Radioimmunotherapy of Lymphoma: A Treatment Approach Ahead of Its Time or Past Its Sell-By Date?

The US Food and Drug Administration (FDA) registration of rituximab (anti-CD20 monoclonal antibody [mAb]) in 1997 was a landmark event, not only because that is when the first antibody for the treatment of cancer was licensed but also because a new era of targeted therapies in the treatment of B-cell malignancies had begun. Although responses with single-agent rituximab were rather modest, the addition of rituximab to chemotherapy (Rchemo) as immunochemotherapy has resulted in impressive improvements in response rates and outcome in patients with a range of B-cell malignances. In contrast, radioimmunotherapy (RIT) is the administration of mAb or mAb-derived constructs that are chemically conjugated to therapeutic radioisotopes targeted to tumors. A wide variety of different mAbs, delivery schedules, radioisotopes, and doses of radioactivity have been tested in RIT, resulting in impressive responses in the treatment of non-Hodgkin’s lymphoma (NHL). For more than a decade, targeting the CD20 antigen has dominated clinical RIT of lymphoma, and a number of pivotal clinical studies ultimately led to FDA approval of two radioimmunconjugates, iodine-131 (I)tositumomab (Bexxar; GlaxoSmithKline, Research Triangle Park, NC) and yttrium-90 (Y) –ibritumomab tiuxetan (Zevalin; Cell Therapeutics Inc, Seattle, WA). Y–ibritumomab tiuxetan was subsequently approved within the European Union in 2004, and in September 2009, it was approved by FDA as a first-line treatment for NHL. The recent approval by the FDA, applauded in the national press by the US Society of Nuclear Medicine, received little or no attention in the clinical community. Despite the fact that both drugs clearly have unique non–cross-reactive mechanisms of action with proven high clinical efficacy in patients resistant to both chemotherapy and rituximab and are arguably the most active drug approaches ever developed for NHL, this treatment modality has failed to be widely adopted by the hemato-oncology community. So what progress has been made with RIT and why is this “designer” targeted therapy so underused? During the last decade, the defining features of RIT using the two licensed radioimmunoconjugates applied to indolent lymphomas have emerged. These features include high response rates, durable remissions, and safe, predictable, and manageable toxicity. Both Itositumomab and Y–ibritumomab have demonstrated high clinical efficacy in heavily pretreated populations, including patients with disease refractory to both chemotherapy and rituximab underlying their unique mechanisms of action of RIT. An analysis of the long-term follow-up of patients who were heavily pretreated for indolent lymphoma with I-tositumomab demonstrated overall response rates (ORRs) of 47% to 68% and complete response (CR) rates of 20% to 38%. At the time of publication, with a median follow-up of 5.3 years, the 5-year progression-free survival (PFS) was 17%, and 81 (32%) of 250 patients had a time to progression of 1 year. For the durable response population, the median duration of response was 45.8 months and, impressively, the median duration of response had not been reached at 5 years for those who had achieved a CR. Interestingly, many of the patients who enjoyed these long durable responses had poor prognostic characteristics, including bone marrow involvement (41%), bulky disease 5 cm (49%), and transformed histology (23%). Forty-three percent of the patients had been treated with more than four prior therapies, and 36% had not responded to their most recent therapy. These durable responses have also been observed after Y–ibritumomab tiuxetan, with about 70% of patients who achieve a CR remaining in remission for years. RIT has also shown highly promising results in the first-line treatment of previously untreated follicular lymphoma as a single treatment or as consolidation therapy after initial chemotherapy. For 76 patients treated with I-tositumomab after a median follow-up of 5.1 years, the actuarial 5-year PFS for all patients was 59%, with a median PFS of 6.1 years. Hematologic toxicity was moderate, with no patients requiring transfusion or granulocyte colony-stimulating factor. Initial US-based phase II studies using RIT as consolidation therapy demonstrated high rates of conversion from partial response (PR) to CR, leading to impressive overall CR rates and PFS. However, these highly encouraging data from phase II studies have been insufficient to change practice, and the clinical community demanded phase III studies. More recently, results were published on a large, phase III randomized European and Canadian intergroup study (n 414) in previously untreated patients with follicular lymphoma. This study confirmed the high conversion rate from PR to CR (53.3% to 87.4%) seen in the early phase II US studies for patients treated with Y– ibritumomab tiuxetan. This high CR rate was almost identical in all subgroups of pretreatment chemotherapy, despite the difference in CR rate between the initial chemotherapy regimens such as chlorambucil (CR rate, 31%) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; CR rate, 56%). This consistently high CR among all of the groups after Y–ibritumomab tiuxetan suggests that JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 18 JUNE 2

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