Radioimmunotherapy: A New Treatment Modality for B-Cell Non-Hodgkin’s Lymphoma

Despite the remarkable results so ably described by Ghobrial and Witzig in this issue of ONCOLOGY, radioimmunotherapy for low-grade and transformed lowgrade lymphoma is a treatment that appears to be currently underutilized by clinicians. The two US Food and Drug Administration (FDA)-approved anti-CD20 radiolabeled antibodies, Y-90 ibritumomab tiuxetan (Zevalin) and tositumomab/iodine-131 (I-131) tositumomab (Bexxar), have produced response rates from 50% to 80% and complete response rates from 20% to 40% in studies of patients with varying resistance to chemotherapy as well as rituximab(Drug information on rituximab) (Rituxan), making these agents probably the most active systemic agents we have available for low-grade B-cell lymphoma. And although the title of the review presented by Ghobrial and Witzig suggests that radioimmunotherapy is a new modality for the treatment of non- Hodgkin's lymphoma, the follow-up of patients treated with tositumomab/ I-131 tositumomab, for instance, extends for over a decade. Thus, there is ample evidence concerning durability of responses as well as long-term consequences of this type of treatment. Timing of Therapy
The optimal time for the use of radioimmunotherapy in a patient's treatment history has not been definitively established. So far, it has been used mostly as salvage after chemotherapy and rituximab have failed. However, there is mounting evidence to support its use earlier in the course of disease. Most telling is the 95% overall and 75% complete response rates when tositumomab/I-131 tostitumomab was used as frontline therapy for follicular lymphoma. The results with radioimmunotherapy being used as consolidative treatment after chemotherapy in the frontline setting are also supportive. Approximately 80% of patients are predicted to remain disease-free at 2 years. Moreover, the durability of responses, especially complete responses-even in chemotherapy- and rituximabrefractory patients-needs to be recognized. Up to 30% of patients with previously treated disease may have remissions lasting years. With additional experience over the years, there is now less concern about "burning bridges" or reducing the ability to treat patients who relapse after radioimmunotherapy. Indeed, patients can be effectively and safely re-treated with radioimmunotherapy in addition to receiving rituximab, chemotherapy, and even hematopoietic stem cell transplantation. Although myelodysplasia and acute myeloid leukemia have been reported after radioimmunotherapy, this has so far only been observed in heavily pretreated patients who were already at risk for developing this problem. With extended follow-up of almost 5 years, no such cases have been observed in patients who have received radioimmunotherapy as a frontline regimen. Toxicity and Convenience
In weighing options for patients, toxicity and convenience need to be considered. In contrast to chemotherapy, which involves multiple treatments (and therefore repetitive, and possibly, cumulative risks) for several months, the administration of the two approved radioimmunotherapeutic agents can be accomplished in 1 week without any repetitive cycles. Although hematologic nadirs can be deep and prolonged, they rarely result in a need for clinical intervention such as transfusions, growth factor support, or hospitalization for neutropenic fevers. Patients often remark on both the lack of toxicity and the convenience of this treatment, compared to what they had previously experienced with chemotherapy. One of the perceived barriers to widespread acceptance of this therapy is the coordination needed among the ordering hematologist/oncologist, nuclear medicine/radiation oncology physician/staff, nuclear pharmacy, and nursing. Indeed, this treatment is unique in its multidisciplinary nature among existing therapies. However, once a system is in place, administration of the therapy can become a smooth and efficient operation. Conclusions
As Ghobrial and Witzig suggest, we have yet to fully explore the potential of radioimmunotherapy for lymphoma. This also extends to its use in histologies other than the lowgrade B-cell lymphomas. With the number of potential agents becoming available, questions about choices among these agents (including those directed against the same antigen) need to be answered. As is so often the case, we learn more about how a therapy can be used after FDA approval than before. Nevertheless, our knowledge will come from prospective clinical trials, in which physicians and patients should be encouraged to participate.