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 after the indeed European studies have not mandated such therapeutic infusion. Although radiation protection imaging procedures (Radford et al., 2003; Morschhauser issues mandate that therapy should be given as an et al., 2004). The therapeutic dosing is administered on inpatient in the UK, in most US states, outpatient days 7–9, and is again preceded by 250 mg/m2 rituximab. administration is permitted (Siegel, 1998), and practical Radioisotope is not deconjugated from the antibody, guidelines for suchadministrations are available (Siegel thus a fixed weight-dependent dose of 0.4 mCi/Kg of Y90 et al., 2002; Vose, 2004). Owing to concerns about

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3616 eliciting severe haematological toxicity, as with Y90 and 16%, respectively (P ¼ 0.04). For those patients ibritumomab tiuxetan, patients with>25% lymphoma- with follicular histology the ORRs were 86 and 56%, tous involvement of the bone marrow are precluded respectively (Po0.001), withan ORRs of 67 and 50% in from therapy; dose escalation studies in such individuals the non-follicular group (P NS). In patients resistant to are in progress (Mones et al., 2004). Marketing approval their last course of chemotherapy, the ORR was higher for the therapeutic regimen was granted by the FDA in for Y90 ibritumomab (64%) compared to rituximab 2003, yet it remains unavailable outside clinical trails in (36%) (P ¼ 0.045). Europe. The product is indicated for the treatment of Despite showing superiority in its primary end point, CD20 positive relapsed or refractory low-grade, folli- the advantage of Y90 ibritumomab tiuxetan did not cular or transformed NHL, including patients with translate into the time-dependent secondary end points. rituximab refractory disease. It should however be noted that the study was not powered to detect suchdifferences. TheKaplan–Meier estimated median TTP was 11.2 months in the Y90 Y90 ibritumomab tiuxetan efficacy data: recurrent and ibritumomab treat group, and 10.1 months for those refractory disease treated withrituximab ( P NS). Similarly, there was no significant difference in median response duration (14.2 Results from the phase I/II dose escalation trial of Y90 months vs 12.1 months; P NS) or time to next therapy ibritumomab tixuetan, given in the format that we (TTNT) (not reached vs 13.1 months; P NS). In recognize as the commercial product administered subgroup analysis, a significantly longer TTNT was today, were published in 1999 (Witzig et al., 1999). A observed among patients withnon-transformed histol- previous phase I/II with Y90-labelled ibritumomab had ogy (median not reached compared with 13.1 months in used ibritumomab before the therapeutic infusion and the rituximab treated group; P ¼ 0.04). The final results dosing levels were escalated according to a flat level of of the study have now been published (Gordon et al., total dose of between 20 and 50 mCi, withdoses below 2003), demonstrating that TTNT was 21.5 months for 40 mCi being found to be nonmyeloablative (Knox patients withFL receiving Y 90 ibritumomab compared et al., 1996). The study of Witzig et al. (1999), to 13.1 months for rituximab; for all patients this was established that the maximum-tolerated dose was 17.6 months compared to 12.4 months. Similarly, in the 0.4 mCi/Kg, reduced to 0.3 mCi/Kg in those with a FL patients, median TTP was 15.0 months compared to baseline platelet count of between 100 and 149 Â 109/l 10.2 months. and replaced the unlabelled ibritumomab with ritux- A open-labelled phase II was conducted in a patient imab 250 mg/m2 given before the dosimetric or ther- population withmild thrombocytopenia (platelets 100– apeutic infusions. In the 51 patients enrolled onto the 149 Â 109/l), receiving Y90 ibritumomab tiuxetan at a study (36 on the phase II arm) the overall response rate dose of 0.3 mCi/Kg (Wiseman et al., 2002a). Thirty- (ORR) was 67%, with26% of patients entering eight patients were treated, 25 with FL, having received complete remission (CR). For patients with‘low-grade’ a median of 2 (range 1–9) previous chemotherapy lymphoma the ORR was 82% (CR 26%), compared to regimens and 63% withevidence of chemotherapy- 43% (CR 29%) in those that had intermediate grade resistant disease. In this setting the ORR was 83%, with disease. In logistic regression analysis, low-grade/folli- 44% of patients achieving either a CR or CR(u); the cular histology, absence of bone marrow involvement ORR in those with follicular histology was 92%. The and non-bulky disease were predictors of favourable median TTP was 9.4 months and 12.4 months in response. No responses were observed in the small responders, extending to 12.6 months in those with FL. number of patients (n ¼ 3) treated withmantle cell Combined analysis of four registration studies, lymphoma (MCL). The estimated median time to comprising 211 patients, demonstrated durable response progression (TTP) was 12.9 months. Long-term fol- (>12 months) in 78 patients (37%). The characteristics low-up of this cohort demonstrated that many of these of these patients demonstrated a predominantly folli- responses were durable, indeed 24% of responders had a cular histology (76%), although 37% had been refrac- TTP of more than 3 years (Gordon et al., 2004). tory to their previous regimen, bulk (defined as X5 cm) In the pivotal phase III study, 143 rituximab naive was present in 37 and 33% had received at least three patients withrelapsed or refractory disease were previous therapies (Witzig et al., 2003a). In these randomized to receive either Y90 ibritumomab tiuxetan individuals, 66% had achieved a CR following Y90 or rituximab administered according to the standard ibritumomab, and the median TTP was 29.3 months, schedule (Witzig et al., 2002b). The majority of patients comparing favourably to a median of 12 months enrolled had FL, with 17 non-follicular low-grade following their previous chemotherapy regimen. lymphomas and 13 patients with disease transformation. The median number of prior therapies was 2 (range 1– 6), of which 45% of patients had failed to respond or progressed within 6 months of their last chemotherapy. I131 tositumomab efficacy data: recurrent and refractory Groups were well-matched, and the ORR was superior disease in the Y90 ibritumomab tiuxetan-treated arm (80%) compared withthecontrol rituximab-treated patients Early clinical trials withI 131 tositumomab, performed at (56%) (P ¼ 0.002). The CR rates were also superior 30 the University of Michigan, established the maximum-

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3617 tolerated total body dose (Kaminski et al., 1993) and the The ‘pivotal’ phase III study employed a ‘patient-as- benefit of predosing withunlabelled antibody, remark- own-control’ design; the primary end point being a able in this first report of 10 patients, six responded. A comparison of the number of patients that had a longer later report of 34 patients withmixed histologies response to their last chemotherapy (>30 days) to the confirmed the initial promising activity and documented number of patients who had a longer duration of the durability of some remissions (Kaminski et al., response after I131 tositumomab (Kaminski et al., 1996). Near complete depletion of the B-cell pool was 2001b). The entry criteria included previous exposure observed, although serum immunoglobulin levels re- to at least two previous chemotherapy regimens, with mained unchanged. failure to respond or relapse within 6 months of their A number of phase II studies have confirmed the last therapy; all patients had either ‘low-grade’ (60%) or efficacy and safety of I131 tositumomab in the relapsed/ transformed disease (38%). Given that this population refractory disease setting. Vose et al. (2000) reported the was refractory to chemotherapy, patient demographics first multicentre study from centres in the US and report a median of four previous chemotherapies with Europe. This study of 47 patients, with either indolent 71% not responding to their last therapy. In this (79%) or transformed disease (21%), validated the population options for treatment were limited, account- practicality and reproducibility of the dosimetric and ing for a study design that lacked a concurrent control administration methodology at multiple sites. Patients arm. All investigator-assessed responses were confirmed had been heavily pretreated, having received a median by an independent masked panel, witha documented for four prior chemotherapies (range 1–8), the majority ORR to I131 tositumomab of 65% and a CR rate of had not responded to their last regimen (n ¼ 26) witha 20%. This compared favourably to the ORR of 28% median previous response time of only 4 months and CR rate of 3% following their last chemotherapy. amongst this cohort. A response was observed in 57% Seventy-four percent of patients had a longer duration of patients, witha median duration of response of 9.9 of response to I131 tositumomab compared withtheirlast months. In 32% of patients, a CR or protocol-specified chemotherapy regimen (28% equivalent duration), with clinical CR (complete disappearance of all lesions, but a median duration of response that was almost twice as an unequivocal statement that the tumour had com- long (6.5 months I131 tositumomab vs 3.5 months last pletely disappeared could not be made) was observed. chemotherapy) and a median progression free survival These individuals in CR had a longer median duration PFS of 8.4 months for I131 tositumomab responders. In of response at 19.9 months. The response rate was multivariate analysis, tumour burden (o500 g) and non- similar in those with indolent disease (57%) and those transformed disease were significantly associated witha withtransformation (60%). In the17 patients withbulk higher-response rate, and low-burden the only variable disease (defined as an estimate of tumour burden associated withlonger duration of response. These >500 g) the ORR was 59%, and in those with an results are remarkable given the documented decline in elevated lactate dehydrogenase (LDH) (n ¼ 18), the response rate and duration of response that is observed ORR was 50%. The methodology of administration with successive conventional chemotherapies in this was practical, and all site dose calculations were within disease group (Johnson et al., 1995). The most recent 10% of those determined at the reference centre. update to this trail reports that seven of the 12 patients In 2000, the University of Michigan single centre in who entered CR remain so between 4.9 and 7.2 years experience of 59 patients was reported (Kaminski et al., following therapy (Kaminski et al., 2004). 2000). This report updated previous efficacy reports Bringing I131 tositumomab forward in the therapeutic (Kaminski et al., 1996; Wahl et al., 1998) of the initial schema to a less heavily pretreated population, the phase I/II and included the first long-term follow-up results of a phase II of patients treated at first or second data. Once again, this was a heavily pretreated popula- recurrence of indolent or transformed indolent lympho- tion (66% of patients having had Xfour prior thera- ma have been reported (Davies et al., 2004). The pies), and many had poor risk features. The histological majority of the 41 patients (71%) had follicular subtypes treated were various, with47% of patients lymphoma, the remaining other indolent histologies having ‘low-grade’ lymphoma, 24% transformed disease (12%) or transformed disease (17%). The ORR was and 29% de novo ‘intermediate’ or ‘high-grade’ disease. 76% with 49% of patients achieving a CR or CR(u); the On an intent to treat basis (six patients had dosimetric later was associated witha prolonged remission dura- but no therapeutic dose) the ORR was 71%, with tion (median not reached at 3.1 years compared to 1.3 34% achieving a CR. At a median follow-up of years for all responders), with11/20 CR/CR(u) patients 3.1 years, the median progression free survival (PFS) remaining in remission for a median of 4.1 years at the was 12 months for all responders and 20.3 months for time of reporting. The highest response rates (79%) were patients that had achieved a CR. In those patients with reported in FL, although it is noteworthy that five out of de novo ‘intermediate’ or ‘high-grade’ disease, the seven patients withtransformed disease responded. In response rate was lower (41% compared to 83% for the univariate analysis, only bulk disease (tumour ‘low-grade’ and transformed), no CRs were achieved diameter X5 cm) predicted for inferior CR rates and and the response duration was short. Responses were relative thrombocytopenia (100–149 Â 109/l) and thus seen in all subgroups of patients; a normal LDH and receipt of attenuated whole body dose (65 cGy), elevated low-tumour bulk predicting for response in univariate b2M and two or more prior chemotherapy regimens analysis. were associated witha shorterremission duration.

