Review Articles on Rituxan
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Overview of Studies: Rituximab maintenance therapy: a step forward in follicular lymphoma http://bit.ly/9pncbR
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Basis for initial marketing approval:
Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.
J Clin Oncol. 1998 Aug;16(8):2825-33. PMID: 9704735
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.
... 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.
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Basis for marketing approval:
Rituximab therapy for indolent non-Hodgkin's lymphoma.
Anticancer Drugs. 2002 Nov;13 Suppl 2:S11-7. Review. PMID: 12710586
In the pivotal study for rituximab, patients with relapsed or refractory indolent or follicular lymphoma (FL) had an overall response rate of 50%.
There is evidence that first-line rituximab therapy may be associated with better response rates; in previously untreated FL with a low tumor burden, rituximab monotherapy has produced an overall response rate of 73%.
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Rituxan and Beyond Medscape (free login req.)
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Rituximab: ongoing and future clinical development.
Semin Oncol. 2002 Feb;29(1 Suppl 2):105-12. Review. PMID: 11842397 | Related Articles
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Rituximab therapy for follicular lymphoma: a comprehensive review of it's efficacy as primary treatment, treatment for relapsed disease, re-treatment and maintenance - Yossi Cohen, et al PDF *
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Bone Marrow Purging with Rituxan
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Rituximab with peripheral blood stem cell transplantation in CD20 lymphoproliferative disorders
Patrizio Mazza, et al. - Haematologica.it (2001)
"Bone marrow involvement in follicular center and mantle cell lymphomas and chronic lymphocytic leukemia is difficult to eliminate. Rituximab, an anti-CD20 specific therapy has been demonstrated to be effective in marrow disease. We used rituximab in combination with peripheral blood stem cell (PBSC) transplantation following BEAM therapy in patients with CD20 positive marrow disease either in residual disease or as a purging approach. Our experience emphasizes that the purging modality is more effective than the treatment of residual disease."
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Novel Strategies in Treatment of MCL - Orion M. Howard, M.D. and David Fisher, M.D. Northwestern Connecticut Oncology and Hematology Associates, L. L. P., Torrington, Connecticut 06790 mssm.edu
" Thirty-one patients had morphologic bone marrow involvement and were therefore assessable for morphologic bone marrow response. Twenty-one (68%) achieved a complete morphologic response in the marrow."
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Rituxan & Bone Marrow Purging: Efficiency of in vivo purging with rituximab followed by high-dose therapy (HDT) with autologous peripheral blood stem cell transplantation (PBSCT) in B-cell lymphomas. A single institution study. Year: 2002 Abstract No: 1139
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Combinations that May Enhance Rituxan?
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Complete response rates with Lenalidomide (Revlimid) plus rituximab for untreated indolent B-cell NHL http://bit.ly/dBQerx
"Response rates were impressive in follicular lymphoma, with nearly all patients 16/17 (94%) attaining a CR. At a median follow up of 14.1 (9.7-18.8) months, one patient experienced progression of disease."
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News ASH: Rituxan in combination
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ASCO 2003 - Increased potential cure for people with aggressive blood cancer -
Three-year follow-up data from GELA study shows greatly improved long term survival for aggressive non-Hodgkin's lymphoma patients treated with MabThera eurekalert.org
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Rituxan + Chemotherapy Related PubMed abstracts
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Combination chemotherapy and rituximab. Anticancer Drugs. 2001 Jun;12 Suppl 2:S15-9. Review. PMID: 11508932 PubMed
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Immunochemotherapy in indolent non-Hodgkin's lymphoma.
Semin Oncol. 2002 Apr;29(2 Suppl 6):11-7. Review. PMID: 12040529 PubMed
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Rituxan Combo for Refractory: Bendamustine/mitoxantrone/rituximab (BMR): a new effective treatment for refractory or relapsed indolent lymphomas Year: 2002 Abstract No: 1127
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Rituxan + Pentostatin: Phase II multicenter trial of pentostatin (P) and rituximab (R) in patients (pts) with previously treated and untreated low grade B-cell non-Hodgkin's lymphoma (NHL)
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Combination with Natural Product?
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Orally administered beta-glucans enhance anti-tumor effects of monoclonal antibodies. Cancer Immunol Immunother. 2002 Nov;51(10):557-64. Epub 2002 Sep 20. PMID: 12384807 | Related abstracts
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Beta-glucan, Complement action, and Rituxan clltopics.org
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Caveat? There is a theoretical concern about using non-specific immune stimulants when you have lymphoma - a cancer of lymphocytes (immune cells). See related and specific articles that come to different conclusions about types of immune cells stimulated by beta-glucans. Related articles
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Immunostimulant oxidized beta-glucan conjugates. Int Immunopharmacol.
