Oncologist. The. Harnessing the Energy: Development of Radioimmunotherapy for Patients with Non-Hodgkin s Lymphoma

The Oncologist Harnessing the Energy: Development of Radioimmunotherapy for Patients with Non-Hodgkin s Lymphoma STEPHANIE A. GREGORY, a KARIN HOHLOCH, b CHRISTIAN GISSELBRECHT, c KENSEI TOBINAI, d MARTIN DREYLING e a Rush University Medical Center, Chicago, Illinois, USA; b Universitätsmedizin Göttingen, Göttingen, Germany; c Hôpital Saint-Louis, Paris, France; d National Cancer Center Hospital, Tokyo, Japan; e Klinikum der Universität München, Munich, Germany Key Words. Radioimmunotherapy Lymphoma Non-Hodgkin s lymphoma Yttrium-90-ibritumomab tiuxetan Patient selection Iodine-131-tositumomab Disclosures: Stephanie A. Gregory: Honoraria: GlaxoSmithKline, Genentech; Karin Hohloch: None; Christian Gisselbrecht: Research funding/contracted research: Bayer Schering Pharma; Kensei Tobinai: None; Martin Dreyling: Honoraria: Roche, Bayer, Schering; Research funding/contracted research: Roche, Bayer, Schering. This article discusses 90 Y-ibritumomab tiuxetan (Bayer Schering Pharma AG, Spectrum Pharmaceuticals, Inc.), a radioimmunotherapeutic agent, to minimize the systemic effects of radiation, as therapy in NHL patients with relapsed low-grade NHL and for consolidation therapy after frontline chemotherapy. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers. ABSTRACT Radioimmunotherapy (RIT) combines the use of targeted monoclonal antibodies with radionuclides for the treatment of non-hodgkin s lymphoma (NHL), taking advantage of its inherent radiosensitivity. A number of trials have shown significantly higher response rates and longer progression-free survival times in patients treated with the CD20-targeted radioimmunoconjugate yttrium-90-ibritumomab tiuxetan compared with the standard of care. Furthermore, these benefits have also been shown in heavily pretreated patients who relapsed or were resistant to rituximab. Currently, a number of different treatment regimens and strategies are available for the treatment of NHL patients. Therefore, in an attempt to minimize toxicity, maximize efficacy, and improve survival, it is crucial to appropriately select patients who are good candidates for individual treatment approaches. A strategy for patient selection has been developed, including the use of existing patient assessment tools, such as the Follicular Lymphoma International Prognostic Index, to determine the optimal regimen for patients with follicular lymphoma according to their disease characteristics and physical condition. Patients who are fit make ideal candidates for potentially curative regimens, which include induction chemotherapy with or without immunotherapy followed by RIT consolidation and, potentially, maintenance therapy. Patients who are considered compromised would also benefit from induction treatment and RIT consolidation, with a view to reducing the lymphoma burden and decreasing the risk for disease progression. Frail patients would be better suited to supportive therapy to control symptoms. This paper explores factors that should be considered when assessing Correspondence: Stephanie A. Gregory, M.D., Section of Hematology, Rush University Medical Center/Rush University, 1725 West Harrison Street, Suite 834, Chicago, Illinois 60612, USA. Telephone: 312-942-5982; Fax: 312-563-4101; e-mail: stephanie_ gregory@rush.edu Received March 27, 2009; accepted for publication July 6, 2009. AlphaMed Press 1083-7159/2009/$30.00/0 doi: 10.1634/theoncologist.2009-S2-4 The Oncologist 2009;14(suppl 2):4 16 www.theoncologist.com

Gregory, Hohloch, Gisselbrecht 5 whether a patient is a good candidate for treatment with RIT, and aids physicians in the selection of the most appropriate therapy for each patient group. The Oncologist 2009;14(suppl 2):4 16 BASIC PRINCIPLES OF RADIOIMMUNOTHERAPY Monoclonal Antibodies: A Targeted Approach The B-cell antigen CD20 provides an excellent immunotherapeutic target for non-hodgkin s lymphoma (NHL) because of its expression patterns [1, 2]. Over 90% of B-cell tumors express CD20, and it is present exclusively on mature B cells and is further amplified in malignant B cells [3]. CD20 is absent from hematopoietic stem cells, pro-b-cells, and normal plasma cells, and does not accumulate as a free protein [3]. Furthermore, when bound by anti-cd20 antibody, CD20 does not shed from the cell surface [4]. The use of targeted monoclonal antibodies in the treatment of cancer has become more prevalent over the last decade. The most widely used antibody, rituximab, is a CD20- targeted monoclonal antibody used as a single agent and in combination therapy in both follicular and relapsed indolent NHL. Monotherapy is often used in patients with a low tumor burden [5, 6]. Rituximab is also often combined with chemotherapy to treat several hematologic malignancies, including low-grade lymphomas, follicular lymphoma (FL), and more aggressive lymphomas [7 9]. Rituximab is indicated for the treatment of patients with: relapsed or refractory low-grade or follicular NHL; nonprogressing low-grade NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; previously untreated follicular B-cell NHL in combination with CVP; and previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens [10]. Rituximab-CHOP (R- CHOP) and rituximab-cvp have been demonstrated to produce superior outcomes in several trials, yielding overall response rates (ORRs) of 80% 95% and longer survival times in low-grade FL and aggressive NHL [7 9]. The superior survival outcomes have been attributed to higher complete response (CR) rates, which are higher in patients with aggressive NHL who receive the R-CHOP combination relative to treatment with chemotherapy alone (76% versus 63%; p.005), as is the 2-year overall survival (OS) rate (70% versus 57%; p.001) [9]. Monoclonal antibodies are also used effectively to treat solid tumors. Radioimmunotherapy for NHL Monoclonal antibodies can be conjugated with radionuclides, becoming radioimmunotherapy (RIT), which harnesses the targeted activity of the antibody to directly deliver radiation to destroy neoplastic cells at the tumor site, unlike the more diffuse delivery historically employed with conventional radiotherapy. This combination of the biologic and radiolytic mechanisms of action is ideal for the treatment of poorly vascularized or bulky tumors, because malignant cells not directly accessible to the monoclonal antibody are still affected by the ionizing radiation of the radionuclide [11]. This crossfire effect of targeting radiation to tumor cells expressing a particular antigen is particularly useful, because with RIT a lower overall dose of radiation is necessary, thus limiting whole-body exposure to radiation and minimizing toxicity to normal cells and organs [12]. A number of factors contribute to the effectiveness of RIT, including the target antigen, specific radionuclide emission properties, and the chemical stability of radioimmunoconjugates [11]. Furthermore, as lymphomas are inherently radiosensitive, CD20-targeted RIT is a promising treatment option for this tumor type [13 15]. Current RIT Treatment Options A crucial consideration that dramatically affects the outcome of treatment with RIT is the choice of radionuclide to be conjugated with the chosen monoclonal antibody. The radioimmunoconjugate iodine-131 ( 131 I)-tositumomab (Bexxar ; GlaxoSmithKline, Research Triangle Park, NC) consists of the murine IgG 2a monoclonal antibody directed against the CD20 antigen covalently linked to 131 I. Although radioiodinated ( 131 I) antibodies are used for the treatment of B-cell lymphomas, their long half-life and the possibility of separation from the antibody can lead to rapid excretion or accumulation in the thyroid, or both [16 18]. The nature of the emissions of 131 I means the same agent can be used for both imaging and therapeutic purposes. Therefore, shielding, careful disposal of bodily fluids, and, in some cases, hospitalization are necessary precautions with any treatment containing 131 I. An alternative radionuclide is the radiometal yttrium-90 ( 90 Y), which emits radiation. It has been reported that radioimmunoconjugates containing 90 Y deliver radioactivity to tumors more effectively than 131 I and are associated with a better therapeutic index [19, 20]. Another advantage of 90 Y is the minimal risk for exposure, because of its emission of pure radiation. As metals cannot be directly incorporated into antibod- www.theoncologist.com

