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Originally published as JCO Early Release 10.1200/JCO.2003.08.043 on February 20 2003 © 2003 American Society for Clinical Oncology Safety of Yttrium-90 Ibritumomab Tiuxetan Radioimmunotherapy for Relapsed Low-Grade, Follicular, or Transformed Non-Hodgkin’s Lymphoma
From the Division of Internal Medicine and Hematology and the Department of Radiology, Nuclear Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN; IDEC Pharmaceuticals Corporation, San Diego, and University of California Los Angeles Medical Center, Los Angeles, CA; Division of Hematology/Oncology and The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; M.D. Anderson Cancer Center, Houston, TX; and Western Pennsylvania Cancer Institute, Pittsburgh, PA. Address reprint requests to Thomas E. Witzig, MD, Mayo Clinic, 620 Stabile Building, Rochester, MN 55905; email: witzig{at}mayo.edu.
Purpose: Radioimmunotherapy (RIT) with yttrium-90 (90Y)-labeled anti-CD20 antibody (90Y ibritumomab tiuxetan; Zevalin, IDEC Pharmaceuticals Corporation, San Diego, CA) has a high rate of tumor response in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL). This study presents the safety data from 349 patients in five studies of outpatient treatment with 90Y ibritumomab tiuxetan. Patients and Methods: Patients received rituximab 250 mg/m2 on days 1 and 8, and either 0.4 mCi/kg (15 MBq/kg) or 0.3 mCi/kg (11 MBq/kg) of 90Y ibritumomab tiuxetan on day 8 (maximum dose, 32 mCi). Patients were observed for up to 4 years after therapy or until progressive disease. Results: Infusion-related toxicities were typically grade 1 or 2 and were associated with rituximab. No significant organ toxicity was noted. Toxicity was primarily hematologic, with nadir counts occurring at 7 to 9 weeks and lasting approximately 1 to 4 weeks depending on the method of calculation. After the 0.4-mCi/kg dose, grade 4 neutropenia, thrombocytopenia, and anemia occurred in 30%, 10%, and 3% of patients, respectively, and after the 0.3-mCi/kg dose, these grade 4 toxicities occurred in 35%, 14%, and 8% of patients, respectively. The risk of hematologic toxicity increased with degree of baseline bone marrow involvement with NHL. Seven percent of patients were hospitalized with infection (3% with neutropenia) and 2% had grade 3 or 4 bleeding events. Myelodysplasia or acute myelogenous leukemia was reported in five patients (1%) 8 to 34 months after treatment. Conclusion: Single-dose 90Y ibritumomab tiuxetan RIT has an acceptable safety profile in relapsed NHL patients with less than 25% lymphoma marrow involvement, adequate marrow reserve, platelets greater than 100,000 cells/µL, and neutrophils greater than 1,500 cells/µL.
IMMUNOTHERAPY WITH the human chimeric antibody rituximab (Rituxan, IDEC Pharmaceuticals, San Diego, CA, and Genentech Inc, South San Francisco, CA) has been a major advance in the treatment of patients with CD20-positive B-cell non-Hodgkin’s lymphoma (NHL).1,2 Radioimmunotherapy (RIT) uses the targeting features of a monoclonal antibody to deliver radiation from an attached radionuclide. Ibritumomab, the murine parent antibody from which rituximab was engineered, has been chemically linked to tiuxetan, which chelates indium-111 (111In) for imaging and yttrium-90 (90Y) for therapy. The first trial of ibritumomab tiuxetan (Zevalin, IDEC Pharmaceuticals Corporation, San Diego, CA) used ibritumomab as the pretreatment unlabeled antibody.3 A subsequent phase I/II trial used rituximab before 111In ibritumomab tiuxetan and 90Y ibritumomab tiuxetan.4 Results from these trials indicated that 0.4 mCi/kg of 90Y ibritumomab tiuxetan was optimal for patients with a platelet count  150,000 cells/µL and 0.3 mCi/kg of 90Y ibritumomab tiuxetan was optimal for patients with a platelet count between 100,000 and 149,000 cells/µL. Subsequent trials have focused on the efficacy of 90Y ibritumomab tiuxetan RIT compared with rituximab immunotherapy. A phase III trial randomly assigned 143 relapsed or refractory, low-grade, follicular, or transformed NHL patients to receive either a standard course of rituximab or 90Y ibritumomab tiuxetan (0.4 mCi/kg).5 The overall response rate (ORR) to 90Y ibritumomab tiuxetan was 80%, compared with 56% for rituximab (P = .002). In the 90Y ibritumomab tiuxetan group, 30% of patients achieved a complete remission, compared with 16% in the rituximab group (P = .04). Another study, in which 0.4 mCi/kg of 90Y ibritumomab tiuxetan was administered to 57 patients in whom rituximab had failed, yielded a 74% ORR.6 Patients with mild thrombocytopenia were treated with 90Y ibritumomab tiuxetan at a dose of 0.3 mCi/kg in a separate trial, resulting in an 83% ORR.7 Results of individual trials have been reported previously; however, this study reports on the integrated safety data from patients treated with 90Y ibritumomab tiuxetan.
