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Radioimmunotherapy (RIT) with tositumomab and iodine 131 tositumomab can produce durable and complete responses in relapsed/refractory low-grade Non-Hodgkin's lymphoma. Patients with bone marrow involvement (BMI) with tumor25% of the intertrabecular space are generally excluded from RIT because of risk of excessive hematologic toxicity. The authors conducted a dose-escalation study of tositumomab and iodine 131 tositumomab to determine whether RIT is feasible in this population. Patients had baseline BMI of25% and platelet count ofor=150,000/mm3. In contrast to the usual 75 cGy total body dose of radiation, dose escalation of Iodine I 131 tositumomab began at a total body dose of 45 cGy, and increased to 55 cGy in a second cohort. Dose-limiting toxicity (DLT) was defined as absolute neutrophil count500 cells/mm3 or platelets25,000/mm3 for17 days, or absolute neutrophil count750/mm3 or platelets50,000/mm3 for24 days. Eleven subjects were enrolled (8 at 45 cGy and 3 at 55 cGy). Estimated BMI ranged from 30 to 65% (median approximately 40%). Patients had received a median of three prior chemotherapies (range 1 - 6). One of the six evaluable patients treated at 45 cGy experienced DLT. Three patients received 55 cGy, one had hematologic DLT concurrent with lymphoma progression and extensive BMI at relapse. Three of 11 (27%) patients received hematologic supportive care. Two patients had objective responses of 1 and 42.4+ months, respectively. RIT with attenuated dose iodine 131 tositumomab for patients with25% BMI has acceptable toxicity and can result in lymphoma responses.

Purpose: The aim of this study was to review advances in radioimmunotherapy (RIT) for non-Hodgkin's lymphoma (NHL) and to discuss the role of the radiation oncologist in administering this important new form of biologically targeted radiotherapy. Methods and Materials: A review of articles and abstracts on the clinical efficacy, safety, and radiation safety of yttrium Y 90 ( 90 Y) ibritumomab tiuxetan (Zevalin) and iodine I 131 tositumomab (Bexxar) was performed. Results: The clinical efficacy of RIT in NHL has been shown in numerous clinical trials of 90 Y ibritumomab tiuxetan and 131 I tositumomab. Both agents have produced significant responses in patients with low-grade, follicular, or transformed NHL, including patients with disease that had not responded or had responded poorly to previous chemotherapy or immunotherapy. Reversible toxicities such as neutropenia, thrombocytopenia, and anemia are the most common adverse events with both agents. Conclusions: Radioimmunotherapy is safe and effective in many patients with B-cell NHL. 90 Y ibritumomab tiuxetan and 131 I tositumomab can produce clinically meaningful and durable responses even in patients in whom chemotherapy has failed. Treatment with RIT requires a multispecialty approach and close communication between the radiation oncologist and other members of the treatment team. The radiation oncologist plays an important role in treating patients with RIT and monitoring them for responses and adverse events after treatment.

Advanced-stage follicular B-cell lymphoma is considered incurable. Anti-CD20 radioimmunotherapy is effective in patients who have had a relapse after chemotherapy or who have refractory follicular lymphoma, but it has not been tested in previously untreated patients.Seventy-six patients with stage III or IV follicular lymphoma received as initial therapy a single course of treatment with 131I-tositumomab therapy (registered as Tositumomab and Iodine I 131 Tositumomab [the Bexxar therapeutic regimen]). This consisted of a dosimetric dose of tositumomab and 131I-labeled tositumomab followed one week later by a therapeutic dose, delivering 75 cGy of radiation to the total body.Ninety-five percent of the patients had any response, and 75 percent had a complete response. The use of polymerase chain reaction (PCR) to detect rearrangement of the BCL2 gene showed molecular responses in 80 percent of assessable patients who had a clinical complete response. After a median follow-up of 5.1 years, the actuarial 5-year progression-free survival for all patients was 59 percent, with a median progression-free survival of 6.1 years. The annualized rate of relapse progressively decreased over time: 25 percent, 13 percent, and 12 percent during the first, second, and third years, respectively, and 4.4 percent per year after three years. Of 57 patients who had a complete response, 40 remained in remission for 4.3 to 7.7 years. Hematologic toxicity was moderate, with no patient requiring transfusions or hematopoietic growth factors. No cases of myelodysplastic syndrome have been observed.A single one-week course of 131I-tositumomab therapy as initial treatment can induce prolonged clinical and molecular remissions in patients with advanced follicular lymphoma.

The treatment for non-Hodgkin's lymphoma (NHL) has improved over the past 20 years, but the natural history of the disease has not improved with conventional therapeutics. New modalities using targeted therapy based on molecular biology and immunology hold promise for better outcomes with less toxicity. Major radionuclides available (iodine I 131 and yttrium 90) are discussed and clinical trial data with the 90 Y–labeled antibody ibritumomab tiuxetan are presented. Long-term toxicity questions are addressed, the use of dosimetry as a means for predicting toxicity is reviewed, and quality-of-life analyses are discussed. Radioimmunotherapy represents a safe and effective treatment modality for patients with NHL.

Targeted radioimmunotherapy, including yttrium 90-labeled ibritumomab tiuxetan (Zevalin) and iodine I 131 tositumomab (Bexxar), has the potential to increase the cure rate for patients with CD20+ B-cell malignancies who are undergoing autologous hematopoietic stem cell transplantation. The results of phase I and II trials suggest that radioimmunoconjugates can be safely combined with high-dose chemotherapy, although the optimal approach remains to be established. This review focuses on the use of 90Y ibritumomab tiuxetan combined with high-dose chemotherapy in the setting of autologous hematopoietic stem cell transplantation.

PurposeAn open-label phase II study was conducted at two centers to establish the efficacy and safety of tositumomab and iodine I 131 tositumomab at first or second recurrence of indolent or transformed indolent B-cell lymphoma.Patients and MethodsA single dosimetric dose was followed at 7 to 14 days by the patient-specific administered radioactivity required to deliver a total body dose of 0.75 Gy (reduced to 0.65 Gy for patients with platelets counts of 100 to 149 × 109/L). Forty of 41 patients received both infusions.ResultsThirty-one of 41 patients (76%) responded, with 20 patients (49%) achieving either a complete (CR) or unconfirmed complete remission [CR(u)] and 11 patients (27%) achieving a partial remission. Response rates were similar in both indolent (76%) and transformed disease (71%). The overall median duration of remission was 1.3 years. The median duration of remission has not yet been reached for those patients who achieved a CR or CR(u). Eleven patients continue in CR or CR(u) between 2.6+ and 5.2+ years after therapy. Therapy was well tolerated; hematologic toxicity was the principal adverse event. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia were observed in 5%, 45%, and 32% of patients, respectively. Secondary myelodysplasia has occurred in one patient. Four patients developed human antimouse antibodies after therapy. Five of 38 assessable patients have developed an elevated thyroid-stimulating hormone; treatment with thyroxine has been initiated in one patient.ConclusionHigh overall and CR rates were observed after a single dose of tositumomab and iodine I 131 tositumomab in this patient group. Toxicity was modest and easily managed.

Learning Objectives After completing this course, the reader will be able to: Describe advances in clinical radioimmunotherapy. Discuss ongoing translational research in radioimmunotherapy. Identify future directions for radioimmunotherapy in cancer medicine. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at http://CME.TheOncologist.com Purpose. Immunotherapy using monoclonal antibodies to specifically target B cells has provided new hope to many patients with indolent lymphomas, particularly those with chemotherapy-refractory disease. Lymphomas are extremely sensitive to radiation, and significant progress has been made over the last decade in the development of radioimmunotherapy with anti-CD20 antibodies. Materials and Methods. Herein we review clinical experience with tositumomab and iodine I 131 tositumomab (Bexxar®; Corixa Corporation; South San Francisco, CA; and GlaxoSmithKline; Philadelphia, PA) in patients with non-Hodgkin's lymphoma. Results. Therapy with Bexxar has demonstrated high response rates and long durations of response compared with unconjugated anti-CD20 antibodies in patients with relapsed low-grade and transformed low-grade non-Hodgkin's lymphomas. Iodine-131 (I-131) has a long history of clinical experience, an excellent safety record, and favorable nuclear and pharmacologic properties. Importantly, the gamma emissions of iodine-131 facilitate accurate dosimetry to calculate the appropriate patient-specific therapeutic activity to deliver a predetermined total-body dose of radiation, thereby minimizing hematologic toxicity. In clinical trials of Bexxar, objective response rates ranged from 54%–71% in heavily pretreated patients. In the pivotal trial, the number of patients with a longer duration of response after treatment with Bexxar was significantly greater than the number of patients with a longer duration of response after their last qualifying chemotherapy regimen. In 76 newly diagnosed patients, the objective response rate was 97%, and 63% of patients achieved complete responses. Conclusion. These data suggest that Bexxar will become an important new option in the treatment of indolent lymphoma.

