Keywords: CD20, follicular lymphoma, iodine I 131 tositumomab, monoclonal antibody, radioimmunotherapy, tositumomab

Transcription

1 Drug Evaluation 1. Introduction 2. Targeting the CD20 antigen with tositumomab and I 131 tositumomab 3. Administration 4. Pharmacokinetics and dosimetry 5. Clinical efficacy 6. Tositumomab and I 131 tositumomab in combination with chemotherapy 7. Safety and tolerability 8. Expert opinion and conclusions A review of tositumomab and I 131 tositumomab radioimmunotherapy for the treatment of follicular lymphoma Andrew J Davies Cancer Research UK Medical Oncology Unit, Barts and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK The CD20 antigen has become a major therapeutic target in the management of follicular and other B cell non-hodgkin s lymphomas. The murine monoclonal antibody, tositumomab, on binding CD20, is able to induce antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and apoptosis. In addition, when radioiodinated, the antibody exploits the tumour s sensitivity to ionising radiation by direct targeting of the malignant cell. Tositumomab and Iodine (I 131 ) tositumomab (Bexxar, GlaxoSmithKline, Philadelphia, PA, USA) is administered in two steps. The dosimetric step determines individual patient pharmacokinetics, allowing a patient- specific dose to be calculated. This is followed by the therapeutic step, with administration of the therapeutic dose between 7 and 14 days after the dosimetric dose. Over a decade s worth of experience in clinical trials has determined the efficacy and safety of the regimen in a variety of clinical circumstances; establishment of exactly where the regimen fits amongst the algorithm for the management of follicular lymphoma continues. Keywords: CD20, follicular lymphoma, iodine I 131 tositumomab, monoclonal antibody, radioimmunotherapy, tositumomab Expert Opin. Biol. Ther. (2005) 5(4): Introduction For reprint orders, please contact: reprints@ashley-pub.com Ashley Publications Follicular lymphoma is a B cell malignancy that represents approximately a quarter of the non-hodgkin s lymphomas in the western world [1]. The median age at diagnosis is 59 years, with the majority of patients (67%) presenting with advanced stage disease (stage III/IV) [1]. Bone marrow involvement is common and is present in > 40% of patients at diagnosis. Lymphadenopathy is the most frequent reason for presentation, although patients typically have only minimal symptoms attributable to their disease, with constitutional B symptoms documented in only 25% of patients at diagnosis. The median survival for patients with follicular lymphoma is long, in the order of 8 10 years [2-4], although the clinical pattern is of multiple episodes of disease recurrence, punctuated by variable periods of remission. Sensitivity of the tumour to radiation is demonstrated by the durability of remissions that are achieved when patients with early stage disease are treated with this modality. Observations from Stanford University indicate that 40% of such patients are relapse-free at 15 years [5]. Based on such data, radiation (when amenable) is considered the treatment of choice for stage I and some patients with stage II disease. For the majority of patients who have advanced stage disease, most will enter remission following either single agent or combination chemotherapy; however, immediate therapy at the time of diagnosis offers no survival benefit [6,7]. As a result, patients are typically managed on an expectant basis or so-called watch and wait, with the deferment of therapy until patients are symptomatic or there is evidence of organ / Ashley Publications Ltd ISSN

2 Tositumomab and I 131 tositumomab compromise. Recent follow-up data from a further patient cohort at Stanford indicates that deferred therapy may also be an acceptable approach in early stage patients [8]. When indicated, options for therapy, both initially and at disease recurrence, are broad and range markedly in their intensity. Patients typically respond to single agent or combination chemotherapy, although after three episodes of disease the response rate typically declines and the remission duration shortens, with the eventual development of a chemotherapyrefractory disease state [4]. Patients die as a result of disease, complications of therapy or transformation to a more aggressive histological phenotype. More recently, monoclonal antibody therapy alone or in combination with chemotherapy primarily targeting the CD20 antigen, radioimmunotherapy, interferon, high-dose therapy with progenitor cells rescue and either conventional or reduced intensity allogeneic transplantation strategies have been explored [9,10]. However, to date there is little evidence to suggest that cure can be a reasonable expectation from therapy. The philosophy of care and expectation from therapy therefore depends largely on the individual patient. Appropriate selection requires consideration of the likely response rate, durability of response, toxicity profile, and patient age and comorbidity; there is no clear consensus as to the preferred algorithm. It is hoped that improvements in both clinical [11] and molecular [12] prognostic markers may help to better predict survival and improve tailoring of therapy to the individual s requirements. The relative longevity associated with follicular lymphoma has resulted in the adoption of the terminology indolent lymphoma to distinguish it from those that are invariably rapidly fatal in the absence of immediate therapy (follicular lymphoma represents > 70% of the indolent lymphomas). Also under this umbrella are a number of less common histological subgroups of B cell lymphomas with a similar disease pattern. These include lymphoplasmacytic lymphoma/waldenstrom macroglobulinaemia, marginal zone lymphoma and small lymphocytic lymphoma. Although this review primarily focuses on the use of radioimmunotherapy in follicular lymphoma, by way of clarification, a number of the reported series have enrolled small numbers of patients with indolent lymphomas without reporting outcomes for individual histological subtypes. 