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Originally published as JCO Early Release 10.1200/JCO.2005.05.3470 on August 28 2006 © 2006 American Society of Clinical Oncology. Multicenter Phase II Clinical Study of Iodine-131–Rituximab Radioimmunotherapy in Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma
From the University of Western Australia, Fremantle Hospital, Fremantle, Western Australia; and Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Address reprint requests to Michael F. Leahy, MD, Department of Haematology, Fremantle Hospital, Alma St, Fremantle WA 6160, Australia; e-mail: Michael.Leahy{at}health.wa.gov.au
PURPOSE: To evaluate efficacy and safety of iodine-131 (131I) –rituximab chimeric anti-CD20 antibody radioimmunotherapy in patients with relapsed or refractory indolent non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: After a standard loading dose of rituximab 375 mg/m2, individualized dosimetry was performed by whole-body gamma imaging of a tracer activity of 131I-rituximab followed by administration of a therapeutic activity of 131I-rituximab to deliver an estimated whole-body radiation absorbed dose of 0.75 Gy. RESULTS: Ninety-one patients were entered onto the trial: 78 patients (86%) had follicular lymphoma, six patients (7%) had mucosa-associated lymphoid tissue/marginal zone lymphoma, and seven patients (8%) had small lymphocytic lymphoma. The objective overall response rate (ORR) was 76%, with 53% attaining a complete response (CR) or CR unconfirmed (CRu). Median duration of response for patients achieving CR/CRu was 20 v 7 months for those with a partial response (P = .0121). Median progression-free survival for the entire cohort was 13 months, with 14% remaining relapse free beyond 4 years. Median follow-up was 23 months, with a 4-year actuarial survival rate of 59% ± 10%. Toxicity was principally hematologic; grade 4 thrombocytopenia occurred in 4% and neutropenia occurred in 16% of patients, with nadirs at 6 to 7 weeks after treatment. CONCLUSION: 131I-rituximab radioimmunotherapy of relapsed or refractory indolent NHL achieves high ORR and CR rates with minimal toxicity.
Non-Hodgkin's lymphoma (NHL) is becoming more prevalent and is now the fifth most common malignancy in the United States.1 The advent of immunotherapy with rituximab anti-CD20 monoclonal antibody (Mab) in combination with chemotherapy results in prolonged remission and improved survival in patients with indolent B-cell NHL,2,3 as exemplified by an estimated 4-year overall survival (OS) rate of 91% after initial treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab.4 For patients with relapsed NHL, immunotherapy with rituximab alone has an overall response rate (ORR) of 50% and median response duration of 11 months.5 Radioimmunotherapy with an anti-CD20 Mab conjugated to a beta-emitting radioisotope will deliver radiation not only to tumor cells that bind the antibody but also, due to a cross-fire effect, to neighboring tumor cells inaccessible to the antibody or with insufficient antigen expression. Indolent NHL cells are inherently radiosensitive and rituximab synergistically enhances radiation-induced apoptosis.6 Anti-CD20 antibodies radiolabeled with yttrium-90 (90Y) –ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, San Diego, CA, and Schering AG, Berlin, Germany) or iodine-131 (131I) –tositumomab (Bexxar; Corixa Corp, Seattle, WA) are available commercially for radioimmunotherapy of relapsed NHL and achieve ORRs of 75% to 80%, including complete response (CR) in 20% to 50% of patients, with a response duration of 10 to 14 months.7,8 Treatment with murine antibody radiolabeled conjugates may induce human antimouse antibodies (HAMA). Neither of the commercially available agents is approved for repeat administration, although there are preliminary data on safety of re-treatment.9 Freedom from HAMA is especially important if first-line radioimmunotherapy is contemplated. Although initial treatment with 131I-tositumomab achieved excellent response rates of 95% and a CR rate of 75%, the 62% incidence of HAMA10 in such relatively immunocompetent patients may compromise therapeutic options at relapse. Given that relapse of indolent NHL is probable despite the increasing efficacy of current therapies, we chose to radioiodinate the human/murine chimeric anti-CD20 Mab rituximab to obviate induction of HAMA and to allow repeat administration. A pilot study of 10 patients with relapsed or refractory indolent B-cell lymphoma demonstrated the efficacy and safety of rituximab 375 mg/m2 administered with 131I-rituximab tracer and a therapeutic prescribed dose of 0.75 Gy to the whole body. The methodology has been described previously, and preliminary data from 31 of the patients in this study were included in that report.11 This was a physician-sponsored trial with individualized prospective dosimetry with nonmyeloablative intent.
