Tositumomab/iodine-131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are radioimmunoconjugates targeting the CD20 antigen. Both agents are approved in the United States for use in relapsed or refractory, indolent or transformed, B-cell lymphoma. These agents are well tolerated and have the highest levels of single-agent activity observed in these histologies. This review will summarize the key trials that led to approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.
Non-Hodgkin's lymphoma (NHL) is the fifth most common malignancy in the United States, with an inexplicable increase in incidence over the past 2 decades. The majority of NHL cases are of B-cell origin, a collectively hetero-geneous group of diseases with a wide variation in clinical phenotype. Classically, effectiveness of therapeutics have varied based on histology, with indolent follicular lymphoma generally regarded as incurable in later stages. Approximately 80% to 85% of patients with follicular lymphoma present with stage III or IV disease, and most will require therapy based on unfavorable risk factors or because of symptoms. After achieving a response in follicular lymphoma, the likelihood of relapse is high. With each subsequent therapy, response rates and duration of response classically diminish.
Antibody Therapy of Lymphoma
Rituximab (Rituxan) is a human-mouse chimeric monoclonal antibody to the CD20 antigen found in over 95% of B cell lymphomas. Approved in 1997 for the treatment of relapsed/refractory follicular lymphoma, this immunotherapeutic agent has had a significant impact on the treatment of indolent lymphoma. In a pivotal trial of 166 patients with relapsed or refractory follicular or low-grade lymphoma, treatment with rituximab at 375 mg/m2 every week for 4 weeks showed an overall response of 48%, comparing favorably to single-agent chemotherapy. Indeed rituximab is effective both as a single agent and combined with chemotherapy.
The overall survival of patients with advanced stages of follicular lymphoma has improved in the past several years, which is possibly attributable to the use of rituximab.[3,4] However, a substantial number of patients with indolent lymphomas do not respond to rituximab. Tumor bulk, heterogeneous expression of antigen, and impaired antibody-mediated cytotoxicity have all been postulated to play a role in rituximab resistance. Furthermore, even if a response is obtained, relapse is inevitable, conferring significant morbidity and mortality. The curability of diffuse large B-cell lymphoma is enhanced when rituximab is added to conventional anthracycline-containing chemotherapy.[6-8] However, despite this major advance, many patients presenting with high-risk disease (as defined clinically, immunophenotypically, or molecularly) are not cured.
To augment the effectiveness of the CD20 antibody, radioimmunoconjugates have been developed.[9,10] These constructs combine the selectiveness of the CD20 antibody with the additional cytotoxicity of radiotherapy. Even if a tumor is bulky or portions lack CD20 expression, the targeted radiation will cause cytotoxicity—ie, the "bystander" effect—while limiting undesirable nonspecific radiation (Figure 1). In 2002, yttrium-90 ibritumomab tiuxetan (Zevalin) became the first radioimmunotherapeutic agent (RIT) approved by the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory low-grade lymphoma including transformed phenotypes. Y-90 is primarily a beta-particle emitter with a relatively long path length (5-10 mm), and as such, has been postulated to work better on penetrating bulky tumors. This isotope also has a favorable half-life of only 2.5 days. The Y-90 is bound to a linker tiuxetan, which is then bound to the antibody.
Similarly, tositumomab/iodine-131 tositumomab (Bexxar), approved by the FDA for similar indications, is a murine CD20 antibody that is directly bound to the isotope. The I-131 isotope contrasts with Y-90 in that it has both beta and gamma radiation (with a path length of 0.8 mm). This shorter path has the advantage of minimizing inadvertent radiation to unwanted sites but theoretically may not work as well on bulky disease. The half-life of I-131 is longer, as is the need for posttreatment precautions. Both constructs use a murine antibody to maximize clearance and avoid prolonged radiation.
The treatment regimen is administered on an outpatient basis and is similar for both RITs (Figure 2). Initially, a nonradiolabeled antibody is administered to allow for binding of circulating lymphocytes to minimize toxicity and to maximize localization of the RIT to the lymphoma disease sites. Rituximab is used for ibritumomab, and unlabeled tositumomab is used for I-131 tositumomab. Then a "dosimetric," low dose of the RIT is given to determine individual total-body clearance of the constructs.
For I-131 tositumomab, three scans total are performed, using a gamma camera on day 0, then on day 2, 3, or 4, and again on day 6 or 7. The therapeutic dose is calculated to deliver a maximum of 75 cGy total-body radiation; however, the dosimetry to the tumor is about 50 times stronger than the dose delivered to vital organs, owing to RIT specificity. Between days 7 and 14, another dose of unlabeled antibody is given, followed immediately by the therapeutic dose. Specific to treatment with I-131 tositumomab is the need for thyroid protection during therapy. Patients are given potassium iodide or Lugol's solution from day 1 until 14 days after the therapeutic dose is administered.
In the case of Y-90 ibritumomab, total-body scans are performed at 2 to 24 hours, then at 48 to 72 hours, with the therapeutic dose calculated based on a maximum tolerated dose of 0.4 mCi/kg usually administered on day 8 to 10 (dosimetry is not needed). Of note, the yttrium isotope is only used for therapy and not used for imaging (given its lack of gamma emission). Instead, indium-111-labeled antibody is used for these scans, which are performed to ensure normal biodistribution. It is recommended that RIT be avoided in patients who, upon gamma scan, have prolonged uptake in the lungs, urinary tract, or bowel, as this may indicate an aberrant distribution and account for increased toxicity.
For either RIT, after the therapeutic dose is administered, appropriate precautions must be undertaken to avoid radiation exposure to others. There are fewer limitations in persons treated with Y-90, but close physical contact should be avoided for the first 24 hours. If treated with I-131, the patient must sleep 6 ft away from his or her partner for at least 7 days. Finally, these patients should avoid contact with children or pregnant women for about 1 week. With both types of RIT treatment, patients must be cognizant of their bodily wastes, which must be restricted to toilets and immediate double-flushing methods. The FDA provides a full list of limitations for RIT patients. Clearly, such treatment requires patient education and input from a team consisting of the medical oncologist, nuclear medicine department, and radiation safety officer. Overall, however, RIT is quite well tolerated, with minimal toxicities.
The clinical development of radioimmunotherapy in the monoclonal antibody treatment era has been challenging. The remainder of this review will summarize the key trials that led to the approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.
Dr. Friedberg is a consultant and speaker for GlaxoSmithKline. He is supported in part by a career development award from the National Cancer Institute (CA-102216).
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