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.
Radioimmunotherapy (RIT) is a method of targeted therapy that utilizes a monoclonal antibody as a radionuclide carrier to deliver high-energy radiation over a short path length to the tumor cell while sparing the normal tissues. From a patient's perspective, RIT is an ideal therapy. The treatment is delivered on an outpatient basis with few immediate side effects beyond the length of the infusion itself. The entire RIT treatment program is complete in 1 week, allowing a rapid return to work and daily activities. The response rate to treatment is high and can be durable. Because RIT does not produce alopecia, there is no outward sign that the patient has recently been in treatment. The only side effect is delayed myelosuppression, which is usually manageable, again through outpatient treatment.
Dr. Schaefer-Cutillo et al have provided an excellent and comprehensive review of the clinical development of the first two US Food and Drug Administration (FDA)-approved radioimmunoconjugates for the treatment of CD20+ B-cell non-Hodgkin's lymphoma (NHL). They also provide an overview of where the field of radioimmunotherapy is heading.
The development of radioimmunotherapy in the 1990s somewhat paralleled the development of the unlabeled human chimeric anti-CD20 antibody rituximab (Rituxan). Rituximab was FDA-approved in 1997 and was in wide use by the time the FDA approved ibritumomab tiuxetan (Zevalin) in 2002 and tositumomab/iodine-131 (131I) tositumomab (Bexxar) in 2003. Rituximab and the two RIT agents are clearly the most important new agents for the treatment of NHL and appear to be having an impact on survival.[2,3] The clinical trials that were designed to demonstrate the efficacy and toxicity of yttrium-90 (90Y)-ibritumomab tiuxetan and 131I-tositumomab were performed in a rational and methodical manner in order to maximize safety and to address the relevant questions of that time. These trials for the most part were focused on patients who had failed other therapies (and, in some cases, rituximab).
As outlined in the review by Schaefer-Cutillo et al, in relapsed follicular NHL, the overall response rate to RIT is approximately 80% with 30% complete remissions, and approximately 20% of patients are achieving a very long progression-free survival. It is gratifying to observe some of these patients still free of relapse 10 years out from treatment. However, as might be expected, most patients have required additional therapy and have relapsed, as these trials focused on heavily pretreated relapsed patients.
How can this highly active and well-tolerated therapy be further utilized to enhance antitumor response and prolong survival? When dealing with patients with relapsed indolent NHL, physicians must take many factors into consideration before choosing treatment, such as the patient's age, performance status, and other comorbidities. In general, when patients relapse they should be treated with the next most effective therapy associated with the fewest side effects. RIT should be considered early in the treatment sequence for the relapsed patient when the disease is nonbulky and the marrow reserve is adequate. It is clear that if RIT is reserved until the patient is very heavily pretreated, the marrow may be compromised with involvement of lymphoma or the platelet count may be too low for RIT.
Because of the high response rates in relapsed patients and the fact that RIT works optimally in patients without bulky disease, trials have been designed that use RIT as adjuvant therapy after chemotherapy or chemo-immunotherapy. The key ongoing trials in Europe and the United States randomize patients with either indolent or aggressive NHL to adjuvant RIT after the completion of standard therapy. If these studies demonstrate a prolongation of disease-free or overall survival, then the use of RIT will move from end-stage to upfront, resulting in a new standard of care for patients and more widespread use of RIT.
The study by Kaminski et al in previously untreated patients has provided evidence that some patients who achieve a complete response with RIT alone can have prolonged disease-free survival, whereas patients who only achieve a partial response will relapse rather promptly. RIT as a single-agent therapy is therefore an option for untreated patients with low-bulk, asymptomatic disease who choose not to be observed but also want to avoid chemotherapy.
As RIT begins to be used as adjuvant therapy, it becomes important to clarify the issue of retreatment, since undoubtedly some patients will relapse. There is already published data on retreatment with 131I-tositumomab or 90Y-ibritumomab tiuxetan. Further data on the safety and efficacy of RIT retreatment in this clinical situation is needed to help determine the timing of retreatment.