Institutional Ethics Committee approval in accordance with Australian National Health and Medical Research Council guidelines and the Declaration of Helsinki, and written informed consent from each patient was obtained. The trial was registered with the Therapeutic Goods Administration of the Commonwealth Government of Australia.
Ninety-one patients with relapsed (n = 76) or refractory (n = 15) follicular, mucosa-associated lymphoid tissue (MALT) /marginal zone, or small lymphocytic NHL were entered onto the study (Table 1) between May 2000 and December 2004 at Fremantle Hospital (Fremantle, Western Australia) and the Peter MacCallum Cancer Centre (Melbourne, Victoria, Australia). Eligible patients were required to have histologically confirmed disease, be
Patients with follicular lymphoma were evaluated further according to the Follicular Lymphoma International Prognostic Index (FLIPI)12 and were stratified into low-, intermediate-, and high-risk groups. In six patients, baseline data were insufficient to assess the FLIPI score.
Dosimetry and Radioimmunotherapy To minimize risk of hypothyroidism from free radio-iodine, administration of Lugol's iodine was commenced 24 hours before the tracer dosimetry study and continued for 7 days after 131I-radioimmunotherapy in the first 35 patients and for 21 days in all subsequent patients, based on evidence of thyroid uptake on post-treatment imaging in the initial cohort. The treatment protocol for the phase II clinical trial was the same at the two institutions. However, referring physicians had discretion to prescribe the standard four-dose regimen of 375 mg/m2 rituximab in conjunction with the radioimmunotherapy. Thus 59 patients were administered two additional 375 mg/m2 doses of rituximab administered during the 2 weeks after the tracer and therapeutic administrations. The remaining 32 patients received only the two unlabeled doses of 375 mg/m2 rituximab administered on the days of the tracer and therapeutic doses of 131I-rituximab. Three patients who received initial treatment with 131I-rituximab before entry to this study and three who experienced relapse on study and were re-treated received only two doses of 375 mg/m2 rituximab.
Response and Toxicity Evaluation The National Cancer Institute Common Toxicity Criteria Version 2 were used.15 Hematologic assessment with full blood counts was carried out weekly from treatment until count recovery, then every 3 months for 2 years. Hepatic and renal function was assessed weekly for 6 weeks, then every 3 months. Thyroid function was monitored at 3-month intervals. Human antichimeric antibodies were not assayed in this study but tracer whole-body dosimetry imaging before radioimmunotherapy in each patient was used to monitor biodistribution of 131I-rituximab.
Statistical Methods
Response to Treatment All 91 enrolled patients (Table 1) received the whole-body prescribed radiation absorbed dose of 0.75 Gy by administered activities of 1.36 to 5.34 GBq 131I-rituximab (median, 2.4 GBq). Objective response was observed in 69 patients (76%). Forty-eight patients (53%) achieved a CR/CR unconfirmed (CRu) at the 12-week assessment. The median duration of response for responding patients was 10 months (range, 1 to 48 months); for patients in CR/CRu, median duration of response was 20 months (range, 1 to 48 months), and for partial response (PR), median duration of response was 7 months (range, 1 to 20 months; Fig 1). The median PFS for all responding patients was 13 months with 14% ± 6% of patients estimated to be free of progression beyond 4 years (Fig 2).
With a median follow-up of 23 months (range, 4 to 58 months) the estimated median survival was 50 months, with a 4-year actuarial survival rate of 59% ± 10% (Fig 2). Survival of complete responders was significantly longer than that of nonresponders (P < .0001; Fig 3).
