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Tositumomab and Iodine I 131 Tositumomab for Recurrent Indolent and Transformed B-Cell Non-Hodgkin’s Lymphoma

From the St Bartholomew’s Hospital, London; Christie Hospital, Manchester, United Kingdom; and Corixa Corp, South San Francisco, CA

Address reprint requests to A.J. Davies, BM, Cancer Research UK Medical Oncology Unit, Department of Medical Oncology, 45 Little Britain, St Bartholomew’s Hospital, London EC1A 7BE, United Kingdom; e-mail: Andrew.J.Davies{at}cancer.org.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
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 10⁹/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.

	INTRODUCTION

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Follicular, small lymphocytic, and lymphoplasmacytoid lymphomas¹ together comprise a group of diseases characterized clinically by a propensity for advanced stage at presentation and longer median survival than other histologic subtypes of B-cell non-Hodgkin’s lymphomas.^2-8 Typically, patients respond to therapy but the clinical course is of multiple episodes of recurrence culminating in death as a result of disease (irrespective of whether transformation to large B-cell pathology has occurred) or complications of therapy. Treatment options at recurrence are increasingly broad,^9,10 yet there has been little significant impact on survival.¹¹

The CD20 antigen has become well established as a target for monoclonal antibody-directed therapy in B-cell lymphoma. This transmembrane phosphoprotein is expressed by more than 95% of B-cell lymphomas and is present on normal B cells except early progenitors and terminally differentiated plasma cells.^12,13 Because there is little shedding into the circulation, no internalization after antibody binding,^14,15 and no antigenic modulation, CD20 provides a suitable and stable target.¹⁶ After four weekly intravenous infusions of the chimeric anti-CD20 monoclonal antibody rituximab, responses are achieved in approximately 50% of patients. The complete remission (CR) rate, however, is low and the duration of response, in general, is short.^17,18 Given the sensitivity of these lymphomas to external-beam irradiation, radioimmunoconjugates directed against CD20 have been developed to overcome some of the deficiencies inherent in the use of cold antibodies.

The murine immunoglobulin G2a anti-B1 antibody tositumomab targets the CD20 antigen.¹² Covalently linked with iodine-131 (¹³¹I), tositumomab and iodine I 131 tositumomab together comprise the BEXXAR therapeutic regimen (Corixa Corp, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA). The dual-emission properties of ¹³¹I result in delivery of high-energy beta particles over short distances, whereas measurements of gamma emissions may be made externally, allowing the determination of patient-specific pharmacokinetics. Encouraging results with tositumomab and ¹³¹I tositumomab, hereafter referred to as ¹³¹I tositumomab, have been achieved in a series of studies during the last decade. In a phase I/II, single-center, dose-escalation study of 59 patients with B-cell lymphomas, the overall response rate (ORR) was 71%.¹⁹ A subsequent, multicenter, phase II trial of 47 heavily pretreated patients (median four prior therapies) with low-grade or transformed B-cell lymphoma reported an ORR of 57%, with 32% of patients achieving a CR.²⁰ These findings were subsequently confirmed in a large expanded-access program.^{21 131}I tositumomab is effective in chemotherapy-refractory patients (ie, those in whom treatment has failed or those who have experienced disease recurrence within 6 months from their last chemotherapy regimen). In this group the ORR was 65% (20% CR), in contrast with a response rate of only 28% and CR rate of 3% after their last regimen.²² Most strikingly, 53% of patients had a longer remission duration after ¹³¹I tositumomab than after their previous regimen.

On the basis of these promising results in a heavily pretreated population, this study was designed to investigate the safety and efficacy of ¹³¹I tositumomab when administered earlier in the clinical course of indolent or transformed indolent B-cell lymphoma.

	PATIENTS AND METHODS

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This was a single-arm, open-label, phase II study to establish the response rate to ¹³¹I tositumomab in patients at first or second recurrence of indolent or transformed indolent B-cell non-Hodgkin’s lymphoma. Duration of response, progression-free survival (PFS), safety, and survival were the secondary end points. The study was conducted at two centers in the United Kingdom. Local research ethics committee approval was granted at both sites and patients gave written informed consent before study entry.