2001 Mar;1(3):539-50. PMID: 11367537
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Stimulation of humoral and cell mediated immunity by polysaccharide from mushroom Phellinus linteus. Int J Immunopharmacol. 1996 May;18(5):295-303. PMID: 8933208
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Consolidation / Maintenance Rituxan Treatment
Dosing and Treatment Cycle of Rituxan
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ASCO 2009: Prolonged Rituximab Extends Remission in Follicular Lymphoma
medscape.com (free login req.)
Of the 202 patients enrolled in the study, 151 were randomized. The median age of the patients was 57 years, 85% of the cohort had stage III or IV disease, 50% had bone marrow involvement, and two thirds had been previously treated with chemotherapy. All participants received rituximab at the standard dose of 375 mg/m2 weekly for 4 weeks, and were re-evaluated at week 12. Patients who responded to the therapy or who had stable disease were then randomized to either no further treatment, which was standard at that time (observation group; n = 78), or to 4 additional doses of rituximab given at 2-month intervals (extended-rituximab group; n = 73). At a median follow-up of 8.9 years, among surviving patients who had been followed for at least 5 years, the median event-free survival (time to progression, relapse, second tumor, or death) was 13 months in the observation group and 24 months in the extended-rituximab group (P = .0012).
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Optimal Schedule of Antibodies: Rituximab in Lymphoma as an Example ASH 2005
Michele Ghielmini asheducationbook.org
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Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004;. PubMed
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ASH 2002: Prolonged Rituximab Treatment Improves Event-Free Survival and Response Duration in Follicular Lymphoma Docguide.com
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Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1998 Sep;9(9):995-1001. PMID: 9818074 PubMed (Note: Serum levels refers to concentration of the drug in the blood.)
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Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001 Apr 15;19(8):2165-70. PMID: 11304768 PubMed | Related Abstracts
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Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol. 1999 Jun;10(6):655-61. PMID: 10442187 PubMed | Related abstracts
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Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. PMID: 9704735 PubMed
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Predicting Response to Rituxan
Also see Related PubMed Abstracts
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Efficacy of rituximab plus chemotherapy in follicular lymphoma depends on Ki-67 expression.
Pathol Int. 2004 Sep;54(9):667-74. PMID: 15363034 | Related articles
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Complement activation determines the therapeutic activity of rituximab in vivo.
J Immunol. 2003 Aug 1;171(3):1581-7. PMID: 12874252 | Related articles
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Predicting response to Rituxan: Two Immunoglobulin G Fc Receptor Polymorphisms (expressed on effector cells) Independently Predict Response in Pts With Follicular NHL. J Clin Oncol. 2003 Sep 15 - PMID: 12975461
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Variation in gene expression patterns in follicular lymphoma and the response to rituximab. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1926-30. PMID: 12571354 PubMed
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Genetic characteristics (FCGR3A genotype) predict response to Rituxan? Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002 Feb 1;99(3):754-8. PMID: 11806974 PubMed
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Rituxan as First Line Treatment?
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ASCO 2009: Prolonged Rituximab Extends Remission in Follicular Lymphoma
medscape.com (free login req.)
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Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation.
http://bloodjournal.hematologylibrary.org/cgi/reprint/97/1/101.pdf
This study is still recruiting: http://clinicaltrials.gov/show/NCT00075946
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Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: A randomized phase II study from the Nordic Lymphoma Group. Leuk Lymphoma. 2008 Jan;49(1):102-12. PMID: 18203019
Extended rituximab is effective and well tolerated and combination with IFN seems to improve both the quality and duration of the responses, providing the opportunity to achieve long-term molecular CRs and prolonged failure-free survival without chemotherapy.
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Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma: interim follow-up of a multicenter phase II trial. Semin Oncol. 2002 Feb;29(1 Suppl 2):25-9. PMID: 11842385 PubMed
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Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. PMID: 12377971 PubMed
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Rituximab as first-line systemic therapy for patients with low-grade lymphoma.
Semin Oncol. 2000 Dec;27(6 Suppl 12):25-9. PMID: 11225997 PubMed
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Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood. 2000 May 15;95(10):3052-6. PMID: 10807768 PubMed
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Low Tumor Burden: Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation.