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3618 100 Durable responses may be achieved in patients with relapsed/refractory disease 80 CR Perhaps the most remarkable observation form these PR trials in relapsed and refractory patients is the durability 60 of response that has been achieved in a proportion of individuals following RIT (Fisher et al., 2005; Wiseman 40 and Witzig, 2005). Combined analysis of 250 patients entered into the five clinical trials that served as the Response (%) 20 population for FDA regulatory approval for I131 tositumomab, identified PFS of X1 year in 32% of 0 patients and X2 years in 21% of patients (Fisher et al., 1st line 2nd line 3rd line 4th line+ 2005). Beyond this time only one relapse was observed (n=141) (n=226) (n=228) (n=540) per 10 person years withan estimated PFS at 5 years of Treatment number 17%. The observation was not unique to any particular trial. Seventy-seven percent of these patients with a PFS Figure 1 Decline in response rate to I 131 tositumomab with 131 successive numbers of previous therapies in 1177 patients. The of X1 year had achieved a CR to I tositumomab, percentage of patients experiencing a progression free survival of despite 43% having had at least four prior regimens, >1 year similarly declines as I 131 tositumomab is used 36% not responding to previous therapy and 63% successively later in the disease course (82, 59, 42 and 27% at deemed refractory to their last treatment regimen. first, second, third and fourth or more line therapy respectively). Data from (Gregory et al., 2005). Furthermore, patients with disease transformation (23%), stage IV disease (63%) or bulk (49%) were well-represented amongst durable responders. The key to suchduration was achieving CR, for all but one of Although the response rates are in line with those those who had maintained a PR for 12 months or more observed with conventional therapies at this stage in the relapsed within 20 months. Data from 4 Y90 ibritumo- disease course, these were achieved with a therapy mab studies on 211 patients identified 78 (32%) patients administered over just 1 week and withremarkably witha TTP of X12 months (Wiseman and Witzig, high-durable CR rate. Analysis of 1177 patients 2005). The population was similarly poor risk, with 33% demonstrates that there is a statistically significant having had three or more prior therapies, 37% had decline in response rate, CR and duration of response failed to respond to their most immediate prior therapy withsuccessive numbers of prior therapies; durable and 30% had bulky disease. Similar to the above study, responses were observed muchmore frequently whenI 131 the majority of patients with durable a responses had tositumomab was given early in the disease course achieved a CR (65%). Taken together, these data (Figure 1) (Gregory et al., 2005). demonstrate a significant clinical benefit in a subset of An expanded access programme was initiated at 65 patients were expectation of success is poor. institutions to establishfurtherefficacy and safety data and also to ensure the practical utility of I131 tositumo- mab in the wider community (Leonard et al., 2001). A total of 475 patients were enrolled withrelapsed or RIT in specific clinical circumstances refractory disease, withefficacy data reported on 394 patients. The ORR was 59% (26% CR) with a median Efficacy following previous treatment with rituximab duration of response of 15 months in a population that The use of rituximab in the treatment of follicular had received a median number of two prior therapies. lymphomas has expanded considerably in recent years I131 tositumomab has been the subject of a further based on the results of a number of randomized studies phase III study in the relapsed refractory setting to (Hiddemann et al., 2005; Marcus et al., 2005; For- determine the relative contribution of the radioimmu- stpointner et al., 2006; van Oers et al., 2006). This begs noconjugate to the regimen based upon the observation the question, what is the efficacy of CD20 targeted RIT that unlabelled tositumomab alone resulted in some in patients that have recurred after exposure to tumour regressions (Davis et al., 2004). Seventy-eight rituximab? There is little to guide us in those patients patients (median two prior therapies) were randomized that have been treated with combined chemoimmu- to receive the standard I131 tositumomab therapeutic notherapy, however, there is clear evidence for both regimen compared withtheidentical dosing of un- agents following single-agent rituximab. In the case of labelled antibody. Not unsurprisingly, response rates I131 tositumomab, Horning et al. (2005) reported the were superior in those patients that received the radio- results of a 40 patient phase II study, comprising immunoconjugate (55 vs 19%; P ¼ 0.002), witha patients predominantly withfollicular lymphoma. In significantly higher CR rate (33 vs 8%; P ¼ 0.012) and this population, who had been exposed to a median of TTP (6.3 months vs 5.5 months; P ¼ 0.035). Nineteen four previous lines of chemotherapy, 88% were con- patients whose disease failed to responded or progress to sidered rituximab refractory having either failed to unlabeled tositumomab were crossed over into the RIT respond or having progressed within 6 months of arm; only three of these had responded with no CRs; completion of rituximab. The ORR to I131 tositumomab 68% went on to have a response with 42% entering CR. was 65, with38% of patients achieving a confirmed

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3619 complete remission. In responding patients the median occurred and contrasts to the experience with full dose, PFS was 10.4 months, reaching 24.5 months in Y90 ibritumomab tiuxetan reported above. The response confirmed responders. Prior response to rituximab did rate in the population studies was 45%. The reduced not influence the response rate or PFS, however 80% of dose of 0.2 mCi/kg has been taken forward for further patients entering CR had either grade 1 or 2 FL and had investigation. low-bulk (no mass >5 cm) disease. Witzig et al. (2002a) 90 reported the Y ibritumomab tiuxetan experience in this Efficacy at the time of disease transformation setting. Analysis for efficacy was reported for 54 patients Histological transformation of follicular lymphoma to a with follicular lymphoma, all of which had what is more aggressive subtype, most typical diffuse large B- considered true rutiximab refractory disease and 74% cell lymphoma is a clear adverse prognostic factor in the withtumours X5 cm in diameter. The ORR was 74, clinical history of the disease (Johnson et al., 1995). with15% of patients achieving a CR witha median TTP Response to chemotherapy in transformed disease is of 8.7 months in responding patients. In terms of typically poor, withoutcomes inferior to the de novo 90 efficacy, Y ibritumomab tixuetan’s performance was disease counterparts (Armitage et al., 1981) and in the clearly superior to previous rituximab, and compared main, survival is short (Cullen et al., 1979; Hubbard favourably to the outcome of the patients last et al., 1982; Bastion et al., 1997). Zelenetz et al. (2002) chemotherapeutic regimen. One would advise caution presented a combined analysis, from a number of in any attempt to draw conclusions regarding efficacy clinical trails, of 71 patients withtransformation of between the two agents in this setting. The patient ‘indolent’ lymphoma that received I131 tositumomab. populations have some important differences in charac- The headline ORR in this setting was 39%, despite a 131 teristics, however, it is interesting to hypothesis that I population typically withmany additional adverse tositumomab may hold some advantage given that it is prognostic features including an elevated LDH, disease targeting a distinct CD20 epitope to the common bulk and high IPI. Responses were durable, at a median epitope shared by rituximab and ibritumomab, and in of 20 months, and for the 25% of patients entering CR it some way may thus be able to circumvent some of the was 36.5 months. There is some word of caution in the mechanism of resistance. interpretation of these data, the median time from documented transformation to therapy was long at 21 months, suggesting perhaps a more favourable patient Efficacy following previous high-dose chemotherapy with profile. Although a smaller data set, the efficacy of Y90 progenitor cell rescue ibritumomab tiuxetan appears similar, withan ORR of For those patients who suffer disease recurrence after 53% (CR 13%) in 15 patients withtransformed disease previous treatment with high-dose chemotherapy and summated from four of the clinical studies (Bartlett progenitor cell rescue, RIT appears to be an option that et al., 2002). The median TTP for responders was 8.5 may safely be considered. From the University of months, with two of the patients remaining in remission 131 Michigan experience with I tositumomab, 14 of 59 over 30 months from therapy. patients had previous myeloablative therapy (Kaminski et al., 2000). The maximum tolerated whole-body dose was lower than that seen in the population without prior Efficacy in aggressive B-cell lymphoma histologies 131 high-dose therapy exposure at 45 cGy, owing to Efficacy in the early phase I/II studies of I tostiumo- haematological toxicity. The ORR was however, a very mab at non-myeloablative dosing was disappointing in respectable 50%, withfive patients entering at CR. aggressive histologies, with no CRs achieved and only Experience in 11 patients from St Bartholomew’s short-lived benefit observed in responders Kaminski 90 Hospital also indicates that at 45 cGy, therapy with et al. (2000). A phase II study of Y ibritumomab I131 tositumomab may also be administered safely to this tiuxetan was conducted in elderly patients withrelapsed population (Davies et al., 2005). In a similar series of or refractory DLBCL; in the refractory setting the heavily pretreated individuals, all eight patients with response rate was 52%, and 53% among those with rituximab refractory disease that had progressed after recurrent disease Morschhauser et al. (2004). In patients high-dose therapy, went on to receive Y90 ibritumomab who had previously been treated with the rituximab– tiuxetan employing a conventional dosing schedule cytoxan, hydroxyrubicin (adriamycin), oncovin (vincris- (Jacobs et al., 2005). Grade 4 thrombocytopenia tine), prednisone (CHOP) regimen, a response was (n 3) and neutropenia (n 1) was observed, although observed in 5/28 patients. In a small numbers of patients ¼ ¼ 90 no patient was in need of blood product support 12 withMCL ( n ¼ 15), objective responses to Y ibritu- weeks after RIT administration. The study included momab tiuxetan were observed in five patients, of which patients witha mixed bag of histologies, with50% of three had remained in CR/CR(u) between 123 and 380 patients having DLBCL; none of them responded. A days at the time of reporting (Oki et al., 2004). CR was achieved in 1/3 patients with FL. By contrast, the approach of Vose et al. (2003) was to perform a Retreatment dose-escalation study withY 90 ibritumomab tixuetan. Data from the phase I/II single-centre experience at the Sixteen patients were treated in three cohorts, the University of Michigan demonstrated that after initial highest dose administered being 0.2 mCi/kg; in this response, retreatment withI 131 tositumomab at the time group, the majority of grade 4 haematological toxicities of progression could result in a clinically meaningful