Patient Eligibility
Adult patients with a histologically confirmed diagnosis of CD20-positive B-cell follicular (grade 1 or 2), small lymphocytic, lymphoplasmacytoid/immunocytoma, or unclassifiable low-grade B-cell lymphoma¹ were eligible for study entry. Patients with transformation from one of the above histologies to large B-cell lymphoma were also eligible. Histologic confirmation of transformation was documented before therapy. Patients were treated at first or second recurrence and had experienced disease progression after their last treatment. Patients were required to have a Karnofsky performance score 60, adequate renal and hepatic function, bidimensionally measurable disease ( 2 x 2 cm by computed tomography scan), neutrophils 1.5 x 10⁹/L, platelets 100 x 10⁹/L, and no more than 25% of the intertrabecular bone marrow space infiltrated with lymphoma (determined by bone marrow trephine biopsy).

Patients were excluded if they had received cytotoxic chemotherapy, radiotherapy, or cytokine therapy within the previous 4 weeks or had experienced disease progression in a field previously irradiated with more than 35 Gy within 1 year. Systemic corticosteroids were discontinued at least 1 week before study entry. Patients were also excluded if they had previously received high-dose chemotherapy or radiotherapy with hematopoietic progenitor cell rescue; had prior exposure to either monoclonal or polyclonal antibodies, known HIV infection, active hydronephrosis, CNS lymphoma, or any other malignancy diagnosed within 5 years; or if they were pregnant or breastfeeding. Previous radioimmunotherapy and allergy to iodine were also exclusions to study entry.

Dosimetric and Therapeutic Doses
Tositumomab was centrally radiolabeled with ¹³¹I (MDS Nordion Inc, Kanata, Canada) and shipped on a patient-specific basis. Administration was performed according to previously described methodology²⁰ (Fig 1). Patients received 120 mg potassium iodide daily, as thyroid blockade, from at least 24 hours before administration of the dosimetric dose until 14 days after the therapeutic administration. Before drug administrations, patients were premedicated with paracetamol 500 mg and chlorpheniramine 4 mg orally. After administration of the dosimetric dose, the effective half-life of total body clearance was calculated from gamma camera counts acquired at three time points. The patient-specific amount of radioactivity required to deliver the total-body therapeutic dose of 0.75 Gy was then calculated as previously described.²³ For patients with platelet counts between 100 and 149 x 10⁹/L, an attenuated total body dose of 0.65 Gy was administered, and for patients weighing more than 137% of their lean body mass, calculations were based on maximum effective mass. The therapeutic dose was administered 7 to 14 days after the dosimetric dose. Patients were hospitalized for this therapeutic phase and isolated in a dedicated facility until the total body activity was sufficiently low to permit discharge under current United Kingdom regulations.

View larger version (18K): [in this window] [in a new window]   Fig 1. Drug administration. The desired total body dose was 0.75 Gy and attenuated to 0.65 Gy for patients with platelet counts 100 to 149 x 109/L.

Evaluation of Toxicity and Safety
All adverse events from study entry through to week 13 were graded according to the National Cancer Institute Common Toxicity Criteria (version 1.0). Any adverse event occurring after this period considered to be possibly or probably related to study drug was also recorded. Full blood counts were performed weekly from week 3 until week 9, or until grade 0 toxicity had been reached, and blood counts were repeated at weeks 13 and 26, and every 3 months thereafter. The use of hematopoietic growth factors and blood products was at the discretion of the treating physician. History, physical examination, and hepatic, renal, and electrolyte studies were performed at weeks 3, 7, 13, and 26, and repeated every 3 months thereafter. Thyroid function tests (thyroid-stimulating hormone [TSH], free T4, and total T3) were performed at week 26 and repeated every 3 months thereafter. From 2 years onward, patients were evaluated every 6 months, and data were collected for disease status, diagnosis of secondary myelodysplasia or secondary acute myeloid leukemia, other secondary malignancy, thyroid dysfunction, and use of thyroid medication. Serum human antimouse antibody (HAMA) and thyroid function analyses were also performed at these times.