Patient Eligibility Patients with relapsed, refractory, or transformed CD20-positive B-cell NHL from five multicenter studies were included in a safety analysis (Table 1  ). Selection criteria were similar among the studies, with the exception of baseline platelet count (Table 2). Patients were required to undergo a bone marrow aspiration and biopsy before treatment. Patients with less than 25% marrow lymphoma as determined by light microscopy were eligible. Patients were rituximab naive, except in study 106-98, which allowed prior rituxan, and in study 106-06, in which the patient was required to be rituximab refractory. Patients who had a prior stem-cell transplantation, CNS- or AIDS-related lymphoma, chronic lymphocytic leukemia, prior RIT, and pleural or peritoneal effusions that were positive cytologically for lymphoma were excluded from all of the studies. All patients were at least 18 years of age and provided written informed consent, and each participating clinical site received approval from its institutional review board.
Study Design All patients received rituximab 250 mg/m2 on days 1 and 8; 182 patients received 111In ibritumomab tiuxetan on day 1 for imaging and/or dosimetry calculations. None of the patients who were administered 111In ibritumomab tiuxetan received an estimated radiation-absorbed dose of 90Y ibritumomab tiuxetan more than 20 Gy to normal organs and more than 3 Gy to red marrow.8,9 All patients received 90Y ibritumomab tiuxetan on day 84,6,10,11 in an outpatient setting; patients with platelet counts between 100,000 and 149,000 cells/µL were treated with 0.3 mCi/kg of 90Y ibritumomab tiuxetan, and patients with platelet counts 150,000 cells/µL received 0.4 mCi/kg of 90Y ibritumomab tiuxetan up to a maximum of 32 mCi.
Physical examination, performance status, and B-symptom assessment were recorded at baseline, and assessments were repeated at predetermined intervals. Patients were re-evaluated every 3 months for the first 2 years and every 6 months for up to 4 years after treatment. Scans of measurable lesions were repeated on all patients approximately 28 days after treatment, with a confirmation scan repeated
Statistical Methods AEs were assigned preferred terms, using the Coding Symbols for Thesaurus of Adverse Reaction Terms dictionary (United States Food and Drug Administration, Rockville, MD), and analyzed by calculating the number and percentage of patients having events. If the same AE was reported on consecutive days, it was recorded as a single event, and the most severe grading among the individual events was used to characterize this unified event. Hematologic AEs (neutropenia, thrombocytopenia, and anemia) were assessed from laboratory values rather than from clinical reports. Duration of neutropenia, thrombocytopenia, or anemia was measured by two methods. In method A, the more conservative method, duration was measured from the date of the last laboratory value before development of grade 3 or 4 toxicity to the date of the first value in grade 2. In method B, duration was measured from the date of the first laboratory value in grade 3 or 4 toxicity to the date of the last value in grade 3 or 4. Given that blood counts were measured on a weekly basis, the values for duration determined by methods A and B differ by approximately 14 days. Descriptive statistics were reported for the hematology and blood chemistry laboratory results. Fisher’s exact two-tailed test was used to describe correlation of hematologic nadir range and baseline predictive factors.