Blood. 2001 Jan 1;97(1):101-6. PMID: 11133748 PubMed
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Frontline and Maintenance: Rituximab as First-Line and Maintenance Therapy for Patients With Indolent Non-Hodgkin's Lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. PMID: 12377971 PubMed
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Mechanisms of Action (How Rituxan Might Work)
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Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy
Jonathan W. Friedberg asheducationbook.org
"Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects."
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Mechanisms of action Related PubMed Abstract
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Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer
Immunol Immunother. 2000 Mar;48(12):673-83. PMID: 10752475 PubMed
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Rituxan Optimized with Biologics and Immune-based Therapies?
Interferon-alpha | CpG ODN | GM-CSF (Leukine)
Also see: Combination with other antibodies | CHOP + Rituxan
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Modulating apoptosis pathways in low-grade B-cell malignancies using biological response modifiers. (Rituxan, TRAIL, retinoid/steroid family nuclear receptors, inhibitors of protein kinases.) T Semin Oncol 2002 Feb;29 abstract
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Research: Beyond immunochemotherapy: combinations of rituximab with cytokines interferon-alpha2a and granulocyte-macrophage colony stimulating factor. Semin Oncol. 2002 Apr;29(2 Suppl 6):7-10. Review. PMID: 12040528 PubMed
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Interferon-alpha
From ASH 2000
Rituximab Plus Interferon-alpha in Low-Grade Lymphoma E. Kimby and colleagues,[11] on behalf of The Nordic Lymphoma Group reported results obtained in 124 evaluable patients with follicular grade 1 or 2 CD20+ lymphoma who had received no prior therapy (n = 90) or who had received no more than 6 months of chlorambucil or other such therapy (n = 34). Treatment was not given unless patients were symptomatically in need.
All patients received 4 weekly doses of rituximab.
Patients who attained CR (11%) received no further therapy.
Patients who attained PR or minor response were then randomized to receive either another 4 weeks of rituximab alone
or
weekly rituximab together with interferon-alpha, given at a dose of 3
MU/day for the first week and then 4.5 MU/day for weeks 2 through 5.
The response rate for interferon plus rituximab was 94% (48% CR), whereas that for continued rituximab alone was 77% (22% CR).
In the combined interferon and rituximab group, grade 3 thrombocytopenia occurred in 2 of 33 patients, with grade 4 neutropenia in 2 of 33. This study indicates that the addition of interferon to rituximab is associated with an increased chance of attaining an objective response, when compared with continued use of rituximab alone.
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Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: A randomized phase II study from the Nordic Lymphoma Group. Leuk Lymphoma. 2008 Jan;49(1):102-12. PMID: 18203019
Extended rituximab is effective and well tolerated and combination with IFN seems to improve both the quality and duration of the responses, providing the opportunity to achieve long-term molecular CRs and prolonged failure-free survival without chemotherapy.
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Beyond immunochemotherapy: combinations of rituximab with cytokines interferon-alpha2a and granulocyte-macrophage colony stimulating factor. Semin Oncol. 2002 Apr;29(2 Suppl 6):7-10. Review. PMID: 12040528 PubMed
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Clinical activity and safety of combination immunotherapy with IFN-alpha 2a and Rituximab in patients with relapsed low grade non-Hodgkin's lymphoma. Haematologica. 2001 Sep;86(9):951-8. PMID: 11532623 PubMed
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Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a. Clin Cancer Res. 2000 Jul;6(7):2644-52.
PMID: 10914705 PubMed | Full Text
CpG ODN
"We conclude that immunostimulatory CpG ODN can enhance antibody dependent cellular cytotoxicity and warrant further evaluation as potential immunotherapeutic reagents in cancer."
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oligodeoxynucleotides abstract
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Rituxan + IL-2: IL-2 plus rituximab results in clinical responses in advanced patients with non-Hodgkin's lymphoma related to the degree of NK expansion.
GM-CSF
 TOPIC SEARCH - Medscape | ASCO.org | PubMed | ClinicalTrials.gov
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GM-CSF potentiates Rituxan in relapsed follicular lymphoma (small, single arm study) revolutionhealth.com
In total, 23 patients (70%) showed an overall response, and there was a "high complete response rate -- 45% -- and prolonged duration of response," Dr. Rossi said. The median progression-free survival was 16.4 months, but it was significantly higher in patients with a complete response (median, 33.2 months) compared with those who had a partial response (median, 7.6 months).
