Monoclonal antibodies (MoAbs) for cancer have been the subject of intense clinical investigation for nearly 2 decades.[1] Although the concept of MoAb therapy is simple, a host of unforeseen difficulties hindered the realization of clinical benefit from this therapeutic approach. The review by McLaughlin and colleagues of rituximab (Rituxan), the first MoAb approved for the treatment of cancer, describes one of the success stories in this field. Many other candidate antibodies have appeared to be equally promising during preclinical testing, only to fail during subsequent clinical trials. The lessons learned from these failures (eg, anti-B4-blocked ricin) and the successes, like rituximab, highlight the challenges involved in the development of an effective MoAb for cancer therapy. Obstacles to the Development of Effective MoAbs One challenge has been the selection of appropriate target antigens. Although hematologic malignancies are relatively unique in their expression of cell surface antigens not present on other tissues, not every antigen has proven to be an optimal target. Studies with antibodies targeting CD5,[2,3] CD19, and CD22[4] demonstrated that these antigens internalize upon antibody binding, making them poor targets for serotherapy with unconjugated antibodies. Furthermore, the tumor must persistently express antigen despite intense negative selection imposed by the antibody; otherwise, the tumor could escape therapy. Rituximab recognizes CD20, which remains stable in the face of antibody binding, making it a nearly ideal target antigen. Optimal dosing and adequate tissue penetration represent further stumbling blocks to effective serotherapy. Unlike studies with conventional cytotoxic agents, initial phase I studies with rituximab never reached a maximum tolerated dose. Some published studies have used larger doses than the currently approved 375 mg/m2 weekly × 4 regimen, For example, Coiffier et al used doses up to 500 mg/m2 in a weekly × 8 regimen in patients with intermediateor high-grade lymphoma.[5] Thus, the best dose and schedule of rituximab remain to be established.[6,7] Moreover, even when serum levels that correspond to effective in vitro cytotoxicity can be achieved, tissue levels may still be subtherapeutic, particularly within poorly vascularized lymphomatous nodes. Studies of the Campath-1H MoAb (anti-CD52) demonstrate effec-tive penetration into bone marrow and spleen but not into lymph nodes and extranodal tissue sites.[8] In contrast, rituximab has shown efficacy even in bulky tumors. Whether its activity is augmented in the minimal disease setting requires further investigation. As with all therapies, the potential toxicities of MoAbs must always be considered. Although acute reactions to all MoAbs are common, particularly during initial infusions, few patients require discontinuation of the agent. Subacute toxicities may vary considerably, depending on the particular antibody. Campath-1H induces significant Tand B-cell depletion, since it targets a cell surface antigen common to both lymphocyte lineages. The resulting profound lymphopenia significantly increases the risk of opportunistic infections. To date, no major toxicity has been seen with rituximab, despite prolonged B-cell depletion following therapy. This minimal side effects profile therefore makes rituximab an attractive agent for combination therapies and as salvage therapy for patients who may have impaired marrow reserve and reduced tolerance for toxicity. Rituximab Combined With Chemotherapy In vitro data suggesting synergy of rituximab with conventional chemotherapy represent the most exciting potential for this agent.[9,10] A phase II trial of rituximab in combination with CHOP

Zevalin (ibritumomab tiuxetan; IDEC Pharmaceuticals Corporation, San Diego, CA, USA) was approved by the United States Food and Drug Administration on February 19, 2002, following 9 years of clinical development. Six clinical studies supported the Zevalin Biologics License Application. The Zevalin regimen is indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), and for those with follicular NHL refractory to Rituxan (rituximab, MabThera; IDEC Pharmaceuticals Corporation, San Diego, CA and Genentech, South San Francisco, CA). In the year following FDA approval, approximately 1300 patients were treated in clinical trials or with the commercially available product.