2. Targeting the CD20 antigen with tositumomab and I 131 tositumomab The CD20 antigen is a human B lymphocyte-specific surface antigen [13], widely expressed during B cell development. The protein makes four transmembrane passes, with both the N and C terminals residing within the cytoplasm [14,15], and complexing as multimers to form calcium ion conductive channels [16] that respond to B cell receptor activation [17]. The pattern of antigen expression during B cell development is an important determinant for therapeutic targeting; it is absent from the terminally differentiated plasma cells and those in the earliest stages of B cell linage commitment, yet it is present on > 95% of B cell lymphomas [13,18]. The utility of CD20 as an antilymphoma target has clearly been demonstrated by the efficacy of the chimeric anti-cd20 monoclonal antibody rituximab (Genentech Inc., South San Francisco, CA and Biogen Idec, Inc., Cambridge, MA, USA). As a single agent, rituximab is able to induce remission in 50% of patients with relapsed indolent lymphoma with only minimal toxicity [19]. Rituximab represents a major therapeutic advance, although the number of patients entering complete remission (CR) is small and the overall duration of remission in the main is short. Furthermore, in combination with chemotherapy, significant improvements in outcome above those achieved with conventional therapy alone have been reported from randomised studies in a range of B cell lymphomas [20-22]. This has resulted in a significant paradigm shift in the management of many lymphomas. Tositumomab is a murine IgG2a lambda monoclonal antibody directed against the CD20 antigen; formally known as anti-b1. Both in vitro and in xenograft models, a number of effects of antigen-antibody binding have been identified. Cell cycle progression is inhibited [23], antibody-dependent cellular cytotoxicity [24] and complement-dependent cytotoxicity may be induced, as may direct induction of apoptosis [25,26]. Importantly, this latter effect is not attenuated by the expression of the antiapoptotic protein bcl-2, one of the hallmarks of follicular lymphoma [27]. In vivo unlabelled tositumomab has clear antitumour activity, with tumour responses observed in 19% of treated patients, some of which have proven to be durable [28]. Enhanced therapeutic activity, however, results from the radioiodination of tositumomab [28]. Performed by covalent linkage of I 131 using the iodogen method [29], irradiation is delivered directly to the tumour site, with the induction of cell death. The dual emission properties of I 131 (t 1/2 = 8 days) makes it an attractive choice of radionuclide. Beta particles may exert an effect over a distance of cell diameters [30,31], with the resulting death of neighbouring malignant cells that have not bound antibody ( cross-fire ), yet path length is short enough to limit normal tissue exposure. Gamma radiation may be detected ex vivo and is employed as a tool for kinetic and biodistribution studies, allowing patient-specific dosing to be performed ( dosimetry ). The downside of I 131 gamma emission, however, is that radiation protection issues are of logistical relevance to the use of radioiodinated tositumomab. 3. Administration Tositumomab and I 131 tositumomab is administered in a standard two-step schedule, and is marketed as the Bexxar therapeutic regimen (GlaxoSmithKline, Philadelphia, PA, USA; formerly developed by Corixa Corp., Seattle, WA, USA) (Figure 1). Marketing approval for the regimen was granted from the US Food and Drug Administration (FDA) in June 2003 and was initially indicated for the treatment of patients with CD20-positive, follicular, non-hodgkin s 578 Expert Opin. Biol. Ther. (2005) 5(4)

3 Davies 1 h postdosimetric dose Dosimetry (day 0) 450 mg unlabelled tositumomab (over 1 h) then 35 mg (5 mci) I 131 tositumomab (over 20 mins) gamma camera scans day 2, 3 or 4 Therapy (on a single day from day 8 14) 450 mg unlabelled tositumomab (over 1 h) then patient-specific whole body dose I 131 tositumomab (over 20 mins) day 6 or 7 Figure 1. Administration of tositumomab and I 131 tositumomab as the Bexxar therapeutic regimen (adapted from [42,83]). lymphoma, with and without transformation, whose disease is refractory to rituximab and who have relapsed following chemotherapy. A supplementary Biologics License Application (sbla) was approved in January 2005, expanding the indication to relapsed or refractory, low-grade, follicular or transformed non-hodgkin s lymphoma, including patients with rituximab-refractory non-hodgkin s lymphoma [32]. In Europe it has been assigned Orphan Medicinal Product status, although to date it is not available outside clinical trials. Infusion of radiolabelled tositumomab in both phases is preceded by an infusion of 450 mg unlabelled tositumomab intravenously over 60 min. Such infusion enhances the tumour targeting of I 131 tositumomab by saturating nonspecific binding sites and antigen sinks of non-malignant B cells, predominantly in the circulation and spleen [33], and reflecting experience gained in preclinical studies [34]. In the first step, referred to as the dosimetric step, individual patient pharmacokinetics are determined following the infusion of a small tracer dose of I 131 tositumomab (5mCi with 35 mg of antibody) over 