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Rituximab Activity Is Potentiated by GM-CSF in Patients with Relapsed, Follicular Lymphoma: Results of a Phase II Study. Session Type: Poster Session 636-II ASH 2005
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Treatment of relapsed B-cell non-Hodgkin's lymphoma with a combination of rituxan and G-CSF: final report on safety and efficacy. Leukemia. 2003 Aug;17(8):1658-1664. PMID: 12886256 PubMed | Related abstracts
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Antibody Dependent Cellular Cytotoxicity and Natural Killer Cell Activity in Patients with Recurrent Indolent Lymphoma Receiving Rituximab in Combination with GM-CSF. Session Type: Poster Session 607-I - ASH [1495] ASH 2003
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Effect of GM-CSF, G-CSF or Methylprednisolone (MP) on Rituximab-Associated Complement-Mediated Cytotoxicity (CMC) on Non-Hodgkin’s Lymphoma (NHL) Cell Lines. ASCO 2001 # 1095
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Mechanisms of G-CSF- or GM-CSF-stimulated tumor cell killing by Fc receptor-directed bispecific antibodies. J Immunol Methods. 2001 Feb 1;248(1-2):103-11. PMID: 11223072 PubMed
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IL-12
"Objective responses occurred in 29 of the 43 patients (69%), with 8 of 11 complete responses seen at IL-12 doses of 300 ng/kg or greater. The optimal immunologic dose of IL-12 in combination with rituximab was determined to be 300 ng/kg
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Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma. Br J Haematol. 2002 Jun;117(4):828-34. PMID: 12060117 PubMed
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ASCO 2002: IL-2 plus rituximab results in clinical responses in advanced patients with non-Hodgkin's lymphoma related to the degree of NK expansion.
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STEROIDS
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Rituxan + steroids: Glucocorticoids and rituximab in vitro: synergistic direct antiproliferative and apoptotic effects. Blood. 2002 Sep 1;100(5):1765-73. PMID: 12176898 PubMed
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MISCELLANEOUS -
Other biologics and agents that may synergize with Rituxan
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Synergistic effects of the fenretinide (4-HPR) and anti-CD20 monoclonal antibodies on apoptosis induction of malignant human B cells. Clin Cancer Res. 2001 Aug;7(8):2490-5. PMID: 11489831 PubMed The retinoid fenretinide (4-HPR): a non-toxic drug related to Vitamin A
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Dynavax Initiates First Human Trial Of ISS Immunotherapy And Rituxin® (Rituximab) press release
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Treatment Indications - Conditions and Treatment Settings
TOPIC SEARCH: PubMed: Bulky Disease | Retreatment
CLL / SLL | Cutaneous follicular | Extranodal and MALT | MCL | Waldenstrom's
The future of determining who a treatment will benefit?
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Rituximab maintenance therapy dramatically improves survival [at 3 years] for patients
with lymphoma eortc.be
"Two years of maintenance therapy with rituximab dramatically improves the chances of survival for patients suffering from one of the most frequent forms of lymphoma, indolent non-Hodgkin’s Lymphoma (NHL). The EORTC 20981 trial reveals that rituxibam maintenance treatment prolongs progression free survival by about 2,5 years, irrespective of initial treatment. Moreover, the risk of death is halved for patients who receive rituximab maintenance therapy, compared to those who receive no maintenance treatment."
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Drug response linked to genes in lymphoma patients GNN
"The researchers identified about 150 genes in lymph tumors that could help predict the drug response. The activity of these genes differed significantly between patients who responded to treatment and those who did not. "
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Aggressive NHL: The role of rituximab and chemotherapy in aggressive B-cell lymphoma: a preliminary report of dose-adjusted EPOCH-R. - Semin Oncol 2002 Feb;29 PubMed
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Aggressive NHL: Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2001 Jan 15;19(2):389-97. PMID: 11208830 PubMed
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Aggressive NHL: The role of rituximab and chemotherapy in aggressive B-cell lymphoma: a preliminary report of dose-adjusted EPOCH-R. - Semin Oncol 2002 Feb;29 abstract
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Bulky Disease: Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab. J Clin Oncol. 1999 Jun;17(6):1851-7. PMID: 10561225 PubMed | Jco.org Full Text
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MALT: Rituxan for MALT: IELSG phase II study of rituximab in MALT lymphoma: final results | PDF
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Refractory NHL: Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. PubMed
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Retreatment With: Re-treatment of relapsed indolent B-cell lymphoma with rituximab.
Int J Hematol. 2001 Feb;73(2):213-21. PMID: 11372734 PubMed
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Retreatment With: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol. 2000 Sep;18(17):3135-43. PMID: 10963642 PubMed
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