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1.
J Clin Oncol ; 41(2): 154-162, 2023 01 10.
Article in English | MEDLINE | ID: mdl-36603541

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.

2.
Leuk Lymphoma ; 47(9): 1830-40, 2006 Sep.
Article in English | MEDLINE | ID: mdl-17064996

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 Outcome
3.
Leuk Lymphoma ; 46(11): 1569-73, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16236611

ABSTRACT

The present study aimed to determine the long-term safety and efficacy of chimeric anti-CD 20 antibody rituxan (rituximab, Biogen IDEC, San Diego, CA, USA; Genentech, South San Francisco, CA, USA) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in previously untreated patients with aggressive non-Hodgkin's lymphoma (NHL). Thirty-three patients with previously untreated aggressive B-cell NHL received six infusions of rituximab (375 mg/m(2) per dose) on day 1 of each cycle of CHOP chemotherapy, given on day 3 of each cycle of therapy. Currently, the patients now have a median follow-up of 63 months (range 34 - 82 months). The overall response (OR) rate was 94% and the complete response (CR) rate was 61% at the end of therapy. Of the 33 patients, 2 patients experienced disease progression and subsequently died of their disease, 2 patients experienced disease progression but were alive at last follow-up following additional therapy, and 2 patients died without experiencing disease progression: one due to a cerebral vascular accident at 9 months after therapy and a second patient due to small cell lung carcinoma at 55 months. The 5-year survival rate was 88% (95% confidence interval (CI) 72 - 97) and the 5-year progression-free survival was 82% (95% CI 64 - 93). There were no long-term adverse events noted directly related to the rituximab. The long-term follow-up of patients in this phase II trial of rituximab with CHOP chemotherapy for previously untreated aggressive NHL demonstrates a high response rate, which remains very durable with high 5-year overall and progression-free survivals.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cause of Death , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/mortality , Lymphoma, Non-Hodgkin/mortality , Male , Middle Aged , Prednisone/administration & dosage , Remission Induction , Rituximab , Survival Analysis , Vincristine/administration & dosage
4.
J Clin Oncol ; 23(4): 694-704, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15681517

ABSTRACT

PURPOSE: To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS: An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION: Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Follicular/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Vidarabine/analogs & derivatives , Vidarabine/administration & dosage , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Female , Flow Cytometry , Genes, bcl-2 , Humans , Lymphoma, Follicular/immunology , Lymphoma, Follicular/mortality , Lymphoma, Non-Hodgkin/immunology , Lymphoma, Non-Hodgkin/mortality , Male , Middle Aged , Rituximab , T-Lymphocyte Subsets/immunology , Vidarabine/adverse effects
5.
Leukemia ; 17(8): 1658-64, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12886256

ABSTRACT

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 , Rituximab
6.
Leukemia ; 16(4): 693-9, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11960351

ABSTRACT

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/immunology
7.
Leuk Lymphoma ; 42(4): 731-8, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11697503

ABSTRACT

Rituximab (IDEC-C2B8, Mabthera, Rituxan), a chimeric monoclonal antibody against the B-cell specific CD20-antigen, has been demonstrated to be effective in the treatment of non-Hodgkin's B-cell lymphoma (B-NHL). Previous in vitro studies have shown that direct complement-dependent cytotoxicity (CDC), ADCC and apoptosis are important in the rituximab-induced killing of lymphoma cells. It is, however, unknown whether rituximab penetrates the blood-brain barrier. Therefore, we studied rituximab levels and complement (C) activation in blood and cerebrospinal fluid (CSF) following intravenous rituximab therapy in a patient with relapsing non-Hodgkin's lymphoma with central nervous system (CNS) involvement. Longitudinal samples from blood and CSF were taken at 13 time-points during the treatment period. The results show that the C cascade becomes activated in blood during the first mAb infusion (C3a-desArg concentration rose from 55 to 138 microg/ml during the first 2 hours). After the first infusion the proportions of lymphocytes positive for the CD19- and CD20-antigens in the peripheral blood were reduced from 41% and 35%, respectively, to a level of 2% (for both). In CSF the rituximab concentration increased after successive infusions, but remained below 0.55 microg/ml (compared to a Cmax of 400 microg/ml in peripheral blood). Although a minor and delayed C activation response was seen in the CSF the treatment did not clear CD20-positive cells away from the CNS. Thus, it appears that an intact blood-brain barrier restricts the entry of rituximab into the CNS. Possible options to circumvent this would be dose escalation or intrathecal rituximab treatment.