Patient Characteristics Patient characteristics were similar across the five studies (Table 3 ). Of 349 patients enrolled to receive 90Y ibritumomab tiuxetan RIT, 99% of patients (345 of 349 patients) completed treatment. Four patients did not receive 90Y ibritumomab tiuxetan but are included in the toxicity analysis. Of the four patients who did not receive 90Y ibritumomab tiuxetan, one was withdrawn after receiving 111In ibritumomab tiuxetan, at the investigator’s discretion. This patient was treated with a full course of rituximab (375 mg/m2 once weekly for 4 weeks). Three patients were withdrawn after receiving rituximab on day 1 because of rapid disease progression (n = 2) or rituximab-associated toxicity (n = 1).
Safety Nonhematologic AEs of possible, probable, or unknown relationship to study treatment (related) during the 13-week treatment period were reported for 80% of patients (279 of 349 patients; Table 4 ). The majority of AEs were grade 1 and 2; the most frequent related events were asthenia (35%), nausea (25%), and chills (21%). Nonhematologic related grade 3 and 4 AEs occurred in 39 patients (11%), with asthenia in six patients (2%), abdominal pain in four patients (1%), and the remainder in less than 1% of the population. Bleeding events in any body system were reported in 62 patients (18%); 56 patients (16%) had grade 1 or 2 events. Grade 3 bleeding events included gastrointestinal hemorrhage (n = 2), vaginal hemorrhage (n = 1), ecchymosis (n = 1), and easy bruisability (n = 1). One event during the treatment period was grade 4 (subdural hematoma), and an additional grade 4 event (intracranial hemorrhage) occurred on day 138 during the follow-up period. Both events occurred after head trauma; one patient was also taking therapeutic oral anticoagulant.
Hematologic Toxicity Hematologic toxicity is summarized in Table 5 and Fig 1. The duration of hematologic toxicity in patients with a grade 3 or 4 nadir measured by method A was a median of 14 days longer than that for method B. Median duration of grade 3 or 4 hematologic toxicity was longer in mildly thrombocytopenic patients who received the reduced 90Y ibritumomab tiuxetan dose of 0.3 mCi/kg than in patients with normal baseline platelet levels receiving 0.4 mCi/kg of 90Y ibritumomab tiuxetan (Table 5). Hematologic toxicity was evaluated using the National Cancer Institute’s Common Toxicity Criteria, version 2.0. Grade 1 or grade 2 neutropenia occurred in 141 patients (40%). Grade 3 or grade 4 neutropenia occurred in 103 (30%) and 105 (30%) patients, respectively. Of patients with grade 3 or 4 nadir, 188 patients (90%) had absolute neutrophil counts that recovered to more than 1,000 cells/µL within 12 weeks after 90Y ibritumomab tiuxetan therapy. The remaining 20 patients (10%) either received subsequent therapy or died before recovery.
Grade 1 or grade 2 thrombocytopenia occurred in 129 patients (37%). Grade 3 or grade 4 thrombocytopenia occurred in 185 (53%) and 35 (10%) patients, respectively. Platelet levels in 196 patients (89%) with grade 3 or 4 thrombocytopenia recovered to 50,000/µL within the 12-week period after treatment. The remaining 24 patients (11%) either received subsequent therapy or died before recovery. Grade 3 anemia occurred in 46 patients (13%), and grade 4 anemia occurred in 14 patients (4%). In the population of 211 patients for whom data were available, 37 (18%) received growth factors. The median duration of grade 3 or 4 neutropenia was 19 days in patients receiving filgrastim, compared with 27 days in those who did not (method A, P = .06). Of 38 patients with grade 3 or 4 anemia, 10 received erythropoietin. The median duration of grade 3 or 4 anemia was not significantly different in patients treated with erythropoietin compared with those who did not receive erythropoietin. Of 211 patients, 43 (20%) received RBC transfusions, and 47 (22%) received platelet transfusions.
Infection and Febrile Neutropenia
Hospitalizations with infection during the treatment period occurred in 23 patients (7%); 13 (4%) had grade 3 or 4 events. Of these 23 patients, febrile neutropenia occurred in six (2%), urinary tract infections occurred in four (1%), sepsis occurred in four (1%), pneumonia occurred in four (1%), cellulitis or abscess occurred in three (1%), and gastroenteritis or diarrhea occurred in two (< 1%). Prophylactic antibiotic therapy was monitored in four studies (N = 211); antibiotics were administered to 17 patients (8%) during the 12-week period after treatment. During the follow-up period (starting 12 weeks after treatment), infection occurred in 21 patients (6%). The most common infection was nonspecific upper respiratory tract infections in four patients (1%); all other infections occurred in less than 1% of patients. Eleven patients (3%) were hospitalized with infection, nine with grade 3 or 4 events. The most common events were pneumonia and respiratory infection in five patients (1%) and bacterial urinary tract infection in three patients (< 1%).