HAMA
Detection of HAMA on serum samples was performed at each site using the ImmuSTRIP HAMA immunoglobulin G enzyme-linked immunosorbent assay test kit (Immunomedics Inc, Morris Plain, NJ). Samples were taken at baseline and at day 5 and evaluated before the administration of the dosimetric and therapeutic doses, respectively. Patients with a positive HAMA at baseline or on day 5 did not receive subsequent ¹³¹I tositumomab therapy. HAMA assessment was repeated at weeks 7, 13, and 26, and as part of long-term follow-up. Independent central analysis also was performed (Covance Central Laboratory Services Inc, Indianapolis, IN).

Statistical Analysis
Data were analyzed through November 2003 for all patients who had received any study drug. Hematologic toxicity was analyzed only for those patients who received a therapeutic dose. The level of significance for all comparative analyses was set at 0.05, with exact confidence limits calculated from binomial distributions. Analyses were performed using SAS version 6.12 (SAS Institute, Cary, NC). Duration of response and survival data were analyzed using the censored data techniques of Kaplan-Meier.²⁵ Differences in response rates across patient subgroups were tested for statistical significance by ² statistic (Yates corrected for two groups) and the log-rank test was used for duration of response by univariate analysis. The logistic regression model was used to perform multivariate analysis of response and the Cox proportional hazards model was used in multivariate analysis of PFS. Cumulative incidence estimates incorporating the presence of competing risk were used for the proportion of patients developing HAMA and hypothyroidism.²⁶

	RESULTS

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Patient Characteristics
Forty-four patients were enrolled onto this phase II study at two institutions between July 2, 1998, and February 22, 2001. Three patients did not receive any study drug and are not included in the analysis (two patients had HAMA at baseline, in the absence of exposure to previous diagnostic or therapeutic murine proteins, and one patient withdrew consent before therapy). Thus, a total of 41 patients received a dosimetric dose of ¹³¹I tositumomab. One patient developed HAMA 12 days after dosimetry and did not receive the therapeutic dose. Clinical characteristics are documented in Table 1. The median age was 59 years (range, 36 to 90 years). Median follow-up of all patients is 3.0 years (3.6 years for responders). The median activity administered to deliver a total body dose of 0.65 or 0.75 Gy was 95.1 mCi (range, 49.2 to 145.3 mCi; median, 3,519 MBq [range, 1,820 to 5,372 MBq]).

View larger version (16K): [in this window] [in a new window]   Fig 2. Duration of response by remission status.

View larger version (15K): [in this window] [in a new window]   Fig 3. Progression-free and overall survival.

View larger version (26K): [in this window] [in a new window]   Fig 4. Nonhematologic adverse experiences possibly or probably related to study drug that occurred in more than 5% of patients. The Coding Symbols for a Thesaurus of Adverse Reaction Terms’ preferred term "infection" includes a subset of all infections (eg, upper respiratory infections). Other infections may be mapped to other preferred terms (eg, pneumonia and sepsis). CTC, National Cancer Institute Common Toxicity Criteria.

View larger version (60K): [in this window] [in a new window]   Fig 5. Hematologic toxicity. (A) Neutrophils; (B) platelets; and (C) hemoglobin. CTC, National Cancer Institute Common Toxicity Criteria.

With 123 patient-years of follow-up, one patient has developed secondary myelodysplasia (therapy-related myelodysplasia [t-MDS]; annualized incidence 0.8%/yr (95% CI, 0.1% to 5.8%/yr). This was diagnosed 53 months after therapy in a patient that had previously received two regimens (chlorambucil and fludarabine plus mitoxantrone plus dexamethasone) before ¹³¹I tositumomab. Bone marrow morphology examination, performed before therapy for recurrence, revealed infiltration with follicular lymphoma and dysplastic features [cytogenetics demonstrated del(13q) by fluorescent in situ hybridization, reported in follicular lymphoma and at a lower frequency in MDS]. The patient’s peripheral blood count remains normal 6 months after diagnosis.

