Ibritumomab tiuxetan

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 (pronounced as ) 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.

Mechanism of action
The antibody binds to the CD20 antigen found on the surface of normal and malignant B cells (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 cells.

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 cytopenia, 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.

Efficacy
Treatment with ibritumomab showed higher response rates in clinical trials 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.

History
Developed by the IDEC Pharmaceuticals, which is now part of Biogen Idec, 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.

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.