20 min. Whole body gamma camera scans are obtained within 1 h (prior to micturition) and repeated at 2 4 days and 6 7 days (both times post-micturition) following dosimetric dose. From whole body imaging, appropriate biodistribution may be determined by inspection, and if abnormal, further drug is not administered. The residence time is calculated by plotting the background corrected activity as a percentage of initial activity at the three imaging time points and, using a line of best fit, the time at which activity is at 37% of injected activity is determined. From this and the activity hours, determined by the patient s maximum effective mass, the I 131 activity for the desired total body dose may be calculated. The maximal tolerated whole-body dose was established as 75 cgy, limited by haematological toxicity [35]. For those patients with relative thrombocytopenia ( /l) the dose is attenuated to 65 cgy due to an excess of grade 4 cytopenias observed in these patients treated with 75 cgy. The therapeutic step, the infusion of I 131 tositumomab (preceded by 450 mg of unlabelled tositumomab), occurs between 7 and 14 days after the dosimetric infusion. Prior to both steps, the patient is premedicated with paracetamol and an antihistamine. Thyroid blockade with potassium iodide or Lugol s solution is initiated at least 24 h prior to the dosimetric infusion and continued for 14 days after the therapeutic dose to saturate the uptake of free iodine. Due to concerns about severe haematological toxicity, only patients with < 25% bone marrow involvement (defined by assessment of the intertrabecular marrow space) are eligible for therapy. Ongoing dose escalation studies are being performed in patients with > 25% bone marrow involvement [36]. A multidisciplinary team approach is essential for safe administration and patient follow-up at discharge. In the US, Nuclear Regulatory Commission regulations now permit patient release after therapy in most states [37]. By contrast, administration in the UK remains strictly on an in-patient basis only. 4. Pharmacokinetics and dosimetry The key principle underlying dosimetry and individualised patient dosing is an attempt to maximise delivery of the radiation dose to the tumour, whilst minimising toxicity to normal tissue [38]. Based on the observed dose-limiting toxicity, the bone marrow was identified as the most sensitive normal organ; however, measurement of marrow doses are technically challenging, so whole blood pharmacokinetics have been employed as a surrogate. The total body residence time correlates with whole blood area under the curve (AUC) and so may be used as a substitute pharmacokinetic parameter. Between individuals, pharmacokinetics are observed to be highly variable, with an eightfold variation in both AUC and clearance [39]. Clearance is influenced by tumour burden, spleen size and bone marrow infiltration; therefore, dosimetric Expert Opin. Biol. Ther. (2005) 5(4) 579

4 Tositumomab and I 131 tositumomab methodology allows delivery of a lower therapeutic activity (in mci) to those with a slower clearance, and greater activity to patients whose clearance is more rapid; administered activity between patients may vary considerably [40]. The described simplified dosimetry methodology [38,41], based on an assumption of homogenous distribution, is highly reproducible and has been shown to be transferable to multiple institutions [42]. Mean tumour dose in 91 patients was cgy/75 cgy and was unaffected by spleen size, marrow involvement and weight, although it was lower in bulky tumours [101]. Individual organ dosimetry indicates that doses to normal tissue are well below tolerance. At 5 days, whole body clearance of I 131 is 67% of the injected dose by decay and excretion. Unconjugated I 131 is renally cleared, with 98% of total body excretion captured in the urine within 5 days postinfusion. For this reason, patients with renal dysfunction or urinary tract obstruction have been excluded from study. 5. Clinical efficacy 5.1 Phase I experience A tremendous wealth of experience in the administration of tositumomab and I 131 tositumomab has come from Drs Kaminski and Wahl at the University of Michigan. The results from the first 10 patients treated, of which 6 responded, were reported in 1993 [33] and later reported for 34 patients with mixed histological subtypes in 1996 [35]. Of 28 patients receiving infusion of labelled tositumomab, tumour responses were observed in 79%, with 64% entering CR, including responses in patients with chemotherapy refractory disease, recurrence after high-dose therapy with stem cell rescue, and high tumour burdens. The durability of these responses were confirmed in a later updated analysis [40].The benefit of predosing with unlabelled tositumomab was established in the Phase I studies, as was the maximal dose of the radioimmunotherapeutic infusion. After 2 of 3 patients who received 85 cgy experienced severe haematological toxicity, the maximally tolerated whole-body dose was determined as 75 cgy. As one would expect from the distribution of CD20, there was near-complete depletion of the B cell compartment in all patients, although the serum immunoglobulin concentration remained unchanged, and incidence of opportunistic infection was low. B cell recovery was documented in nearly all patients at 3 months. 5.2 Phase II/III studies Recurrent disease A number of trials have established the efficacy and safety of tositumomab and I 131 tositumomab in the Phase II (and III) setting. These have in the main explored the utility in patients with relapsed/refractory disease, for which the product is now indicated. Forty-seven patients with either indolent or transformed indolent B cell lymphoma were entered into the first multicentre Phase II study conducted in the US and Europe [42]. This study established the practicality and reproducibility of the dosimetry and administration methodology at multiple sites. Enrolled patients were heavily chemotherapy pretreated (median of 4 prior therapies), with only 46% having responded to their last therapy. In patients with indolent disease (n = 37), the overall response rate (ORR) was 57%, with 27% achieving a CR. Six out of ten patients with previous indolent histology that had transformed to a more aggressive lymphoma responded, with five entering a CR. No analysis is available for specific indolent histological subtypes. The median duration of responses was 10 months, and for those entering a CR it was 20 months. In an analysis of poor prognostic factors, responses were documented in 59% of patients with high tumour burdens (estimated > 500g) and 50% of patients with an elevated level of lactate dehydrogenase (LDH). The original Phase I study of 34 patients was extended on establishment of the dosing regimen into a single-centre Phase I/II study, recruiting a total of 59 patients (median of 3 prior therapies) at the University of Michigan. Long-term follow-up of these patients has been published and, based on intention to treat, the ORR was 71%, with 34% achieving a CR [40]. With a median follow-up of 3.1 years, median progression-free survival was 12 months for all patients and 20 months for those entering a CR. Those patients with indolent histology (n = 42) had favourable response rates (86%), compared to de novo aggressive histology (41%), with no CRs in the latter and short duration of remission. Without doubt, the radio-iodination adds significance to the efficacy of the parent monoclonal. This has been demonstrated in a randomised multi-centre study where tositumomab was compared with the tositumomab and I 131 tositumomab regimen with the option for crossover in those failing cold antibody [28]. Seventy-eight rituximab-naive patients were randomised (median of two prior therapies), with well-matched demographics and prognostic factors. The ORR was 19 and 55% in each group, respectively (CR 8 and 33%). Of 19 patients that crossed over to receive radioimmunotheapy, 42% entered a CR, none having achieved a CR with tositumomab alone. In the pivotal Phase III study, 60 patients received tositumomab and I 131 tositumomab. These patients had received at least two prior chemotherapeutic regimens, but had not responded (n = 43) or progressed within 6 months of their last regimen (n = 17) [43]. The median time from diagnosis to protocol entry was 53 months. All investigator-assessed responses were confirmed by a masked independent review panel. A response was documented in 65% of these chemotherapy-refractory individuals, with 20% entering CR. Using the patients as their own controls (a design that has been subject to some debate), their response to radioimmunotherapy was compared with the response that had been achieved following their last chemotherapy (ORR 28%, CR 3%). The median duration of response to tositumomab and I 131 tositumomab was 6.5 months compared with 3.4 months following chemotherapy, with 53% of patients having a longer duration of response to radioimmunotherapy than the previous chemotherapy. Despite some 580 Expert Opin. Biol. Ther. (2005) 5(4)

5 Davies potential for the generation of bias in the trial design, these results are remarkable given the documented decline in response rate and remission duration observed following conventional therapy [4]. The patient population had many unfavourable disease characteristics: the median number of prior chemotherapies was 4, but ranged from 2 to 13, 56% had bone marrow involvement, 44% an elevated LDH, 38% a high tumour burden and 38% had histologically transformed disease. Although responses were observed in all subgroups, in the univariate analysis, amongst significant variables, it is of note that patients with lower tumour burdens had a superior response to therapy and a longer duration of response. At the time of the most recent update, 7 of 12 patients continue in CR years following therapy [44]. The results of this study formed the basis of the sbla approval by the FDA in January Results from a Phase II study enrolling a less heavily pretreated patient group that were treated at the time of first or second recurrence (n = 41) has recently been reported [45]. The majority of patients (71%) had follicular histology (other indolent histology [12%], transformed histology [17%]), and had received a median of just one prior therapy (66%) with a median duration of previous remission of 9 months. Bone marrow involvement was documented in 54%, although the LDH was elevated in only 12%. The ORR was 76%; of these, 49% of patients entered a CR/CR(u) that was associated with a prolonged remission duration (not reached with a median follow-up of 3.1 years compared with a median of 1.3 years for all responders). Indeed, at the time of publication, 11 of 20 patients who achieved a CR remained in CR between 2.6 and 5.2 years. The highest response rate (79%) was observed in the 29 patients with follicular lymphoma, and a respectable 5 of 7 patients with transformation responded. Although the response rate is perhaps in line with conventional therapy at this stage in the clinical course, enthusiasm for use early in the disease history comes from the remarkable number of patients achieving a durable CR. In order to establish efficacy and practical utility in a wider setting, an Expanded Access Programme was initiated in 65 institutions. Through this programme, 475 patients with relapsed or refractory disease were enrolled; efficacy data has been published in abstract form for 394 patients [46]. The median number of prior therapies for this population was two, the overall response rate 59% (26% CR) and the median duration of response 15 months. Data for non-follicular indolent histology is limited, largely because n has been small, and series have infrequently published responses in these more uncommon subtypes. In a summated analysis from the Expanded Access Programme and clinical trials, the ORR of 89 patients with relapsed or refractory small lymphocytic lymphoma was inferior to that of grade 1/2 follicular lymphoma (n = 651) (42 versus 65%; p < 0.001), although median response durations were comparable [47]. Original FDA approval was based on efficacy in patients with follicular lymphoma that had disease relapse following chemotherapy and were refractory to rituximab. Horning et al. [48] have recently reported in full the study that led to the above approval. Forty patients were entered into this multicentre study. They had failed a median of four prior therapies (59% defined as chemotherapy-resistant) and had either failed to respond to rituximab (n = 24), had progressed within 6 months (n = 11) or had progressed > 6 months after rituximab (n = 5). By definition, 88% were truly rituximab refractory. Ten patients had transformed disease. The ORR was 65%, with 38% of patients achieving a CR. Eighty per cent of the patients who attained a CR had grade 1 or 2 follicular histology with low tumour bulk (defined as 7cm) and, interestingly, response was independent of the previous outcome to rituximab. For complete responders, the estimated 3-year progression-free survival (PFS) was 73%, with a median PFS of 24.5 months for responders and 10.4 months for all patients. Given that therapeutic options are increasingly limited in this group of patients, such data are of great interest and help guide the physician in patient selection. The durability of some CRs observed in the above studies have been more closely examined by summating data from 230 patients derived from five of the Phase II trials. Of 55 patients who achieved a CR of 12 months or longer, 75% remain in ongoing CR at a median follow-up of 4.6 years [49]. This cohort also demonstrates a decline in ORR to tositumomab and I 131 tosituomab when used as later therapy (second therapy ORR 74%, third therapy 64%, fourth therapy ORR 52%, fifth therapy ORR 48%, sixth therapy ORR 52% and seventh therapy or more ORR 42%); however, the percentages of patients with durable responses ( 5 years) were initially fairly consistent (41, 21, 25, 35, 36 and 9% when used at second, third, fourth, fifth and sixth relapse, respectively) [50] Efficacy in transformed disease Histological transformation of follicular lymphoma to a more aggressive subtype, most typically diffuse large B cell lymphoma, is a clear adverse prognostic feature [4]. Indeed, the biological and clinical features of transformed disease are very different from the antecedent indolent disease from which it arose. Responses of transformed disease to conventional chemotherapy are typically poor, with outcomes inferior to their de novo disease counterparts [51]. During licensing discussions, the FDA requested the sponsor to provide summated data from clinical trials on this population of patients for further analysis. The analysis of 71 patients has been presented in abstract form [52] and indicates that there is a practical utility in this population with an overall response rate of 39%. Typical of this subgroup, many patients had additional adverse prognostic features, including an elevated LDH, bulk disease (defined for this study as > 5 cm) and high International Prognostic Index scores, yet responses were seen in all these subgroups. Responses were durable (median 20 months) and, once again, superior in those 25% of patients entering a CR (36.5 months). There may, however, be a caveat to this population; the median time from diagnosis of transformation to study entry was long at 21 months (range 0 123), perhaps indicating a degree of population bias with some selection of the better actors. Expert Opin. Biol. Ther. (2005) 5(4) 581

6 Tositumomab and I 131 tositumomab Following a central pathology review of this population, updated results were reported as part of the Biological License Application to the FDA [101]. Although largely because of non-availability of sufficient diagnostic material to review years after the initial diagnosis, the population reported was reduced to 47 (only 5 of 53 patients with sufficient material were not confirmed to have transformation), response rates and durations were similar to the overall population of 71 reported in abstract form. Full publication of these data are awaited Front-line therapy It is not without surprise that scheduling of tositumomab and I 131 tositumomab earlier in the disease course has generated some remarkable efficacy data in the Phase II setting. Kaminski et al. [53] report their single centre results from 76 previously untreated patients with stage III IV follicular lymphoma. Ninety-five per cent of patients responded, with 75% achieving a confirmed CR. At a median follow-up of 5.1 years, the progression-free survival was 59% (median 6.1 years), and of 57 patients achieving CR, 40 remain in ongoing CR between 4.3 and 7.7 years. Molecular remissions were observed in 36 out of 39 patients that carried a polymerase chain reaction-detectable IGH/BCL2 translocation. Such responses and durability of response are of great interest, although this must to some degree be tempered by concerns in the long-term concerning the potential development of myelodysplasia. The follow-up data for this study suggest that as yet this has not been an issue; indeed, there has been no case of myelodysplasia reported at a median of 5.1 years follow-up [53,54]. One should note that tositumomab and I 131 tositumomab is not indicated as initial therapy at this time Retreatment For those patients that have responded to tositumomab and I 131 tositumomab, retreatment at the time of later progression appears viable with a meaningful response rate [55]. The retreatment Phase II study enrolled 32 patients who were human antimouse antibody (HAMA)-negative and had a minimum response to tositumomab and I 131 tositumomab of 3 months (56 and 38% of patients, respectively, had achieved a CR or partial response [PR]). At a median of 21 months (range 7 73) following the first course of tositumomab and I 131 tositumomab, responses were observed in 56% of patients (22% CR) with a median duration of response of 10.7 months. The quality of response appeared independent of that achieved after the first exposure to tositumomab and I 131 tositumomab. Why patients should fail to respond on repeat exposure is not clear. 6. Tositumomab and I 131 tositumomab in combination with chemotherapy Sequential administration of tositumomab and I 131 tositumomab following conventional therapeutic regimens has been investigated with the intent of improving and consolidating outcome. The addition of rituximab to conventional chemotherapy has already demonstrated promise in follicular lymphoma [20-22,56]. The potential for heightened toxicity arising from coadministration of radioimmunoconjugate and chemotherapy has led investigators to a sequential scheduling methodology of chemotherapy induction followed by consolidation with tositumomab and I 131 tositumomab. This approach is attractive given that optimal tumour responses to tositumomab and I 131 tositumomab are likely to be observed when tumour volumes are small [40,45]. Furthermore, bone marrow infiltration may be reduced or cleared by chemotherapy, allowing patients access to radioimmunotherapy who would have otherwise been precluded by the degree of marrow infiltration. The SouthWest Oncology Group (SWOG) has reported their results from a Phase II trial of 6 cycles of conventional CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by tositumomab and I 131 tositumomab 4 8 weeks after completion of chemotherapy in patients with untreated follicular lymphoma. Of 90 eligible patients, 86 completed CHOP and 77 patients completed both phases. Objective responses were observed in 81/90 patients (90%), including 54% of patients reaching CR. Of 47 patients not in a CR after CHOP, but who had responded with either a PR or unconfirmed CR, 57% had an improvement in their response to CR after radioimmunotherapy. At a median follow-up of 2.3 years, the 2-year PFS was estimated at 81%. Toxicity following the radioimmunotherapy phase was generally milder than that experienced following CHOP; indeed the majority of grade III/IV toxicities followed chemotherapy. Such sequential administration is now in direct comparison with CHOP-rituximab combination in a SWOG Phase III study as upfront treatment of patients with follicular lymphoma. Planned accrual is 500 patients. Recently, the results of similar sequential administration after fludarabine [57] and CVP (cyclophosphamide, vincristine, and prednisone) [58] have been reported in abstract form in untreated patients. By way of contrast, in mantle cell lymphoma tositumomab and I 131 tositumomab is being investigated as an initial cytoreductive agent followed by CHOP chemotherapy [59]. Myeloablative doses of I 131 tositumomab have been investigated alone [60-62] and in combination with chemotherapy [63,64]. As stem cell rescue is employed in this setting, the major doselimiting toxicity of myelosuppression is overcome and wholebody and tumour dose may be increased. Such an approach has generated some evocative data, although this is beyond the scope of this review. 7. Safety and tolerability The safety profile of tositumomab and I 131 tositumomab has been established through the wealth of clinical experience gained over a decade. Integrated safety information has been reported from 995 patients, including summated data from 230 patients treated in the context of five clinical trials. These represent the main patient population documented on the 582 Expert Opin. Biol. Ther. (2005) 5(4)

7 Davies box label for acute safety data [65] and are supplemented by an additional 765 patients from the Expanded Access Programme for long-term toxicity data. Hypersensitivity reactions, including anaphylactoid reactions, consistent with experience of infusion of a foreign protein, are reported in 6% of patients. Infusion should therefore be administered in facilities where suitable resources are available for a rapid response to such reactions. Infusional-related toxicities, including fever, chills, rigors and nausea, are typically mild and managed by a reduced infusion rate or temporary administration interruption. Patients are premedicated with paracetamol and an antihistamine prior to commencement of the infusion. The most common short-term non-haematological adverse events, regardless of relationship to study drug, were asthenia (46%), fever (37%), nausea (36%), increased cough (21%), pain (19%), chills (18%), rash (17%), headache (16%), vomiting (15%) and abdominal pain (15%). The principle short-term toxicity of tositumomab and I 131 tositumomab is bone marrow suppression (toxicity across studies is documented in Table 1). In contrast to conventional cyclical chemotherapy, a single haematological nadir is observed at 4 6 weeks post-therapy, with recovery (to grade 2) by 9 weeks post-therapy. In the population of 230 patients