Review article Radiolabeled immunotherapy in non-Hodgkin’s lymphoma treatment: the next step Andreas Otte a,b , Christophe van de Wiele b and Rudi A. Dierckx c Radiolabeled immunotherapy (RIT) is becoming a significant step forward in the treatment management of non-Hodgkin’s lymphoma (NHL). In this state-of-the-art review article, general details, practical and health economic aspects, and next steps of RIT in NHL are reviewed from the existing literature and latest abstracts. As 90 Y-ibritumomab tiuxetan is the only marketed RIT in NHL in Europe, the special focus of this review is on 90 Y-ibritumomab tiuxetan, although the whole spectrum of available RIT concepts is highlighted. There is strong evidence to suggest that RIT is not only a safe and efficacious add-on treatment option in third or second line to chemotherapy, but is also a convincing asset as first-line therapy in various indications of lymphoma. Nucl Med Commun 30:5–15  c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. Nuclear Medicine Communications 2009, 30:5–15 Keywords: chemotherapy, 131 I-labeled tositumomab (Bexxar), non-Hodgkin’s lymphoma, radiolabeled immunotherapy, 90 Y-ibritumomab tiuxetan (Zevalin) a Clinical Trials Center, University Medical Center, Freiburg, Germany, b Division of Nuclear Medicine, University Hospital, Gent, Belgium and c Department of Nuclear Medicine and Molecular Imaging, University Medical Center, Groningen, Netherlands Correspondence to Professor Dr Andreas Otte, MD, Clinical Trials Center, University Medical Center, Elsa ¨sser Str. 2, D-79110 Freiburg, Germany Tel: +49 761 270 7211; fax: +49 761 270 7373; e-mail: andreas.otte@uniklinik-freiburg.de Received 13 March 2008 Revised 6 August 2008 Accepted 7 August 2008 Introduction The development of radiolabeled immunotherapy (RIT) is a significant step forward in the treatment of patients with non-Hodgkin’s lymphoma (NHL) and has substan- tially improved over the last two decades. Highly convincing efficacy [1–3] and safety [4] data are available to support the benefits of radiolabeled consolidation immunotherapy in follicular lymphoma. In addition, other entities, such as indolent and aggressive NHL [5], relapsed diffuse large B-cell lymphoma (DLBCL) [6–10], mantle cell lymphoma [11–14], pediatrics [15], multiple myeloma [16], primary central nervous system lymphoma [17–19], Hodgkin’s lymphoma [20], marginal zone lymphoma [21], or Richter syndrome [22], have been evaluated with convincing results. Apart from the consolidation indications, monotherapy concepts are under evaluation [23]. In addition, RIT offers significant quality-of-life benefits to patients [1,2] and convenience when compared with older chemotherapy combinations. The following state-of-the-art review is aimed at addres- sing the question of what the next step in RIT of NHL is and how to best use the available products approved for marketing – 90 Y-ibritumomab tiuxetan and 131 I-tositumo- mab – in the clinical disease course. As 90 Y-ibritumomab tiuxetan is the only up-to-date RIT with market authorization in Europe, the special focus of this review is on 90 Y-ibritumomab tiuxetan. Radioimmunotherapy models The distribution of a radiolabeled monoclonal antibody (MoAb) throughout the vascular compartment of lym- phomatous tissue depends on vascularity and blood flow rate, blood vessel wall morphology, and interstitial pressure (IP). In angiogenesis assays, lymphoma cells were shown to have angiogenic properties, and vascular- ization proved higher in lymphoma tissue when compared with reactive lymph nodes [24,25]. However, the vascularization pattern in NHL is often heterogeneous, with the presence of well-vascularized as well as poorly perfused necrotic areas [26]. Although vascularization is increased, lymphomas have a considerably lower blood flow when compared with the surrounding normal tissue; attributed factors that may explain this discrepancy include increased blood viscosity, increased hematocrit, and intermittent blood vessel shutdown because of poor innervation and thrombus formation [27]. The second physiological barrier for MoAbs is the blood vessel wall. Limited available data suggest that vessels in lymphoma are fenestrated and resemble blood vessels found in nonglial and metastatic brain tumors [28]. Theoretically, the presence of these fenestrations in addition to other factors such as a lack of basal membrane and vascular endothelial growth factor-mediated increases in endothe- lial cell permeability may result in extravasation of large molecules and a subsequent increase in IP hampering MoAb penetration [24,29]. Limited available data, how- ever, suggest that IP values in lymphoma are significantly lower when compared with values obtained in solid tumors [30]. Whether or not this finding is related to the existence of pronounced lymphangiogenesis that may reduce IP in lymphoma is currently unclear [31]. Available radiolabeled immunotherapy concepts Although the application practice of standard therapies in NHL needs further improvement, the options have 0143-3636  c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/MNM.0b013e328313e565 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.