Advanced follicular lymphoma is incurable with conventional chemotherapy and radiotherapy. The Southwest Oncology Group (SWOG) conducted a phase 2 trial (S9911) of a novel regimen consisting of 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed 4 to 8 weeks later by tositumomab/iodine I 131 tositumomab (anti-CD20 antibody) in 90 eligible patients with previously untreated, advanced stage follicular lymphoma. Treatment was well tolerated. Reversible myelosuppression was the main adverse event and was more severe during CHOP chemotherapy than following radioimmunotherapy. The overall response rate to the entire treatment regimen was 90%, including 67% complete remissions (CRs plus unconfirmed CRs [CRu's]) and 23% partial remissions (PRs). Twenty-seven (57%) of the 47 fully evaluable patients who achieved less than a CR with CHOP improved their remission status after tositumomab/iodine I 131 tositumomab. With a median follow-up of 2.3 years, the 2-year progression-free survival (PFS) was estimated to be 81%, with a 2-year overall survival of 97%. This study has established the feasibility, tolerability, and efficacy of this regimen for patients with advanced follicular lymphoma. This novel treatment appears promising compared with the SWOG's historical experience using CHOP alone and is currently being compared with CHOP plus rituximab in a randomized phase 3 trial (S0016).

Radioimmunotherapy with radiolabeled anti-CD20 antibodies is a promising new treatment approach for low-grade non-Hodgkin's lymphoma. However, the administration of radiolabeled antibodies presents some added complexity. At the University of Nebraska Medical Center (Omaha, NE), an institutional model has been developed that ensures the efficient and safe delivery of tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corp, South San Francisco, CA and GlaxoSmithKline, Philadelphia, PA). An integrated, multidisciplinary treatment team is responsible for managing all aspects of treatment. Using this model, it is possible to administer tositumomab and iodine I 131 tositumomab safely and effectively in the outpatient setting. Patients can usually be released immediately after treatment. Guidelines and instructions for patient release have been developed and validated and are provided herein. These instructions ensure that radiation exposure of family members and caregivers who are exposed to the patient is maintained as low as reasonably achievable and well within regulatory limits. Semin Oncol 30 (suppl 4):39-49. © 2003 Elsevier Inc. All rights reserved.

Radioimmunotherapy (RIT) is a promising emerging therapy for non-Hodgkin's lymphoma and may ultimately prove useful in the treatment of other tumors. The most extensively investigated RIT agent is tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corp, South San Francisco, CA, and GlaxoSmithKline, Philadelphia, PA) which has been administered to over 1,000 patients during the past 9 years. As with most drugs, there is considerable interpatient variability in the clearance rate (or total body residence time) of radioimmunoconjugates. The clearance rate of iodine I 131 tositumomab in clinical trials has varied by as much as five-fold. The advantage of RIT with iodine-131, which emits both gamma photons and beta particles, is that by scanning it allows for the determination of the patient-specific total body residence time by the administration of a trace-labeled dose of the radionuclide (ie, dosimetric dose). By administration of the dosimetric (trace-labeled) dose, and determination of the patient's residence time (a measure of how long the radionuclide is retained in the body), the therapeutic dose can be precisely adjusted to maximize the therapeutic effect and minimize toxicity. Tositumomab and iodine I 131 tositumomab is a specific therapeutic at two levels: first, it specifically targets the tumor, delivering a log or more radiation to tumor compared with the rest of the body; and second, the administered dose of radioactivity is patient-specific. The paradigm of a targeted drug with a patient-specific dose may become more routine as targeted therapies are further developed along with better assays to directly measure drug levels. For the present, whole-body dosimetry is routinely applied for RIT with tositumomab and iodine I 131 tositumomab and has proven to be a reliable method to determine the patient-specific maximally tolerated therapeutic radiation dose to maximize efficacy while minimizing organ and bone marrow toxicity. Semin Oncol 30 (suppl 4):31-38. © 2003 Elsevier Inc. All rights reserved.

Enthusiasm for the use of monoclonal antibodies, such as rituximab, has markedly changed the approach to patients with non-Hodgkin lymphomas (NHLs). Nevertheless, more effective therapies are needed. Radioimmunotherapy as a form of targeted radiation therapy may add significantly to our therapeutic options. Yttrium Y 90 ibritumomab tiuxetan, recently approved by the Food and Drug Administration, and iodine I 131 tositumomab have demonstrated a high level of activity in patients whose NHL has failed to respond to chemotherapy and rituximab. Toxicities have primarily included prolonged myelosuppression, with a potential risk of treatment-associated myelodysplastic syndrome and acute myelogenous leukemia. Ongoing clinical trials are attempting to better characterize the role of these promising agents.

PURPOSE: To evaluate the efficacy and safety of tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corp, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA) in patients with chemotherapy-refractory low-grade or transformed low-grade non-Hodgkin’s lymphoma (NHL) and to compare its efficacy to the patients’ last qualifying chemotherapy (LQC) regimens. PATIENTS AND METHODS: Sixty patients who had been treated with at least two protocol-specified qualifying chemotherapy regimens and had not responded or progressed within 6 months after their LQC were treated with a single course of iodine I 131 tositumomab. RESULTS: Patients had received a median of four prior chemotherapy regimens. A partial or complete response (CR) was observed in 39 patients (65%) after iodine I 131 tositumomab, compared with 17 patients (28%) after their LQC (P < .001). The median duration of response (MDR) was 6.5 months after iodine I 131 tositumomab, compared with 3.4 months after the LQC (P < .001). Two patients (3%) had a CR after their LQC, compared with 12 (20%) after iodine I 131 tositumomab (P < .001). The MDR for CR was 6.1 months after the LQC and had not been reached with follow-up of more than 47 months after iodine I 131 tositumomab. An independent review panel verified that 32 (74%) of the 43 patients with nonequivalent durations of response (> 30 days difference) had a longer duration of response after iodine I 131 tositumomab (P < .001). Only one patient was hospitalized for neutropenic fever. Five patients (8%) developed human antimurine antibodies, and one (2%) developed an elevated TSH level after treatment. Myelodysplasia was diagnosed in four patients in follow-up. CONCLUSION: A single course of iodine I 131 tositumomab was significantly more efficacious than the LQC received by extensively pretreated patients with chemotherapy-refractory, low-grade, or transformed low-grade NHL and had an acceptable safety profile.

CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine 131I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P = .005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine 131I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL.

PURPOSE: This multicenter phase II study evaluated the efficacy, dosimetry methodology, and safety of iodine-131 tositumomab in patients with chemotherapy-relapsed/refractory low-grade or transformed low-grade non-Hodgkin’s lymphoma (NHL). PATIENTS AND METHODS: Patients received a dosimetric dose that consisted of 450 mg of anti-B1 antibody followed by 35 mg (5 mCi) of iodine-131 tositumomab. Serial total-body gamma counts were then obtained to calculate the patient-specific millicurie activity required to deliver the therapeutic dose. A therapeutic dose of 75 cGy total-body dose (attenuated to 65 cGy in patients with platelet counts of 101,000 to 149,000 cells/mm3) was given 7 to 14 days after the dosimetric dose. RESULTS: Forty-five of 47 patients were treated with a single dosimetric and therapeutic dose. Twenty-seven patients (57%) had a response. The response rate was similar in patients with low-grade (57%) or transformed low-grade (60%) NHL. The median duration of response was 9.9 months. Fifteen patients (32%) achieved a complete response (CR; 10 CRs and five clinical CRs), including five patients (50%) with transformed low-grade NHL. The median duration of CR was 19.9 months, and six patients have an ongoing CR. Treatment was well tolerated, with the principal toxicity being hematologic. The most common nonhematologic toxicities that were considered to be possibly related to the treatment included mild to moderate fatigue (32%), nausea (30%), fever (26%), vomiting (15%), infection (13%), pruritus (13%), and rash (13%). Additionally, one patient developed human-antimouse antibodies. CONCLUSION: Iodine-131 tositumomab produced a high overall response rate, and approximately one third of patients had a CR despite having chemotherapy-relapsed or refractory low-grade or transformed low-grade NHL.

Tositumomab and iodine I 131 tositumomab (Bexaar) therapeutic regimen targets monoclonal antibodies against the CD20 antigen expressed in non-Hodgkin lymphoma. This article reviews the mechanism of action and clinical indications for this regimen.

BACKGROUND Iodine I-131 tositumomab is a well tolerated and effective therapy for recurrent low-grade and transformed low-grade non-Hodgkin lymphoma (NHL). Hematologic reserve after radioimmunotherapy (RIT) is an important consideration when subsequent therapy is required. METHODS One hundred fifty-five patients who received treatment with I-131 tositumomab were assessed, and 68 patients had progressive disease after RIT. The median age (n = 68 patients) was 59 years (range,18–82 yrs), and patients received a median of 2 pre-RIT regimens (range,1–8 regimens), including 66% who received anthracycline, 19% who received platinum, and 50% who received fludarabine. RESULTS The median time to disease progression (among progressors) was 168 days (range, 19–771 days). At the time they developed recurrent disease, patients had median white blood cell count (WBC) of 4.9 K cells/μL (range, 1.1–21.4 K cells/μL), a median absolute neutrophil count (ANC) of 3.25 K cells/μL (range, 0.59–8.20 K cells/μL), a median platelet count of 130 K cells/μL (range, 9–440 K cells/μL), and there was no significant difference between pre-RIT and recurrence values except for the platelet count (P < 0.05). No patient demonstrated a WBC < 1.0 K cells/μL or an ANC < 0.5 K cells/μL, although 1 patient had a platelet count < 10 K cells/μL. Twenty-four patients subsequently received no further chemotherapy; and, in 21 patients (88%), hematologic parameters appeared to allow subsequent chemotherapy if necessary (blood counts: National Cancer Institute Grade 0–2). Among 44 patients (65%) who received further chemotherapy (median, 2 regimens; range, 1–4 regimens), 19 patients (43%) were treated with anthracyclines, 17 patients (39%) were treated with platinum, 10 patients (23%) were treated with fludarabine, and 13 patients (30%) underwent stem cell transplantation. Disease improvement occurred in most patients, although 18 patients died (40%) after further chemotherapy, predominantly from refractory lymphoma. CONCLUSIONS Most patients with progressive disease after treatment with iodine I-131 tositumomab were able to receive subsequent therapy, including cytotoxic chemotherapy and stem cell transplantation. Cancer 2006. © 2005 American Cancer Society.

Purpose To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma. Patients and Methods Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab. Results After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT. Conclusion Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.

Purpose: A multicenter, randomized study was undertaken to estimate the single agent activity of Tositumomab and to determine the contribution of radioisotope-labeling with 131I to activity and toxicity by comparing treatment outcomes for Tositumomab and Iodine I 131 Tositumomab (BEXXAR) to an equivalent total dose of unlabeled Tositumomab.Experimental Design: Seventy-eight patients with refractory/relapsed non-Hodgkin’s lymphoma were randomized to either unlabeled Tositumomab or Iodine I 131 Tositumomab. Patients progressing after unlabeled Tositumomab could cross over to receive Iodine I 131 Tositumomab. The median follow-up at analysis was 42.6 months (range 1.9 to 71.5 months).Results: Responses in the Iodine I 131 Tositumomab versus unlabeled Tositumomab groups: overall response 55% versus 19% (P = 0.002); complete response 33% versus 8% (P = 0.012); median duration of overall response not reached versus 28.1 months (95% confidence interval: 7.6, not reached); median duration of complete response not reached in either arm; and median TTP 6.3 versus 5.5 months (P = 0.031), respectively. Of the patients who had a complete response after initial Iodine I 131 Tositumomab therapy, 71% (10 of 14) continued in complete response at 29.8 to 71.1 months. Two patients who achieved a complete response after unlabeled Tositumomab had ongoing responses at 48.1 to 56.9 months. Nineteen patients received Iodine I 131 Tositumomab crossover therapy. Responses after crossover versus prior response to unlabeled Tositumomab were as follows: complete response rates of 42% versus 0% (P = 0.008); overall response 68% versus 16% (P = 0.002); median durations of overall response 12.6 versus 7.6 months (P = 0.001); and median TTP 12.4 versus 5.5 months (P = 0.01), respectively. Hematologic toxicity was more severe and nonhematologic adverse events were more frequent after Iodine I 131 Tositumomab than after Tositumomab alone. Elevated thyrotropin occurred in 5% of patients. Seroconversion to human antimurine antibody after Iodine I 131 Tositumomab, unlabeled Tositumomab, and Iodine I 131 Tositumomab-crossover was 27%, 19%, and 0%, respectively.Conclusions: Unlabeled Tositumomab showed single agent activity, but in this direct comparison, all of the therapeutic outcome measures were significantly enhanced by the conjugation of 131I to Tositumomab.

Objectives To provide information regarding the most important properties of the new therapeutic agents marketed in 2003. Data Sources Product labeling supplemented selectively with published studies and drug information reference sources. Study Selection By the author. Data Extraction By the author. Data Synthesis The 28 new therapeutic agents marketed in the United States during 2003 are reviewed in this article: adalimumab, agalsidase beta, ale- facept, alfuzosin hydrochloride, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, bortezomib, daptomycin, efalizumab, eletriptan hydrobromide, emtricitabine, enfuvirtide, eplerenone, gefitinib, icodextrin, laronidase, memantine hydrochloride, mequinol/tretinoin, miglustat, nitazoxanide, omal- izumab, palonosetron hydrochloride, pegvisomant, rosuvastatin calcium, tadalafil, tositumomab and iodine I 131 tositumomab, and vardenafil hydrochloride. Indications and information on dosage and administration for these agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. When possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. Conclusion A number of the new therapeutic agents marketed in 2003 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.

The majority of patients with non-Hodgkin's lymphoma (NHL) who respond to conventional chemotherapy will relapse and eventually become refractory to chemotherapy. Each subsequent remission is typically of similar or shorter duration than the last. Recent developments in radioimmunotherapy using monoclonal antibodies to specifically target malignant B cells have yielded promising results in relapsed and refractory NHL patients. The radiolabeled anti-CD20 antibody tositumomab and iodine 131 tositumomab (Bexxar; Corixa Corp, South San Francisco, CA and GlaxoSmithKline, Philadelphia, PA) has been shown to be safe and effective in the treatment of patients with relapsed low-grade (indolent) NHL. Objective responses were achieved in 57% to 71% of patients in phase I to phase III trials, and remission durations were significantly longer in the phase III trial compared with the last remission induced by chemotherapy. In addition, tositumomab and iodine I 131 tositumomab was shown to be effective in the subset analysis of patients with transformed low-grade NHL, which is particularly resistant to conventional therapies. The incidence of transient, nonhematologic adverse events was low and mainly mild to moderate in severity. Hematologic toxicity is the major dose-limiting toxicity associated with radioimmunotherapy; however, patient-specific dosimetry maintained hematologic toxicity within predictable, transient, and manageable limits in the phase II and phase III trials of tositumomab and iodine I 131 tositumomab. Although approximately 10% of patients treated with tositumomab and iodine I 131 tositumomab developed human-antimouse antibodies, treatment with tositumomab does not preclude the administration of subsequent chimeric antibody therapies. In conclusion, these studies show that tositumomab and iodine I 131 tositumomab treatment is safe and induces high response rates and durable remissions in heavily pretreated patients with low-grade or transformed low-grade NHL. Semin Oncol 30 (suppl 4):22-30. © 2003 Elsevier Inc. All rights reserved.

Radioimmunotherapy with anti-CD20 antibodies is a promising treatment approach for relapsed low-grade non-Hodgkin's lymphoma. Under revised Nuclear Regulatory Commission regulations (May 1997), patients may be released following treatment provided the maximum dose to any individual is not likely to exceed 500 mrem. Non-Hodgkin's lymphoma patients have been studied to evaluate radiation exposure to caregivers/family members after outpatient treatment with tositumomab and iodine I 131 tositumomab (Bexxar® therapy). Estimates of total radiation doses to individuals expected to be maximally exposed to patients posttreatment have revealed that the doses should be within revised guidelines. In a University of Nebraska Medical Center study, the predicted total radiation doses (based on patient dose rate at 1 meter) ranged from 95–423 mrem. Family members were provided radiation-monitoring devices to directly monitor radiation exposure. Measured doses ranged from 10–409 mrem. In this and other studies, estimated and measured dose equivalents to maximally exposed individuals were below 500 mrem. Measured doses were, in most instances, lower than those predicted by patientspecific calculations, thus confirming the validity of the calculated dose predictions. Therefore, radioimmunotherapy with tositumomab and iodine I 131 tositumomab can be safely conducted on an outpatient basis.

While the use of radioimmunotherapy for lymphoma increases, the feasibility and efficacy of autologous stem cell transplant for subsequent relapse remains unknown. We report a 48-year-old male with transformed follicular mixed non-Hodgkin's lymphoma. After treatment with three different combination chemotherapy regimens, at relapse he received radioimmunotherapy with iodine (131)I tositumomab (anti-CD20), with very good response. At later relapse, a second course of (131)I tositumomab was given unsuccessfully. He underwent peripheral blood stem cell harvest, chemoradiotherapy conditioning and autologous transplantation with prompt engraftment and without significant complications. He remains in complete remission with normal blood counts 25 months post autograft.

PURPOSE The CD20 B-lymphocyte surface antigen expressed by B-cell lymphomas is an attractive target for radioimmunotherapy, treatment using radiolabeled antibodies. We conducted a phase I dose-escalation trial to assess the toxicity, tumor targeting, and efficacy of nonmyeloablative doses of an anti-CD20 monoclonal antibody (anti-B1) labeled with iodine-131 (131I) in 34 patients with B-cell lymphoma who had failed chemotherapy. PATIENTS AND METHODS Patients were first given tracelabeled doses of 131I-labeled anti-B1 (15 to 20 mg, 5 mCi) to assess radiolabeled antibody biodistribution, and then a radioimmunotherapeutic dose (15 to 20 mg) labeled with a quantity of 131I that would deliver a specified centigray dose of whole-body radiation predicted by the tracer dose. Whole-body radiation doses were escalated from 25 to 85 cGy in sequential groups of patients in 10-cGy increments. To evaluate if radiolabeled antibody biodistribution could be optimized, initial patients were given one or two additional tracer doses on successive weeks, each dose preceded by an infusion of 135 mg of unlabeled anti-B1 one week and 685 mg the next. The unlabeled antibody dose resulting in the most optimal tracer biodistribution was also given before the radioimmunotherapeutic dose. Later patients were given a single tracer dose and radioimmunotherapeutic dose preceded by infusion of 685 mg of unlabeled anti-B1. RESULTS Treatment was well tolerated. Hematologic toxicity was dose-limiting, and 75 cGy was established as the maximally tolerated whole-body radiation dose. Twenty-eight patients received radioimmunotherapeutic doses of 34 to 161 mCi, resulting in complete remission in 14 patients and a partial response in eight. All 13 patients with low-grade lymphoma responded, and 10 achieved a complete remission. Six of eight patients with transformed lymphoma responded. Thirteen of 19 patients whose disease was resistant to their last course of chemotherapy and all patients with chemotherapy-sensitive disease responded. The median duration of complete remission exceeds 16.5 months. Six patients remain in complete remission 16 to 31 months after treatment. CONCLUSION Nonmyeloablative radioimmunotherapy with 131I-anti-B1 is associated with a high rate of durable remissions in patients with B-cell lymphoma refractory to chemotherapy.

Abstract 4916 Introduction: The Bexxar® Therapeutic Regimen for relapsed/refractory follicular lymphoma (FL) is administered in 2 steps: a dosimetric dose and a therapeutic dose. Radioactive counts, obtained from sequential gamma camera scans of the whole body at several time points after the dosimetric dose, determine the patient (pt)-specific clearance (total body residence time, TBRT) and, along with pt body size, allow determination of the prescribed activity (PA) of the therapeutic dose. Pts do not receive the therapeutic dose if TBRT is outside 50 to 150 hrs and/or gamma camera images show altered biodistribution. TBRT is used to calculate the mCi of I-131 (PA) required to deliver the appropriate therapeutic dose of 65 or 75 cGy to the total body, depending on platelet count. Our aims were 1) to evaluate an alternative, inexpensive sodium iodide probe (probe) detector-based method of measuring radioactive counts for determination of TBRT and 2) to evaluate the clinical benefit of visually assessing gamma camera images for altered biodistribution. Methods: We retrospectively compared probe and gamma camera methods from a phase II study (RIT-II-001) and evaluated altered biodistribution assessed by gamma camera images from a post-marketing observational study. Forty-one of 47 FL pts enrolled in RIT-II-001 from December 1995 to November 1996 were included in the retrospective analysis of TBRT and PA. Pts received a median of 5 prior chemotherapies (range 2–13). Thirty of 41 (73%) pts had low-grade B-NHL, 90% had stage III or IV disease, 51% had bone marrow involvement, 88% had an International Prognostic Index score ≥ 2, and 16 of 34 (47%) pts had bulky disease >500 g. Dosimetry analysis was performed at 3 time points (Day 0; Day 2, 3, or 4; and Day 6 or 7) after dosimetric dose, as currently required for determining PA. The PAs of the therapeutic dose using TBRTs derived from probe and gamma camera counts were compared. Also, we retrospectively evaluated cases of altered biodistribution in an observational post-marketing study (BEX114606) of 2,649 pts who received a dosimetric dose from June 2003 to February 2010. Dosimetry and gamma camera images were independently reviewed from reported cases of altered biodistribution to evaluate the clinical benefit of visually assessing gamma camera images. Results: The mean TBRTs from the clinical study were 94.5 and 95.0 hrs from the probe and gamma camera methods, respectively, and individual TBRTs were highly correlated (r = 0.98). The mean PAs of the therapeutic dose, derived from probe and gamma camera TBRTs, were 85.8 mCi and 85.3 mCi, respectively. The point estimate for the ratio of the PA was 0.995 and the 90% CI (0.984, 1.006) was well within the typical range of 0.80 to 1.25 for demonstrating bioequivalence. The observational study found that only 5 of 2,649 (0.2%) pts did not receive the therapeutic dose due to suspected altered biodistribution. Dosimetry data and gamma camera images were available for 3 pts. Independent review confirmed that all 3 pts had accurately determined TBRTs, but only 1 pt had confirmed altered biodistribution by visual assessment of gamma camera images and TBRTs. Conclusion: TBRTs derived from probe and gamma camera counts were highly comparable. Thus, the probe and gamma camera methods to determine TBRT and calculate the PA of the therapeutic dose of Bexxar appear equivalent. Altered biodistribution prevented only 5 of 2,649 (0.2%) pts from receiving the therapeutic dose of Bexxar. Only 1 pt (0.04%) was independently confirmed to have altered biodistribution by visual assessment of gamma camera images, consistent with the TBRT. Therefore, visual assessment of gamma camera images added no benefit beyond TBRT in determining whether to administer the therapeutic dose of Bexxar. These data indicate that either sequential probe or gamma camera-based dosimetry is sufficient for determining whether to administer the therapeutic dose, and that visual assessment of gamma camera images does not appear to be necessary to detect the rare instance of an altered biodistribution. Disclosures: Horner: GlaxoSmithKline: Employment. Off Label Use: The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) is indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory non-Hodgkin's lymphoma. Siegel: GlaxoSmithKline: Consultancy. Jewell: GlaxoSmithKline: Employment. Lunger: GE Healthcare: Employment. Young: GlaxoSmithKline: Employment. Wynne: GlaxoSmithKline: Employment. Williams: GlaxoSmithKline: Employment. Lin: GlaxoSmithKline: Employment. Kaminski: GlaxoSmithKline: Patents & Royalties, Research Funding. Wahl: GlaxoSmithKline: Consultancy, Patents & Royalties; Nihon Medi Physics: Consultancy; Spectrum Pharmaceuticals: Consultancy; Naviscan PET systems: Consultancy; Threshold Pharmaceuticals: Equity Ownership. Vleisides: GlaxoSmithKline: Employment.

Abstract 3960 Introduction: The efficacy and safety of tositumomab and iodine I 131 tositumomab (TST/I-131-TST), the Bexxar® Therapeutic Regimen, were evaluated in 60 patients (pts) with chemotherapy-refractory low-grade (LG) or transformed B-cell non-Hodgkin's lymphoma (B-NHL) who had received at least 2 chemotherapy regimens and had either not responded to (72%) or had progressed within 6 months of their last regimen (28%) (J Clin Onc 2001; 19:3918 and Blood 2004; Abstract 2631). The primary efficacy endpoint was comparison of the number of pts who had a longer duration of response to TST/I-131-TST with the number of pts with a longer duration of response to their last qualifying chemotherapy (LQC). Thirty-nine (65%) pts, including 20% who attained a complete response (CR), responded to TST/I-131-TST, compared to 17 (28%) pts, including 3% CR, after their LQC (p Patients and Methods: Pts were enrolled from 22 November 1996 to 06 March 1998. Pts alive at the last report date (1 March 2004) were followed for long-term safety and survival, and pts in remission at the last report date were followed for continued response. Results: Sixty pts received the dosimetric dose, and 58 of 60 pts received both the dosimetric and therapeutic doses of TST/I-131-TST. The median number of prior chemotherapies was 4 (range, 2–13). Fifty-nine of 60 (98%) pts had stage III/IV disease, 56% had bone marrow (BM) involvement, and 88% had ≥ two IPI risk factors at study entry. Thirty-six pts had LG B-NHL, 23 pts had a history of transformed B-NHL, and 1 pt had mantle cell NHL (MCL). Forty-eight (80%) pts have died, of whom 77% died due to lymphoma progression. Twelve pts were alive, and 6 pts were in CR at last follow-up. One pt withdrew consent for further follow-up but was in CR at 5.0 years, and the other 5 pts (4 LG, 1 transformed B-NHL) were in CR of ≥ 10 years' duration. The pts who continued in CR had received a median of 3 different prior chemotherapy regimens (range, 2–5), and no pts had received prior rituximab. For all 12 pts who attained CR, the median duration of response was 9.9 years (range, 0.7–11.7 years). Long-term toxicity included 7 pts who developed hypothyroidism. Secondary cancers included 1 lung adenocarincoma, 1 colon cancer, and 7 skin cancers which were reported previously. In addition, 1 developed a myeloproliferative disorder (MPD). No cases of MDS beyond the 4 previously reported were observed. Conclusion: A single course of TST/I-131-TST achieved durable remissions in chemotherapy-refractory LG and transformed B-NHL pts, with 5 of the 12 pts who achieved CR still in remission ≥ 10 years later. No additional cases of MDS were observed, but 1 pt developed a MPD since the last report. Thus, the final results of this study demonstrate that TST/I-131-TST is able to attain long-lasting durable CRs, with an acceptable toxicity profile, in a subset of pts with chemotherapy-refractory LG and transformed B-NHL. Disclosures: Kaminski: GlaxoSmithKline: Patents & Royalties, Research Funding. Zelenetz:GlaxoSmithKline: Research Funding. Press:GlaxoSmithKline: Research Funding; Spectrum Pharmaceuticals: Honoraria; Roche/Genentech: Honoraria. Saleh:GlaxoSmithKline, Novartis, Imcoline, Celgene: Honoraria, Speakers Bureau. Leonard:GlaxoSmithKline: Consultancy. Lister:GlaxoSmithKline: Chairman of Safety Monitoring Board for GSK. Horner:GlaxoSmithKline: Employment. Williams:GlaxoSmithKline: Employment. Lin:GlaxoSmithKline: Consultancy, Employment. Vleisides:GlaxoSmithKline: Employment. Knox:GlaxoSmithKline: Research Funding. Wahl:GlaxoSmithKline: Consultancy, Patents & Royalties; Nihon Medi Physics: Consultancy; Spectrum Pharmaceuticals: Consultancy; Naviscan PET systems: Consultancy; Threshold Pharmaceuticals: Equity Ownership. Vose:GlaxoSmithKline: Research Funding.

Abstract 3759 Poster Board III-695 Purpose Tositumomab and iodine I 131 tositumomab (Bexxar® Therapeutic Regimen) has been found effective in relapsed/refractory follicular lymphoma. We now report updated results of a single center, single-arm, Phase II trial of a single one-week course of this treatment for 76 previously untreated, stage III and IV, follicular lymphoma patients (reporting period June 1996 to May 2009). Patients and Methods Patients had a median age of 49 years (range 23 to 69) and received a dosimetric dose followed by a single total body dose of 75 cGy iodine I-131 tositumomab one week later. Seventy percent had stage IV disease and 70% of patients had histological grade 1 follicular lymphoma, 29% had grade 2, and 1 patient had mantle-cell lymphoma. Bone marrow involvement was present in 64% of patients; 43% of patients had at least one tumor 3 5 cm in diameter; LDH was elevated in 30%. Overall, 35% of patients had high risk Follicular Lymphoma International Prognostic Index (FLIPI) scores and 50% had intermediate risk scores. Patients entered long-term follow-up after disease progression or after 2 years on study. Response, second malignancy occurrence and thyroid medication use were assessed every 6 months for 5 years and yearly thereafter up to 12 years post treatment. Results As previously reported (NEJM 352:441, 2005), the overall response rate was 97% with 57 patients (75%) achieving a complete remission. Hematologic toxicity, although common, was modest to moderate (grade 4 neutropenia in 5% of patients and no grade 4 thrombocytopenia). After a median of 10 years follow-up (range 0.7 to 12.3 years), the median duration of response was 6 years (95% CI: 2.5, 10.8), with approximately 40% remaining progression-free at 10 years. For the 57 complete responders, median progression-free survival was 10.9 years (95% CI: 8.3, NR). Ten-year overall survival was approximately 82%. Five cases (7%) of hypothyroidism occurred 0.5 to 2.9 years after treatment and were managed with thyroid hormone replacement. Eleven patients (14%) were diagnosed with second malignancies including 4 skin neoplasms (2 basal cell and 2 squamous cell) and 7 visceral neoplasms (3 breast, 2 prostate, 1 endometrial cancer, 1 glioblastoma). One case of myelodsyplastic syndrome was diagnosed about 8 years after treatment. Conclusion A single course of treatment with Bexxar therapeutic regimen can commonly produce durable responses, especially durable complete responses lasting over a decade in patients with untreated follicular lymphoma. Further studies comparing this monotherapy to other regimens, including combination therapies, are warranted. Disclosures: Kaminski: GlaxoSmithKline: Honoraria, Patents & Royalties, Research Funding, Speakers Bureau. Off Label Use: Radioimmunotherapeutic for treatment of frontline treatment of follicular lymphoma. On-label use is for relapsed/refractory patients. Horner:GlaxoSmithKline: Employment. Williams:GlaxoSmithKline: Employment. Vleisides:GlaxoSmithKline: Employment. Wahl:Nordion: Honoraria; GlaxoSmithKline: Patents & Royalties.

Abstract 2732 Poster Board II-708 PURPOSE: Patients with indolent lymphoma generally require a number of therapies to address the relapsing course of disease and it is therefore important to provide long-term safety and efficacy data for novel therapeutics. We evaluated such data from the original phase II trial of the tositumomab and iodine-131 tositumomab therapeutic regimen in patients with indolent, follicular large-cell, or transformed B-cell lymphoma, progressive after rituximab METHODS: From July 1998 to November 1999, 40 patients with a median age of 57 years (24 rituximab nonresponders: 11 with response 7 cm and 20 patients (50%) had tumor masses >5 cm. The median number of prior treatments was 4 (range 1–11); 59% of patients were chemotherapy-resistant. Histology included follicular grade 1–2 (26), grade 3 (2), other indolent (2), and transformed (10). After 2 years on study or after disease progression, long term follow-up was conducted every 6 months for 10 years with CT and laboratory studies. This report presents an update, with investigator-assessed tumor evaluation, from the J Clin Oncol 23:712, 2005. RESULTS: The median duration of follow-up from the dosimetric dose was 54 (range 1–119) months. The overall response rate was 72% (28 of 39 evaluable patients with 9 complete responders). The median duration of overall response was 18.9 months; the proportion of patients maintaining response at 5 years is estimated at 40% with just two known relapses after two years. Five of 9 complete responders have been continuously maintained. For all 40 study patients, the median progression-free survival (PFS) was 10.4 months (95% CI: 5.7, 18.6) and the estimated 5 year PFS is 28%. The estimated median overall survival for all patients is 80.0 months. To date, 20 deaths have been reported, 10 without documented disease progression. Six second cancers have occurred: 2 acute leukemia, 1 prostate, 2 skin (1 squamous, 1 Merkel cell) and 1 primary hepatic. The incidence of secondary leukemia remains the same as previously reported in 2005 at 5% (2 of 40 patients). Seven of the 40 patients enrolled in this study had elevated thyroid stimulating hormone (TSH) levels prior to receiving the therapeutic dose of iodine-131 tositumomab and 2 patients did not have baseline TSH data. Of the 31 patients with normal baseline TSH levels prior to treatment, 3 developed elevated TSH as of July 2009 and as reported previously (J Clin Oncol 23:712, 2005). There were no cases of hypothyroidism reported as an adverse event by investigators as of July 2009. CONCLUSIONS: The group of extensively pretreated (median = 4) patients participating in this phase II study survived a median of 6.7 years after receiving the BEXXAR® therapeutic regimen. No additional cases of leukemia were seen and no unexpected toxicities were observed. Of the 72% of patients responding to treatment, about 40% were estimated to continue their response at 5 years, including 5 of 9 complete responders. These data demonstrate durable efficacy of BEXXAR® in an indolent lymphoma population with disease progression after rituximab. Disclosures: Horning: GlaxoSmithKline: Honoraria, Research Funding. Podoloff:GE Healthcare: Honoraria, Research Funding. Horner:GlaxoSmithKline: Employment. Williams:GlaxoSmithKline: Employment. Vleisides:GlaxoSmithKline: Employment.