PURPOSE:Radioimmunotherapy (RIT) with yttrium-90 ((90)Y)-labeled anti-CD20 antibody ((90)Y ibritumomab tiuxetan; Zevalin, IDEC Pharmaceuticals Corporation, San Diego, CA) has a high rate of tumor response in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL). This study presents the safety data from 349 patients in five studies of outpatient treatment with (90)Y ibritumomab tiuxetan.PATIENTS AND METHODS:Patients received rituximab 250 mg/m(2) on days 1 and 8, and either 0.4 mCi/kg (15 MBq/kg) or 0.3 mCi/kg (11 MBq/kg) of (90)Y ibritumomab tiuxetan on day 8 (maximum dose, 32 mCi). Patients were observed for up to 4 years after therapy or until progressive disease.RESULTS:Infusion-related toxicities were typically grade 1 or 2 and were associated with rituximab. No significant organ toxicity was noted. Toxicity was primarily hematologic, with nadir counts occurring at 7 to 9 weeks and lasting approximately 1 to 4 weeks depending on the method of calculation. After the 0.4-mCi/kg dose, grade 4 neutropenia, thrombocytopenia, and anemia occurred in 30%, 10%, and 3% of patients, respectively, and after the 0.3-mCi/kg dose, these grade 4 toxicities occurred in 35%, 14%, and 8% of patients, respectively. The risk of hematologic toxicity increased with degree of baseline bone marrow involvement with NHL. Seven percent of patients were hospitalized with infection (3% with neutropenia) and 2% had grade 3 or 4 bleeding events. Myelodysplasia or acute myelogenous leukemia was reported in five patients (1%) 8 to 34 months after treatment.CONCLUSION:Single-dose (90)Y ibritumomab tiuxetan RIT has an acceptable safety profile in relapsed NHL patients with less than 25% lymphoma marrow involvement, adequate marrow reserve, platelets greater than 100,000 cells/ micro L, and neutrophils greater than 1,500 cells/ micro L.

PURPOSE:Rituximab is commonly used as a single agent or in combination therapy for non-Hodgkin's lymphoma (NHL). Ibritumomab tiuxetan radioimmunotherapy targets the same antigen as rituximab and has demonstrated efficacy in rituximab-naïve NHL. This study evaluated ibritumomab tiuxetan in the treatment of rituximab-refractory follicular NHL. PATIENTS AND METHODS:Eligible patients were refractory to rituximab; this was defined as no objective response to rituximab (375 mg/m(2) weekly for 4 weeks) or time to progression (TTP) of < or = 6 months. The ibritumomab tiuxetan treatment regimen consisted of pretreatment with rituximab (250 mg/m(2) intravenously on days 1 and 8) to deplete peripheral blood B cells, then yttrium-90 ibritumomab tiuxetan (0.4 mCi/kg; maximum, 32 mCi) intravenously on day 8, administered on an outpatient basis. An imaging/dosimetry dose of indium-111 ibritumomab tiuxetan (5 mCi) was injected after rituximab (day 1) in 28 patients. RESULTS:Fifty-seven patients were treated. The median age was 54 years, 74% had tumors > or = 5 cm, and all were extensively pretreated (median, four prior therapies; range, one to nine). The estimated radiation-absorbed doses to healthy organs were below the study-defined limit in all patients studied with dosimetry. The overall response rate for the 54 patients with follicular NHL was 74% (15% complete responses and 59% partial responses). The Kaplan-Meier-estimated TTP was 6.8 months (range, 1.1 to > or = 25.9 months) for all patients and 8.7 months for responders. Adverse events were primarily hematologic; the incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 35%, 9%, and 4%, respectively. CONCLUSION:Ibritumomab tiuxetan radioimmunotherapy is effective in rituximab-refractory patients. The only significant toxicity is hematologic.

