Ibritumomab tiuxetan
Encyclopedia
Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody
radioimmunotherapy
treatment for some forms of B cell
non-Hodgkin's lymphoma, a lymphoproliferative disorder and thus affects the lymphatic system
. The drug uses the monoclonal mouse IgG1 antibody
ibritumomab in conjunction with the chelator tiuxetan, to which a radioactive isotope (either yttrium-90
or indium-111) is added. Tiuxetan is a modified version of DTPA whose carbon backbone contains an isothiocyanatobenzyl and a methyl group.
antigen
found on the surface of normal and malignant B cell
s (but not B cell precursors), allowing radiation from the attached isotope
(mostly beta emission) to kill it and some nearby cells. In addition, the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity
(CDC), and apoptosis
. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid
stem cell
s.
, platelet and neutrophil counts are also taken pretreatment. Since a murine antibody is used, the patient might also be tested for human anti mouse antibodies (HAMA
). Having bulky disease does not disqualify a patient.
The ibritumomab regimen takes 7–9 days, with two administrations of ibritumomab. Each dose is preceded by rituximab
, in order to pre-deplete B lymphocytes. The dose of rituximab given here is less than the usual dose.
The first dose uses indium-111 ibritumomab for imaging. Indium-111 emits gamma radiation, which can be picked up by the gamma camera
. A scan is done to assess biodistribution of the drug. This test dose is used to determine that no excess amounts go to the marrow, liver, etc. in this particular patient.
If the gamma scan shows no altered biodistribution, then the second dose is given, using yttrium-90 ibritumomab as the actual treatment. Yttrium-90 emits the cell-killing beta radiation.
Ibritumomab tiuxetan is administered by intravenous infusion which usually lasts around 10 minutes. Only acrylic shielding is needed, not lead.
s compared to treatment with only rituximab (similar to ibritumomab, but without the attached radioisotope), and showed very promising results for patients who no longer respond to rituximab.
In patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, where no prior anti-CD20 therapy was allowed, the OR was 80% / 50% and CR was 34% / 20%, comparing ibritumomab to rituximab.
Recently, extended follow-up data for the ZEVALIN ([90Y]-ibritumomab tiuxetan) First-line Indolent (FIT) study presented at the American Society of Hematology (ASH) Annual Meeting demonstrated the continued improvement in progression-free survival (PFS) following ibritumomab consolidation therapy for patients with follicular B-cell non-Hodgkin's lymphoma who achieved a response to first-line therapy over chemotherapy alone. Additionally, ibritumomab consolidation did not adversely affect the use of various effective second-line treatments including stem cell transplants in patients who relapsed.
In a Phase II study on patients with relapsed and refractory mantle cell lymphoma
, the OR was 42% and CR was 26%.
A study demonstrated that rituximab followed by single agent ibritumomab in a front-line setting for patients with MALT lymphoma and low-grade follicular lymphoma that primarily involved the conjunctiva or orbit, produced a complete response rate of 83 percent.
, ibritumomab tiuxetan was the first radioimmunotherapy drug approved by the Food and Drug Administration
(FDA) in 2002 to treat cancer. It was approved for the treatment of patients with relapsed or refractory, low‑grade or follicular B‑cell non‑Hodgkin's lymphoma (NHL), including patients with rituximab refractory follicular NHL.
In December 2007, Cell Therapeutics Inc acquired the U.S. rights to sell, market, and distribute this radioimmunotherapy antibody from Biogen for approximately US$30 million, or the equivalent of about two years' net sales revenue in the U.S. for the drug. Outside of the U.S., Bayer Schering Pharma continues to have the rights to the drug.
In March 2009, Spectrum Pharmaceuticals acquired 100% control of RIT Oncology, LLC, to commercialize Zevalin in the US. Now Spectrum Pharmaceuticals is responsible for all activities relating to Zevalin in the US.
In September 2009, ibritumomab received approval from the FDA for an expanded label for the treatment of patients with previously untreated follicular non-Hodgkin's Lymphoma (NHL), who achieve a partial or complete response to first-line chemotherapy.
Monoclonal antibody therapy
Monoclonal antibody therapy is the use of monoclonal antibodies to specifically bind to target cells or proteins. This may then stimulate the patient's immune system to attack those cells...
radioimmunotherapy
Radioimmunotherapy
Radioimmunotherapy uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. In cancer therapy, an antibody with specificity for a tumor-associated antigen is used to deliver a lethal dose of radiation to the tumor cells...
treatment for some forms of B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
non-Hodgkin's lymphoma, a lymphoproliferative disorder and thus affects the lymphatic system
Lymphatic system
The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...
. The drug uses the monoclonal mouse IgG1 antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
ibritumomab in conjunction with the chelator tiuxetan, to which a radioactive isotope (either yttrium-90
Yttrium-90
Yttrium-90 is a medically significant isotope of yttrium.It emits beta rays of 2.3 MeV.Yttrium-90 is a decay product of Strontium-90 which makes up about 5% of the Nuclear daughter isotopes when Uranium is fissioned....
or indium-111) is added. Tiuxetan is a modified version of DTPA whose carbon backbone contains an isothiocyanatobenzyl and a methyl group.
Mechanism of action
The antibody binds to the CD20CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
found on the surface of normal and malignant B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s (but not B cell precursors), allowing radiation from the attached isotope
Isotope
Isotopes are variants of atoms of a particular chemical element, which have differing numbers of neutrons. Atoms of a particular element by definition must contain the same number of protons but may have a distinct number of neutrons which differs from atom to atom, without changing the designation...
(mostly beta emission) to kill it and some nearby cells. In addition, the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity
Cytotoxicity
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
(CDC), and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid
Lymphoid
Lymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s.