In the phase III randomized comparison study (N = 143), a greater incidence of infection occurred during the 12-week period after treatment in patients treated with 90Y ibritumomab tiuxetan than in patients receiving rituximab (43% v 20%, respectively; Table 6
Relationship of Hematologic Toxicity With Prior Therapy and Bone Marrow Lymphoma Involvement
Bone marrow toxicity was also examined with respect to the number of prior chemotherapy regimens (  two regimens v two regimens). Sixteen percent of patients with more than two prior chemotherapy regimens had grade 4 thrombocytopenia, compared with 7% of those patients with two or less prior regimens. The number of prior chemotherapy regimens was not associated with a longer median duration of grade 3 or 4 neutropenia, thrombocytopenia, or anemia. Patients previously treated with fludarabine (n = 95) had a significantly longer duration from diagnosis to treatment with 90Y ibritumomab tiuxetan, compared with patients not previously treated with fludarabine (n = 254; 4.5 years v 3.3 years, respectively; P = .005), received significantly more prior chemotherapy regimens (four regimens v two regimens, respectively; P < .001), and had significantly lower baseline platelet counts (P = .001) and hemoglobin concentrations (P = .020). The fludarabine-treated patients were more likely to develop grade 3 or 4 neutropenia (P = .050), thrombocytopenia (P = .025), and anemia (P < .001), and had a significantly longer median duration of grade 3 or 4 thrombocytopenia (P = .029; 28 days for those previously treated with fludarabine v 22 days for those without prior fludarabine treatment, method A).
Immunology
Geriatric Evaluation Toxicity data from patients less than 65 years of age (n = 217) were compared with those from patients 65 years of age or older (n = 132). Patient characteristics of sex, bone marrow involvement, and median number of prior regimens were similar in both age groups, except for the International Prognostic Index risk group (P = .001), which tended to be higher in the older group. The analysis of safety in the geriatric subset revealed no clinically significant age-related effects in nonhematologic AEs, hematologic toxicity, or duration and incidence of grade 3 or 4 AEs.
Secondary Malignancies
Survival
Y ibritumomab tiuxetan RIT is a novel therapeutic modality for the treatment of relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. This report presents an integrated safety analysis for 349 patients treated with a single dose of either 0.3 or 0.4 mCi/kg of 90Y ibritumomab tiuxetan (maximum dose, 32 mCi) in five separate multicenter clinical trials. 90Y ibritumomab tiuxetan was administered in an outpatient setting and was well tolerated. The primary toxicity was reversible myelosuppression, which typically developed by week 4 to 6, reached nadir at weeks 7 to 9, and recovered within 1 to 4 weeks, depending on the method of calculation. This pattern of myelosuppression is different from that experienced with myelosuppressive chemotherapy, which usually occurs in 10 to 14 days and recovers by day 21. The prophylactic use of growth factors was not permitted 2 weeks before and for the first few weeks after the treatment regimen because of concern about radiation-induced cell injury. However, 18% of patients were administered growth factors after development of cytopenias, and patients given filgrastim responded with fewer days of neutropenia (data not shown). Ongoing studies of 90Y ibritumomab tiuxetan RIT are evaluating whether growth factor use can decrease the incidence and duration of grade 4 hematopoietic toxicity.
