antigens, CD20/physiology , Antineoplastic Agents/immunology , Apoptosis/drug effects , Clinical Trials as Topic/history , Combined Modality Therapy , History, 20th Century , Humans , Lymphoma, Non-Hodgkin/therapy , RituximabABSTRACT
We conducted a prospective pilot phase I/II clinical trial to evaluate the toxicity and response rate of the chimeric anti-CD20 monoclonal antibody, rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceutical Corporation, San Diego, CA), in the treatment of patients with immune thrombocytopenic purpura. Patients with a clinical diagnosis of idiopathic thrombocytopenic purpura who had failed corticosteroid therapy and whose platelet count was less than 75,000/microL were eligible for the study. Rituximab was administered in a dose-escalation fashion using doses ranging from 50 to 375 mg/m2 weekly for 4 weeks. Thirteen patients have been enrolled on the trial to date and 12 have completed the full course of treatment. No unusual toxicity was noted in this patient population. None of the three patients at the lowest dose level achieved a clinical response. Three of nine patients (30%) who have received rituximab at doses close or equal to the full dose have shown an objective clinical response (two complete responses, one partial response). The study is currently ongoing, and conclusions regarding the overall response rate, clinical parameters that influence response, surrogate markers of response, and the underlying mechanism of response remain to be addressed. The current study should provide answers to a number of important questions regarding the role of rituximab in the treatment of this and other autoimmune disorders.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Clinical Protocols , Combined Modality Therapy , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Pilot Projects , Purpura, Thrombocytopenic, Idiopathic/surgery , Rituximab , SplenectomyABSTRACT
Rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA) is a genetically engineered monoclonal antibody for the treatment of non-Hodgkin's lymphoma. This chimeric mouse/human, immunoglobulin GI kappa anti-CD20 antibody mediates complement-dependent cell lysis and antibody-dependent cellular cytotoxicity. It also has been shown to sensitize chemoresistant human lymphoma cell lines and to induce apoptosis. It was approved by the Food and Drug Administration on November 26, 1997, for the indication of relapsed or refractory, CD-20 positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma Rituximab is the first monoclonal antibody approved for the treatment of cancer and the first single agent approved specifically for therapy of a lymphoma. The recommended dose is rituximab 375 mg/m2 intravenously weekly x4 infusions. Treatment is well tolerated and outpatient therapy is feasible. Adverse events are mostly grades I and 2, occurring primarily with the first infusion. In a phase II single-agent clinical trial, the overall response rate was 50%, with a median time to progression in responders of 10.2 months. In a larger multicenter trial involving 166 patients, the overall response rate was 48% with 6% complete and 42% partial responses. Median time to progression for responders was 13.2 months and median duration of response was 11.6 months. A 40% response rate has been observed on re-treatment with rituximab. Activity also has been seen in patients with bulky disease. Combination studies have been performed with interferon, cyclophosphamide/doxorubicin/vincristine/prednisone, and radioimmunotherapy. Rituximab, the first monoclonal antibody approved for the treatment of cancer, is safe and effective in treating patients with relapsed or refractory, CD-20 positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma.