Oncogene (2007) 26, 3614–3628 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I131 tositumomab AJ Davies Department of Medical Oncology, St Bartholomew’s Hospital, London, UK Radioimmunotherapy, targeting the CD20 antigen, in The B-cell NHLs represent a group of diseases with B-cell lymphoma hasclearly demonstratedefficacy and diverse clinical behaviour, which are becoming an tolerability over the preceding 15 years. As a result, two increasing burden in terms of incidence. The majority productsare available with Food and Drug Administration of cases will be accounted for by two histological approval for marketing – Y90 ibritumomab tiuxetan and subtypes in the Western World, diffuse large B-cell I131 tositumomab, given as the Zevalin and Bexxar lymphoma (DLBCL) and follicular lymphoma (FL) therapeutic regimens, respectively. Both demonstrate (The Non-Hodgkin’s Lymphoma Classification Project, high-response rates and durability of remission in the 1997). The terminology ‘indolent’ lymphoma is often relapsed/refractory disease setting. Data are emerging used to describe the latter and a number of other less regarding their utility asinitial therapy, and furthermore, common histological forms (FL comprises B70% of they are been investigated for use sequentially with this group). Together, these ‘indolent’ diseases are chemotherapy, and in the myeloablative setting. As yet characterized by a relatively long-median survival; however, how to best use these agents in the clinical 8–10 years in the case of FL (Gallagher et al., 1986; disease course remains uncertain. Horning, 1993) and the clinical course is typically one Oncogene (2007) 26, 3614–3628. doi:10.1038/sj.onc.1210378 of multiple disease episodes, punctuated by variable periods of remission. The tumours are sensitive to Keywords: radioimmunotherapy; non-Hodgkin’s lym- external beam radiotherapy, as demonstrated by the phoma; tositumomab; ibritumomab; monoclonal anti- long-periods of relapse-free survival observed in patients bodies; CD20 withearly stage disease treated withthismodality (Mac Manus and Hoppe, 1996). For the majority of patients however, who have advanced stage disease, an initial policy of observational management is not disadvantageous in the absence of symptoms or organ Introduction compromise (Ardeshna et al., 2003). When therapy is required, most patients will respond to single-agent or It is in the field of B-cell non-Hodgkin’s lymphomas combination cytotoxics, however, disease resistance (NHL) that radioimmunotherapy (RIT) has emerged inevitably develops. DLBCL represents the most com- and translated rapidly to being a commercially viable mon of the ‘aggressive’ lymphomas, a group of disease therapeutic modality. The methodology allows delivery that are invariably fatal in the absence of immediate of ionising radiation directly to the tumour site, whilst therapy. minimising toxicity to normal tissue, by the generation Key to the success of RIT in B-cell lymphoma has of a construct between a monoclonal antibody and a been the target antigen. CD20, a B-cell specific surface radioisotope. Two products, bothtargeting theB-cell- antigen, was initially described in 1980 (Nadler et al., associated CD20 antigen, are now approved by the 1980). The pattern of CD20 expression is critical, for United States Food and Drug Administration (FDA); although it is present on >95% of malignant B cells and the first, Y90 ibritumomab tiuxetan (Zevalin, Biogen- is expressed during normal B-cell development, it is IDEC Pharmaceuticals, San Diego, CA, USA) was later absent from the terminally differentiated plasma cell and followed by tositumomab and I131 tositumomab (here those at the earliest stages of B-cell lineage commitment after known as I131 tositumomab) (Bexxar, GlaxoSmith, (Stashenko et al., 1980; Anderson et al., 1984). The Kline, Philadelphia, PA, USA) (Table 1). This review unconjugated chimeric monoclonal antibody rituximab summarizes the characteristics of these agents and the (Genentech, South San Francisco, CA, USA and Roche, clinical trial experience available to date. Basel, Switzerland) targeting CD20 has demonstrated significant single agent efficacy in ‘indolent’ disease (McLaughlin et al., 1998), but more significantly has resulted in a paradigm shift in the management of B-cell Correspondence: Dr AJ Davies, Department of Medical Oncology, 7th Floor Gloucester House, St Bartholomew’s Hospital, London, EC1A NHL through its use in combination with chemotherapy 7BE, UK. (Coiffier et al., 2002; Hiddemann et al., 2005; Marcus E-mail: [email protected] et al., 2005; Forstpointner et al., 2006; Pfreundschuh Radioimmunotherapy for B-cell lymphoma AJ Davies 3615 Table 1 Properties of