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3620 response Kaminski et al. (2000). Based upon this and the demonstrated inferior PFS (35% compared with70% at observation that responses of many years duration had 5 years). It has been commented that this population been observed, Kaminski et al. (2005a) investigated the may represent a selected group witha more favourable role of retreatment in a wider patient cohort that had prognostic profile (Connors, 2005); however, the data either achieved a CR or PR, lasting >3 months, after are encouraging, and in contrast to conventional I131 tositumomab. From 32 enrolled patients, 28 received cytotoxics, achieved with a therapy that can be both the dosimetric and therapeutic doses; 56% had had administered over the period of just 1 week. Rando- a previous CR/CR (unconfirmed (CR(u)) and the mized phase III studies are clearly warranted. median time from initial I131 tositumomab to retreat- An alternative approachhasbeen to use CD20 ment was 21 months (range 7–73). The ORR was 56%, targeted RIT sequentially after chemotherapy in a bid with25% of patients entering CR. Themedian duration to improve and consolidate response. This approach is of response on retreatment was 15.2 months, having attractive as initial tumour debulking may result in been 13.6 months for their initial therapy. For those optimal circumstances for RIT success (Kaminski et al., patients reaching a CR/CR(u), the median duration of 2000; Davies et al., 2004), and may also permit clearance response on retreatment was 35 months. No variable of the bone marrow thus improving haematological significantly predicted response to retreatment or dura- tolerance. This strategy should also permit RIT in tion of response. The short-term haematological toxicity candidates previously ineligible because of heavy mar- was similar in depthand duration to thatobserved row infiltrate. The SWOG S9911 protocol administered 131 following initial therapy, however either MDS or I tositumomab to untreated patients withstage II X-IV therapy-related acute myeloid leukaemia (tAML) has FL following six cycles of conventional CHOP che- been reported in five patients, withan annualized motherapy (Press et al., 2003). Of 90 eligible patients, 86 incidence of 5.5% per annum after retreatment. Infu- completed CHOP and 77 bothphases. Eighty-one sion-related reactions may have been more evident on (90%) had a documented response following CHOP repeat exposure to I131 tositumomab, withtwo patients plus I131 tositumomab; 54% entered a CR and 12% had requiring discontinuation of therapy. Similar to other an unconfirmed CR. The addition of I131 tositumomab studies, human anti-mouse antibody (HAMA) deve- improved the best response in 57% of patients who were loped in 10% of patients. For Y90 ibritumomab tiuxetan not in CR after CHOP (49% from PR/CR(u) to CR and the data are limited, and restricted to just 10 reported 9% from CR(u) to CR). Toxicity following RIT was patients; therapy is feasible and second responses have generally milder than following CHOP. Recently, long- been observed (Shah et al., 2006). term follow-up data for this study have been published (median 5.1 years), reporting estimated PFS and overall survival (OS) of 67 and 87%, respectively at 5 years RIT as front-line therapy in B-cell lymphoma (Press et al., 2006). These figures were compared with an A number of groups have published results of the use of historical control population of patients treated with RIT as first-line agents in B-cell lymphoma demonstrat- CHOP alone in previous SWOG studies; an absolute ing that scheduling RIT early in the clinical course of the benefit of 23% in bothPFS and OS was seen in those disease results in some remarkable efficacy. These data patients treated sequentially withI 131 tositumomab comprise use of RIT as a single agent and also following CHOP. Comparisons withhistoricalpopula- sequenced with chemotherapy. Kaminski et al. (2005b) tions are fraught with confounders, and thus an reported on 76 previously untreated patients withFL, Intergroup phase III study is currently underway to median age 49, and all with p25% BM involvement compared six cycles of CHOP withconcurrent ritux- who received conventional 75 cGy dosing of I131 imab against CHOP Â 6 followed by I131 tositumomab. tositumomab. Ninety-five per cent of patients res- Planed accrual is 500 patients. Late toxicity using the ponded, with75% achieving a CR. At 5 years, an sequenced approachhasbeen low, withone case only of estimated 77% of the latter were disease free; the therapy-related myelodysplasia (tMDS) and 9% of outcome for those whose response was only partial patients developing an elevated thyroid-stimulating faired less well, all progressing at a median of 0.6 years. hormone (TSH). From 20 patients who had a polymerase chain reaction Leonard et al. (2005) have used three cycles of (PCR) detectable IGH/BCL2 gene rearrangement at fludarabine as debulking chemotherapy before I131 baseline and entered a CR, in 16 cases this was no longer tositumomab. This abbreviated fludarabine chemo- evident at 6 months. These patients had a superior PFS therapy course was chosen for acceptable tolerability compared with those in whom molecular remission was and efficacy in indolent NHL. Furthermore, in vivo not achieved. Both tumour bulk (o5 cm) and BM synergy withI 131 tositumomab favours fludarabine over involvement were associated witha decreased CR rate, alkyators (Johnson and Press, 2000) and the immuno- and BM involvement predicted inferior PFS; in a later suppressant properties of fludarabine could potentially analysis the FLIPI did not appear to predict outcome reduce the incidence of HAMA development. In 35 (Kaminski et al., 2006). Haematological toxicity was less patients, the ORR following fludarabine was 89%, than that reported in studies where I131 tositumomab has increasing to 100% following administration of I131 been used in the relapsed setting, although HAMA tositumomab. Only 9% of these were in a CR after developed frequently (63% of patients). In a post hoc chemotherapy, increasing to 86% on completion of both analysis, those patients with the highest HAMA titres phases. The estimated 5-year progression-free survival

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3621 was 56%; for those patients harbouring an IGH/BCL2 were administered, patients receiving a median of two translocation, PFS was improved if they were rendered (range 1–7) subsequent regimens. In only two patients PCR negative. In contrast to single agent I131 tositumo- was the dose of cytotoxic therapy reduced owing to mab as first-line therapy (Kaminski et al., 2005b), the cytopenias. Included in the population were eight addition of Fludarabine suppressed HAMA formation patients who underwent a high-dose chemotherapy withan incidence of only 6% in thisstudy. One patient, procedure withautologous progenitor cell rescue. In withdisease progression, developed MDS at 58 months all but one of these cases, adequate numbers of after initial therapy. The results of a regimen comprising progenitor cells could be harvested using growth factor six cycles CVP followed by I131 tositumomab has been mobilization alone and a peripheral harvest. Compared reported in abstract form (Link et al., 2004). The ORR to a ‘matched’ control group, treated with the same in 30 patients withstage II X–IV previously untreated FL regimen at the same time point in their illness, there was was similarly high at 100%, with the CR rate increasing no difference in the rate of grade 4 cytopenias, episodes from 50% following CVP to 80% following I131 of febrile neutropenia, transfusion requirements or use tositumomab; at a median follow-up of 2.3 years, 77% of G-CSF. From Cornell University, experience in 68 of patients remained in continued remission. patients treated withI 131 tositumomab who failed to There is less data in the first line setting for Y90 respond or progressed after therapy is reported (Dosik ibritumomab tiuxetan, all reported in abstract. In a et al., 2006). Sixty-five per cent of these patients went on randomised phase III study of untreated FL patients Y90 to a range of subsequent cytotoxic therapies including ibritumomab tiuxetan consolidation thereby is feasible anthracyclines, platiniums, fludarabine and both auto- and well tolerated following chemotherapy induction, logous and allogeneic stem cell transplantation. From the the efficacy of such an approach is awaited (Radford presented data it appears that blood count did not appear et al., 2003). In 40 patients withFL, 4 weekly infusions to compromise the deliver of therapy. In the remaining of rituximab were followed by three cycles of conven- 35% of patients, 13 had no further therapy and 11 either tional R-CHOP witha resulting ORR of 100% (Shipley external beam radiation or rituximab. Analyses of these et al., 2005). After 5 weeks, Y90 ibritumomab tiuxetan patients indicate that in >90% of cases, the decision not was administered to responders, increasing the CR rate to administer cytotoxic therapy was not a reflection of from 28 to 67%; at 2 years, PFS was 77%. The use of concerns about potential haematological toxicity, but single-agent upfront Y90 ibritumomab tiuxetan has been more a reflection of disease status. Data published in reported in only a very few number of patients to date abstract form suggest that treatment is well tolerated (Sweetenham et al., 2004), although the response rate is following the use of I131 tositumomab as first-line therapy; encouraging. In untreated MCL, early results of the the report is very preliminary however, yet only one of 22 ECOG E1499 study have demonstrated a significant patients required discontinuation of therapy owing to improvement in the ORR and CR rates achieved after cytopenias (Kaminski et al., 2001a). The overall summa- four cycles of R-CHOP by the subsequent delivery of tion is that subsequent therapy may be safely delivered Y90 ibritumomab tiuxetan (CR from 14 to 45%) (Smith following RIT without compromise on delivery or et al., 2006). excessive toxicity; however, there is a clear need for In contrast to the above sequencing strategies, RIT additional data in this field. followed by chemotherapy has been investigated in Radioresistance may develop in cells that have been MCL (Zelenetz et al., 2006). The response rate to RIT exposed to chronic low-dose irradiation, thus introdu- was high at 83%, with some improvement in the CR rate cing similar concern regarding the efficacy of external following administration of CHOP; this was however beam radiotherapy following RIT. Justice et al. (2006) inactive at eliminating minimal residual disease. have addressed this in their report of 19 patients who had previously been exposed to Y90 ibritumomab and developed symptomatic recurrences requiring palliative Ability to tolerate subsequent therapy after RIT RIT . The response rate from 29 treated sites was 90%, It is a matter of concern that further cytotoxic therapy witha CR rate of 41% and indeed in bulky sites the may be subsequently delivered to patients previously ORR was similarly high. There appeared to be no exposed to RIT without adverse toxicity or a need to significant increase in the severity of adverse events. compromise dosing because of diminished marrow reserve. Suchconsiderations are particularly of impor- tance when therapy is applied early in the disease course. There are some data sets that are available when Incorporation of RIT into myeloablative regimenswith considering such a question, although they suffer as a progenitor cell rescue result of being relatively small, typically single-centre experiences and are based upon patients who, in general, High-dose chemotherapy with or without total body have received RIT later in the disease course (Kaminski irradiation (TBI) has come to play a major role in the et al., 2001a; Ansell et al., 2002; Schilder et al., 2002; management of malignant lymphoma. In ‘aggressive’ Dosik et al., 2006). From the Mayo Clinic, data are lymphoma, the benefit of such an approach has been reported from 58 patients who received Y90 tiuxetan demonstrated to be superior to conventional salvage ibritumomab on a number or experimental protocols chemotherapy in patients with relapsed disease (Philip (Ansell et al., 2002). A wide range of cytotoxic therapies et al., 1995) and has an accepted role in those patients

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3622 whose disease is primary refractory to conventional ration for survival in the RIT group was 0.4 (95% CI: therapy (Vose et al., 1993; Shipp et al., 1999). In 0.2–0.9; P ¼ 0.02) and 0.6 (95% CI: 0.3–1.0; P ¼ 0.06) follicular lymphoma, long-term freedom from recur- for PFS. When adjusted for elevated LDH and the rence may be achieved in those with recurrent disease presence of transformed disease, these were 0.3 (95% (Freedman et al., 1999; Apostolidis et al., 2000; CI: 0.1–0.7; P ¼ 0.004) and 0.5 (95%CI: 0.–0.9; Hunault-Berger et al., 2002), and indeed in a rando- P ¼ 0.03), respectively. There was no difference in mized study an advantage in bothPFS and OS was transplant-related toxicity, time to engraftment or late demonstrated (Schouten et al., 2003). However, many tMDS/tAML. patients do not derive long-term benefit from these Based upon the observed relapse rate and the procedures coupled withconcern about theirtoxicity hypothesis that most curative strategies for B-cell has necessitated an urgent need for an improved lymphoma require a combination of agents, the approach. The incorporation of RIT into preparative conventional etoposide, cyclophosphamide and TBI regimens therefore holds a significant attraction over preparative regimen has been investigated in a phase I/ TBI; with a targeted approach higher doses of ionizing II study withsubstitution of theTBI for I 131 tositumo- radiation may be delivered to the tumour sites, while mab (Press et al., 2000). The target I131 tositumomab sparing normal organ toxicity. The investigative ap- dose was incremented from 20 to 27 Gy followed by proach has been two pronged, looking at high-dose RIT infusions of etoposide (60 mg/kg, not given in first as a single agent withprogenitor cell rescue and also in cohort) and cyclophosphamide (100 mg/kg), with auto- combination withconventional cytotoxic therapy. logous purged rescue. Fifty-two patients received all The myeloablative approach was pioneered by Press facets of the planned administration, of which 73% had et al. (1993) publishing the results of a phase I dose FL and 28% either de novo DLBCL or transformed FL. escalation study in 1993. Given as a single agent, I131 Eight patients had primary refectory disease, two tositumomab, withprogenitor cell rescue, was dose patients chemotherapy-resistant relapse and the remain- escalated to a maximum dose of 27.25 Gy to normal ing 42 had demonstrated chemotherapy sensitivity at organs, limited by cardiopulmonary toxicity. Remark- recurrence; seven patients had been rejected by other ably in the 19 patients who had favourable biodistribu- transplant centres as not suitable for an high-dose tion, defined by higher absorbed doses to the tumour procedure. The maximal tolerated dose was 25 Gy of I131 than critical organs, a CR was achieved in 84% of tositumomab, with23 patients treated at thislevel. patients witha median duration of response of 11 Mucositis, nausea and infection, as expected, were months. Antibody distribution was favourable in those frequent and there were four infection-related deaths. patients withlow-tumour burdens and withoutspleno- Thirty-one patients were evaluable for response, 18 megaly. On the basis of these results, a phase II study having been cytoreduced before therapy to a non- was conducted in 25 patients, predominantly with evaluable disease state, withan ORR of 87% and CR follicular lymphoma, to receive a therapeutic infusion rate of 77%. The 2 years progression-free survival was calculated to deliver 25–31 Gy to the normal organ 68% withOS at thattime being 83%. Comparison with receiving the greatest dose of radiation (Press et al., a non-randomized control group that had received TBI 1995). Of the 21 patients given a therapeutic infusion in combination with etoposide and cyclophosphamide (19 withprogenitor cell rescue), 16 achieved a CR and demonstrated an apparent benefit bothfor indolent and two a PR, with81% of patients progression free at a aggressive disease in favour of the I131 tositumomab median follow-up of 12 months. Reporting back on containing regimen, withsimilar toxicities. long-term follow up of patients in these two trials at The retrospective experience of 16 patients with MCL a median follow-up of 42 months, 12 of 39 patients treated with the combined chemo-RIT regimen has been remained in continuous complete remission, withthose reported (Gopal et al., 2002). This disease is character- patients with indolent lymphoma gaining most from this ized by adverse features, short remission durations and approach(Liu et al., 1998). In terms of late toxicity, limited median survival (Andersen et al., 2002). Eleven 60% of patients were found to have an elevated TSH patients had evaluable disease (five were without level and two patients had developed myelodysplasia. In radiological evidence of disease before therapy), and of a small number of patients, Y90 ibritumomab tiuxetan these 91% achieved a CR and 60% a molecular has been escalated with progenitor cell support, to 24 Gy remission. The 3-year OS is reported at 93%, with a to the liver (Flinn et al., 2004). Toxicity has been PFS of 61% at that time, comparing favourably to haematological, with therapy being delivered as an results withmore conventional regimens. outpatient; of six evaluable patients, four entered CR; In a similarly designed phase I/II study, Y90 ibritu- further data are eagerly awaited. momab tiuxetan was combined withetoposide and Using multivariable analysis, patients withFL who cyclophosphamide followed by autologous progenitor had received high-dose I131 tositumomab (n ¼ 27) were cell rescue, with31/41 patients of mixed histological compared withthosetreated withan historicalcontrol subtypes completing planned therapy (Nademanee population treated with conventional high-dose pre- et al., 2005). The dose of Y90 ibritumomab tiuxetan parative regimens (n ¼ 98) (Gopal et al., 2003). The was calculated to deliver 10 Gy to normal tissue, with populations were generally well matched, although toxicity similar to that observed in similar TBI contain- patients witha highIPIand elevated LDH were ing regimens. All of 13 patients withevaluable disease at overrepresent in the RIT group. The unadjusted hazard the time of study entry entered CR, with 2-year

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3623 estimates of relapse-free survival and OS of 78 and 92%, Table 2 Haematological toxicity of RIT respectively. In this study, 45% of patients had DLBCL, Y90 ibritumomab I131 131 a much higher proportion than the I tositumomab tiuxetan tositumomab studies; results in this group were promising. The above approach to myeloablative therapy require Neutrophils Median nadir 0.8  109/l 0.69  109/l considerable expertise in terms of dosimetry, thus Incidence 1.0 109/l neutrophils 57% 63% 131 o  standard non-myeloablative doses of bothI tositu- Incidence o0.5  109/l neutrophils 30% 25% momab and Y90 ibritumomab tiuxetan have used in Median duration of 22 days 31 days combination withstandard conditioning regimens neutrophils o1.0  109/l (Fung et al., 2003; Vose et al., 2005). After dosimetry, Platelets and starting at 0.3 Gy escalating to 0.75 Gy, the Median nadir 41x10/9/l 43  109/l 131 therapeutic dose of I tositumomab was given at day Incidence platelets o50  109/l 61% 53% À12, withconventional BEAM starting at day À6to23 Incidence platelets o25  109/l 10% 21% Median duration of 24 days 32 days patients in a phase I study (Vose et al., 2005). Eleven 9 patients were refractory to primary therapy, and platelets o50  10 /l comprised 14 patients withDLBCL, five withMCL Data for conventional non-myeloablative dosing and is obtained from and four withgrade 3 FL. Bothhaematological and bothproducts datasheets. non-haematological toxicities were similar to those encountered with conventional BEAM, although there was a non-significant trend to and increased frequency for Y90 ibritumomab tiuxetan. Despite suchtoxicity, in of mucositis. The ORR was 65%, and at a median of 38 the main requirement for blood product support has months follow-up, the event-free survival was 395 with been low, withacceptable rates of febrile neutropenia. In OS of 55%. Two patients developed tMDS, although the elderly population, no significant excess in haema- one remains asymptomatic and the other died as a result tological toxicity is observed (Gregory et al., 2001; of progressive disease. In a similar population of 12 Witzig et al., 2003b), and similarly the degree of patients treated with0.4 mCi/kg Y 90 ibritumomab myelosuppression is comparable (Kaminski et al., tiuxetan and BEAM, 11 patients remain disease-free at 2005a) following retreatment. a median follow-up of 9 months (Fung et al., 2003). There has been some concern that systemic exposure The myeloablative approach in the reported phase I/ to radiation may result in an increased frequency of II studies is clearly provocative and begs the need for tMDS/tAML following RIT. A review of 1071 patients randomized phase III studies. Evaluation of RIT is now with‘low-grade’ lymphoma treated withI 131 tositumo- underway in reduced intensity allogeneic transplanta- mab identified 35 cases, witha crude incidence of 3.3% tion (Gopal et al., 2006). and annualized to 1.4% per person year of follow-up (Bennett et al., 2005). Among 76 patients receiving the agent as initial therapy for FL, no cases were reported, highlighting the role of previous therapies in the Safety of RIT development of tMDS/tAML. In an independent review of 25 of the tMDS/tAML cases, 40% were found to The toxicity profile of these RIT agents has become have had tMDS before I131 tositumomab exposure and firmly established during the decade or so of clinical in 8% of patients there was actually no evidence tMDS; development. Publications from integrated safety data- the revised crude incidence was 2.2%, and annualized bases that span a number of trials (Witzig et al., 2003b; incidence of 0.9%/year (cumulative incidence of 0.8 and Gregory et al., 2004), indicate that non-haematological 5.0% at 2 and 5 years, respectively. These figures are in toxicity is typically mild, largely comprising asthenia, line with the expected frequency based upon their prior nausea and chills. Hypersensitivity reactions at the time chemotherapy; the experience with Y90 ibritumomab of drug infusion occur in small numbers of patients (2% tiuxetan would appear to concur withthisobservation grade 3/4 reactions following I131 tositumomab, and (Czuczman et al., 2002). In multivariate analysis, more frequently occurring during the rituximab infusion previous exposure to fludarabine containing regimens at the time of Y90 ibritumomab tiuxetan therapy). and a baseline platelet count o150  109 l were asso- The principle short-term toxicity associated with ciated with significantly higher rated of tMDS/tAML. either RIT regimen is reversible bone marrow suppres- Five patients from the series 349 patients treated with sion. In contrast to cyclical chemotherapy, there is a Y90 ibritumomab tiuextan, and all withprevious single haematological nadir observed at 4–6 weeks post- alkylating agent exposure, have developed tAML/tDMS therapy, with recovery (to grade 2) by 9 weeks. The (annualized incidence 1.1%/year) (Witzig et al., 2003b). degree of toxicity appears similar; data are summarized Despite the use of thyroid blockade with high-doses in Table 2. Factors predicting for haematological of iodine at the time of therapy, hypothyroidism is a toxicity include the presence of bone marrow involve- recognized long-term sequelae following I131 tositumo- ment and number of previous therapies (Witzig et al., mab therapy with a cumulative incidence of 8.7% at 2 2003b; Gregory et al., 2004). Indeed, very clear years and 16.6% at 5 years (Gregory et al., 2004). correlation between the degree of marrow infiltration HAMA may develop in response to infusion of murine and grade III or IV cytopenias has been demonstrated protein; the cumulative incidence was 9.8% at 2 years

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3624 (Gregory et al., 2004), the majority having developed but include logistics of administration withtheneed for within 6 months of therapy. The relative immunocom- coordination between Nuclear Medicine facilities and petency of the patient is a major determinant of HAMA the Oncologist, cost, issues surrounding reimbursement development; in the previously untreated patients the and concerns about long-term toxicity. It seems likely rate was very muchhigherat 63% (Kaminski et al., that as more experience is gathered with their use, we 2005b). The consequence of HAMA development is will see a shift towards earlier administration in the unclear, and does not appear to compromise response to disease course and sequentionally withchemotherapy. therapy (Davies et al., 2004). The rate of HAMA is At present, there is little, except experience, to guide muchlower following Y 90 ibritumomab tiuxetan, at 1% selection of either agent where both are available, (Witzig et al., 2003b); in the latter regimen, exposure to however the FDA has mandated a randomized compari- murine protein in less. son study between Y90 ibritumomab and I131 tositumo- mab, withtheaim of recruiting 350 patients withFL. In terms of their use in the myeloablative setting, data is Conclusions still tantalizing, and phase III studies are starting to progress. Although the exact place for these agents is The addition of RIT has added significantly to our still being established, newer radioimmunoconjugates therapeutic armamentarium in the management of B- are under development. I131 rituximab has shows cell lymphoma, and affords the patient a high chance of significant efficacy in the phase II setting, without achieving a potentially durable remission. They have the immunogenicity (Leahy et al., 2006), and Y90 epratuzu- advantage of a short administration time with tolerable mab (targeting CD22) is in early phase clinical trials toxicity; however, their uptake has been slow in the (Chatal et al., 2004). RIT will continue to emerge as an practising community. The reasons for this are complex, important tool in the management of NHL.

References

Andersen NS, Jensen MK, de Nully Brown P, Geisler CH. in patients withnon-Hodgkin lymphomatreated with (2002). A Danishpopulation-based analysis of 105 mantle tositumomab and iodine I131 tositumomab. Blood 105: cell lymphoma patients: incidences, clinical features, res- 4576–4582. ponse, survival and prognostic factors. Eur J Cancer 38: Buchsbaum DJ, Wahl RL, Glenn SD, Normolle DP, 401–408. Kaminski MS. (1992a). Improved delivery of radiolabeled Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, anti-B1 monoclonal antibody to Raji lymphoma xenografts Schlossman SF, Nadler LM. (1984). Expression of human B by predosing withunlabeled anti-B1 monoclonal antibody. cell-associated antigens on leukemias and lymphomas: a Cancer Res 52: 637–642. model of human B cell differentiation. Blood 63: 1424–1433. Buchsbaum DJ, Wahl RL, Normolle DP, Kaminski MS. Ansell SM, Ristow KM, Habermann TM, Wiseman GA, (1992b). Therapy with unlabeled and 131I-labeled Witzig TE. (2002). Subsequent chemotherapy regimens are pan-B-cell monoclonal antibodies in nude mice bearing well tolerated after radioimmunotherapy with yttrium-90 Raji Burkitt’s lymphoma xenografts. Cancer Res 52: ibritumomab tiuxetan for non-Hodgkin’s lymphoma. J Clin 6476–6481. Oncol 20: 3885–3890. Chatal JF, Harousseau JL, Griesinger JM, Meller J, Renner C, Apostolidis J, Gupta RK, Grenzelias D, Johnson PW, Pappa KirschCM et al. (2004). Radioimmunotherapy in non- VI, Summers KE et al (2000). High-dose therapy with Hodgkin’s lymphoma (NHL) using a fractionated schedule autologous bone marrow support as consolidation of of DOTA-conjugated, 90Y-radiolabeled, humanized anti- remission in follicular lymphoma: long-term clinical and CD22 monoclonal antibody, epratuzumab. Proc Am Soc molecular follow-up. J Clin Oncol 18: 527–536. Clin Oncol 22: (Abstract 2545). Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, Cheson BD. (2003). Radioimmunotherapy of non-Hodgkin MacLennan KA et al. (2003). Long-term effect of a watch lymphomas. Blood 101: 391–398. and wait policy versus immediate systemic treatment for Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, asymptomatic advanced-stage non-Hodgkin lymphoma: a BouabdallahR et al. (2002). CHOP chemotherapy plus randomised controlled trial. Lancet 362: 516–522. rituximab compared withCHOP alone in elderly patients Armitage JO, Dick FR, Corder MP. (1981). Diffuse histiocytic withdiffuse large-B-cell lymphoma. N Engl J Med 346: lymphoma after histologic conversion: a poor prognostic 235–242. variant. Cancer Treat Rep 65: 413–418. Connors JM. (2005). Radioimmunotherapy – hot new treat- Bartlett N, Witzig T, Gordon L, Beck T, Fehrenbacher L, ment for lymphoma. N Engl J Med 352: 496–498. Kornmehl E et al. (2002). 90Y-ibritumomab tiuxetan Conti PS, White C, Pieslor P, Molina A, Aussie J, Foster P. (Zevalin) radioimmunotherapy for transformed B-cell non- (2005). The role of imaging with (111)In-ibritumomab Hodgkin‘s lymphoma (NHL) patients. Proc Am Soc Clin tiuxetan in the ibritumomab tiuxetan (Zevalin) regimen: Oncol 21: (abstr: 51). results from a Zevalin Imaging Registry. J Nucl Med 46: BastionY,SebbanC,BergerF,FelmanP,SallesG,DumontetC 1812–1818. et al. (1997). Incidence, predictive factors, and outcome of Cragg MS, Glennie MJ. (2004). Antibody specificity controls lymphoma transformation in follicular lymphoma patients. in vivo effector mechanisms of anti-CD20 reagents. Blood J Clin Oncol 15: 1587–1594. 103: 2738–2743. Bennett JM, Kaminski MS, Leonard JP, Vose JM, Zelenetz AD, Cullen MH, Lister TA, Brearley RI, Shand WS, Stansfeld AG. Knox SJ et al. (2005). Assessment of treatment-related (1979). Histological transformation of non-Hodgkin’s myelodysplastic syndromes and acute myeloid leukemia lymphoma: a prospective study. Cancer 44: 645–651.