e19529 Background: Radioimmunotherapy is a therapeutic option for relapsed or refractory indolent, follicular and transformed non Hodgkin's lymphoma and mantle cell lymphoma. Although prolongued myelotoxicity has been described with use of iodine I 131 tositumomab (TOSI) and yttrium 90 ibritumomab tiuxetan (IBRI), analysis of toxicity according to patients’ age at therapy still lacks. Methods: Utilizing the Rush University Medical Center database 61 subjects who received RIT between November/2003 and June/2008, either with TOSI or IBRI were divided in 2 groups according to age at time of therapy. Group 1 included patients between 33 and 60 (51.8±6.5) years of age (N=29) and group 2 included patients 61 years old or older (70.1±7.8) (N=32). Parameters compared between groups were: Time to nadir of lowest absolute neutrophil count (ANC), time to recovery ANC above 1000/mcL, time to nadir of lowest hemoglobin levels, time to recovery to hemoglobin levels above 8g/dL, time to lowest platelet count and time to recovery to platelet count above 100,000/mcL. Incidence o myelodysplastic syndrome (MDS) was also compared between groups. Groups characteristics such as sex, type of RIT, presence of disease in bone marrow, FLIPI/IPI and use of G-CSF were noted. Results: There was no significant statistical difference between groups in time (number of days) to achieve nadir of ANC (group 1 85.3±208; group 2 50.3±19.9), nadir of hemoglobin levels (group 1 106±60.6; group 2 84±57.0) and time to nadir of platelet level (group 1 53.5±70.7; group 2 41.8±9.6). There was no statistical significant difference between groups in duration of cytopenias, except for time for platelet recovery which was significant longer in group 2 using the Pearson Correlation analysis. (p=0.008). (Days for platelets recovery to levels above 100,000/mcL group 1 29.4±27.7; group 2 108.8 ±207.3). One patient in group 1 and three patients on group 2 were diagnosed with MDS but were also treated with different chemotherapy regimens. Conclusions: RIT should be considered a safe therapeutic modality in patients with refractory or relapsed indolent, follicular, NHL, transformed and Mantle Cell lymphoma regardless of age. [Table: see text]

It has been proposed that treatment failures in multiple myeloma (MM) are related to the chemoresistance of a subset of malignant myeloma cells with clonogenic potential to the anti-myeloma drugs (Matsui et al., Cancer Research2008, 68:190). Studies suggest that these putative myeloma stem cells (MSC) are CD138neg and express CD20, which is usually absent in more differentiated malignant plasma cells (Matsui et al., Blood2004, 15:2332). These findings provided a rationale for a treatment strategy to eliminate chemoresistant clonogenic MSC using anti-CD20 antibodies. To evaluate the clinical effects of anti-CD20 treatment, we developed a phase II trial with Bexxar as a consolidation treatment for MM. We hypothesized that Bexxar would be more efficacious than unlabeled antibody in the eradication of highly radiosensitive myeloma cells by both direct and cross-fire effects. Preclinical studies showed that tositumomab, the antibody used in Bexxar, inhibited colony formation of clonogenic myeloma cells. To be eligible for Bexxar treatment, patients must have completed at least 4 cycles of therapy (1st to 3rd line) and have measurable disease in a plateau of at least partial response (PR). To date, 10 of 30 patients have been enrolled, of which 5 were treated with Bexxar after completion of initial therapy prior to proceeding to autologous stem cell transplant (ASCT). Patients proceeding to ASCT required hematopoietic stem cells collection prior to Bexxar and 3 months after Bexxar. Eight patients are evaluable for response and toxicities. At 3 months post Bexxar, 1 patient achieved a partial response (PR), 4 patients had stable disease (SD), and 1 patient progressed (PD). At 1 year post Bexxar, 1 patient with initial PR achieved CR and remains in CR, 1 patient is in unconfirmed CR, 2 are in partial response (PR), and 3 remain in SD. After a median 20 months of followup (range 4–24), all patient are alive, 4 in continued response, 3 with SD. Hematological toxicities were mild to moderate (1 patient grade 3 and 4 patients grade 2 thrombocytopenia, 4 patients grade 2 neutropenia). Non-hematological toxicity was limited to HAMA (6 patients). Out of patients who received Bexxar prior to transplant, 3 collected stem cells post-Bexxar without problems, one requires re-collection. Three patients who proceeded to ASCT to date using the post-Bexxar stem cell collection, engrafted at 11–12 days, and had no unexpected toxicities with ASCT. We also analyzed CD20+ cells in bone marrow aspirates (BM) and stem cell collections (SCC) using samples collected from 4 patients before and after Bexxar. Bexxar treatment eliminated a median 80% of CD20+ cells (range 23–97). For a given patient, elimination of CD20+ cells from SCC correlated with elimination of CD20+ cells from BM. The most complete elimination of CD20+ cells from BM was observed in 2 patients who at 1 year achieved CR (94% and 97%), compared to patients who achieved PR (23% and 68%). We conclude that anti-CD20 consolidation treatment of myeloma patients with Bexxar used as targeted therapy against clonogenic myeloma cells is feasible and well tolerated. Clinical outcomes to date are encouraging considering that clonogenic MSC represent

Objective : CD20 has been recently recognized as a potential immunotherapeutic target in Hodgkin’s lymphoma (HL), being expressed in all malignant cells in lymphocyte-predominant HL (LPHL), a subset of classical HL (cHL), and in normal surrounding B-cells. Recent data also suggest that the cancer stem cell in cHL is phenotypically distinct from Reed-Sternberg cells and expresses B-cell antigens including CD20 (Jones RJ et al, Blood2006; 108: abstract 470). Given the single agent activity of the unlabeled antiCD20 monoclonal antibody, rituximab, in HL, we are conducting a phase I/II study of tositumomab and Iodine I 131 (131I-) tositumomab (BEXXAR ®, GlaxoSmithKline) for HL in the relapsed/refractory setting, regardless of tumor CD20 expression. We report on feasibility and initial safety. Methods : Separate dose-escalation studies were performed for patients with and without prior stem cell transplantation, starting at 55 and 75 cGy total body radiation doses (TBD), respectively. Dosimetry imaging studies were performed after administration of 450 mg tositumomab and 5 mCi 131I-tositumomab. Patients then received a single patient-specific therapeutic dosage of 450 mg tositumomab and 131I-tositumomab. The TBD was escalated or de-escalated based on a continual reassessment method (CRM). Results : Seven patients with relapsed/refractory disease (6 cHL, 1 LPHL; mean age 36 ± 9) have been enrolled. Four patients with cHL were negative for CD20 on malignant Reed-Sternberg cells and two had mixed expression. Three patients who had failed transplant received a 55 cGy TBD of 131I-tositumomab and three ineligible for transplant received 75 cGy. No dose-limiting toxicities were observed and based on the CRM, the TBD was escalated to 79 cGy for the post-transplant group and to 87 cGy for the no transplant group. To date, one in the next post-transplant cohort received 79 cGy and experienced grade 1 thrombocytopenia and grade 3 lymphopenia with count recovery. No adverse reactions occurred during infusion of unlabeled or radiolabeled tositumomab, and the agent was generally well-tolerated in all dosing cohorts. The expected hematologic adverse events were common and are summarized in the Table. No patients experienced grade 3 or 4 non-hematologic toxicity. One patient had grade 1 or 2 fever, chills, joint and muscle pain suggesting possible human anti-mouse antibody formation and immune complex mediated inflammation. One patient with LPHL had a complete response, two with cHL had stable disease (1 mixed CD20 expression, 1 CD20 negative) and 4 with cHL had progressive disease (1 mixed CD20 expression, 3 CD20 negative) at 12 weeks post-131I-tositumomab. Conclusions : Tositumomab and 131I-tositumomab can be safely administered to patients with relapsed/refractory HL. Major toxicities are hematologic, similar to its effect in patients with non-Hodgkin’s lymphoma. The CRM was used successfully for determining TBD for subsequent cohorts, and the transplant recipients have tolerated higher doses than those previously reported in non-Hodgkin’s lymphoma. These encouraging preliminary data support further dose escalation and suggests some therapeutic effect of tositumomab and 131I-tositumomab against HL. Hematologic Adverse Events All (n=7) Grade Range of Duration of Grade 3/4 Toxicity (days) 1/2 3 4 Thrombocytopenia 6 0 1 1 7–34 Neutropenia 2 1 0 1 7 Lymphopenia 7 2 3 2 1–35 Anemia 2 1 1 0 4