FDA approved RIT products available for therapy in B-cell NHL Modified from (Cheson, 2003) and (Stern and Herrmann, 2005) Y90 ibritumomab tiuxetan I131 tositumomab Predosing antibody Rituximab (250 mg/m2) Tositumomab (450 mg) Therapeutic antibody Ibritumomab Tositumomab Radioisotope Y90 I131 Radioisotope conjugation Tiuxetan linked-chelator Direct covalent iodination of tyrosine residues Therapeutic dosing Per Kg body weight Based upon whole body clearance Isotope t1/2 64 hours 8 days Emission bband g Pathlength 0.8 mm 5.3 mm ( b) Abbreviations: FDA, United States Food and Drug Administration; NHL, non-Hodgkin’s lymphomas. et al., 2006). RIT extends the activity of unconjugated (t1/2 ¼ 64 h) ibritumomab tiuxetan is administered to a antibody, allowing the delivery of radiation to multiple maximum dose of 32 mCi. In the presence of relative disease sites, minimizing normal organ toxicity. With thrombocytopenia (platelets 100–149 Â 109/l), this is effective tumour targeting, radioisotope emissions may attenuated to 0.3 mCi/Kg. result in the death of adjacent antigen-negative cells in the so called crossfire effect. Additionally, the direct 131 effects of antibody–antigen ligation may also be I tositumomab mechanistically important in eliciting cellular cytotoxi- Tositumomab, formally known as anti-B1, is a murine city (Tedder et al., 1986; Buchsbaum et al., 1992b; Cragg IgG2a-l monoclonal antibody directed against the 131 and Glennie, 2004; Davis et al., 2004). CD20 antigen. I (t1/2 ¼ 8 days) is covalently linked by the iodogen method (Fraker and Speck, 1978) to the tyrosine residues on the monoclonal. Deconjugation Y90 ibritumomab tiuxetan may occur, resulting in clearance of free iodine in the Y90 ibritumomab tiuxetan was approved for marketing urine, determination of residence time is required so that in 2002 by the FDA, the first in kind, with an indication patient-specific therapeutic dosing may be performed. for the treatment of patients with relapsed or refractory I131 has dual b- and g-emission properties, allowing both low-grade, follicular or transformed B-cell NHL, therapy and dosimetry to be performed with a single including patients that are refractory to rituximab. radioisotope. An unlabelled predose of tositumomab Ibritumomab is a murine IgG1-k monoclonal, and is (450 mg) is given on day 0 to saturate nonspecific the parent from which chimeric rituximab is derived. binding sites and antigen sinks (Buchsbaum et al., Covalently bonded is the linker-chelator tiuxetan, which 1992a; Kaminski et al., 1993). This is followed by provides high-affinity chelation sites for either Y90 or infusion of a small tracer dose of 5 mCi I131 tositumomab In111 (used for bioimaging). Given that Y90 is a pure b- (35 mg antibody). Whole body gamma camera scans are emitter, therapy may be delivered as a single outpatient then obtained, initially within 1 h and repeated at days administration; however, a two-step regimen is em- 2–4 and 6–7. Appropriate biodistribution is determined ployed using the g-emitting radionuclide In111 to ensure by visual inspection, and the residence time calculated that there is acceptable biodistribution following serial by plotting background corrected activity as a percen- gamma camera imaging. Dosimetry is unnecessary and tage of initial activity from eachacquired study and a does not correlate withhaematological toxicity (Wise- line of best-fit drawn. From this the I131 activity of the man et al., 2002b, 2003). Patients receive an infusion of for the total body dose may be derived (Wahl, 2003). rituximab at a dose of 250 mg/m2, to optimize tumour The maximum tolerated whole body dose was estab- targeting, followed by 5.0 mCi In111 ibritumomab lished as 75 cGy in the phase I study, limited by tiuxetan given over 10 min. Although previously, two haematological toxicity, with attenuation to 65 cGy in imaging scans have been acquired at 2–24 and 48–72 h those patients with relative thrombocytopenia (platelets after administration (withan optional thirdscan at 90– 100–149 Â 109/l) (Kaminski et al., 1993, 1996). The 120 h), a recent FDA amendment reduced this require- therapeutic step is performed at days 8–14, where a ment to a single scan at 48–72 h. Data from the Zevalin further infusion of unlabelled tositumomab is followed Imaging Registry indicates that the rate of altered by the patient-specific whole body dose of I131 tositu- biodistribution, which may help identify patients where momab. Patients receive oral thyroid protection (potas- excessive radiation could be delivered to normal tissue, sium iodine) throughout the period of administration is actually very low (0.6%) (Conti et al., 2005), and from day 0 and continuing for 14 days