Subject(s)
Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/therapeutic use , Complement Activation/drug effects , Complement C3a/analogs & derivatives , Lymphoma, B-Cell/drug therapy , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , Blood Circulation/immunology , Blood-Brain Barrier , Central Nervous System/immunology , Cerebrospinal Fluid/chemistry , Cerebrospinal Fluid/cytology , Cerebrospinal Fluid/drug effects , Complement C3a/cerebrospinal fluid , Complement C3a/drug effects , Complement C3a/metabolism , Humans , Lymphoma, B-Cell/cerebrospinal fluid , Lymphoma, B-Cell/pathology , Male , Middle Aged , Rituximab
8.
J Clin Oncol ; 19(8): 2153-64, 2001 Apr 15.
Article in English | MEDLINE | ID: mdl-11304767

ABSTRACT

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 Outcome
9.
Ann Oncol ; 12(1): 109-14, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11249036

ABSTRACT

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 & dosage
10.
Annu Rev Med ; 52: 125-45, 2001.
Article in English | MEDLINE | ID: mdl-11160771

ABSTRACT

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 Outcome
11.
J Clin Oncol ; 19(2): 389-97, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11208830

ABSTRACT

PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan (375 mg/m2 per dose) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle. RESULTS: The ORR by investigator assessment confirmed by the sponsor was 94% (31 of 33 patients). Twenty patients experienced a complete response (CR) (61%), 11 patients had a partial response (PR) (33%), and two patients were classified as having progressive disease. In the 18 patients with an International Prognostic Index (IPI) score > or = 2, the combination of Rituxan plus CHOP achieved an ORR of 89% and CR of 56%. The median duration of response and time to progression had not been reached after a median observation time of 26 months. Twenty-nine of 31 responding patients remained in remission during this follow-up period, including 15 of 16 patients with an IPI score > or = 2. The most frequent adverse events attributed to Rituxan were fever and chills, primarily during the first infusion. Rituxan did not seem to compromise the ability of patients to tolerate CHOP; all patients completed the entire six courses of the combination. The bcl-2 translocation of blood or bone marrow was positive at baseline in 13 patients; 11 patients had follow-up specimens obtained (eight CR, three PR), and all had a negative bcl-2 status after therapy. Only one patient has reconverted to bcl-2 positivity, and all patients remain in clinical remission. CONCLUSION: This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with standard-dose CHOP in the treatment of aggressive B-cell lymphoma. The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity. The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen. The ability to achieve sustained remissions in patients with an IPI score > or = 2 warrants further investigation with a randomized study.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Drug Administration Schedule , Female , Genes, bcl-2 , Humans , Lymphoma, Non-Hodgkin/genetics , Male , Middle Aged , Polymerase Chain Reaction , Prednisone/administration & dosage , Remission Induction , Rituximab , Survival Analysis , Vincristine/administration & dosage
13.
Curr Pharm Biotechnol ; 2(4): 279-91, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11762410

ABSTRACT

The non-Hodgkin's lymphomas are a diverse groups of lymphoid neoplasms that collectively rank fifth in cancer incidence and mortality. Conventional treatment for patients with newly-diagnosed non-Hodgkin's lymphoma (NHL) includes radiation or chemotherapy. In addition, those with asymptomatic low-grade disease may follow a "watch and wait" approach. Single agent oral alkylating therapy and CVP (cyclophosphamide, vincristine, and prednisone) have become a mainstay of treatment for low-grade NHL. High intensity chemotherapy consisting of the anthracycline, doxorubicin along with cyclophosphamide, vincristine and prednisone (CHOP) is offered as standard treatment for intermediate-grade NHL. Following relapse, salvage therapy rarely results in long-term survival in patients with low-grade NHL. Up to 50% of patients die within five years of first relapse. For patients with intermediate-grade NHL who relapse after or do not respond to first-line treatment, a range of combination regimens can be offered, composed of non-cross resistant drugs not typically used during first-line treatment. However, less than half of patients with intermediate-grade disease achieve prolonged disease-free survival. With today's' conventional treatments, cure is only a possibility for a minority of patients with intermediate-grade disease and a limited group of patients with indolent NHL who are diagnosed at early stages. Novel approaches to treatment are therefore needed. Monoclonal antibodies may fulfill this need, administered either as single agents or in conjunction with conventional cytotoxic approaches. The task now lies in determining how best to use this new modality, with the hope of bringing a cure to a greater number of patients.


Subject(s)
Lymphoma, Non-Hodgkin/therapy , Animals , Antineoplastic Agents/therapeutic use , Bone Marrow Transplantation , Combined Modality Therapy , Humans , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/pathology , Lymphoma, Non-Hodgkin/radiotherapy , Prognosis , Survival Analysis
14.
Curr Pharm Biotechnol ; 2(4): 301-11, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11762412

ABSTRACT

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 , Male
15.
Br J Haematol ; 115(4): 807-11, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11843813

ABSTRACT

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/analysis
16.
J Clin Oncol ; 18(17): 3135-43, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10963642

ABSTRACT

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 , Rituximab
17.
Eur J Nucl Med ; 27(7): 766-77, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10952488

ABSTRACT

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 , Rituximab
18.
Clin Cancer Res ; 6(7): 2644-52, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10914705

ABSTRACT

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 Factors
19.
Ann Oncol ; 11(4): 399-408, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10847457

ABSTRACT

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 Outcome
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