It has been proposed that treatment failures in multiple myeloma (MM) may be related to chemoresistance of malignant myeloma clonogenic cells (myeloma stem cells). Studies suggest that these cells are CD138− and express CD20, which is usually absent in more differentiated malignant plasma cells (Matsui et al, Blood 2004,15:2332). These findings provided a rationale for a treatment strategy to eliminate clonogenic myeloma cells using anti-CD20 antibodies. We conducted preclinical studies in vitro with tositumomab, the unlabeled anti-CD20 antibody in Bexxar. Bone marrow aspirates from MM patients were depleted of CD138 and CD34 to obtain CD138−CD34− cell populations by MACS separation using antibodies coupled to magnetic microbeads. These cells were treated with tositumomab for 24 hrs and plated in methylcellulose media. After 3 weeks of incubation, tositumomab inhibited colony formation of clonogenic myeloma cells. To evaluate the clinical effects of anti-CD20 treatment we developed a phase II trial with Bexxar as a consolidation treatment of MM. We hypothesized that Bexxar would be more efficacious than unlabeled antibody in eradication of highly radiosensitive myeloma cells by direct and cross-fire effects. To be eligible for Bexxar treatment, patients must have completed at least 4 cycles of therapy (1st to 3rd line) and have measurable disease in a plateau of at least partial response (PR) lasting at least 6 weeks. Patients undergoing first line therapy who are eligible for transplant are required to collect stem cells prior to Bexxar and have a second stem cell collection 3 months after Bexxar treatment. Samples for clonogenic studies are collected prior to Bexxar treatment, and at 3 months and 1 year post treatment. To date, 7 of 30 patients have been enrolled, 3 after completion of first line therapy with Velcade, Doxil, Dexamethasone (VDD) and prior to autologous stem cell transplant (ASCT), 4 in a plateau of PR after ASCT. Bexxar treatment was tolerated well in all patients with expected toxicities. Hematologic toxicities were mild. Two patients developed grade 3, and 4 grade 2 neutropenia, 4 patients grade 2 thrombocytopenia, and 1 grade 2 anemia. One patient (post ASCT) developed symptomatic HAMA requiring admission and 3 other patients (1 post ASCT, 2 prior to ASCT) developed HAMA titers without symptoms. Three patients who proceeded to ASCT collected stem cells prior to and after Bexxar treatment and all used post-Bexxar stem cell collections for ASCT. There were no difficulties encountered with stem cell collection. All engrafted at 11–12 days and had no unexpected toxicities with ASCT. Patients who proceeded to ASCT had stable disease (SD) at the end of 3-month period of Bexxar treatment. All remain in remission 6–9 months post Bexxar treatment (all in VGPR). Of patients who were treated with Bexxar post ASCT, 1 achieved a minor response (> 25%), 2 have SD with a followup of 1–12 months, and 1 had progressive disease at 3 months with subsequent 9 months of SD without intervention. The effects of Bexxar treatment on clonogenic myeloma cells are under evaluation and will be presented. We conclude that anti-CD20 consolidation treatment of myeloma patients with Bexxar used as targeted therapy against clonogenic myeloma cells is feasible and well tolerated. Clinical outcomes to date are encouraging, since clonogenic myeloma cells represent

6561 Background: Tositumomab and Iodine I 131 Tositumomab (the BEXXAR Therapeutic Regimen) has been studied in clinical trials of pts with previously untreated, relapsed, and refractory NHL. The re...

6560 Background: Tositumomab and Iodine I 131 Tositumomab (the BEXXAR Therapeutic Regimen, hereafter Iodine I 131 Tositumomab) yields high rates of durable and complete (CR) responses in pts with r...

Objective: Pts are first diagnosed with NHL at a median age of 60 yrs. There is increasing support for the idea that physicians should evaluate older pts for cancer treatment on the basis of their health status and cognitive function rather than on chronologic age. Five core clinical trials and an expanded-access program included 995 pts with relapsed/refractory LG follicular or transformed NHL treated with BEXXAR. Data were analyzed to establish the efficacy and safety of BEXXAR as a function of age. Safety data have been presented previously (Gregory et al. Blood. 2003;102. Abstract 1485). Overall toxicity and acute hematologic toxicity associated with BEXXAR in older pts is similar to that observed in pts ≤60 yrs. Methods: BEXXAR efficacy was analyzed by age: group 1 pts, ≤60 yrs (n=586); group 2 pts, >60–≤70 yrs (n=250); group 3 pts, >70 yrs (n=159). Median age at time of BEXXAR was 58 yrs (range, 21–88 yrs). Inclusion criteria included KPS ≥60, platelet count ≥100,000/mm3, ANC ≥1,500 cells/mm3, bone marrow involvement ≤25%, and no impaired renal, hepatic, or cardiac function. Results: All 3 pt groups had received multiple therapies for NHL before receiving BEXXAR (1–3 prior treatments, 63%–65%; ≥4 prior treatments, 34%–37%). In addition to the known poorer prognosis with older age, pts in groups 2 and 3 more frequently had other poor prognostic features, ie, transformed histology and prior radiotherapy ( P 60–≤70 yrs (23% vs 12%) and tripled for pts >70 yrs (23% vs 7%). Conclusions: Of all previously treated pts >60 yrs, ≥50% achieved a response post-BEXXAR. Nearly 25% of pts >60 yrs achieved a CR, with a median duration of CR of 32.3 mos. Response rates and durations of response are somewhat better in younger pts than in pts >60 yrs, but pts >60 yrs presented with poorer prognostic features (as above). Overall toxicity and acute hematologic toxicity associated with BEXXAR in older pts is similar to that observed in pts ≤60 yrs (Gregory et al. Blood. 2003;102. Abstract 1485). BEXXAR can be administered safely and effectively to older pts with low-grade follicular or transformed NHL. Table 1 Response results to BEXXAR by age, N = 995 | Age groups | Overall response, % | CR, % | Median CR duration, mos | |:-----------------:| ------------------- | ----- | ----------------------- | | ≤ 60 | 66 | 37 | 59.1 | | (n=586) | | | 95% CI = 45.8, NR) | | 60 to ≤70 N = 250 | 50 | 23 | 21.8 | | (n=250) | | | (95% CI = 15.7, 69.1) | | >70 | 54 | 23 | 36.4 | | (n=159) | | | (95% CI = 22.6, NR)

Background: Tositumomab and Iodine I 131 Tositumomab (BEXXAR®) is approved for the treatment of recurrent LG or transformed CD20+ NHL refractory to Rituximab or relapsed after chemotherapy. In 5 trials and an expanded access program (>995 pts), response rates were 47%–68% (durable CRs in up to 30%) with median response durations of 12–18 months. Most pts who relapsed post-BEXXAR tolerated subsequent cytotoxic regimens, stem cell transplant, localized radiation, Rituximab, and Bexxar re-treatment. Methods: A retrospective analysis of 49 pts with relapsed/refractory LG NHL and transformed NHL treated at Rush U. Medical Center (1998–2001) evaluated treatments pre-Bexxar, responses to BEXXAR, and treatments post-BEXXAR. All pts received BEXXAR as previously described (JCO. 19:3918). Median age was 57 yrs (range, 28–88 yrs); 88% had stage III/IV disease, and 49% had bone marrow involvement. Median time from diagnosis to Bexxar treatment was 31 mo (range, 8–204 mo); median prior treatments was 3 (range, 1–7). Prior therapies included anthracycline/ anthracenedione-based therapy in 36 (73%) pts, fludarabine in 22 (45%) pts, both in 16 (33%) pts, and Rituximab in 22 (45%) pts. Median time from last treatment failure or relapse was 3 mo (range, 1–15 mo). Results: Overall response rate to BEXXAR was 63%, with CR in 16 (33%) pts, and PR in 15 (30%) pts. Four (8%) pts had SD. Median duration of response was 11 mo (range, 3–41 mo). Of 16 CRs, 12 (75%) were durable (TTF >12 mo). After a median follow-up of 5.3 yrs (range, 2.7–6.1 yrs), 24 (77%) of 31 responders were alive. Of the 18 nonresponders, 14 died within 1 year, and 4 pts were alive after subsequent therapy. Overall, 19 pts died from progressive disease and 2 from other causes (lung cancer and MDS/AML). Relapse After BEXXAR. 17 pts relapsed after BEXXAR and received other therapies: 11 of 12 patients who received monoclonal antibodies (Rituximab or BEXXAR) have responded and were alive at last follow up (Table 1). Retreatment With BEXXAR. After a median follow-up of 3.4 yr since BEXXAR re-treatment, 3 pts remained in CR (2 with no further therapy); 2 were alive with disease. Interestingly, CR duration after Bexxar re-treatment compared favorably with the first Bexxar treatment in 3 pts (Table 2). Conclusion: Radioimmunotherapy (RIT) is one of the most efficacious treatments for relapsed LG NHL and is delivered over a single week with tolerable toxicity, most of which is hematologic and reversible. Our results suggest that pts who relapse after RIT can be safely and effectively treated with various therapies and responses comparable to pts without prior RIT. We have shown that BEXXAR re-treatment may lead to significantly longer duration of remission compared to initial BEXXAR therapy. Table 1. Relapsed Patients:Treatment After BEXXAR Treatment Alive Dead No Further Treatment 2 0 Rituxan alone 3 0 BEXXAR 5 0 RT only 1 0 Rituximab/Chemo/RT 2 1 Rituximab/Chemo/BMT 1 0 Chemo 0 1 Chemo for Lung Ca 0 1 Table 2. Response to Retreatment With BEXXAR (All Received Fludarabine Prior to Bexxar) Patient Response, Bexxar #1 # Treatments Response, Bexxar #2 1 CR 7 mo 0 CR 3.5 years to date 2 CR 13 mo 0 CR 3 years to date 3 CR 6 mo 1 CR 3 years, alive with disease 4 CR 12 mo 2 CR 9 mo, alive with disease 5 CR 10 mo 2 PR 3 mo, alive with disease

