The review by Schaefer-Cutillo et al on radioimmunotherapy (RIT) of lymphoma highlights many of the important studies that justified the US Food and Drug Administration (FDA) approval of two RIT agents for relapsed/refractory low-grade or transformed low-grade lymphoma as well as the promising data from studies that have potential to expand the indications for RIT in the future. Indeed, all the data presented are remarkable in terms of the high response rates obtained and the years of durability of the responses. Yet, despite all these positive results, the use of RIT in medical practice appears to be a small fraction of what has been estimated that it could be. And this fraction may be in danger of further shrinkage with the recent withdrawal of promotion and marketing support of yttrium (Y)-90 ibritumomab tiuxetan (Zevalin) by its manufacturer.
Before I discuss this underutilization issue further, a few points specifically about this review are worth emphasizing and clarifying.
Points Deserving Emphasis
Schaefer-Cutillo et al give the impression that iodine (I)-131 tositumomab (Bexxar) and Y-90 ibritumomab tiuxetan are equivalent in efficacy and safety. Yet, as an example, they cite studies of RIT using these agents in rituximab (Rituxan)-refractory patients showing the median time to progression in responders to Y-90 ibritumomab tiuxetan of 8.7 months vs 24.5 months for responders to I-131 tositumomab. Other data, not directly compared in their report, concerning durability of responses in long-term responders (longer than 12 months) have shown longer time to progression with I-131 tositumomab (48.5 months) than with Y-90 ibritumomab tiuxetan (29.3 months). Granted, nothing short of a randomized comparative trial of the two agents will definitively determine whether differences exist, but available data need to be acknowledged rather than dismissed.
Moreover, there are potential reasons for these differences. They include, but are not limited to, the different epitopes of CD20 that these antibodies recognize, the different dosing strategies (individualized for clearance for I-131 tositumomab and by body weight for Y-90 ibritumomab tiuxetan), and the path length of the beta particles. It is entirely possible that one of these agents may be superior in certain situations (such as different tumor burdens or tumor sizes), but no studies have deciphered such differences to date.
Although Schaefer-Cutillo et al discuss the excellent results seen with RIT in the front-line setting for follicular lymphoma, it is important to note that very good results are achieved in the relapsed setting, especially if RIT is given earlier in the course of the disease rather than as a last resort. This is true for both agents. Indeed, when used as second-line treatment, complete response rates of up to 50% with remissions lasting years can be achieved. These results need to be considered in making choices among the various options available for patients as they experience the natural history of the disease.
With regard to front-line RIT in follicular lymphoma, although the results using RIT as consolidation after cytoreduction with chemotherapy are excellent, how different are they from using RIT as a single agent? Even when the high-risk Follicular Lymphoma International Prognostic Index (FLIPI) patients are compared between the Southwest Oncology Group (SWOG) combination trial and the single-agent I-131 tositumomab trial, the 5-year progression-free survival is the same, at 52%. This raises the issue of whether combination therapy is for everyone, especially considering the extra toxicity and time spent in treatment (several months vs 1 week).
Moreover, there are theoretical concerns about using RIT as it is currently administered in the setting of minimal residual disease (complete clinical remission). Because so much unlabeled antibody is administered during treatment, there is concern that unlabeled antibody may mask CD20-binding sites from the radioactive antibody. Future trials may need to explore different dosing regimens for patients in this setting. Another consideration is the order in which chemotherapy and RIT are given. Perhaps reversing the order-giving RIT first followed by chemotherapy as a mop-up-may take maximum advantage of both treatments. Still, single-agent RIT may be sufficient for some patients.