It is crucial to carefully assess the bone marrow before 90Y ibritumomab tiuxetan therapy because the risk of grade 4 hematologic toxicity correlates with the level of lymphomatous involvement. This is intuitive, because the more marrow involvement with NHL, the greater the amount of 90Y ibritumomab tiuxetan distributed to the marrow compartment. Patients receiving the 90Y ibritumomab tiuxetan therapeutic regimen should have less than 25% lymphoma marrow involvement, adequate bone marrow reserve, platelet count greater than 100,000 cells/µL, neutrophil count greater than 1,500 cells/µL, no evidence of hypocellular bone marrow ( Chemotherapy-associated malignancies, such as MDS or AML, have occurred in both myeloablative12,13 and nonmyeloablative14–18 settings. To date, five cases of MDS have occurred in the 349 patients (1.4%) treated with 90Y ibritumomab tiuxetan. The exact contribution of the RIT to the development of MDS is difficult to determine because all five patients had previously received at least 1 year of alkylator-based chemotherapy. Published reports have quoted a cumulative incidence of MDS in NHL patients who have not undergone dose-intense therapy of approximately 4% to 8%14,18 or a general risk of 1% to 1.5% per year from 2 to at least 9 years after the start of therapy.19 Therefore, the incidence of MDS in this patient population is similar to that seen in patients with lymphoproliferative disorders who were treated with alkylating agents. MDS has also been reported in patients treated with other radioimmunoconjugates.20 Caution should be exercised in determining whether to treat patients who have cytogenetic or morphologic changes typical of MDS on bone marrow examinations with radioimmunoconjugates. Nonhematologic AEs from 90Y ibritumomab tiuxetan RIT were mild (grade 1 or 2) and included asthenia, chills, fever, headache, throat irritation, abdominal pain, flushing, nausea, vomiting, ecchymosis, dyspnea, pruritus, and rash. These AEs are common in patients receiving rituximab,1 and because the 90Y ibritumomab tiuxetan regimen includes two doses of rituximab, it was not surprising that these effects were encountered. The 90Y ibritumomab tiuxetan injections are given intravenously over 10 minutes at the end of the rituximab infusion and typically are not associated with any infusion-related toxicity. The incidence of nausea or vomiting was less than half the occurrence associated with chemotherapy,21 and symptoms were neither severe nor prolonged. Hepatotoxicity was not a problem in these studies of 90Y ibritumomab tiuxetan. The 90Y ibritumomab tiuxetan regimen resulted in a depletion of peripheral-blood B cells for 6 to 9 months. However, in general, gamma globulin levels and blood T-cell numbers were preserved, and significant infections and hospitalizations were unusual. Another reason for the low serious infection rate is that 90Y ibritumomab tiuxetan did not cause mucositis or disruption of other mucosal barriers. With the use of murine and chimeric antibodies, there is a risk of immunogenicity that could potentially restrict repeated monoclonal antibody administration22; however, in this study, HAMA or HACA developed in less than 2% of patients, and no patient with HAMA or HACA experienced unusual AEs. The rates of HAMA range from 2% to 64% in studies of other radioimmunoconjugates.20,23–26 It is clear that radioimmunoconjugates represent a new therapeutic modality for B-cell NHL. The safety data presented in this study provide a framework for planning future studies. The next generation of clinical trials will aim to improve the complete response rate by providing higher single doses or multiple doses of radioimmunoconjugates and combinations of RIT with chemotherapy or biologic agents.
Supported by grants from IDEC Pharmaceuticals Corporation, San Diego, CA. Two of the authors (C.A.W. and P.S.M.) have declared a financial interest in a company whose product was studied in this article.