Low grade NHL with or without transformation is characterized by recurrence. Initial response rates with chemotx are high, but all patients ultimately relapse, and the response rates and durations of response typically decline with each subsequent course of chemotx. In the pivotal trial of Bexxar (JCO 19:3918 2001) there were significantly more patients with longer durations of response than after their last qualifying chemotx. The aim of the current retrospective study was to evaluate the efficacy of Bexxar and prior chemotx by course of treatment in a larger group of patients. Response rates (RR) and duration of response data were available from the treatment histories of the 230 patients from five clinical studies. Demographics: median age, 56 years; age > 60, 34%; median number of prior regimens, 3 (range 1–13); bone marrow involvement, 48%; bulky disease, 32%; transformed histology 28%; IPI score ≥ 2, 81%; and refractory to their preceding regimen, 80%. The patient-specific dosing regimen for Bexxar was previously described (JCO 19:3918). RR and durations for chemotx used as the 2nd, 3rd, 4th, 5th, 6th and >6th treatment were compared to Bexxar for the same numerical treatment. At each successive treatment course, there was a consistently higher RR and duration of response after Bexxar than after chemotx (Table). The actual differences in RR may be greater, as the data for Bexxar are based on responses observed on at least 2 evaluations >4 weeks apart, as assessed by an independent, blinded Masked Independent Randomized Radiology and Oncology (MIRROR) panel. The reported RR for chemotx are based on Investigator-assessed unconfirmed responses. Of note, the % responding pts in continuous response at ≥ five year after receiving Bexxar for the 2nd, 3rd, 4th, 5th, 6th and >6th relapse were 41%, 21%, 25%, 35%, 36 and 9%, respectively. While RR decreased with number of prior therapies, the durations of response and percent in continuous response after Bexxar were substantial and consistent across the range of the number of prior therapies. | Treatment/Regimen Number | | Chemotx | | | Bexxar | | |:------------------------ | --- | --------------------------- | ------------------------------------ | -- | ------------------------- | ------------------------------------ | | | n | Response Rate (Unconfirmed) | Median Duration of Response (months) | n | Response Rate (Confirmed) | Median Duration of Response (months) | | 2 | 183 | 51% | 8.0 | 27 | 74% | 14.4 | | 3 | 145 | 52% | 5.0 | 44 | 64% | 47.2 | | 4 | 98 | 45% | 5.0 | 54 | 52% | 10.8 | | 5 | 45 | 40% | 4.0 | 48 | 54% | 11.0 | | 6 | 33 | 36% | 4.0 | 21 | 52% | 27.0 | | 7 or more | 48 | 19% | 3.5 | 36 | 42% | 9.6

6573 Background: In an overall population of 995 pts, Iodine I 131 Tositumomab was administered to 740 eligible pts with relapsed/refractory follicular grade 1/2 (n = 651) and small lymphocytic (n = 89) NHL. To be eligible, pts had to have a platelet count ≥ 100,000/mm3 and ≤ 25% of bone marrow involvement with lymphoma. Methods: Independently assessed data from 5 clinical trials (N = 230) were integrated with investigator-assessed data from an expanded access program (N = 765). Correlation between investigator- and independently reviewed responses was > 90%. The median follow-up was 25.5 mo (range, 0.1–117.7 mo). Results: Demographics (for follicular vs small lymphocytic NHL): male: 55%, 64%; age >65: 23%,37%; stage III/IV: 88%,92%; median time from diagnosis: 42mo,41mo; ≥ 4 prior therapies: 30%,35%; BM involvement: 44%, 62%; tumor diameter ≥ 5 cm: 48%,44%; prior Rituximab: 45%,60%; prior radiation: 21%,17%. The OR rate for follicular grade 1/2 NHL was significantly higher than for small lymphocytic (P

6518 Background: The sequential combination of chemotherapy and radioimmunotherapy offers a novel strategy for the initial management of NHL. Tositumomab and iodine I 131 tositumomab (Bexxar) have been demonstrated to have substantial clinical activity in both untreated and relapsed/refractory low-grade NHL. Fludarabine synergizes in vitro with unlabeled and radiolabeled antibodies and can be employed as a “debulking” agent prior to radioimmunotherapy. Methods: Patients with previously untreated, advanced low-grade NHL were treated with IV fludarabine 25 mg/m2/day for 5 days, every 5 wks for 3 cycles followed in 6 to 8 wks by Bexxar therapy. Results: Between August 1998 and June 1999, 38 pts (51% follicular mixed, 49% follicular small cleaved) were enrolled and 97% had stage III/IV disease. Thirty-five subjects received both fludarabine and Bexxar therapy. Three patients came off study before or during fludarabine therapy (one due to cytopenias, 2 unrelated to toxicity or lymphoma progression). Response t...

6732 Background: The Bexxar (tositumomab and iodine I 131 tositumomab [B]) therapeutic regimen yields high rates of complete and durable responses in pts with relapsed/refractory LG NHL. Methods: The safety of B therapy was reviewed for 995 pts with relapsed/refractory LG NHL, including 230 pts in 5 clinical trials and 765 pts in an expanded access program (EAP). Demographics and risk factors were similar for both groups except that pts from EAP were less heavily pretreated (median, 2 vs 4 prior therapies) and more frequently received Rituximab (56% vs 17%). All adverse events (AEs) occurring within 13 wks of treatment were reported, regardless of relationship to study drug. Median follow-up was 24 mo (range, 0.1 - 118 mo). Results: Most frequent hematologic (heme) AEs were grade (gr) 3/4 neutropenia (41%), thrombocytopenia (37%), and anemia (12%), requiring supportive care in 27% of pts (G-CSF, 12%; erythropoietin, 10%; platelet transfusions 12%; packed RBCs, 16%). Bleeding events occurred in 7% of pts (...

6575 Introduction: The Bexxar therapeutic regimen can produce durable and complete responses in patients with relapsed/refractory low-grade NHL. Virtually all previous studies of radioimmunotherape...

6520 Background: A phase II, open-label, multicenter study was conducted to determine the efficacy of Bexxar therapy following CVP in pts with previously untreated follicular NHL. Methods: Pts rece...

In an accompanying editorial, Schein, Scheffler, and Carter provide an insightful and comprehensive assessment of the current status of cancer drug development in the U.S. They point out that, despite the great progress that has been made in understanding cancer biology and in the identification of new “targets” for drug discovery, the rate of cancer drug approvals remains distressingly low. Not counting monoclonal antibodies, only two new “targeted” small molecules have won approval in the past decade: imatinib mesylate and gefitinib, and the latter after a difficult and controversial debate. They point out that the accelerated approval mechanism of the U.S. Food and Drug Administration (FDA) has hastened the marketing of few new chemical entities in its 13-year history. In the past several months, a minor flurry of new agents (imatinib mesylate for gastrointestinal stromal tumors, bortezomib for myeloma, gefitinib for non-small cell lung cancer [NSCLC], and tositumomab & iodine I 131 tositumomab for lymphoma) have been granted accelerated approval, but with postmarketing requirements for additional trials. Only two (bortezomib and gefitinib) represent new chemical entities, and neither are a true “breakthrough” agent at this point. As Schein and colleagues point out, there clearly is a