Radioimmunotherapy using Zevalin(TM) (Y-90-ibritumomab tiuxetan) is a novel treatment for non-Hodgkin's lymphoma that is highly effective even in refractory patients. Here, we present safety results on 349 patients treated in five major clinical trials. Hematological side-effects were acceptable and immune recovery was rapid. Median T-cell counts were unaffected by Zevalin(TM) therapy, and median CD3(+)/CD4(+) and CD3(+)/CD8(+) T-cell counts remained within the normal range. During 3 months of follow-up, only 6.6% patients required hospitalization for infection. Unlike chemotherapy, Zevalin(TM) treatment does not disrupt mucosal membranes, which may account for the relatively low rate of infection. In conclusion, the Zevalin(TM) regimen was safe and well tolerated in these patients.

Mildly thrombocytopenic patients with relapsed or refractory low-grade non-Hodgkin lymphoma (NHL) have an increased risk of chemotherapy-induced myelosuppression following treatment. The safety and efficacy of radioimmunotherapy with a reduced dose of (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]; maximum 32 mCi [1.2 GBq]) was evaluated in 30 patients with mild thrombocytopenia (100-149 x 10(9) platelets/L) who had advanced, relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. The ibritumomab tiuxetan regimen included an infusion of rituximab (250 mg/m(2)) and injection of (111)In ibritumomab tiuxetan (5 mCi [185 MBq]) for dosimetry evaluation, followed 1 week later with rituximab (250 mg/m(2)) and (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]). Patients (median age, 61 years; 90% stage III/IV at study entry; 83% follicular lymphoma; and 67% with bone marrow involvement) had a median of 2 prior therapy regimens (range, 1-9). Estimated radiation-absorbed doses were well below the study-defined maximum allowable for all 30 patients. With the use of the International Workshop criteria for NHL response assessment, the overall response rate was 83% (37% complete response, 6.7% complete response unconfirmed, and 40% partial response). Kaplan-Meier estimated median time to progression (TTP) was 9.4 months (range, 1.7-24.6). In responders, Kaplan-Meier estimated median TTP was 12.6 months (range, 4.9-24.6), with 35% of data censored. Toxicity was primarily hematologic, transient, and reversible. The incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 33%, 13%, and 3%, respectively. Reduced-dose ibritumomab tiuxetan is safe and well tolerated and has significant clinical activity in this patient population.

The Fifteenth International Symposium of the Foundation for Promotion of Cancer Research entitled 'New Horizons in the Diagnosis and Treatment of Hematological Malignancies Based on Molecular Genetic Features' was held in Tokyo on January 15-17, 2002. Twenty-nine invited speakers, including 12 from abroad and 17 from Japan, presented the updated results of their research. After an overview of the classification of hematological malignancies, new findings on some disease entities based on novel immunophenotypic and molecular genetic features were presented. The results of gene expression profiling and BCL6 and C-MYC gene rearrangement in diffuse large B-cell lymphoma were presented and oncogenic mechanism of acute myeloid leukemia was discussed. In the treatment of non-Hodgkin's lymphoma and acute leukemia, the present consensus and future directions were discussed based on the results of multicenter trials in the USA and Japan. As a molecular targeting therapy, the remarkable effect of a BCR-ABL tyrosine kinase inhibitor, STI571, in chronic myeloid leukemia and gastrointestinal stromal tumor was presented. Thereafter, promising results of active immunotherapy, chimeric anti-CD20 monoclonal antibody, anti-CD20 radioimmunoconjugate and anti-CD22 immunotoxin for B-cell lymphoma were presented. Finally, recent advances in allogeneic hematopoietic stem cell transplantation were discussed, focusing on reduced-intensity preparative regimens. The recent advances in basic and clinical research on hematological malignancies would lead to further improvement in the prognosis and quality of life of patients suffering from leukemia or lymphoma.

Ibritumomab tiuxetan (Zevalin) is a murine anti-CD20 monoclonal antibody covalently bound to the chelator tiuxetan, which can securely chelate yttrium-90. We performed a randomized controlled trial