drawn from clinical trials who had been extensively pretreated, 53% of patients experienced grade 3/4 thrombocytopenia (platelets < /l), and 63% grade 3/4 neutropenia (neutrophils < /l). The median duration of grade 3/4 toxicity was 32 and 31 days, respectively. Anaemia of < 8 g/dl was encountered in 29% of patients. Significant predictors of toxicity included the number of prior therapies, baseline blood counts, degree of bone marrow involvement and prior exposure to fludarabine therapy. Although such haematological toxicity might seem alarming to the non-oncologist, they are in line with experience with many moderately intensive chemotherapeutic regimens. Furthermore, a low incidence of bleeding events (< 1% grade 3/4) and serious infections (8%) occurred. The requirement for blood product support was low, 15% requiring platelet transfusions, 12% granulocyte colony-stimulating factor and 16% red cell transfusions. It is reassuring to note a similar toxicity profile in the elderly population (patients aged > 70) [66]. In patients that have been retreated with tositumomab and I 131 tositumomab, haematological toxicity was broadly in line with previous experience (see Table 1), with grade 4 neutropenia and thrombocytopenia each occurring in 19% of patients. In terms of long-term late adverse events, protection from hypothyroidism by thyroid blockade pretreatment seems reasonably effective. The cumulative incidences of an elevated thyroid-stimulating hormone, either symptomatic or asymptomatic, were 9.1 and 17.4% at 2 and 4 years, respectively. Longterm follow-up of treated patients is clearly mandated. The risk of therapy-related myelodysplasia and acute myelogenous leukaemia (tmds/taml) has generated much discussion. Among 995 heavily pretreated patients (median 3, range 1 13 prior therapies), 35 cases of tmds/taml were reported. Of these, pre- and post-tositumomab and I 131 tositumomab bone marrows have been independently reviewed [54]. From the 25 available, 2 patients had no evidence of tmds/taml; in the remaining 23 patients the diagnosis was confirmed. It is of note, however, that 10 patients were found to have tmds in their pretreatment marrow. The annualised incidence with a median follow-up of 2 years (range ) was reported at 1.1%/year based on the review. This is in line with the incidence observed following conventional chemotherapy or radiotherapy for indolent B cell lymphoma [67]. The therapeutic exposure prior to and following radioimmunoconjugate is of clear importance in determining risk. As previously stated, in those patients that have received single agent tositumomab and I 131 tositumomab as first therapy for follicular lymphoma, no tmds/taml has been reported at a median of 4.6 years [54]. HAMA may develop in response to infusion of murine protein, and are detected using an enzyme-linked immunosorbent assay. Gregory et al. report in the integrated safety population a cumulative incidence of 9.8% at 2 years and 10.1% at 5 years [68]. The majority of patients develop HAMA at or prior to their 6-month post-therapy evaluation. The frequency of HAMA development is dependent on the relative immunocompetency of the patient. The incidence in patients that have received chemotherapy prior to tositumomab and I 131 tositumomab is between 2 and 27% [28,40,42,43,45], yet following front-line therapy, HAMA are observed in 63% of patients [53]. In patients retreated, HAMA only developed in 10%. The consequence of HAMA development is unclear; response rates are not disadvantaged [45] and further treatment with rituximab is not precluded [69]. No studies have been performed to establish the impact upon gonadal function. The mutagenic properties of radiation are well-established. As I 131 is concentrated in breast milk, nursing mothers should discontinue feeding. Given the pattern of recurrence of follicular lymphoma, the impact of tositumomab and I 131 tositumomab on the ability to subsequently deliver therapy at recurrence is of importance. Multiple therapeutic modalities have been employed [45,70-72], although detailed information about tolerability is limited. 8. Expert opinion and conclusions The efficacy and safety of the non-myeloablative dose of tositumomab and I 131 tositumomab administered as the Bexxar therapeutic regimen has been established in a number of studies. Over a decade s worth of experience has been gained in its administration. Its utility in a number of clinically difficult situations, including chemotherapy-refractory, rituximabrefractory disease and transformation, adds a new player to those therapies previously available. Indeed, much has been written of the excitement afforded by its potential, although tempered by a little reserve [73-75]. The product affords the patient a good chance of achieving a CR, with many remissions proving to be durable, often in patients in whom expectations from further therapy is low. It has the advantage of being administered as a one-off and is associated with an Expert Opin. Biol. Ther. (2005) 5(4) 583

