First immunotherapeutic for lymphomas clears FDA

March 4, 2002

Zevalin recommended for approval for treating non-Hodgkin's lymphomas.

Non-Hodgkin's lymphomas (NHL) are a diverse group of malignancies that attack the B and T lymphocytes of the immune system. More than 50,000 Americans develop NHL annually, and nearly 50% of them die of the disease.

Conventional treatment of NHL is limited to chemotherapy, with burdensome side effects and variable clinical outcomes. If the lymphoma is localized, the choice of therapy is radiation, but targeting external beam radiation to cancerous immune system cells throughout the body is difficult and complex. More recently, monoclonal antibodies (MAbs) administered alone or in conjunction with conventional cytotoxic approaches are making a strong impact in the management of relapsed or refractory low-grade NHL. However, patients who have stopped responding to any of these therapies are left with few treatment options.

Zevalin (90Y-ibritumomab tiuxetan, IDEC Pharmaceuticals), the first radioimmunotherapeutic agent that aims to combine the targeting power of MAbs with the cancer-killing ability of radiation, has been approved by the Food & Drug Administration as an adjunct to Rituxan (rituximab, IDEC), an already marketed MAb-based product for low-grade B-cell NHL. 90Y-ibritumomab tiuxetan is indicated for the treatment of low-grade, follicular or transformed B-cell NHL in patients who are refractory to the current standard chemotherapy, including monotherapy with rituximab.

90Y-ibritumomab is a mouse MAb linked to the radioisotope yttrium-90 by a chelating agent. The mouse antibody was selected as the carrier of the radioisotope because it is eliminated from the body faster than rituximab, a combination of human and mouse antibodies, and its half-life is comparable to that of yttrium-90 (64 hours).

IDEC conducted four clinical studies in support of its Biological License Application in relapsed or refractory, low-grade, follicular, or transformed B-cell NHL patients.

"The combined therapy of 90Y- ibritumomab and rituximab achieved an overall response rate of 80% compared with 56% and 74% in those receiving rituximab or 90Y-ibritumomab alone, respectively," said Thomas E. Witzig, M.D. He is a Mayo Clinic oncologist/hematologist and a key investigator in the clinical trials. "Responses were seen even in patients with such adverse prognostic factors as large tumors or chemotherapy-resistant disease. Furthermore, the median duration of response after 90Y-ibritumomab was 8.4 months versus four months after the use of rituximab alone," he added.

Witzig explained that "though 90Y-ibritumomab demonstrated slightly greater toxicity as compared with rituximab, patients nevertheless tolerated the radioactive drug better than traditional chemotherapy. It is easier to use and significantly more convenient for both the patient and the physician." The treatment regimen consists of a dose of rituximab followed by Indium-111 Zevalin (a low-dose radioactive chemical for screening purposes). If the tumor is targeted properly, a second infusion of rituximab along with Yttrium-90 Zevalin is administered IV over 10 minutes in an outpatient setting and the patient may go home without any ill feeling. The rationale for giving rituximab first is based on data indicating that the binding of a radioimmunoconjugate to lymphoma is enhanced by pretreatment with antibody.

For 90Y-ibritumomab, the recommended dose is 0.4 mCi/kg IV for patients with platelet counts greater than 150,000 and 0.3-mCi/kg IV for patients with platelet counts between 100,000 and 149,000. 90Y- ibritumomab is not recommended for patients with platelets below 100,000. In either case, the maximum tolerable dose is 32 mCi.

The primary toxicity associated with 90Y-ibritumomab therapies is reversible myelosuppression, which includes neutropenia, thrombocytopenia, and anemia. Patients with impaired bone marrow reserve or with greater involvement of the bone marrow in the malignancy itself were more likely to experience hematologic toxicity. However, blood counts returned to normal within four to eight weeks in most patients. Seven percent of patients with decreased blood counts needed to be hospitalized for infection and less than 1% experienced life-threatening bleeding.

The labeling for 90Y-ibritumomab carries a black box warning about the risk of fatal infusion reaction, including death, within 24 hours following rituximab administration. Moreover, based on the clinical studies completed, most patients treated with 90Y-ibritumomab will develop prolonged and severe cytopenias.

Experts think 90Y-ibritumomab appears to offer a more effective tumor-specific therapy for patients with relapsed, refractory, or low-grade NHL as compared with other currently available treatments. Results of clinical studies completed to date suggest that some patients may achieve long-term remission or even disease-free survival.

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