In a univariate analysis (Table 2), stage I/II disease and fewer than two prior chemotherapy regimens were associated with a higher ORR (P  .02), whereas age 60, stage I/II disease, and low FLIPI score were associated with a significantly higher CR/CRu rate (P 0.012). Histology was not associated strongly with response, although all six patients with MALT/marginal zone NHL responded. The presence of marrow involvement, prior rituximab treatment, elevated serum levels of ß2-microglobulin and lactate dehydrogenase, and tumor bulk were not associated with a significant reduction in ORR or CR rate. Bulky tumors accumulated high levels of 131I-rituximab activity (Fig 4).
The median duration of response for the FLIPI low-, intermediate-, and high-risk groups was 14, 12, and 9 months, respectively (P = .377) but neither this trend nor OS were significantly different between these groups. Of the six patients who were re-treated, four had achieved CR and two had achieved PR with initial therapy. The median response duration was 12 months (range, 5 to 49 months). Four of these patients achieved a second response (three CRs and one PR), with a median response duration of 11 months (range, 8 to 14 months). The median time interval between radioimmunotherapy treatments was 23 months (range, 9 to 54 months). Hematologic toxicity was not increased with re-treatment (Table 3).
Toxicity Toxicity was principally hematologic, with grade 4 thrombocytopenia occurring in 4% and grade 4 neutropenia in 16% of patients (Table 4). Three patients required platelet transfusion, one patient required packed RBCs, and one patient received granulocyte colony-stimulating factor. Oral antibiotics were administered to one patient for febrile neutropenia, but no patient was hospitalized with infection. The median time to platelet nadir was 6 weeks (80 x 109/L; range, 4 to 223 x 109/L), 7 weeks for neutrophils (1.6 x 109/L; range, 0.03 to 9.1 x 109/L), and 8 weeks for hemoglobin (118 g/L; range, 75 to 151).
Platelet nadirs were lower in patients with bone marrow involvement  25%, but the incidence of grade 4 toxicity did not differ from that observed in patients with less than 25% bone marrow involvement (Table 5).
Five patients (5.5%), median age 66 years (range, 48 to 70 years), developed a myelodysplastic syndrome (MDS) after a median follow-up of 23 months. One patient experienced disease progression to acute myeloid leukemia (AML). All of the MDS patients had received prior chemotherapy (median, two prior therapies; range, one to four prior therapies), two had received external-beam radiotherapy, and one had received two prior treatments with 131I-rituximab. At the time of study entry, an elevated thyroid-stimulating hormone or pre-existing clinical hypothyroidism requiring thyroxine replacement was present in 10 patients. At follow-up, an additional seven patients had an elevated thyroid-stimulating hormone, representing a 9% incidence of treatment-related subclinical or clinical hypothyroidism.
A single therapeutic dose of 131I-rituximab resulted in a high ORR (76%) and CR/CRu (53%). Median duration of response was 10 months for all responders and 20 months for CR/CRu. These results are comparable to 131I-tositumomab therapy median response duration in relapsed/refractory follicular NHL of 13.6 months, of whom 18 of 32 had a CR of median duration 14.5 months.9 They are also in accord with results of radioimmunotherapy of NHL using 90Y-ibritumomab tiuxetan.7,8 In a comparison of 90Y-ibritumomab tiuxetan with single-agent rituximab in patients with low-grade refractory or relapsed or transformed CD20+ NHL, radioimmunotherapy resulted in an ORR of 80% (34% CR/CRu and 45% PR) compared with an ORR of 56% (20% CR/CRu and 36% PR) for rituximab therapy alone.7 Our study shows similarly high response and CR rates with 131I-rituximab radioimmunotherapy. The additional expense of radiolabeling rituximab in-house above the acquisition cost of the drug is modest, at around US $1,000. The main toxicity of 90Y-ibritumomab tiuxetan radioimmunotherapy is reversible