The Oncologist, Vol. 12, No. 3, 338-340, March 2007; doi:10.1634/theoncologist.12-3-338
© 2007 AlphaMed Press
Safe Administration of Iodine-131 Tositumomab After Repeated Infusion-Related Reactions to Rituximab
John Hayslip,
Robert Fenning
Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
Key Words. Follicular lymphoma • Antibodies • Monoclonal • Radioimmunotherapy • Adverse effects
Correspondence: John Hayslip, M.D., 96 Jonathan Lucas Street, CSB 903, PO Box 250635, Charleston, South Carolina 29425, USA. Telephone: 843-792-4271; Fax: 843-792-0644; e-mail: hayslip{at}musc.edu
Received October 17, 2006;
accepted for publication December 21, 2006.
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ABSTRACT
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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.
Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION
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The development of rituximab (Rituxan®; Genentech, South San Francisco, CA), an anti-CD20 monoclonal antibody, has significantly impacted the treatment of CD20-expressing malignancies. Most patients tolerate rituximab therapy well, experiencing mild, transient toxicities when present. Severe infusion-related reactions have been reported in 8% of patients during their first infusion [1]. However, most patients are able to complete their planned treatment, because severe reactions recur in only 1% of patients during subsequent infusions [1]. Rarely, patients experience repeated severe infusion-related reactions and are subsequently counseled to discontinue rituximab. It is unclear whether these patients should be considered for subsequent treatment with iodine-131 tositumomab (Bexxar®; GlaxoSmithKline, Research Triangle Park, NC) if future lymphoma treatment is required. We review the case of a patient with repeated severe infusion-related reactions to rituximab who received iodine-131 tositumomab without incident.
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CASE
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A 43-year-old professional skateboarder presented with complaints of dyspnea and left-sided chest pain. He had also noted firm, mobile, lymph nodes in his neck for approximately 3 years and more recently bilaterally in his groin. He denied night sweats, chills, or weight loss. His hemoglobin was 8.5 g/dl, white blood count was 17,300/mm3, lymphocyte count was 9,900/mm3, and lactate dehydrogenase was 355 IU/l. Computed tomography revealed pleural effusions with an asymmetric ground-glass opacity within the left upper lobe and adenopathy in the periportal, retroperitoneal, iliac, and inguinal regions. He was admitted to the hospital and underwent thoracentesis and lymph node biopsy. The lymph node biopsy was histologically consistent with grade III follicular lymphoma, stained positive for Bcl-2 and CD20, and flow cytometry was positive for CD20 and kappa light chain restriction. A bone marrow biopsy was also positive for lymphoma involvement (Fig. 1).
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Figure 1. Biopsies of the affected lymph nodes (A–C) and bone marrow (D) were consistent with grade III follicular lymphoma. (A): Follicular pattern seen at low magnification. (B): Greater than 15 lymphoblasts/high-powered field. (C): Malignant cells stain for Bcl-2. (D): Malignant cells stain for CD20.
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His dyspnea resolved after the thoracentesis and he was discharged to follow-up in the office. While completing the evaluation, scheduling central catheter placement, and awaiting final pathology determinations, he received one dose of rituximab with the plan of starting R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) chemotherapy within the coming week. After premedication with diphenhydramine and acetaminophen, rituximab was started at a rate of 50 ml/hour and increased to 100 ml/hour after 30 minutes. Twenty minutes after this rate increase, he began shaking, complained of chills, appeared grey, and developed dyspnea and high-pitched wheezing. Dexamethasone, additional diphenhydramine, and s.c. epinephrine were given and the symptoms resolved. The infusion was not restarted. One week later he was to receive R-CHOP and received diphenhydramine, acetaminophen, and prednisone prior to rituximab with the same dose-escalation algorithm. His lymphocyte count was 5,200/mm3 on that day. He again experienced a similar episode during the rituximab infusion requiring s.c. epinephrine and nebulized albuterol. No further rituximab administration was attempted and his lymphoma progressed after the second cycle of CHOP.
He received salvage regimens of multiagent chemotherapy and achieved a significant response with the resolution of his pleural effusions and lymphadenopathy. Unfortunately, he developed grade 3 treatment-related sensory neuropathy that limited his ability to skate competitively. Ultimately, his disease progressed within 3 months of completing chemotherapy and he was again symptomatic. He next received anti-CD20 radioimmunotherapy with iodine-131 tositumomab with diphenhydramine, acetaminophen, and dexamethasone premedication and tolerated this regimen well without any adverse infusion events. He remained in remission for 12 months, the longest remission of his course, before having another recurrence. During his year-long remission, the neuropathy partially improved and he became active in skateboarding exhibitions with the cancer survivorship advocacy group "Grind For Life" (http://www.grindforlife.org) (Fig. 2).
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DISCUSSION
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Rituximab, an anti-CD20 chimeric antibody, is widely used in the treatment of hematologic neoplasms that express the CD20 antigen. With prophylactic administration of acetaminophen and diphenhydramine, rituximab infusions are typically well tolerated with low-grade toxicities. Although beyond the scope of this report, reviews of rituximab's toxicities are available [2, 3].
Severe, grade 3 or 4, infusion-related reactions are uncommon and are unlikely to recur during future administrations [4, 5]. While our patient exhibited chills, bronchospasm, and dyspnea, prior to rescue interventions, arrhythmia, angioedema, acute respiratory distress syndrome, hypotension, and death have also been reported [4, 6–8]. Clinical characteristics, including advanced age, high circulating tumor burden, and poor performance status, have been identified as potential risk factors for developing severe infusion-related reactions [9–11]. Empiric dose reduction on the first day of infusion with completion of the full-dose on the subsequent day has been suggested for patients with these characteristics and has typically been well tolerated in our experience [10].
Iodine-131 tositumomab is a radiolabeled murine immunoglobulin that is specific to the CD20 antigen. Although rituximab and tositumomab both bind the CD20 antigen, it is unknown whether these agents bind related epitopes. Impressive response rates of 57%–71% have been reported with iodine-131 tositumomab, including in patients who were refractory to rituximab-containing regimens [12, 13]. Although treatment with radiolabeled antibodies can result in significant cytopenias, severe infusion-related reactions are rarely seen and some studies have failed to report any grade 3 or 4 infusion toxicities [13, 14]. It is unclear from published studies how many patients with previous severe infusion-related reactions with rituximab proceeded to receive radiolabeled antibodies.
In conclusion, we believe this to be the first reported case of a patient with recurrent severe infusion-related reactions to rituximab who proceeded to receive iodine-131 tositumomab. Changes in the patient's tumor burden and performance status, and differences between the drugs themselves may have contributed to the patient's better experience with iodine-131 tositumomab. Based upon this experience, even repeated severe infusion-related reactions may not preclude the use of other targeted antibodies within the same patient. This decision must be made with caution and careful consideration of the risks, benefits, and other viable treatment options.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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The authors indicate no potential conflicts of interest.
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ACKNOWLEDGMENTS
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We are indebted to Lydia Christiansen, M.D., and John Lazarchick, M.D., for generously reviewing the pathologic details and providing the micrographs.
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REFERENCES
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- Winkler U, Jensen M, Manzke O et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999;94:2217–2224.[Abstract/Free Full Text]
- Zelenetz AD. A clinical and scientific overview of tositumomab and iodine I 131 tositumomab. Semin Oncol 2003;30(suppl 4):22–30.[Medline]
- 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 2005;23:712–719.[Abstract/Free Full Text]
- 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 2000;18:1316–1323.[Abstract/Free Full Text]
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Abstract
Introduction