Phase I/II studies combining RIT with high-dose therapy and stem cell support are mature.[7-9] Two approaches have been taken-high-dose RIT using dosimetry to calculate the dose based on normal organ dosimetry[9,10] or a standard dose of RIT, ie, similar to doses administered without stem cell support. An ongoing randomized trial of rituximab/BEAM (carmustine [BCNU], etoposide, cytarabine [Ara-C], melphalan [Alkeran]) vs BEAM with standard-dose
I-tositumomab aims to determine whether adding standard-dose RIT to BEAM is beneficial. This trial will not address the use of high-dose RIT and BEAM that has been used in other phase I trials. It is unlikely that another phase III trial will be initiated until the first one is completed.
The above approaches sequence the RIT before or after chemotherapy or use RIT with stem cell support so that the myelosuppression is not an issue. It is more difficult to actually combine agents concomitantly with RIT without stem cell support. The agents of potential use would be unlabeled monoclonal antibodies, immunostimulatory agents, or nonmyelosuppressive agents such as corticosteroids.
The single most important toxicity of RIT is myelosuppression. Studies to date have not demonstrated an increase in the incidence of myelodysplasia or leukemia,[12,13] and there have been no cases of myelodysplastic syndrome in the previously untreated group treated by Kaminski et al. This is encouraging, but the follow-up is still relatively short.
In summary, RIT is an established FDA-approved modality for relapsed B-cell lymphoma. RIT works best in relapsed indolent NHL. The current trials discussed above and in the review by Schaefer-Cutillo et al that focus on the use of RIT as an adjuvant agent, with stem cell support, and with other immunostimulatory agents or radiosensitizers, will largely determine the level of RIT use in the future.
Thomas E. Witzig, MD
Dr. Witzig is on the advisory board for and receives research support from Biogen Idec.
1. Schaefer-Cutillo J, Friedberg JW, Fisher RI: Novel concepts in radioimmunotherapy for non-Hodgkin's lymphoma. Oncology 21:203-212, 2007.
2. 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.
3. Marcus RE, Solal-Celigny P, Imrie K, et al: MabThera (Rituximab) plus cyclophosphamide, vincristine and prednisone (CVP) chemotherapy improves survival in previously untreated patients with advanced follicular non-Hodgkins lymphoma (NHL) (abstract 481). Blood 108(11):146a, 2006.
4. 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.
5. Kaminski MS, Radford JA, Gregory SA, 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.
6. Wiseman G, Colgan J, Inwards D, et al: Yttrium-90 Zevalin phase I sequential dose radioimmunotherapy trial of patients with relapsed low grade and follicular B-cell non-Hodgkins lymphoma (NHL): Preliminary results (abstract 1387). Blood 100:358a, 2002.
7. Nademanee A, Forman S, Molina A, et al: A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood 106:2896-2902, 2005.
8. Nademanee A, Krishnan A, Tsai N, et al: 90Y-Ibritumomab tiuxetan (Zevalin) in combination with high-dose therapy (HDT) followed by autologous stem cell transplant (ASCT) may improve survival in patients with poor-risk follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL): Results of a retrospective comparative analysis (abstract 327). Blood 108:127a, 2006.
9. Winter JN, Inwards D, Spies S, et al: 90Y Ibritumomab tiuxetan (Zevalin; 90YZ) doses calculated to deliver up to 1500 cGy to critical organs may be safely combined with high-dose BEAM and autotransplant in NHL (abstract 330). Blood 108:127a, 2006.
10. Gopal AK, Gooley TA, Maloney DG, et al: High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: A multivariable cohort analysis. Blood 102:2351-2357, 2003.
11. Vose JM, Bierman PJ, Enke C, et al: Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin's lymphoma. J Clin Oncol 23:461-467, 2005.
12. Bennett JM, Kaminski MS, Leonard JP, et al: Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine I131 tositumomab. Blood 105:4576-4582, 2005.
13. Czuczman M, Emmanouilides C, Darif M, et al: Analysis of the incidence of treatment-related myelodysplastic syndrome and acute myelogenous leukemia in registration and compassionate-use trials of ibritumomab tiuxetan radioimmunotherapy (RIT) (abstract 485). Blood 108:147a, 2006.