Survival
The median survival from the dosimetric dose has not been reached (95% CI, 2.9 years to not yet reached). Sixteen patients have died, all as a result of progressive lymphoma (Fig 3). Eight of these patients had responded to ¹³¹I tositumomab, including two patients who had achieved a CR after therapy; none of the eight patients, however, had a duration of response longer than 1 year. Twenty-four patients have received a median of two (range, one to five) additional therapies after ¹³¹I tositumomab; in the minority of patients, dose reductions were necessary (Table 5).

	DISCUSSION

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Historical data, derived from an unselected population of patients with follicular lymphoma, shows that even in an era before monoclonal antibody therapies, high response rates can be anticipated early in the clinical course of the disease.⁵ In general, chemotherapy resistance is not a significant issue, with 78% and 76% of patients responding to conventional modalities at first and second recurrence, respectively. The pitfalls of comparison aside and focusing on follicular lymphoma, our experience with ¹³¹I tositumomab in terms of ORR is entirely consistent with the historical data set. However, what gives cause for enthusiasm is the superior CR rate after radioimmunotherapy (59%) and longer median duration of remission (2.3 years for all responders and 3.3 years for those entering CR or CR(u), compared with the historical series [CR 28%; median remission duration, 13 months]). Treatment strategies, however, have evolved, and from the options now available, selection of an appropriate approach requires careful consideration of both the goals of therapy and the potential toxicity.

Fludarabine-based combinations have resulted in some remarkable response rates in recurrent indolent lymphoma,^35-37 yet concerns exist about opportunistic infections and the later ability to collect adequate numbers of peripheral-blood stem cells. Single-agent rituximab is an alternative less intensive option, but the number of patients achieving CR is low, and the duration of remission generally is short.^28,38 Radioimmunotherapy results in high response rates, albeit with more hematologic toxicity; however, despite a superiority in CR rates, no advantage in time to progression was observed when ytrrium-90-labeled ibritumomab tiuxetan was tested against rituximab.²⁹ The use of antibody in combination with chemotherapy is now widespread, with toxicity only minimally more than that of chemotherapy alone. The rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) combination seems impressive, with all patients in receipt of therapy responding,^39,40 and furthermore, a randomized study has shown a survival advantage by adding rituximab to the fludarabine, cyclophosphamide, and mitoxantrone regimen.⁴¹ High-dose chemotherapy with autologous stem-cell rescue at recurrence has now shown an advantage in PFS over CHOP alone,⁴² reigniting some lost interest. For many patients, however, high-dose therapy may not be an appropriate option. Promising results have been observed with allogeneic transplantation using reduced-intensity conditioning regimens.⁴³ This procedure, however, is available to only the minority of patients. Against this backdrop, the use of ¹³¹I tositumomab, with its acceptable toxicity profile and potential for durable remissions, seems to be an attractive option for use early in the clinical disease course.

Concerns about toxicity will influence the choice of therapeutic strategy. Consistent with previous experience, toxicity in this study was principally hematologic.^{19,20,22,29,30,44,45} In addition, consistent with previous experience, there was a low requirement for blood products and growth factor support, along with a low rate of serious infections. To date, one patient with t-MDS has been documented in this study population. After ¹³¹I tositumomab was administered in a group of heavily pretreated patients, the incidence of t-MDS or therapy-related acute myelogenous leukemia has been reported as 1.1%/yr (95% CI, 0.7% to 1.6%/yr) based on an independent hematopathologist’s assessment at a median of 2.0 years follow-up.⁴⁶ Cytogenetic analysis revealed in the majority of patients at least one deletion or abnormality of chromosome 5 or 7. The influencing effect of prior chemotherapy is clearly important,⁴⁷ a factor that may favor early use, given that in a group of previously untreated patients with a median of 2.7 years follow-up there has been no reported cases of t-MDS/t-AML. Clearly, long-term follow-up of this study cohort is imperative. The incidence of either clinical or subclinical hypothyroidism remains low, and hypothyroidism is treated easily and safely. The frequency of HAMA development was consistent with published experience in pretreated individuals,²² in contrast to the much higher incidence (63%) after first-line therapy.²⁷ HAMA had no influence on response rate or duration of remission, and the low seroconversion rate should permit consideration of re-treatment in the majority of patients who experience relapse after a response (reported ORR, 56%⁴⁸). The presence of HAMA also does not seem to have a detrimental effect on later safe administration of rituximab.⁴⁹

