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First Radioimmunotherapy Approved by FDA

First Radioimmunotherapy Approved by FDA

The US Food and Drug Administration (FDA) has approved ibritumomab tiuxetan (Zevalin) for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL), including rituximab (Rituxan)-refractory disease. A monoclonal antibody linked to a radioisotope, ibritumomab tiuxetan targets the CD20 antigen on the surface of mature B cells and B-cell tumors, inducing cellular damage in the target and neighboring cells. The regimen is administered in two parts: Patients first receive rituximab followed by indium-111-ibritumomab tiuxetan for screening purposes. If tumors are successfully targeted with this procedure, 7 to 9 days later patients receive another infusion of rituximab with yttrium-90-ibritumomab tiuxetan.

Efficacy Data

The FDA approval was based on two major efficacy studies conducted in the United States. Determination of the effectiveness of the ibritumomab tiuxetan regimen in a relapsed or refractory patient population was based on overall response rates. The effects of the regimen on survival are not known.

The first study was conducted in 54 patients with relapsed follicular lymphoma who no longer responded adequately to rituximab. An overall response rate of 74% was reported, with 15% achieving a complete remission, according to the International Workshop Response Criteria. The second study, a phase III randomized, controlled trial, was conducted in 143 patients with relapsed or refractory, low-grade or follicular NHL, or transformed B-cell NHL. The overall response rate for the 73 patients who received the ibritumomab tiuxetan regimen was 80%, compared to 56% for the 70 patients who received rituximab alone. Among patients in the ibritumomab tiuxetan group, 30% achieved a complete remission and 4% an unconfirmed complete remission, compared to 16% in the rituximab group with a complete remission and 4% with an unconfirmed complete remission.

Adverse Reactions

In safety data based on 349 patients, the most serious adverse reactions to the ibritumomab tiuxetan regimen included severe infusion reactions (hypotension, angioedema, hypoxia, or bronchospasm) and severe and prolonged cytopenias including thrombocytopenia (61% of patients with platelet counts < 50,000 cells/µL) and neutropenia (57% of patients with absolute neutrophil counts < 1,000 cells/µL) in patients with 150,000 platelets/µL or higher prior to treatment. Severe infections (predominantly bacterial in origin) and hemorrhage, including fatal cerebral hemorrhage, have occurred in a minority of patients in clinical studies.

In addition, myeloid malignancies and dyscrasias (myelodysplastic syndrome) were seen. The most common toxicities reported were neutropenia, thrombocytopenia, anemia, gastrointestinal symptoms, increased cough, dyspnea, dizziness, arthralgia, anorexia, and ecchymosis. Hematologic toxicity was often severe and prolonged, whereas most nonhematologic toxicity was mild.

"Zevalin represents a major advance in the treatment of certain non-Hodgkin’s lymphomas, especially among patients who have become refractory to other treatment options," said Thomas E. Witzig, MD, a hematologist at the Mayo Clinic, Rochester, Minnesota, and a key investigator in the trials. "Zevalin is a significant step forward in managing patients with adequate bone marrow reserves who have failed standard chemotherapy, rituximab therapy, or a combination of chemotherapy and Rituxan."

He added, "Unlike standard chemotherapy, which is given over as many as 4 to 6 months, Zevalin can be administered in an outpatient setting over 8 days with approximately 12 weeks of follow-up."

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