1. McLaughlin P, Grillo-López AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a 4-dose treatment program. J Clin Oncol 16:2825–2833, 1998[Abstract]
2. Hainsworth JD, Burris HA, Morrisey LH: Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin’s lymphoma. Blood 95:3052–3056, 2000 3. Knox SJ, Goris ML, Trisler K, et al: Yttrium-90-labeled anti-CD20 monoclonal antibody therapy of recurrent B-cell lymphoma. Clin Cancer Res 2:457–470, 1996[Abstract]
4. Witzig TE, White CA, Wiseman GA, et al: Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell non-Hodgkin’s lymphoma. J Clin Oncol 17:3793–3803, 1999
5. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol 20:2453–2463, 2002 6. Witzig TE, White CA, Flinn IW, et al: Zevalin radioimmunotherapy of rituximab-refractory follicular non-Hodgkin’s lymphoma. Blood 96:507a, 2000 (abstr 2183) 7. Witzig TE, Gordon LI, Wiseman GA, et al: Reduced dose Zevalin is safe and effective in patients with relapsed or refractory, low grade, follicular or CD20+ transformed B cell non-Hodgkin’s lymphoma (L/F/T NHL) and mild thrombocytopenia. Blood 96:728a, 2000 (abstr 3149) 8. Chinn PC, Morena RA, Wiseman GA, et al: Clinical experience with preparation of Zevalin (ibritumomab tiuxetan, IDEC-Y2B8/IDEC-In2B8) using a radiolabeled kit. Eur J Nucl Med 27:1163, 2000 (abstr) 9. Wiseman GA, White CA, Sparks RB, et al: Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. Crit Rev Oncol Hematol 39:181–194, 2001[Medline] 10. Witzig TE, White CA, Gordon LI, et al: Reduced-dose Zevalin radioimmunotherapy for relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL) patients with pre-existing thrombocytopenia: report of interim results of a phase II trial. Blood 94:92a, 1999 (abstr 400) 11. Witzig TE, White CA, Gordon L, et al: Response to Zevalin is superior to response to rituximab regardless of age and extent of disease. Proc Am Soc Clin Oncol 20:279a, 2001 (abstr 1115)
12. Micallef IN, Lillington DM, Apostolidis J, et al: Therapy-related myelodysplasia and secondary acute myelogenous leukemia after high-dose therapy with autologous hematopoietic progenitor-cell support for lymphoid malignancies. J Clin Oncol 18:947–955, 2000
13. Pedersen-Bjergaard J, Andersen MK, Christiansen DH: Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation. Blood 95:3273–3279, 2000 14. Kantarjian HM, Keating MJ: Therapy-related leukemia and myelodysplastic syndrome. Semin Oncol 14:435–443, 1987[Medline] 15. Travis LB, Curtis RE, Boice JD Jr, et al: Second cancers following non-Hodgkin’s lymphoma. Cancer 67:2002–2009, 1991[CrossRef][Medline]
16. Travis LB, Curtis RE, Stovall M, et al: Risk of leukemia following treatment for non-Hodgkin’s lymphoma. J Natl Cancer Inst 86:1450–1457, 1994
17. Pedersen-Bjergaard J, Andersen MK: Secondary or therapy-related MDS and AML and their chromosome aberrations: Important to study but difficult to establish causality. Haematologica 83:481–482, 1998 18. Kyle RA, Greipp PR, Gertz MA, et al: Waldenstrom’s macroglobulinaemia: A prospective study comparing daily with intermittent oral chlorambucil. Br J Haematol 108:737–742, 2000[CrossRef][Medline]
19. Pedersen-Bjergaard J, Ersboll J, Sorensen HM, et al: Risk of acute nonlymphocytic leukemia and preleukemia in patients treated with cyclophosphamide for non-Hodgkin’s lymphomas: Comparison with results obtained in patients treated for Hodgkin’s disease and ovarian carcinoma with other alkylating agents. Ann Intern Med 103:195–200, 1985
20. 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 lymphomas. J Clin Oncol 19:3918–3928, 2001 21. Berger AM, Clark-Snow RA, Rosenberg SA: Adverse effects of treatment: Nausea and vomiting, in DeVita VT Jr, Hellman S, et al (eds): Cancer, Principles and Practice of Oncology (ed 5). Philadelphia, PA, JB Lipincott Co, 1997, pp 2705–2714 22. Goldenberg DM: Monoclonal antibodies in cancer detection and therapy. Am J Med 94:297–312, 1993[CrossRef][Medline]
23. DeNardo SJ, DeNardo GL, Kukis DL, et al: 67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma. J Nucl Med 40:302–310, 1999 24. Kaminski MS, Press OW, Lister TA, et al: Iodine I 131 tositumomab for patients with small lymphocytic lymphoma (SLL): Overall clinical trial experience. Blood 94:88a, 1999 (abstr 386)
25. Vose JM, Wahl RL, Saleh M, et al: Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 18:1316–1323, 2000 26. Vose JM, Colcher D, Gobar L, et al: Phase I/II trial of multiple dose 131iodine-MAb LL2 (CD22) in patients with recurrent non-Hodgkin’s lymphoma. Leuk Lymphoma 38:91–101, 2000[Medline] Submitted August 7, 2002; accepted December 17, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