myelosuppression with grade 4 neutropenia seen in 32%, thrombocytopenia seen in 5%, and anemia seen in 3% of patients.7 Grade 3-4 myelosuppression occurred in 30% to 40% of patients with relapsed NHL receiving 131I-tositumomab, with nadirs typically at week 4 to 6.8 Grade 4 neutropenia occurred in 16%, grade 4 thrombocytopenia occurred in 3%, and grade 4 anemia occurred in 2% of 677 previously treated patients.8 These figures are similar to our study, in which grade 4 neutropenia occurred in 16% and grade 4 thrombocytopenia occurred in 4% of patients. All patients in the current study had had significant prior therapy, rendering evaluation of MDS risk (MDS occurred in five patients) difficult. The incidence of MDS/AML in 995 patients with relapsed/refractory low-grade NHL treated with 131I-tositumomab was 3.5%, with an annualized incidence of 1.6%,16 compared with our study of 91 patients in which the incidence of MDS was 5.5%. The rate of development of MDS/AML in NHL after radioimmunotherapy is comparable to that of conventionally treated NHL patients of 1% to 1.5% per year of therapy.17 The relatively modest hematologic toxicity of radioimmunotherapy using 131I-tositumomab or 131I-rituximab is likely to be related to calculation of prospective individualized dosimetry, allowing a standard prescribed whole-body radiation dose of 0.75 Gy.11,18 Prospective quantitative dosimetry cannot be performed with 90Y-ibritumomab tiuxetan due to the absence of gamma emission from 90Y, but surrogate imaging of 111In-ibritumomab tiuxetan showed no correlation of hematologic toxicity with estimates of total body absorbed radiation dose or dose to red marrow.19 Monte Carlo–based dosimetric analysis of quantitative single-photon emission CT–CT images in 27 of our patients after 131I-rituximab radioimmunotherapy validated the whole-body dosimetry method and demonstrated that the standard prescribed radiation absorbed dose of 0.75 Gy corresponded with a median dose to red marrow of 1.9 Gy.20 This radiation exposure of hematopoietic marrow was less than the 2-Gy threshold for myelotoxicity and is reflected in the minor, self-limited myelosuppression encountered in this study. Hematologic toxicities associated with 131I-tositumomab treatment of NHL have not been shown to correlate with the extent of bone marrow involvement.21 In our patients the incidence of CR/CRu to 131I-rituximab was the same for those with (50%) as without (54%) baseline bone marrow involvement (Table 2), and toxicities were comparable. Humanized Mab is cleared from the circulation at a slower rate than murine antibodies, thus prolonging radiation exposure and potentially increasing dose to normal tissue and increasing toxicity.22 Our study using 131I-rituximab has shown similar efficacy to those reported using 131I-tositumomab or 90Y-ibritumomab tiuxetan7,8,23 without increased incidence of myelosuppression. The biodistribution and tissue kinetics of 131I-rituximab have been shown to be specific for each patient and remain constant during unlabeled antibody therapy.24 Radioimmunotherapy radiation doses can therefore be extrapolated reliably from a preceding dosimetry study using the whole-body effective half-life normalized to ideal body weight to calculate an administered activity of 131I-rituximab radioimmunotherapy sufficient to deliver a prescribed whole-body radiation dose of 0.75 Gy.20 The advent of combined immunochemotherapy regimens for treatment of follicular NHL has resulted in major clinical benefits, both in untreated patients2,3 and those with relapsed/refractory disease.25,26 Rituximab immunotherapy as a single-agent treatment of newly diagnosed advanced follicular NHL has also been advocated as an alternative to previous watch-and-wait policies, with reported ORR of 72% with 36% CR and median time to progression of 2.2 years.27 Thus, it may be anticipated that the majority of patients with relapsed or refractory indolent NHL referred for consideration of radioimmunotherapy will have been exposed to rituximab previously. In our patient population, two thirds had received prior rituximab, but the subsequent response to radioimmunotherapy with 131I-rituximab was not impaired (Table 2). Radioimmunotherapy with 131I-tositumomab has also been shown to be effective in follicular grade 1 and 2 NHL with progression after prior rituximab, with ORR of 86%, including CR in 57% and 3-year PFS 48% in nonbulky disease.28