The ability to deliver effective chemotherapy later for those who experience relapse after ¹³¹I tositumomab also may influence any decision regarding use earlier in the clinical course. In this study, and after use as first-line therapy, subsequent treatment options, including high-dose therapy, have not been precluded,⁵⁰ and in heavily pretreated patients, both autologous and allogeneic stem-cell procedures have been performed after therapy.⁵¹

Putting aside matters of cost-benefit, where then should radioimmunotherapy be integrated in the treatment algorithm? One could argue, on the basis of the remarkable response rates,⁵⁰ that first-line use is advantageous. An alternative approach would be to reserve radioimmunotherapy for situations in which treatment options are more limited, and where its efficacy has been well studied, such as after multiple therapies,^19,20 in chemotherapy-resistant patients,²² and in rituximab-refractory patients.⁵² Alternatively, given that lower response rates are seen in patients with lymph node masses 5 cm, sequential administration after chemotherapy may be the most appropriate choice. This has proven effective at the time of first therapy with either CHOP⁵³ or fludarabine.⁵⁴

This study presents data demonstrating that ¹³¹I tositumomab is safe, effective, and produces complete, durable responses when used at first or second recurrence of indolent or transformed indolent B-cell lymphoma. The optimal timing of radioimmunotherapy will become clear only with longer follow-up and future randomized studies. Studies comparing rituximab to ¹³¹I tositumomab and comparing ¹³¹I tositumomab to yttrium-90-labeled ibritumomab tiuxetan are underway.

	Authors’ Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have 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. Owns stock (not including shares held through a public mutual fund): S. Kroll, Corixa Corp. Received more than $2,000 a year from a company for either of the last 2 years: S. Kroll, Corixa Corp; T.A. Lister, Corixa Corp.

	Acknowledgment

 
We thank the medical and nursing staff of the Bodley Scott Unit, St Bartholomew’s Hospital, and the Lymphoma Unit, Christie Hospital, along with the staff of both Nuclear Medicine Departments. We also thank Sue Lee, Tanya Massey, Andrew Wilson, and Janet Matthews for assistance with data management.

	NOTES

 
Supported by Corixa Corp (South San Francisco, CA), Cancer Research UK, Barts and the London NHS Trust, and Christie Hospital NHS Trust, United Kingdom.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
1. Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361-1392, 1994[Free Full Text]

2. Horning SJ, Rosenberg SA: The natural history of initially untreated low-grade non-Hodgkin’s lymphomas. N Engl J Med 311:1471-1475, 1984[Abstract]

3. Gallagher CJ, Gregory WM, Jones AE, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4:1470-1480, 1986[Abstract/Free Full Text]

4. Bastion Y, Berger F, Bryon PA, et al: Follicular lymphomas: Assessment of prognostic factors in 127 patients followed for 10 years. Ann Oncol 2:123-129, 1991 (suppl 2)[Abstract/Free Full Text]

5. Johnson PW, Rohatiner AZ, Whelan JS, et al: Patterns of survival in patients with recurrent follicular lymphoma: A 20-year study from a single center. J Clin Oncol 13:140-147, 1995[Abstract/Free Full Text]

6. Armitage JO, Weisenburger DD: New approach to classifying non-Hodgkin’s lymphomas: Clinical features of the major histologic subtypes—Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 16:2780-2795, 1998[Abstract]

7. Berger F, Felman P, Sonet A, et al: Non follicular small B-cell lymphomas: A heterogeneous group of patients with distinct clinical features and outcome. Blood 83:2829-2835, 1994[Abstract/Free Full Text]