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3625 Czuczman M, Witzig T, Gaston I, Skikne BS, Dimitrov G, radioimmunotherapy versus conventional high-dose therapy Gordon L et al. (2002). Zevalint radioimmunotherapy is and autologous hematopoietic stem cell transplantation for not associated withan increased incidence of secondary relapsed follicular non-Hodgkin lymphoma: a multivariable myelodysplastic syndrome or acute leukaemia. Blood 100: cohort analysis. Blood 102: 2351–2357. 357a (abstract 1386). Gopal AK, Pagel JM, Rajendran JG, Maloney DG, Davies AJ, Howell S, Rohatiner AZ, Matthews J, Clayton J, Appelbaum FR, Sorror ML et al. (2006). Improving the Massey T et al. (2005). Long-term follow-up of patients efficacy of reduced intensity allogeneic transplantation for recieving tositumomab and I31 tositumomab for recurrent lymphoma using radioimmunotherapy. Biol Blood Marrow and refractory B-cell lymphoma. Ann Oncol 16: v112 Transplant 12: 697–702. (abstract 256). Gopal AK, Rajendran JG, Petersdorf SH, Maloney DG, Davies AJ, Rohatiner AZ, Howell S, Britton KE, Owens SE, Eary JF, Wood BL et al. (2002). High-dose chemo- Micallef IN et al. (2004). Tositumomab and iodine I 131 radioimmunotherapy with autologous stem cell support tositumomab for recurrent indolent and transformed B-cell for relapsed mantle cell lymphoma. Blood 99: 3158–3162. non-Hodgkin’s lymphoma. J Clin Oncol 22: 1469–1479. Gordon L, Witzig T, Murray MS, Czuczman M, Emmanouilides Davis TA, Kaminski MS, Leonard JP, Hsu FJ, Wilkinson M, C, Joyce RM et al. (2003). Yttrium-90 ibritumomab tiuxetan Zelenetz A et al. (2004). The radioisotope contributes radioimmunotherapy produces high response rates and dur- significantly to the activity of radioimmunotherapy. Clin able remissions in patients withrelapsed or refractory low Cancer Res 10: 7792–7798. grade, follicular or transformed B-cell NHL: Final results of a DosikAD,ColemanM,KostakogluL,FurmanRR,FioreJM, randomized controlled trial. Proc Am Soc Clin Oncol 22:576 Muss D et al. (2006). Subsequent therapy can be administered (abstract 2315). after tositumomab and iodine I-131 tositumomab for non- Gordon LI, Molina A, Witzig T, Emmanouilides C, Raubtischek Hodgkin lymphoma. Cancer 106: 616–622. A, Darif M et al. (2004). Durable responses after ibritumomab Fisher RI, Kaminski MS, Wahl RL, Knox SJ, Zelenetz AD, tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: Vose JM et al. (2005). Tositumomab and iodine-131 long-term follow-up of a phase 1/2 study. Blood 103: tositumomab produces durable complete remissions in a 4429–4431. subset of heavily pretreated patients with low-grade and Gregory SA, Leonard J, Knox SJ, Zelenetz A, Armitage JO, transformed non-Hodgkin’s lymphomas. J Clin Oncol 23: Kaminski M. (2004). The iodine I-131 tositumomab 7565–7573. therapeutic regimen: Summary of safety in 995 patients Flinn IW, Kahl B, Frey EC, Bianco JA, Hammes RJ, Biling LS withrelapsed/refractory low grade (LG) and transformed et al. (2004). Dose finding trial of Yttrium 90 (90Y) LG non-Hodgkin’s lymphoma (NHL). Proc Am Soc Clin ibritumomab tiuxetan withautologous stem cell transplanta- Oncol 22: 6732. tion (ASCT) in patients withrelapsed or refractory Gregory SA, Leonard J, Vose J, Zelenetz A, Horning S, B-Cell Non-Hodgkin’s lymphoma (NHL). Blood 104: Knox SJ et al. (2005). Superior outcomes associated with (abstract 897). earlier use: experience withtositumomab and iodine I 131 Forstpointner R, Unterhalt M, Dreyling M, Bock HP, tositumomab in 1,177 patients (pts) withlow-grade, Repp R, Wandt H et al. (2006). Maintenance therapy with follicular, and transformed non-Hodgkin’s lymphoma rituximab leads to a significant prolongation of response (NHL). Proc Am Soc Clin Oncol 23: 585 (Abstract 6561). duration after salvage therapy with a combination of Gregory SA, Zelenetz A, Knox SJ, Vose J, Magnuson D, rituximab, fludarabine, cyclophosphamide and mitoxan- Kaminski M. (2001). The BEXXARs therapeutic regimen trone (R-FCM) in patients withrelapsed and refractory (tositumomab and iodine I 131 tositumomab) can be safely follicular and mantle cell lymphomas – results of a administered to patients over the age of 70. Blood 102: 409a prospective randomized study of the German low grade (abstract 1485). lymphoma study group (GLSG). Blood 108: 4003–4008. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder Fraker PJ, Speck Jr JC. (1978). Protein and cell membrane E, Schmits R et al. (2005). Frontline therapy with rituximab iodinations witha sparingly soluble chloroamide,1,3,4,6- added to the combination of cyclophosphamide, doxorubi- tetrachloro-3a,6a-diphrenylglycoluril. Biochem Biophys Res cin, vincristine, and prednisone (CHOP) significantly Commun 80: 849–857. improves the outcome for patients with advanced-stage Freedman AS, Neuberg D, MauchP, Soiffer RJ, Anderson KC, follicular lymphoma compared with therapy with CHOP Fisher DC et al. (1999). Long-term follow-up of autologous alone: results of a prospective randomized study of the bone marrow transplantation in patients withrelapsed German Low-Grade Lymphoma Study Group. Blood 106: follicular lymphoma. Blood 94: 3325–3333. 3725–3732. Fung H, Forman S, Nademanee A, Molina A, Yamauchi R, Horning SJ. (1993). Natural history of and therapy for Speilberger N et al. (2003). A new preparative regimen for the indolent non-Hodgkin’s lymphomas. Semin Oncol 20: older patients withaggressive CD 20-positive B-cell lym- 75–88. phoma utilizing standard-dose Yttrium-90 ibritumomab Horning SJ, Younes A, Jain V, Kroll S, Lucas J, Podoloff D tiuxetan (Zevalin) radioimmunotherapy (RIT) combined et al. (2005). Efficacy and safety of tositumomab and iodine- with high-dose BEAM followed by autologous hematopoie- 131 tositumomab (Bexxar) in B-cell lymphoma, progressive tic cell transplantation (AHCT): targeted intensification after rituximab. J Clin Oncol 23: 712–719. without increased transplant-related toxicity. Blood 102: Hubbard SM, Chabner BA, DeVita Jr VT, Simon R, Berard (Abstr act 870). CW, Jones RB et al. (1982). Histologic progression in Gallagher CJ, Gregory WM, Jones AE, Stansfeld AG, non-Hodgkin’s lymphoma. Blood 59: 258–264. Richards MA, Dhaliwal HS et al. (1986). Follicular Hunault-Berger M, IfrahN, Solal-Celigny P. (2002). Intensive lymphoma: prognostic factors for response and survival. J therapies in follicular non-Hodgkin lymphomas. Blood 100: Clin Oncol 4: 1470–1480. 1141–1152. Gopal AK, Gooley TA, Maloney DG, Petersdorf SH, Jacobs SA, Vidnovic N, Joyce J, McCook B, Torok F, Avril Eary JF, Rajendran JG et al. (2003). High-dose N. (2005). Full-dose 90Y ibritumomab tiuxetan therapy is

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3626 safe in patients with prior myeloablative chemotherapy. Clin Leonard J, Frenett G, Dillman RO, Gregory SA. (2001). Cancer Res 11: 7146s–77150s. Intermin saftey and effiacy results of Bexxart in a large Johnson PW, Rohatiner AZ, Whelan JS, Price CG, Love S, multicenter expanded acess study. Blood 98: 133a (abstr.). Lim J et al. (1995). Patterns of survival in patients with Leonard JP, Coleman M, Kostakoglu L, Chadburn A, recurrent follicular lymphoma: a 20-year study from a single Cesarman E, Furman RR et al. (2005). Abbreviated center. J Clin Oncol 13: 140–147. chemotherapy with fludarabine followed by tositumomab Johnson TA, Press OW. (2000). Synergistic cytotoxicity of and iodine I 131 tositumomab for untreated follicular iodine-131-anti-CD20 monoclonal antibodies and chemo- lymphoma. J Clin Oncol 23: 5696–5704. therapy for treatment of B-cell lymphomas. Int J Cancer 85: Link B, Kaminski M, Coleman M, Leonard J. (2004). Phase II 104–112. study of CVP followed by tositumomab and iodine I 131 Justice TE, Martenson JA, Wiseman GA, Witzig TE. (2006). tositumomab (Bexxar therapeutic regimen) in patients with Safety and efficacy of external beam radiation therapy for untreated follicular non-Hodgkin’s lymphoma. J Clin Oncol non-Hodgkin lymphoma in patients with prior 90Y- 22: (Abstract 6520). ibritumomab tiuxetan radioimmunotherapy. Cancer 107: Liu SY, Eary JF, Petersdorf SH, Martin PJ, Maloney DG, 433–438. Appelbaum FR et al. (1998). Follow-up of relapsed B-cell Kaminski M, Bahm V, Estes J, Ratanatharathorn V. (2001a). lymphoma patients treated with iodine-131-labeled anti- Tolerence of treatment sunbsequent to frontline Bexxart CD20 antibody and autologous stem-cell rescue. J Clin (tositumomab and I131 tositumomab) in patients with Oncol 16: 3270–3278. follicular lymphoma. Blood 98: (abstract 603a). Mac Manus MP, Hoppe RT. (1996). Is radiotherapy curative Kaminski M, Hamstra D, Estes J, Wahl RL. (2006). The for stage I and II low-grade follicular lymphoma? Results of impact of FLIPI on outcome of frontline treatment with a long-term follow-up study of patients treated at Stanford single-agent I-131 tositumomab for follicular lymphoma. University. J Clin Oncol 14: 1282–1290. J Clin Oncol 24: (abstract 560a). Marcus R, Imrie K, BelchA, CunninghamD, Flores E, Kaminski M, Zelenetz A, Press O, SalehM, Leonard J, Catalano J et al. (2005). CVP chemotherapy plus rituximab Fehrenbacher L et al. (2004). Tositumomab and Iodine I 131 compared withCVP as first-line treatment for advanced tositumomab (the BEXXARs therapeutic regimen) pro- follicular lymphoma. Blood 105: 1417–1423. duced ongoing, durable remissions of more than 5 years in 9 McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman patients withNon-Hodgkin’s lymphoma(NHL) in a pivotal MS, Williams ME et al. (1998). Rituximab chimeric anti- study of patients refractory to their last chemotherapy. CD20 monoclonal antibody therapy for relapsed indolent Blood 104: (abstract 2631). lymphoma: half of patients respond to a four-dose treatment Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, program. J Clin Oncol 16: 2825–2833. Tuck M et al. (2000). Radioimmunotherapy with iodine Mones J, Coleman M, Kostakoglu L, Fiore J, Muss D, (131)I tositumomab for relapsed or refractory B-cell non- Furman RR et al. (2004). A dose-escalation study of Hodgkin lymphoma: updated results and long-term follow- tositumomab and iodine I 131 tositumomab (Bexxar) in up of the University of Michigan experience. Blood 96: pts withpreviously treated non-Hodgkin’s lymphoma 1259–1266. (NHL) with>25% bone marrow involvement. Proc Am Kaminski MS, Radford JA, Gregory SA, Leonard JP, Knox Soc Clin Oncol 22: (Abstract 6575). SJ, Kroll S et al. (2005a). Re-treatment withI-131 Morschhauser, Huglo D, Martinelli G, Paganelli G, Zinzani tositumomab in patients withnon-Hodgkin’s lymphoma PL, Hadjiyiannakis D et al. (2004). Yttrium-90 ibritumomab who had previously responded to I-131 tositumomab. J Clin tiuxetan (Zevalin) for patients withrelapsed/refractory Oncol 23: 7985–7993. diffuse large B-cell lymphoma not appropriate for auto- Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, logous stem cell transplantation: results of an open-label Zasadny K et al. (2005b). 131I-tositumomab therapy as phase II trial. Blood 104: (Abstract 130). initial treatment for follicular lymphoma. N Engl J Med 352: Nademanee A, Forman S, Molina A, Fung H, SmithD, Dagis 441–449. A et al. (2005). A phase 1/2 trial of high-dose yttrium-90- Kaminski MS, Zasadny KR, Francis IR, Fenner MC, Ross ibritumomab tiuxetan in combination with high-dose etopo- CW, Milik AW et al. (1996). Iodine-131-anti-B1 radio- side and cyclophosphamide followed by autologous stem immunotherapy for B-cell lymphoma. J Clin Oncol 14: cell transplantation in patients withpoor-risk or relapsed 1974–1981. non-Hodgkin lymphoma. Blood 106: 2896–2902. Kaminski MS, Zasadny KR, Francis IR, Milik AW, Ross Nadler LM, Stashenko P, Hardy R, Kaplan WD, Button LN, CW, Moon SD et al. (1993). Radioimmunotherapy of B-cell Kufe DW et al. (1980). Serotherapy of a patient with a lymphoma with [131I]anti-B1 (anti-CD20) antibody. N Engl monoclonal antibody directed against a human lymphoma- J Med 329: 459–465. associated antigen. Cancer Res 40: 3147–3154. Kaminski MS, Zelenetz AD, Press OW, SalehM, Leonard J, Oki Y, Pro B, Delpassand ES, Ballaster V, McLaughlin P, Fehrenbacher L et al. (2001b). Pivotal study of iodine I 131 Romaguera J et al. (2004). A phase II study of yttrium 90 tositumomab for chemotherapy-refractory low-grade or (90Y) ibritumomab tiuxetan (Zevalins) for treatment of transformed low-grade B-cell non-Hodgkin’s lymphomas. patients withrelapsed and refractory mantle cell lymphoma J Clin Oncol 19: 3918–3928. (MCL). Blood 104: (Abstract 2632). Knox SJ, Goris ML, Trisler K, Negrin R, Davis T, Liles TM Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, et al. (1996). Yttrium-90-labeled anti-CD20 monoclonal Trneny M, Imrie K et al. (2006). CHOP-like chemotherapy antibody therapy of recurrent B-cell lymphoma. Clin Cancer plus rituximab versus CHOP-like chemotherapy alone in Res 2: 457–470. young patients withgood-prognosis diffuse large-B-cell Leahy MF, Seymour JF, Hicks RJ, Turner JH. (2006). lymphoma: a randomised controlled trial by the MabThera Multicenter phase II clinical study of iodine-131-rituximab International Trial (MInT) Group. Lancet Oncol 7: 379–391. radioimmunotherapy in relapsed or refractory indolent non- Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie Hodgkin’s lymphoma. J Clin Oncol 24: 4418–4425. H, Bron D et al. (1995). Autologous bone marrow