In our study the CR/CRu rate of 43% was reduced modestly in patients with tumors Although post-therapy single-photon emission CT–CT imaging provides validation of marrow dosimetry,20 quantitation of radiation absorbed dose to tumor remains challenging. External-beam radiotherapy is pulsed intermittently at approximately 60 Gy/h, but effective dose rates as low as 0.05 Gy/h can stop the growth of radiosensitive NHL cells.30 However, measurement of such a parameter in radioimmunotherapy patients is difficult. In the few patients in whom tumor dose has been reported, the mean 2.86 Gy/GBq for 131I-anti CD 20 murine Mab (n = 5) is similar to the mean of 3.86 Gy/GBq for 131I-rituximab.31 Tumor dose estimates in three patients on our study ranged from 6.9 to 20.8 Gy (data not shown), which is comparable to the mean of 15 Gy to tumor reported for 131I murine anti-CD 20 Mab.31 It is likely that there is a threshold for effective radiation dose to tumor, which apparently is attained when a surrogate whole-body dose of 0.75 Gy is used. A prescribed whole-body 131I-rituximab dose of 0.45 Gy appeared to be less clinically effective in patients with aggressive lymphoma who were more heavily pretreated than in our study.32 However, this study also used a reduced loading dose of cold antibody, 2.5 mg/kg rituximab, in contrast to the 375 mg/m25 used in our study. Whether the total dose of unlabeled antibody influences the efficacy of radioimmunotherapy is conjectural, and no significant difference in outcome was evident in our study between patients receiving two or four doses of cold rituximab in association with 131I-rituximab radioimmunotherapy. Our study demonstrates that 131I-rituximab radioimmunotherapy of patients with relapsed or refractory indolent NHL is safe and effective. This nonmyeloablative approach may be performed on an outpatient basis and preserves radioimmunotherapeutic re-treatment options for relapse.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C)
published online ahead of print at www.jco.org on August 28, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. National Cancer Institute: Surveillance, Epidemiology and End Results. http://www.seer.cancer.gov 2. Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417-1423, 2005 3. Hiddemann W, Kneba M, Dreyling M, et al: Front-line therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) significantly improves the outcome of patients with advanced-stage follicular lymphomas compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group. Blood 106:3725-3732, 2005 4. Fisher RI, LeBlanc M, Press OW, et al: New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 23:8447-8452, 2005 5. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD 20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract] 6. Skvortsova I, Popper B-A, Skvortsov S, et al: Pretreatment with rituximab enhances radiosensitivity of non-Hodgkin's lymphoma cells. J Radiat Res 46:241-248, 2005[Medline] 7. Kaminski MS, Zelenetz AD, Press OW, et al: Pivotal study of iodine I-131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphoma. J Clin Oncol 19:3918-3928, 2001 8. Witzig TE, Gordon LI, Cabanillas F, et al: Randomised controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20:2453-2463, 2002 9. Kaminski MS, Radford JA, Gregory A, et al: Re-treatment with I-131 tositumomab in patients with non-Hodgkin's lymphoma who had previously responded to I-131 tositumomab. J Clin Oncol 23:7985-7993, 2005 10. Kaminski MS, Tuck M, Estes J, et al: 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352:441-449, 2005 11. Turner JH, Martindale AA, Boucek J, et al: 131I-anti CD 20 radioimmunotherapy of relapsed or refractory non-Hodgkin's lymphoma: A phase II clinical trial of nonmyeloablative dose regimen of chimeric rituximab radiolabeled in a hospital. Cancer Biother Radiopharm 18:513-524, 2003[CrossRef][Medline] 12. Solal-Céligny P, Pascal R, Colombat P, et al: Follicular Lymphoma International Prognostic Index. Blood 104:1258-1265, 2004 13. Kaminski MS, Estes J, Zasadny KR et al: Radioimmunotherapy with iodine 131I-tositumomab for relapsed or refractory B-cell non-Hodgkin's lymphoma: Updated results and long-term follow-up of the University of Michigan experience. Blood 96:1259-1266, 2000 14. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphoma. J Clin Oncol 17:1244-1253, 1999 15. Common toxicity criteria, version 2, March 1998. http://ctep.info.nih.gov/reporting/ctc_archive.html 16. Bennett JM, Kaminski MS, Leonard JP, et al: Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin's lymphoma treated with tositumomab and iodine I131 tositumomab. Blood 105:4576-4582, 2005 17. Otte A, Dierckx RA: Myelosuppressive side-effects of radioimmunotherapy of non-Hodgkin's lymphoma: Is there an increased risk? Nucl Med Commun 26:1045-1047, 2005[CrossRef][Medline] 18. Davies AJ, Rohatiner AZS, Howell S, et al: Tositumomab and iodine I-131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 22:1469-1479, 2004 19. Wiseman GA, Leigh B, Erwin WD, et al: Radiation dosimetry results for Zevalin radioimmunotherapy of rituximab-refractory non-Hodgkin's lymphoma. Cancer 94:1349-1357, 2002[CrossRef][Medline] 20. Boucek JA, Turner JH: Validation of prospective whole body bone marrow dosimetry by SPECT/CT multimodality imaging in 131I-anti-CD 20 rituximab radioimmunotherapy of non-Hodgkin's lymphoma. Eur J Nucl Med Mol Imaging 32:458-469, 2005[CrossRef][Medline] 21. Gregory SA, Leonard J, Coleman A et al: Relationship of degree of bone marrow involvement with hematologic toxicity in patients with non-Hodgkin's lymphoma treated with tositumomab and iodine I-131 tositumomab. Proc Am Soc Clin Oncol 22:575, 2003 (abstr 2314) 22. Oriuchi N, Higuchi T, Hanaoka H, et al: Current status of cancer therapy with radiolabeled monoclonal antibody. Ann Nucl Med 19:355-365, 2005[Medline] 23. Juweid ME: Radioimmunotherapy with 131I-rituximab: What we know and what we don't know. Cancer Biother Radiopharm 18:489-495, 2003[CrossRef][Medline] 24. Antonescu C, Bischof-Delaloye A, Kosinski M, et al: Repeated injections of 131I-rituximab show patient-specific stable bio-distribution and tissue kinetics. Eur J Nucl Med Mol Imaging 32:943-951, 2005[CrossRef][Medline] 25. Forstpointner R, Dreyling M, Repp R, et al: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomised study of the German low-grade lymphoma study group. Blood 104:3064-3071, 2004 26. Lenz G, Dreyling M, Hoster E, et al: Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: Results of a prospective randomised trial of the German low grade lymphoma study group (GLSG). J Clin Oncol 23:1984-1992, 2005 27. Witzig TE, Vukov AM, Habermann TM, et al: Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: A phase II trial in the North Central Cancer treatment Group. J Clin Oncol 23:1103-1108, 2005 28. Horning SJ, Younes A, Jain V, et al: Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol 23:712-718, 2005 29. Gokhale AS, Mayadev J, Pohlman B: Gamma camera scans and pretreatment tumor volumes as predictors of response and progression after Y-90 anti-CD 20 radioimmunotherapy. Int J Radiat Oncol Biol Phys 63:194-201, 2005[CrossRef][Medline] 30. DeNardo GL: Treatment of non-Hodgkin's lymphoma (NHL) with radiolabeled antibodies. Semin Nucl Med 35:202-211, 2005[CrossRef][Medline] 31. Kaminski MS, Zasadny KR, Francis IR, et al: Radioimmunotherapy of B-cell lymphoma with [131I]- anti-B1 (anti-CD 20) antibody. N Engl J Med 329:459-465, 1993 32. Bienert M, Reisinger I, Srock S, et al: Radioimmunotherapy using 131I-rituximab in patients with advanced stage B-cell non-Hodgkin's lymphoma: Initial experience. Eur J Nucl Med Mol Imaging 32:1225-1233, 2005[CrossRef][Medline] Submitted January 20, 2006; accepted July 20, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