8. The Non-Hodgkin’s Lymphoma Classification Project: A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma—The Non-Hodgkin’s Lymphoma Classification Project. Blood 89:3909-3918, 1997[Abstract/Free Full Text]

9. Horning SJ: Follicular lymphoma: Have we made any progress? Ann Oncol 11:23-27, 2000[Abstract/Free Full Text]

10. Cabanillas F, Horning S, Kaminski M, et al: Managing indolent lymphomas in relapse: Working our way through a plethora of options. Hematology (Am Soc Hematol Educ Program) 166-179, 2000

11. Horning SJ: Natural history of and therapy for the indolent non-Hodgkin’s lymphomas. Semin Oncol 20:75-88, 1993[Medline]

12. Stashenko P, Nadler LM, Hardy R, et al: Characterization of a human B lymphocyte-specific antigen. J Immunol 125:1678-1685, 1980[Abstract]

13. Anderson KC, Bates MP, Slaughenhoupt BL, et al: Expression of human B cell-associated antigens on leukemias and lymphomas: A model of human B cell differentiation. Blood 63:1424-1433, 1984[Abstract/Free Full Text]

14. Einfeld DA, Brown JP, Valentine MA, et al: Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. Embo J 7:711-717, 1988[Medline]

15. Press OW, Howell-Clark J, Anderson S, et al: Retention of B-cell-specific monoclonal antibodies by human lymphoma cells. Blood 83:1390-1397, 1994[Abstract/Free Full Text]

16. Press OW, Farr AG, Borroz KI, et al: Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies. Cancer Res 49:4906-4912, 1989[Abstract/Free Full Text]

17. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al: IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol 15:3266-3274, 1997[Abstract]

18. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90:2188-2195, 1997[Abstract/Free Full Text]

19. Kaminski MS, Estes J, Zasadny KR, et al: Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: Updated results and long-term follow-up of the University of Michigan experience. Blood 96:1259-1266, 2000[Abstract/Free Full Text]

20. 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[Abstract/Free Full Text]

21. Leonard J, Frenett G, Dillman RO, et al: Interim safety and efficacy results of Bexxar in a large multicenter expanded access study. Blood 98:133a, 2001 (abstr 559)

22. 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[Abstract/Free Full Text]

23. Wahl RL, Kroll S, Zasadny KR: Patient-specific whole-body dosimetry: Principles and a simplified method for clinical implementation. J Nucl Med 39:14S-20S, 1998 (suppl 8)

24. Cheson BD, Horning S, Coiffier B, et al: Report of an International Workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17:1244-1253, 1999[Abstract/Free Full Text]

25. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

26. Anderson PK, Borgan Gill RD, et al: Statistical models based on counting processes. New York, NY, Springer-Verlag, 1992

27. Kaminski MS, Tuck M, Regan D, et al: High response rates and durable remissions in patients previously untreated, advanced stage, follicular lymphoma treated with tositumomab and iodine I-131 tositumomab (Bexxar). Blood 100:1384a, 2002 (abstr 1381)

28. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 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]

29. 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[Abstract/Free Full Text]

30. Wiseman GA, Gordon LI, Multani PS, et al: Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: A phase II multicenter trial. Blood 99:4336-4342, 2002[Abstract/Free Full Text]

31. Zelenetz AD, Saleh M, Vose JM, et al: Patients with transformed low grade lymphoma attain durable responses following outpatient radioimmunotherapy with tositumomab and Iodine I 131 tositumomab (Bexxar). Blood 100:357a, 2002 (abstr 1384)

32. Cullen MH, Lister TA, Brearley RI, et al: Histological transformation of non-Hodgkin’s lymphoma: A prospective study. Cancer 44:645-651, 1979[CrossRef][Medline]

33. Yuen AR, Kamel OW, Halpern J, et al: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13:1726-1733, 1995[Abstract/Free Full Text]

34. Bastion Y, Sebban C, Berger F, et al: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15:1587-1594, 1997[Abstract]

35. McLaughlin P, Hagemeister FB, Romaguera JE, et al: Fludarabine, mitoxantrone, and dexamethasone: An effective new regimen for indolent lymphoma. J Clin Oncol 14:1262-1268, 1996[Abstract/Free Full Text]

