Iodine-131 tositumomab (Bexxar): radioimmunoconjugate therapy for indolent and transformed B-cell non-Hodgkin's lymphoma

Tositumomab is an immunoglobulin G murine monoclonal antibody that binds to the CD20 antigen on the surface of normal and malignant human B-cells. Tositumomab is linked covalently with iodine-131 to produce the radioimmunoconjugate iodine-131 tositumomab (Bexxar). The iodine-131 tositumomab regimen was approved by the US Food and Drug Administration in June 2003 for the treatment of patients with CD20-positive, follicular non-Hodgkin's lymphoma, both with and without transformation, whose disease is refractory to rituximab (Rituxan) and has relapsed following chemotherapy. The dose-limiting toxicity of iodine-131 tositumomab is bone marrow suppression and resulting cytopenias. Unlike chemotherapy, the majority of nonhematologic adverse events associated with iodine-131 tositumomab are mild to moderate in nature and usually self limited. Iodine-131 tositumomab represents one of the most active single agents for the treatment of recurrent indolent and transformed B-cell non-Hodgkin's lymphoma, as demonstrated by several clinical trials summarized in this review. At the present time, the use of radioimmunoconjugate therapy is largely limited to patients with disease refractory to rituximab therapy and transformed disease not amenable to high-dose therapy and autologous stem cell support. Longer follow-up of ongoing clinical trials should provide reassurance as to safety and insights as to the additive stem cell toxicity from iodine-131 tositumomab administration. Studies are also addressing the role of iodine-131 tositumomab as a component of initial therapy for indolent non-Hodgkin's lymphoma and in additional histologies of non-Hodgkin's lymphoma.     

Safe administration of iodine-131 tositumomab after repeated infusion-related reactions to rituximab

Infusion-related reactions during administration of monoclonal antibody therapy are often mild and unlikely to recur with subsequent treatment. If patients experience another severe reaction upon reattempting treatment, future treatments with the same agent are typically not pursued. It is unclear whether different monoclonal antibodies that bind the same tumor cell or antigen are likely to induce similar infusion reactions. Here, we report the case of a patient with repeated severe infusion reactions with rituximab who subsequently safely received treatment with iodine-131 tositumomab and discuss the relevant literature.     

Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I(131) tositumomab

Radioimmunotherapy, targeting the CD20 antigen, in B-cell lymphoma has clearly demonstrated efficacy and tolerability over the preceding 15 years. As a result, two products are available with Food and Drug Administration approval for marketing - Y(90) ibritumomab tiuxetan and I(131) tositumomab, given as the Zevalin and Bexxar therapeutic regimens, respectively. Both demonstrate high-response rates and durability of remission in the relapsed/refractory disease setting. Data are emerging regarding their utility as initial therapy, and furthermore, they are been investigated for use sequentially with chemotherapy, and in the myeloablative setting. As yet however, how to best use these agents in the clinical disease course remains uncertain.     

Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma.

PURPOSE: An 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 METHODS: A 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 x 10(9)/L). Forty of 41 patients received both infusions. RESULTS: Thirty-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. CONCLUSION: High 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.     

Subsequent therapy can be administered after tositumomab and iodine I-131 tositumomab for non-Hodgkin lymphoma

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/microL (range, 1.1-21.4 K cells/microL), a median absolute neutrophil count (ANC) of 3.25 K cells/microL (range, 0.59-8.20 K cells/microL), a median platelet count of 130 K cells/microL (range, 9-440 K cells/microL), 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/microL or an ANC<0.5 K cells/microL, although 1 patient had a platelet count<10 K cells/microL. 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.     

Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas.

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/mm(3)) 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.     

Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin's lymphoma.

PURPOSE: To determine the maximum outpatient dose of iodine-131 tositumomab (up to 0.75 Gy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem-cell transplantation (ASCT) for the treatment of chemotherapy-resistant relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Twenty-three patients with chemotherapy-refractory or multiply-relapsed B-cell NHL were treated in a phase I trial combining iodine-131 tositumomab (ranging from 0.30 to 0.75 Gy total-body dose [TBD]) with high-dose BEAM followed by ASCT. RESULTS: The complete response rate after transplantation was 57%, and the overall response rate was 65%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 38 months (range, 27 to 60 months), the overall survival (OS) rate was 55%, and the event-free survival (EFS) rate was 39%. CONCLUSION: There were no significant added toxicities apparent with the addition of iodine-131 tositumomab up to a dose of 0.75 Gy TBD to high-dose BEAM chemotherapy followed by ASCT. The EFS and OS were encouraging in this group of chemotherapy-resistant or refractory B-cell NHL patients. A follow-up phase II trial with iodine-131 tositumomab at the dose of 0.75 Gy TBD with BEAM is currently ongoing.     

利妥昔单抗联合CHOP方案治疗B细胞非霍奇金淋巴瘤的疗效观察

目的探讨利妥昔单抗联合环磷酰胺+多柔比星+长春新碱+泼尼松(CHOP方案)治疗B细胞非霍奇金淋巴瘤的疗效及安全性。方法选取2018年10月至2020年12月间湘乡市人民医院收治的76例B细胞非霍奇金淋巴瘤患者,采用单双号抽签方式分为观察组和对照组,每组38例。对照组患者采用常规CHOP方案治疗,观察组患者采用利妥昔单抗联合CHOP方案治疗,比较两组患者疾病控制情况、远期生存率及治疗期间不良反应。结果观察组患者治疗有效率为86.8%,高于对照组的65.8%,差异有统计学意义(P <0.05)。观察组患者1年和3年无进展生存时间(PFS)和总生存时间(OS)均高于对照组,差异均有统计学意义(均P <0.05);观察组患者5年PFS和OS均高于对照组,但差异无统计学意义(P> 0.05)。两组患者白细胞下降、血小板减少、恶心呕吐、脱发及贫血等不良反应发生率比较,差异无统计学意义(P> 0.05)。结论 B细胞非霍奇金淋巴瘤患者采用利妥昔单抗联合CHOP方案治疗,近期效果较好,可提高远期生存率,且不增加不良反应,临床值得推广。     

Re-treatment with I-131 tositumomab in patients with non-Hodgkin's lymphoma who had previously responded to I-131 tositumomab.

PURPOSE: To study efficacy and safety of re-treatment with I-131 tositumomab in patients with low-grade, follicular, or transformed low-grade B-cell lymphoma who relapsed following a response to I-131 tositumomab. PATIENTS AND METHODS: A prior response > or = 3 months to I-131 tositumomab was required. The single therapeutic dose following a dosimetric dose was adjusted to give the same total body dose (in Gy) as that used for the original dose, or was attenuated if the platelet count was less than 150,000 per mm(3) or if the prior treatment resulted in grade 4 cytopenias lasting longer than 7 days. RESULTS: Of 32 patients enrolled, 28 completed the therapeutic dose. A median of four therapies were given before re-treatment. Eighteen (56%) of 32 patients had a complete or partial response (median duration, 15.2 months); eight (25%) had a complete response (median duration, 35 months). Five continue in response from 1.8 to 5.7 years, with a median follow-up of 35 months. The overall median response duration was not significantly different for the two treatments, with no clinical factors predicting response or its duration. Ten of 18 re-responders had longer responses with re-treatment, with five having responses > or = 1.5 years longer. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 43% of patients, respectively, similar to initial treatment. Antimouse antibodies developed in 10% of patients, and 12% developed elevated serum thyroid-stimulating hormone. Six patients were diagnosed with second malignancies, including four patients who developed myelodysplastic syndrome (one who had not received the therapeutic dose) and one with acute myelogenous leukemia. CONCLUSION: Re-treatment with I-131 tositumomab following a previous response can produce second responses that can be durable.     

Iodine 131 tositumomab in the treatment of non-Hodgkin's lymphoma

Iodine 131 (I131) tositumomab is composed of murine anti-CD20 antibody linked to the radioisotope I131. I131 tositumomab exploits the specificity of monoclonal antibody therapy and the radiosensitivity of non-Hodgkin's lymphoma to exact a combined antitumor effect. It is currently approved in the USA for treatment of relapsed or refractory low-grade (and transformed) non-Hodgkin's lymphoma. High response rates in this setting, with some patients achieving a remission of longer duration than that of their prior treatment, provided the basis for approval of the drug. Studies using I131 tositumomab as initial treatment for low-grade non-Hodgkin's lymphoma (with or without chemotherapy), and in conditioning regimens for autologous transplantation, have yielded promising results. Randomized, comparative trials are needed to define its optimal clinical use.     

Dose-attenuated radioimmunotherapy with tositumomab and iodine 131 tositumomab in patients with recurrent non-Hodgkin's lymphoma (NHL) and extensive bone marrow involvement

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 tumor >25% 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 of >25% and platelet count of >or=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 count <500 cells/mm3 or platelets <25,000/mm3 for >17 days, or absolute neutrophil count <750/mm3 or platelets <50,000/mm3 for >24 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 with >25% BMI has acceptable toxicity and can result in lymphoma responses.     

Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma.

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.     

Repeat treatment with iodine-131-rituximab is safe and effective in patients with relapsed indolent B-cell non-Hodgkin's lymphoma who had previously responded to iodine-131-rituximab

BackgroundSmall series suggest retreatment of indolent lymphomas with murine anti-CD20 radioimmunotherapy is effective. The longer half-life of iodine-131 (¹³¹I)-rituximab may result in increased bone marrow exposure, with greater toxicity on repeat administration. We examined the effects of a second ¹³¹I-rituximab in patients with indolent lymphoma following relapse.Patients and methodsWe analyzed two institutional databases from January 2000 to July 2007 for retreatment with ¹³¹I-rituximab. The severity of cytopenia, development of myelodysplasia (MDS), acute myeloid leukemia (AML) and hypothyroidism was noted. We compared response duration and toxicity of the treatments.ResultsFourteen of 16 patients responded with nine complete responses (CRs), with a median duration of 10.5 months in responders. Six of 13 reresponders had the same or a longer response and six more remain in complete response. The median event-free survival was not significantly different for the two treatments. There was no significant difference in the severity of myelosuppression. Four patients developed hypothyroidism with three requiring thyroxine. One patient developed AML, with no other cases of MDS. The actuarial progression-free survival rate at 12 months was 36%.ConclusionsRepeat ¹³¹I-rituximab induces high response rates, some of which result in durable remissions in patients who had previously responded.     

Phase 1 studies comparing safety,tolerability, pharmacokinetics and pharmacodynamics of HLX01 (a rituximab biosimilar) to reference rituximab in Chinese patients with CD20-positive B-cell lymphoma

ObjectiveThis study aimed to compare the pharmacokinetic, pharmacodynamic and safety profiles of HLX01 (a rituximab biosimilar) and reference rituximab sourced from China (MabThera^®; rituximab-CN). MethodsHere we report the results of two phase 1 studies. In the phase 1a, open-label, dose-escalation study ({"type":"clinical-trial","attrs":{"text":"NCT03218072","term_id":"NCT03218072"}}NCT03218072, CTR20140400), eligible patients received 250, 375 and 500 mg/m² HLX01 sequentially at 7-day intervals, after confirming no dose-limiting toxicity (DLT). In the phase 1b, double-blind study ({"type":"clinical-trial","attrs":{"text":"NCT02584920","term_id":"NCT02584920"}}NCT02584920, CTR20140764), eligible patients were given a single dose of 375 mg/m² HLX01 or rituximab-CN. The primary endpoints included safety and tolerability parameters for the phase 1a and the area under the plasma concentration-time curve from time zero to day 91 (AUC_{0−91 d}) for the phase 1b study. Equivalence was concluded if 90% confidence interval (90% CI) for the geometric least squares mean ratio (GLSMR) fell in the pre-specified equivalence criteria (80%−125%). ResultsBetween June 20, 2014 and January 5, 2015, 12 patients were enrolled in the phase 1a study. The pharmacokinetics of HLX01 showed dose proportionality and accumulation to steady state. HLX01 was well tolerated, with no serious adverse events (AEs), discontinuations or DLTs. Between November 8, 2014 and August 13, 2015, 87 eligible patients were enrolled in the phase 1b study, including 43 who received HLX01 and 44 who were treated with rituximab-CN. The equivalence endpoint was met with GLSMR for AUC_{0−91 d} being 89.6% (90% CI: 80.4%−99.8%). AEs, anti-drug antibodies, and CD19+ and CD20+ B lymphocyte counts were similar between the HLX01 and rituximab-CN treatment groups. ConclusionsTreatment with HLX01 was safe and well tolerated in Chinese patients with B-cell lymphoma. HLX01 and rituximab-CN have similar pharmacokinetic, pharmacodynamic and safety profiles.     

Histological and immunophenotypic changes in 59 cases of B-cell non-Hodgkin's lymphoma after rituximab therapy

Rituximab is a chimeric monoclonal antibody that recognizes the CD20 antigen. It has been used to treat B-cell non-Hodgkin lymphoma (B-NHL), but recently rituximab resistance has been a cause for concern. We examined histological and immunohistochemical changes in 59 patients with B-NHL after rituximab therapy. The patients comprised 32 men and 27 women with a median age of 59 years. Pre-rituximab specimens comprised 34 follicular lymphomas (FL), 11 diffuse large B-cell lymphomas (DLBCL), 10 mantle cell lymphomas, two marginal zone B-cell lymphomas (MZBCL), and two chronic lymphocytic leukemias (CLL). CD20 expression in lymphoma cells was evaluated by immunohistochemistry or flow cytometry. Post-rituximab materials were taken a median of 6 months (4 days to 59 months) after rituximab therapy. Sixteen cases (27%) showed loss of CD20 expression with four histological patterns: pattern 1, no remarkable histological change (FL, 5; DLBCL, 3; and CLL, 2); pattern 2, proliferation of plasmacytoid cells (FL, 2; DLBCL, 1; and MZBCL, 1); pattern 3, transformation to classical Hodgkin's lymphoma (FL, 1); and pattern 4, transformation to anaplastic large cell lymphoma-like undifferentiated lymphoma (FL, 1). Loss of CD20 was unrelated to the interval of biopsies, treatment regimen, clinical response, and frequency of rituximab administration. Loss of CD20 within 1 month of rituximab therapy (3/14, 21%) and regain of CD20 (2/7, 29%) were not frequent. CD20-positive relapse with transformation occurred most frequently in cases of early relapse. In conclusion, B-NHL showed various histological and immunophenotypic changes after rituximab therapy, including not only CD20 loss but also proliferation of plasmacytoid cells or transformation to special subtypes of lymphoma. ( Cancer Sci 2009; 100: 54–61)     

利妥昔单抗治疗B细胞非霍奇金淋巴瘤的耐药机制研究进展

 抗CD20单克隆抗体利妥昔单抗已经成为治疗B细胞非霍奇金淋巴瘤（NHL）的重要组成部分。尽管临床应用广泛,但肿瘤细胞对利妥昔单抗的耐药机制尚不明确。文章阐述了利妥昔单抗的作用机制、耐药的发生以及潜在的耐药机制,并对调节抗体、肿瘤细胞和宿主的免疫状况等克服耐药的方法进行了探讨。     

Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas.

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.