Early Data Support Use of Monoclonal Antibody Ibritumomab Tiuxetan in Refractory NHL

NEW ORLEANS—The radioactive monoclonal antibody ibritumomab tiuxetan (Zevalin, IDEC-Y2B8) may be a useful therapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma (NHL). In addition, Y2B8 can be used safely in patients with mild thrombocytopenia, researchers reported at the ASH meeting.

Y2B8 is an anti-CD20 murine monclonal antibody conjugated to tiuxetan, which forms a strong chelate with the pure beta emitting isotope yttrium 90. Y2B8 destroys cancer cells presumably by direct induction of apoptosis and by the effects of the radiation from yytrium 90.

Open Label Study

Leo I. Gordon, MD, of Northwestern University in Chicago reported interim results of an open-label, nonrandomized, controlled, multicenter trial of Y2B8 at a dose of 0.4 mCi/kg in patients with follicular NHL refractory to rituximab (Rituxan). These patients either did not respond to rituximab or responded but suffered disease progression in 6 months or less.

Median number of prior therapies was 4 (range 1 to 9). Patients had absolute neutrophil count (ANC) greater than 1,500 cells/mm³ at entry and platelet counts greater than 150,000 cells/mm³. Exclusion criteria included prior bone marrow or stem cell transplant, prior radioimmunotherapy, central nervous system lymphoma, chronic lymphoblastic leukemia or AIDS lymphoma, pleural or peritoneal invasion, elevated total bilirubin or creatinine, prior external beam irradiation to more than 25% of active bone marrow, or presence of human antimurine or antichimeric antibodies.

At study entry, 38% of patients had bone marrow involvement, 10% had splenomegaly, 80% had bulky disease larger than 5 cm (including 56% with disease larger than 7 cm), and 76% were resistant to chemotherapy.

Safe and Effective

“Adverse events [at this interim analysis of the first 29 patients treated] were primarily hematologic, transient, and reversible,” Dr. Gordon reported. “The ANC median nadir was 800 cells/mm³. Patients with Grade 3 and 4 nadirs recovered in a median of 9 days. The median platelet nadir was 34,000 cells/mm³. Patients with Grade 3 and 4 nadirs recovered in a median of 14 days. Median hemoglobin nadir was 10.5 g/dL. Grade 4 thrombocytopenia occurred in 14% of patients, and Grade 4 neutropenia occurred in 28% of patients.”

Two patients with infection were hospitalized, and both recovered. No patients developed human antimouse antibodies (HAMA) or antichimeric antibodies (HACA).

Overall response rate was 46% in the 28 patients evaluable for response. All were partial responses, with median tumor measurement reduction (sum of the products of the perpendicular diameters) of 80% in responders.

“This interim analysis suggests that Zevalin radioimmunotherapy is safe and effective in patients with rituximab-refractory follicular NHL,” Dr. Gordon concluded.

Pre-existing Thrombocytopenia

Reduced doses of Y2B8 (5.0 mCi of indium 111 Zevalin, 0.3 mCi/kg of yttrium 90 Zevalin) can be used safely and effectively in patients with mild thrombocytopenia, according to Thomas Witzig, MD, of the Mayo Clinic in Rochester. A common problem in patients with relapsed or refractory B-cell NHL, pre-existing thrombocytopenia often limits future therapeutic options.

“Zevalin dosing based on weight and baseline platelet count can be used for NHL patients with no history of autologous bone marrow transplant (ABMT) and less than 25% bone marrow involvement, obviating the need for dosimetry,” Dr. Witzig noted. He reported on an open-label, single-arm, phase II study of 26 patients with relapsed or refractory low-grade, follicular, or transformed NHL. All patients had mild thrombocytopenia (100,000-149,000 cells/mm³) and ANC greater than 1,500/mm³. None had been previously treated with rituximab.

Patients were treated initially with rituximab and indium 111 Y2B8 for imaging studies, then with rituximab and yttrium 90 Y2B8 infusions. Interim analysis in 24 patients showed an overall response rate of 67%, which included a 21% complete response (CR) rate and a 46% partial response (PR) rate.

“Toxicity was primarily hematologic, transient, and reversible,” Dr. Witzig said. Median nadirs for patients receiving 0.3 mCi/kg were ANC of 600/mm³, platelets of 34,000/mm³ and hemoglobin of 10.0 g/dL. Grade 4 hematologic patients included neutropenia (31%), thrombocytopenia (12%), and anemia (4%).

Dr. Witzig pointed out that dosimetry did not predict hematologic toxicity. “Relapsed or refractory, low-grade, follicular or transformed CD20+ B-cell NHL patients with mild thrombocytopenia can be safely treated with reduced-dose (0.3 mCi/kg) Zevalin with excellent clinical response,” Dr. Witzig concluded.