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Adapted from the NCI Cancer Bulletin, vol. 5/no. 21, Oct. 21, 2008 (see the current issue).

Treatment with a radiolabeled monoclonal antibody appears to be highly effective as consolidation after first-line therapy in patients with indolent, advanced-stage follicular lymphoma, according to results of a large phase III clinical trial published October 14, 2008, in the Journal of Clinical Oncology (see the journal abstract).

The results showed that consolidation therapy - a form of adjuvant therapy after initial or "induction" therapy to induce remission - with a single dose of yttrium-90 (⁹⁰Y)-ibritumomab tiuxetan (Zevalin®) significantly improved progression-free survival in all patient subgroups compared to patients in the control arm, who received induction therapy but not consolidation therapy. ⁹⁰Y-ibritumomab is a monoclonal antibody with a radioactive isotope attached to it.

The improvement in progression-free survival held up regardless of whether patients had a complete response (CR) or partial response (PR) to induction therapy: 53.9 months vs. 29.5 months for CR and 29.3 months vs. 6.2 months for PR. In addition, the multinational research team, led by investigators at the Universitair Medisch Centrum Utrecht in the Netherlands, reported 77 percent of patients in the treatment arm with a PR to induction therapy "converted" to a CR after receiving ⁹⁰Y-ibritumomab.

"This constitutes one of the highest PR-to-CR conversion rates reported in published phase III randomized studies in first-line follicular lymphoma," they wrote. Considering the efficacy and modest toxicity associated with ⁹⁰Y-ibritumomab in the trial, consolidation therapy with this monoclonal antibody "may be considered as part of the current treatment algorithm of follicular lymphoma," they concluded.

Seattle-based Cell Therapeutics, Inc., which manufactures ⁹⁰Y-ibritumomab, is now seeking approval from the U.S. Food and Drug Administration to begin marketing the drug for first-line consolidation therapy in patients with follicular lymphoma, a type of non-Hodgkin lymphoma. ⁹⁰Y-ibritumomab is already approved in the United States to treat follicular lymphoma that has recurred or is unresponsive to available treatment regimens.

The Firstline Indolent Trial included 414 patients from 77 medical centers across Europe. Patients received a variety of induction therapy regimens, which included different chemotherapy agents and, in approximately 15 percent of patients, also included the monoclonal antibody rituximab (Rituxan®). After induction therapy, patients were randomized to no consolidation therapy or consolidation with a two-course "priming" dose of rituximab followed by a single dose of ⁹⁰Y-ibritumomab. Because of the limited follow-up, there are no data from the trial yet on overall survival.

Given the positive results seen even in patients who received less aggressive induction regimens, the authors added, ⁹⁰Y-ibritumomab "has the potential to maximize tumor response without using aggressive induction regimens and may reduce the need for aggressive chemotherapy."

The limited use of rituximab as part of induction therapy in the trial hinders the interpretation of its results, Dr. Oliver W. Press, chair for lymphoma research at Fred Hutchinson Cancer Research Center, cautioned in an accompanying editorial. While calling the trial a "landmark study," he noted that, based on results from several phase III clinical trials, combining rituximab "with each cycle of induction chemotherapy has become a worldwide standard."

Even so, says Dr. John Leonard, director of the Center for Lymphoma and Myeloma at Weill Cornell Medical College in New York, its good safety profile and the fact that it is well tolerated by patients makes ⁹⁰Y-ibritumomab "particularly attractive for [use in] older patients," who may not handle more toxic chemotherapy regimens very well.

Radioimmunotherapy, as the use of radiolabeled monoclonal antibodies is often called, has not been widely adopted, Dr. Leonard notes, in part because it's not as easy for oncologists to use as other available treatments, including rituximab. For one thing, it has to be administered in a facility specially equipped to handle radioactive compounds.

A number of trials, Dr. Leonard continues, are ongoing that should help to clarify the role of radioimmunotherapy in patients with newly diagnosed, advanced follicular lymphoma.

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