New directions in radioimmunotherapy of non-Hodgkin's lymphoma.

trial, which revealed that partial and complete remission were several times greater in the 90 Y ibritumomab tiuxetan arm (0.4 mCi/kg) than in the rituximab arm (375 mg/m 2 weekly for 4 weeks). Based on the pivotal phase III studies, 90 Y ibritumomab tiuxetan and 131 I tositumomab have been approved for the treatment of patients with relapsed or refractory low-grade follicular, or transformed CD20 + Bcell NHL, including patients with rituximab-refractory follicular NHL. A 90 Y ibritumomab tiuxetan trial in patients with rituximabrefractory disease resulted in a 74% response rate. 2 In an additional study, reduced-dose 90 Y ibritumomab tiuxetan (0.3 mCi/kg) in patients with mild thrombocytopenia had a response rate of 83%. 3 The success of RIT in NHL is due in large part to rapid and efficient binding of the MAb to lymphoma cells. Radiolabeled MAbs are especially attractive because lymphoma cells and lymphocytes are highly radiosensitive. Radiometals like 90 Y ibritumomab tiuxetan have been shown to have residualizing properties, advantageous when the MAb is localized on malignant cells, as reviewed here by DeNardo et al. Because the pivotal phase III trials were conducted in patients with < 25% NHL marrow involvement by biopsy, neither drug is approved for patients having more extensive NHL marrow disease. Monoclonal antibodies have been shown to be effective in the presence of marrow disease when “fractionated” into multiple radionuclide doses given in amounts near or at the maximum tolerated dose (MTD). 4 Training and good judgment make it feasible to use these drugs safely, perhaps even with greater safety than that associated with cancer chemotherapeutics. As reviewed by Borghaei et al, toxicities were primarily hematologic, transient, and reversible. Quality of life scores were compared between the 90 Y ibritumomab tiuxetan arm and the rituximab arm in the randomized trial. Quality of life was significantly better after 90 Y ibritumomab tiuxetan. Radioimmunotherapy does not preclude subsequent NHL treatments. Finally, an open-labeled study provided additional safety data. Emmanouilides et al analyzed the safety and efficacy of 90 Y ibritumomab tiuxetan therapy in patients aged ≥ 65 years. 5 Efficacy was not compromised in the older patients. The 90 Y ibritumomab tiuxetan regimen was not associated with the adverse events that are usually associated with chemotherapy, such as hair loss, severe mucositis, or persistent nausea or emesis. Radioimmunotherapy with hematopoietic transplantation has proven feasible and permitted dose escalation. Press et al pioneered the use of RIT in autologous hematopoietic stem cell transplantation for NHL. 6 As reviewed here by Winter, investigators at Northwestern University and the Mayo Clinic are combining 90 Y ibritumomab tiuxetan and high-dose BEAM (carmustine/etoposide/cytarabine/melphalan) chemotherapy in a phase I study that carefully doses the radioimmunoconjugate according to dosimetry. Toxicities have been similar to those reported with high-dose BEAM alone. Thus far, overall survival for all treated patients at all dose levels is 60% at 3 years, and progression-free survival is 47% at 2 and 3 years. Toxicities included mucositis, fever, and skin rash. There are many ongoing trials of ibritumomab tiuxetan with different dose schedules and dose intensities in combination with chemotherapy and autologous or allogeneic stem cell transplantation in an attempt to improve response rate and duration, and to study its effectiveness in other B-cell lymphomas, including mantle cell lymphoma and diffuse large cell lymphoma. Micallef reviews these studies here. In a phase I study of 2 sequential doses of 90 Y ibritumomab tiuxetan for relapsed low-grade B-cell NHL, MTD without prophylactic growth factor support was 0.4 mCi/kg followed by 0.2 mCi/kg. A recent trial of 90 Y ibritumomab tiuxetan for minimal residual disease in chronic lymphocytic leukemia (CLL) with < 25% bone marrow involvement revealed that 7 of 13 patients had a response. Significant cytopenias were observed. These data suggest that myelosuppression is more frequent in patients with CLL receiving 90 Y ibritumomab tiuxetan, and are similar to data for another radiolabeled MAb in CLL. 7 A recent phase II study of 90 Y ibritumomab tiuxetan for the treatment of relapsed or refractory mantle cell lymphoma by Younes et al has shown that 90 Y ibritumomab tiuxetan had clinical activity. 8 All patients had full hematologic recovery.