36. Zinzani PL, Bendandi M, Magagnoli M, et al: Fludarabine-mitoxantrone combination-containing regimen in recurrent low-grade non-Hodgkin’s lymphoma. Ann Oncol 8:379-383, 1997[Abstract/Free Full Text]

37. Crawley CR, Foran JM, Gupta RK, et al: A phase II study to evaluate the combination of fludarabine, mitoxantrone and dexamethasone (FMD) in patients with follicular lymphoma. Ann Oncol 11:861-865, 2000[Abstract/Free Full Text]

38. Foran JM, Gupta RK, Cunningham D, et al: A UK multicentre phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol 109:81-88, 2000[CrossRef][Medline]

39. Czuczman MS, Grillo-Lopez AJ, LoBuglio AF, et al: Patients with low-grade NHL treated with rituximab + CHOP experience prolonged clinical and molecular remission. Blood 102:411a, 2003 (abstr 1493)

40. Czuczman MS, Grillo-Lopez AJ, White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268-276, 1999[Abstract/Free Full Text]

41. Dreyling MH, Forstpointner R, Repp R, et al: Combined immuno-chemotherapy (R-FCM) results in superior remission and survival rates in recurrent follicular and mantle cell lymphoma final results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. Blood 102:103a, 2003 (abstr 351)

42. Schouten HC, Qian W, Kvaloy S, et al: High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918-3927, 2003[Abstract/Free Full Text]

43. Khouri IF, Saliba RM, Giralt SA, et al: Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 98:3595-3599, 2001[Abstract/Free Full Text]

44. 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[Abstract/Free Full Text]

45. Witzig TE, Flinn IW, Gordon LI, et al: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 20:3262-3269, 2002[Abstract/Free Full Text]

46. Bennett JM, Kaminski M, Knox SJ, et al: Assessment of treatment-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML) in patients with low-grade non-Hodgkin’s lymphoma (LG-NHL) treated with tositumomab and iodine-131 tositumomab (the BEXXAR therapeutic regimen). Blood 102:30a, 2003 (abstr 91)

47. Armitage JO, Carbone PP, Connors JM, et al: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin’s lymphoma patients. J Clin Oncol 21:897-906, 2003[Abstract/Free Full Text]

48. Kaminski M, Knox SJ, Radford JA, et al: Re-treatment with tositumomab and iodine I 131 tositumomab (the BEXXAR therapeutic regimen) in patients with non-Hodgkin’s lymphoma (NHL) with a previous response to the BEXXAR therapeutic regimen. Blood 102:407a, 2003 (abstr 1478)

49. Kaminski MS, Tuck M, Fang Y, et al: Development of HAMA after Bexxar does not preclude treatment with rituximab. Blood 96:734a, 2000 (abstr 3172)

50. Kaminski MS, Bahm V, Estes J, et al: Tolerance of treatment subsequent to frontline Bexxar (tositumomab and I 131 tositumomab) in patients with follicular lymphoma. Blood 98:603a, 2001 (abstr 2526)

51. Ratanatharathorn V, Uberti JP, Ayash L, et al: Hematopoietic stem cell transplantation in lymphoma patients receiving prior therapy with tositumomab and iodine I 131 tositumomab (Bexxar). Blood 98:200a, 2001 (abstr 836)

52. Horning S, Younes A, Lucas J, et al: Rituximab treatment failures: Tositumomab and iodine I 131 tositumomab [Bexxar] can produce meaningful durable responses. Blood 100:357a, 2002 (abstr 1385)

53. Press OW, Unger JM, Braziel RM, et al: A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood 102:1606-1612, 2003[Abstract/Free Full Text]

54. Leonard JP, Coleman M, Kostakoglu L, et al: Triple modality therapy for follicular low-grade lymphoma: Initial treatment with fludarabine followed by Bexxar (tositumomab and iodine I 131 tositumomab). Blood 98:844a, 2001 (abstr 3505)

Submitted June 13, 2003; accepted February 4, 2004.

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