8 Tositumomab and I 131 tositumomab Table 1. Comparative toxicity of tositumomab and I 131 tositumomab across clinical studies. Study Package insert summated patient data Singlecentre Phase I/II [40] Multi-centre Phase II [42] Pivotal study [43] Tositumomab versus I 131 tositumomab [28] First or second recurrence [45] Progression after rituximab [48] Retreatment [55] Previously untreated patients [53] I 131 tositumomab arm Unlabelled tositumomab arm n Median number of prior chemotherapeutic regimens (range) Grade 3/4 neutropenia 3 3 (1 13) 4 (1 8) 4 (2 13) 2 (1 4) 2 (1 5) 1 (1 3) 4 (1 11) 2 (1 8) 0 63% 35% 33% 8% 45% 43% 44% 34% Grade 4 neutropenia 25% 20% 18% 17% 1% 20% 18% 19% 5% Median neutrophil nadir ( 10 9 /l) Grade 3/4 thrombocytopenia Grade 4 thrombocytopenia Median platelet nadir ( 10 9 /l) % 20% 33% 0% 32% 25% 38% 17% 21% 20% 22% 12% 26% 13% 10% 19% 0% Grade 3/4 anaemia 29% 5% 5% 10% 0% Grade 4 anaemia 5% 5% 0% 0% 0% Median haemoglobin nadir (g/dl) Elevated TSH * 9% (2 yr cumulative) % 2% 7% (+3% from crossover) 3% 14% (2 yr cumulative) 10% (3 yr cumulative) 11% 13% (5 yr cumulative) HAMA 11% 17% 0% (2%) 8% 27% 19% 10% 5% 10% 63% tmds/taml 8.3% 8% (@ yrs) 7% (@ yrs) 5% (1.76%/yr) 0 2% (0.8%/yr) 5% (@ yrs) 9% (4.1%/yr) 0 Data extracted from published literature. Unavailable data represented by a blank in table. Grade 3 neutropenia < /l, grade 4 < /l. Grade 3 thrombocytopenia < /l, grade 4 < /l. Grade 3 anaemia < /l and grade 4 < 6.5g/dl. *Where available data are from assessable patients not documented to have elevated TSH prior to study entry. One patient that received three doses of tositumomab became positive for HAMA. None of those patients receiving tositumomab according to protocol developed HAMA. HAMA: Human antimouse antibody; tmds/taml: Therapy-related myelodysplasia and acute myelogenous leukaemia; TSH: Thyroid-stimulating hormone. 584 Expert Opin. Biol. Ther. (2005) 5(4)

9 Davies anecdotal high degree of patient satisfaction. Short-term, non-haematological toxicity is generally well-tolerated, and the single haematological nadir encountered is well within the realms of that readily managed by the haematological oncologist. Furthermore, it is free of many of the distressing side effects of conventional chemotherapy, including mucositis and alopecia; however, careful ongoing monitoring and evaluation for the long-term toxicity is required. Where then does tositumomab and I 131 tositumomab fit in with the spectrum of other therapeutic options available for the management of follicular and other indolent lymphomas, and why have physicians been slow to embrace radioimmunotherapy more fully since it became commercially available? Indeed, sales have come at a pace too slow for Corixa to continue to support, and in December 2004 worldwide rights and responsibilities for Bexxar manufacturing, development and commercialisation were transferred to GlaxoSmithKline [76]. The answers to these questions are complex. Data supporting the initial FDA approved indication in rituximab-refractory patients has only recently been published in full. Similarly, for transformed disease, the retrospective data summated from a number of studies requires publication so that those patients that are most likely to benefit in this difficult situation may be more clearly identified, and an attempt should be made to prospectively evaluate this group of patients. Wider dissemination can only improve awareness in the oncology community and stimulate discussion. How will the recent sbla approval and expansion of indication to include relapsed or refractory patients modify demand for tositumomab and I 131 tositumomab? It is in this relapsed setting that the data are most accessible and the number of eligible patients greater. The choice of tositumomab and I 131 tositumomab at the time of recurrence, cost aside, is much dependent on the individual patient. For younger and fitter patients, pursing high-dose chemotherapy with stem cell rescue appears advantageous [77] and allogeneic transplantation strategies appear to be full of promise [78]; however, in patients that are less able or inclined to consider such approaches, tositumomab and I 131 tositumomab provides an attractive alternative to conventional chemotherapy with a high chance of entering an often durable remission. How it fairs in direct comparison against other modalities is also unknown at present. An ongoing Phase III trial is comparing tositumomab and I 131 tositumomab with rituximab for patients who have failed a minimum of three therapies. The question, however, remains should it be used at early or late recurrence given ongoing concerns about long-term toxicity? Response rates to tositumomab and I 131 tositumomab, as with chemotherapy, decline later in the disease course and adverse prognostic factors may become more apparent. What then of the compelling data arising from the pilot study of untreated patients? These results are exciting and suggest that early use may be preferable; the continued long-term follow-up of this cohort is, however, essential. In the future, sequential administration after chemotherapeutic debulking may be the favoured methodology; the results of the SWOG Phase III trial will determine whether this direction will be further pursued. The optimal timing of tositumomab and I 131 tositumomab therapy is far from clear. Such unknowns may be a barrier to wider usage. The radioimmunotherapy marketplace is further complicated by the presence of another directly competing CD20- directed radioimmunoconjugate, ytrrium-90-labelled ibritumomab tiuxetan (Zevalin, Biogen Idec, Inc.) [79-82]. The latter has the current advantage of an earlier FDA approval date and, until the recent sbla, a broader indication. Bar local experience with either product, there is little information at present to guide the physician between either product. In an FDAmandated Phase III study, tositumomab and I 131 tositumomab will compete head to head with ytrrium-90-labelled ibritumomab tiuxetan and may guide patient selection for either approach. Radioimmunotherapy must draw upon the expertise of many disciplines; coordination of these professionals to ensure appropriate selection of patients, safe dosing and administration, and appropriate post-exposure follow-up is required within the framework of a multidisciplinary team. 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