Administration
In order to qualify for ibritumomab, a patient needs to have bone marrow involvement of < 25% and > 15% bone marrow cellularity. Since ibritumomab is known to cause cytopeniaCytopenia
Cytopenia is a reduction in the number of blood cells. It takes a number of forms:*Low red blood cell count: resulting in anemia.*Low white blood cell count: leukopenia or neutropenia .*Low platelet count: thrombocytopenia.*Low granulocyte count: granulocytopenia*Low red blood...
, platelet and neutrophil counts are also taken pretreatment. Since a murine antibody is used, the patient might also be tested for human anti mouse antibodies (HAMA
Hama
Hama is a city on the banks of the Orontes River in west-central Syria north of Damascus. It is the provincial capital of the Hama Governorate. Hama is the fourth-largest city in Syria—behind Aleppo, Damascus, and Homs—with a population of 696,863...
). Having bulky disease does not disqualify a patient.
The ibritumomab regimen takes 7–9 days, with two administrations of ibritumomab. Each dose is preceded by rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
, in order to pre-deplete B lymphocytes. The dose of rituximab given here is less than the usual dose.
The first dose uses indium-111 ibritumomab for imaging. Indium-111 emits gamma radiation, which can be picked up by the gamma camera
Gamma camera
A gamma camera, also called a scintillation camera or Anger camera, is a device used to image gamma radiation emitting radioisotopes, a technique known as scintigraphy...
. A scan is done to assess biodistribution of the drug. This test dose is used to determine that no excess amounts go to the marrow, liver, etc. in this particular patient.
If the gamma scan shows no altered biodistribution, then the second dose is given, using yttrium-90 ibritumomab as the actual treatment. Yttrium-90 emits the cell-killing beta radiation.
Ibritumomab tiuxetan is administered by intravenous infusion which usually lasts around 10 minutes. Only acrylic shielding is needed, not lead.
Efficacy
Treatment with ibritumomab showed higher response rates in clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s compared to treatment with only rituximab (similar to ibritumomab, but without the attached radioisotope), and showed very promising results for patients who no longer respond to rituximab.
In patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, where no prior anti-CD20 therapy was allowed, the OR was 80% / 50% and CR was 34% / 20%, comparing ibritumomab to rituximab.
Recently, extended follow-up data for the ZEVALIN ([90Y]-ibritumomab tiuxetan) First-line Indolent (FIT) study presented at the American Society of Hematology (ASH) Annual Meeting demonstrated the continued improvement in progression-free survival (PFS) following ibritumomab consolidation therapy for patients with follicular B-cell non-Hodgkin's lymphoma who achieved a response to first-line therapy over chemotherapy alone. Additionally, ibritumomab consolidation did not adversely affect the use of various effective second-line treatments including stem cell transplants in patients who relapsed.
In a Phase II study on patients with relapsed and refractory mantle cell lymphoma
Mantle cell lymphoma
Mantle cell lymphoma is one of the rarest of the non-Hodgkin's lymphomas , comprising about 6% of NHL cases. There are only about 15,000 patients presently in the U.S. While it is difficult to treat and seldom considered cured, investigations into better treatments are actively pursued worldwide...
, the OR was 42% and CR was 26%.
A study demonstrated that rituximab followed by single agent ibritumomab in a front-line setting for patients with MALT lymphoma and low-grade follicular lymphoma that primarily involved the conjunctiva or orbit, produced a complete response rate of 83 percent.
History
Developed by the IDEC Pharmaceuticals, which is now part of Biogen IdecBiogen Idec
Biogen Idec, Inc. is a biotechnology company specializing in drugs for neurological disorders, autoimmune disorders and cancer. The company was formed in 2003 by the merger of Cambridge, Massachusetts-based Biogen Inc. and San Diego, California-based IDEC Pharmaceuticals...
, ibritumomab tiuxetan was the first radioimmunotherapy drug approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in 2002 to treat cancer. It was approved for the treatment of patients with relapsed or refractory, low‑grade or follicular B‑cell non‑Hodgkin's lymphoma (NHL), including patients with rituximab refractory follicular NHL.
In December 2007, Cell Therapeutics Inc acquired the U.S. rights to sell, market, and distribute this radioimmunotherapy antibody from Biogen for approximately US$30 million, or the equivalent of about two years' net sales revenue in the U.S. for the drug. Outside of the U.S., Bayer Schering Pharma continues to have the rights to the drug.
In March 2009, Spectrum Pharmaceuticals acquired 100% control of RIT Oncology, LLC, to commercialize Zevalin in the US. Now Spectrum Pharmaceuticals is responsible for all activities relating to Zevalin in the US.
In September 2009, ibritumomab received approval from the FDA for an expanded label for the treatment of patients with previously untreated follicular non-Hodgkin's Lymphoma (NHL), who achieve a partial or complete response to first-line chemotherapy.
Costs
Ibritumomab which is not available in a generic form because it is still under patent protection, is currently the most expensive drug available given in a single dose, costing over US$ 24,000 (€ 17,000) for the average dose. However, ibritumomab is essentially an entire course of lymphoma therapy which is delivered in 7–9 days, with one visit for imaging, one visit for a gamma scan, and one visit for the actual therapeutic dose. Compared to other monoclonal antibody treatments (many of which are well over US$ 40,000 for a course of therapy), this drug is priced in the middle for many of these therapies.See also
- TositumomabTositumomabTositumomab is a drug for the treatment of follicular lymphoma. It is a IgG2a anti-CD20 monoclonal antibody derived from immortalized mouse cells....
, an alternative radioimmunotherapy treatment for non-Hodgkin's lymphoma.