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3627 transplantation as compared with salvage chemotherapy in tositumomab and (131)I-tositumomab therapy. J Nucl Med relapses of chemotherapy-sensitive non-Hodgkin’s lympho- 43: 354–363. ma. N Engl J Med 333: 1540–1545. Smith MR, Chen H, Gordon L, Foran JM, Kahl B, Press OW, Eary JF, Appelbaum FR, Martin PJ, Badger CC, Advani R et al. (2006). Phase II study of rituximab+CHOP Nelp WB et al. (1993). Radiolabeled-antibody therapy of B- followed by 90Y-ibritumomab tiuxetan in patients with cell lymphoma with autologous bone marrow support. N previously untreated mantle cell lymphoma: an Eastern Engl J Med 329: 1219–1224. Cooperative Oncology Group Study (E1499). J Clin Oncol Press OW, Eary JF, Appelbaum FR, Martin PJ, 24 (Abstract 7503). Nelp WB, Glenn S et al. (1995). Phase II trial of 131I-B1 Stashenko P, Nadler LM, Hardy R, Schlossman SF. (1980). (anti-CD20) antibody therapy with autologous stem Characterization of a human B lymphocyte-specific antigen. cell transplantation for relapsed B cell lymphomas. Lancet J Immunol 125: 1678–1685. 346: 336–340. Stern M, Herrmann R. (2005). Overview of monoclonal Press OW, Eary JF, Gooley T, Gopal AK, Liu S, Rajendran antibodies in cancer therapy: present and promise. Crit JG et al. (2000). A phase I/II trial of iodine-131-tositumo- Rev Oncol Hematol 54: 11–29. mab (anti-CD20), etoposide, cyclophosphamide, and auto- Sweetenham JW, Dicke K, Arcaroli J, Kogel K, Rana TM, logous stem cell transplantation for relapsed B-cell Rice LL. (2004). Efficacy and safety of yttrium 90 (90Y) lymphomas. Blood 96: 2934–2942. ibritumomab Tiuxetan (Zevalin(R)) therapy with rituximab Press OW, Unger JM, Braziel RM, Maloney DG, Miller TP, maintenance in patients withuntreated low-grade follicular Leblanc M et al. (2006). Phase II trial of CHOP lymphoma. ASH Annual Meeting Abstracts 104: 2633. chemotherapy followed by tositumomab/iodine I-131 tosi- Tedder TF, Forsgren A, Boyd AW, Nadler LM, Schlossman tumomab for previously untreated follicular non-Hodgkin’s SF. (1986). Antibodies reactive with the B1 molecule inhibit lymphoma: five-year follow-up of Southwest Oncology cell cycle progression but not activation of human B Group Protocol S9911. J Clin Oncol 24: 4143–4149. lymphocytes. Eur J Immunol 16: 881–887. Press OW, Unger JM, Braziel RM, Maloney DG, Miller TP, The Non-Hodgkin’s Lymphoma Classification Project (1997). LeBlanc M et al. (2003). A phase 2 trial of CHOP A clinical evaluation of the International Lymphoma Study chemotherapy followed by tositumomab/iodine I 131 Group classification of non-Hodgkin’s lymphoma. Blood 89: tositumomab for previously untreated follicular non-Hodg- 3909–3918. kin lymphoma: Southwest Oncology Group Protocol S9911. van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Blood 102: 1606–1612. Gascoyne RD et al. (2006). Rituximab maintenance Radford JA, Ketterer N, Sebban C, Zinzani PL, Delaloye AB, improves clinical outcome of relapsed/resistant follicular Rohatiner AZ et al. (2003). Ibritumomab tiuxetan (Zevalin) non-Hodgkin’s lymphoma, both in patients with and therapy is feasible and safe for the treatment of patients with without rituximab during induction: results of a prospective advanced B-cell follicular NHL in first remission: interim randomized phase III intergroup trial. Blood. analysis for safety of a multicenter, phase III clinical trial. Vose J, Bierman PJ, LynchJC, Bociek G, Multani P, Armitage Blood 102 (Abstract 1484). JO. (2003). Phase I clinical trial of Zevalin (90Y-Ibritumo- Schilder R, Witzig T, Gordon L, Emmanouilides C, Bartlett mab) in patients withB-cell Non-Hodgkins lymphoma N, Flinn IW et al. (2002). 90Y ibritumomab tiuxetan (NHL) with relapsed disease following high-dose chemo- (Zevalin) radioimmunotherapy does not preclude effective therapy and autologous stem cell transplantation (ASCT). delivery of subsequent therapy for lymphoma Proc. Am Soc Blood 102 (abstract 92). Clin Oncol 21: 267a (abtract 1065). Vose JM. (2004). Bexxar: novel radioimmunotherapy for the Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H, treatment of low-grade and transformed low-grade non- Johnson HE et al. (2003). High-dose therapy improves Hodgkin’s lymphoma. Oncologist 9: 160–172. progression-free survival and survival in relapsed follicular Vose JM, Anderson JR, Kessinger A, Bierman PJ, Coccia P, non-Hodgkin’s lymphoma: results from the randomized Reed EC et al. (1993). High-dose chemotherapy and European CUP trial. J Clin Oncol 21: 3918–3927. autologous hematopoietic stem-cell transplantation for Shah J, Harrough D, Savill W, Mueh J, Lister J, Jasthy S et al. aggressive non-Hodgkin’s lymphoma. J Clin Oncol 11: (2006). Safety and efficacy of retreating follicular non- 1846–1851. Hodgkin’s lymphoma (NHL) with 90Y ibritumomab Vose JM, Bierman PJ, Enke C, Hankins J, Bociek G, Lynch tiuxetan. J Clin Oncol 24 (Abstract 17528). JC et al. (2005). Phase I trial of iodine-131 tositumomab Shipley DL, Greco FA, Spigek DR, Edwards D, Mayfield M, with high-dose chemotherapy and autologous stem-cell Yost K et al. (2005). Rituximab withshortduration transplantation for relapsed non-Hodgkin’s lymphoma. chemotherapy followed by 90Y ibritumomab tiuxetan as J Clin Oncol 23: 461–467. first-line treatment for patients withfollicular lymphoma: Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ, Update of a Minnie Pearl Cancer ResearchNetwork phase Radford JA et al. (2000). Multicenter phase II study of II trial. J Clin Oncol 23 (Abstract 6577). iodine-131 tositumomab for chemotherapy-relapsed/refrac- Shipp MA, Abeloff MD, Antman KH, Carroll G, Hagenbeek tory low-grade and transformed low-grade B-cell non- A, Loeffler M et al. (1999). International consensus Hodgkin’s lymphomas. J Clin Oncol 18: 1316–1323. conference on high-dose therapy with hematopoietic stem Wahl RL. (2003). The clinical importance of dosimetry in cell transplantation in aggressive Non-Hodgkin’s lympho- radioimmunotherapy with tositumomab and iodine I 131 mas: report of the jury. J Clin Oncol 17: 423–429. tositumomab. Semin Oncol 30: 31–38. Siegel JA. (1998). Revised nuclear regulatory commission Wahl RL, Zasadny KR, MacFarlane D, Francis IR, Ross regulations for release of patients administered radioactive CW, Estes J et al. (1998). Iodine-131 anti-B1 antibody for materials: outpatient iodine-131 anti-B1 therapy. J Nucl B-cell lymphoma: an update on the Michigan Phase I Med 39: 28S–33S. experience. J Nucl Med 39: 21S–27S. Siegel JA, Kroll S, Regan D, Kaminski MS, Wahl RL. Wiseman GA, Gordon LI, Multani PS, Witzig TE, (2002). A practical methodology for patient release after Spies S, Bartlett NL et al. (2002a). Ibritumomab tiuxetan

Oncogene Radioimmunotherapy for B-cell lymphoma AJ Davies 3628 radioimmunotherapy for patients with relapsed or refrac- Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, tory non-Hodgkin lymphoma and mild thrombocytopenia: Emmanouilides C, Joyce R et al. (2002b). Randomized a phase II multicenter trial. Blood 99: 4336–4342. controlled trial of yttrium-90-labeled ibritumomab tiuxetan Wiseman GA, Kornmehl E, Leigh B, Erwin WD, Podoloff radioimmunotherapy versus rituximab immunotherapy for DA, Spies S et al. (2003). Radiation dosimetry results and patients withrelapsed or refractory low-grade, follicular, or safety correlations from 90Y-ibritumomab tiuxetan radio- transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol immunotherapy for relapsed or refractory non-Hodgkin’s 20: 2453–2463. lymphoma: combined data from 4 clinical trials. J Nucl Med Witzig TE, White CA, Gordon LI, Wiseman GA, Emmanoui- 44: 465–474. lides C, Murray JL et al. (2003b). Safety of yttrium-90 Wiseman GA, LeighB, Erwin WD, Lamonica D, Kornmehl ibritumomab tiuxetan radioimmunotherapy for relapsed E, Spies SM et al. (2002b). Radiation dosimetry results for low-grade, follicular, or transformed non-hodgkin’s lym- Zevalin radioimmunotherapy of rituximab-refractory non- phoma. J Clin Oncol 21: 1263–1270. Hodgkin lymphoma. Cancer 94: 1349–1357. Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanoui- Wiseman GA, Witzig TE. (2005). Yttrium-90 (90Y) ibritumo- lides C, Raubitschek A et al. (1999). Phase I/II trial of mab tiuxetan (Zevalin) induces long-term durable responses IDEC-Y2B8 radioimmunotherapy for treatment of relapsed in patients withrelapsed or refractory B-Cell non-Hodgkin’s or refractory CD20(+) B-cell non-Hodgkin’s lymphoma. lymphoma. Cancer Biother Radiopharm 20: 185–188. J Clin Oncol 17: 3793–3803. Witzig T, Molina A, Gordon L, Emmanouilides C, Schilder R, Zelenetz A, Noy A, Pandit-Taskar N, Scordo M, Rijo I, Flinn IW et al. (2003a). Yttrium 90 ibritumomab tiuxetan Zhou JA et al. (2006). Sequential radioimmunotherapy (Zevalin) radioimmunotherapy (RIT) induces durable withtositumomab/Iodine I131 tositumomab followed by remissions in patients withrelapsed or refractory B-cell CHOP for mantle cell lymphoma demonstrates RIT Non-Hodgkins lymphoma (NHL): analysis of long-term can induce molecular remissions. J Clin Oncol 24 responders. Blood 102 (abstract 1480). (Abstract 7560). Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czucz- Zelenetz A, SalehM, Vose J, Younes A, Kaminski M. (2002). man MS, SalehMN et al. (2002a). Treatment with Patients withtransformed low grade lymphomaattain ibritumomab tiuxetan radioimmunotherapy in patients with durable responses following outpatient radioimmuno- rituximab-refractory follicular non-Hodgkin’s lymphoma. therapy wit tositumomaba and I131 tostitumomab (Bexxar). J Clin Oncol 20: 3262–3269. Blood 100: 357a (abstract).

Oncogene