6 Radioimmunotherapy for NHL Patients Figure 1. Yttrium-90 ( 90 Y)-ibritumomab tiuxetan binding to a B cell via the CD20 antigen. ies, chelator linkers have been developed, such as MX- DTPA (tiuxetan), which forms a stable chelate of radionuclide and antibody without compromising antibody specificity, altering the metabolism of the complex, or allowing measurable elution of 90 Y [21, 22]. Tiuxetan strongly chelates 90 Y and covalently binds to the IgG 1 anti-cd20 monoclonal antibody ibritumomab, forming the therapeutic radioimmunoconjugate 90 Y-ibritumomab tiuxetan (Zevalin ; Spectrum Pharmaceuticals, Inc., Irvine, CA; Bayer Schering Pharma AG, Berlin, Germany) (Fig. 1) [4]. For imaging purposes, indium-111 ( 111 In), a emitter, is used as a substitute for 90 Y [23, 24]. Ibritumomab is the parent murine antibody from which the chimeric murine and human monoclonal antibody rituximab is derived [11]. Both ibritumomab and rituximab target the CD20 antigen found on B cells [25] and have been shown to have antiproliferative and proapoptotic effects in vitro [26]. Patients treated with radiation emitted by 90 Y-ibritumomab tiuxetan (half-life, 64 hours) do not need to be isolated [27] and can be treated in an outpatient setting [28]. Key differences between 90 Y-ibritumomab tiuxetan and 131 I-tositumomab are highlighted in Table 1. INDICATIONS FOR RIT Relapsed or Refractory Low-Grade or Follicular B-Cell NHL The initial U.S. indication for 90 Y-ibritumomab tiuxetan, the first RIT approved by the U.S. Food and Drug Administration (FDA), is for the treatment of patients with relapsed or refractory low-grade or follicular B-cell NHL, and for those with FL refractory to rituximab. This indication is supported by a number of clinical trials that have been performed in patients with NHL. A phase I/II trial compared two dose levels of rituximab (100 mg/m 2 and 250 mg/m 2 ) followed by 90 Y-ibritumomab tiuxetan (three dose levels: 0.2 mci/kg, 0.3 mci/kg, and 0.4 mci/kg) in patients with relapsed or refractory CD20 B- cell, low- or intermediate-grade NHL or mantle cell lymphoma to determine the maximum-tolerated dose (MTD) and evaluate safety and efficacy [29]. All patients had received prior chemotherapy, with a median of two prior regimens (range, 1 7), and 47 (92%) had received prior anthracyclines. The MTD of 90 Y-ibritumomab tiuxetan was found to be 0.4 mci/kg, or 0.3 mci/kg for patients with baseline platelet counts of 100,000 149,000/ l. A larger phase III trial was performed in a similar patient group to assess the ORR using an independent, blinded, lymphoma expert panel [30]. Patients were treated with either four doses of rituximab (375 mg/m 2 ) weekly (n 70) or a single dose of 90 Y-ibritumomab tiuxetan (0.4 mci/kg) preceded by two doses of rituximab (250 mg/m 2 ) and one dose of 111 In-ibritumomab tiuxetan for imaging and dosimetry (n 73). An ORR of 80% was observed for those treated with RIT, compared with 56% for those who received rituximab alone (p.002), with CR rates of 30% and 16%, respectively (p.04). The median duration of response was 14.2 months in the RIT group, versus 12.1 months in the rituximab group (p.6), although the rates of durable responses 6 months were 64% and 47%, respectively (p.030). The most frequent adverse event (AE) associated with RIT was reversible myelosuppression, with median durations of 27 days (absolute neutrophil count), 23 days (platelets), and 15 days (hemoglobin). A

Gregory, Hohloch, Gisselbrecht 7 Table 1. Key differences between 90-Y ibritumomab tiuxetan and 131-I tositumomab Properties 90-Y ibritumomab tiuxetan 131-I tositumomab Specific targeting Malignant and non-malignant CD20-positive B cells Malignant and non-malignant CD20-positive B-cells Radiation Pure beta emitter Gamma and beta emitter Physical properties Rapid radioactive Decays to produce both beta and gamma emissions decay to 90-Zr, a stable and nontoxic daughter product Half-life 64 hours 8 days Energy 2.3 MeV Principal beta emission: 2.9 MeV Principal gamma emission: 364.5 kev Treatment regimen Dosing Stability Single dose, combined with rituximab preinfusions; typically completed within 1 week Optimal dose is based on patient s baseline platelet count and body weight Stable at 4 C for 48 hours Single dose, combined with tositumomab pre-infusion, completed within 7 14 days Gamma scans are helpful for dosimetry Dose to deliver 65 75 cgy total-body dose, based on clearance of tositumomab from patient (specific dosimetry) Stable at 2 8 C for 8 hours In vitro Therapeutic response Witzig 2002 30 Wiseman 2002 32 Horning 2005 35 Kaminski 2001 36 Complete response 30% 37% 38% 20% Overall response rate 80% 83% 65% 65% Adverse events Safety 12.6 months a 14.2 months b 10.4 months (24.5 months for responders, not reached for complete responders) Moderate hematologic toxicity that usually recovers by 13 weeks No isolation needed, hospitalbased outpatient therapy is feasible Bodily fluids may be radioactive Moderate hematologic toxicity that usually recovers by 13 weeks Lead shielding for handling is required Most US states allow for outpatient treatment. Radiation safety (keep away from children and pregnant women; separate eating utensils and sleeping in a separate bed) should be followed for 1 week after therapeutic dose 8.4 months (for responders, median duration of response 47 months for complete responders) (continued) www.theoncologist.com

8 Radioimmunotherapy for NHL Patients Table 1. (Continued) Properties 90-Y ibritumomab tiuxetan 131-I tositumomab Contraindicated for use in pregnancy Subsequent therapy Most common subsequent therapies are rituximab monotherapy, rituximab plus chemotherapy, and rarely stem cell transplantation Subsequent therapy has been well tolerated with good responses, including some patients with stem cell transplants a Median duration of response; b Median time to progression. study of long-term responders from four clinical trials of patients with relapsed or refractory NHL who were treated with 90 Y-ibritumomab tiuxetan demonstrated that 60% of CR patients achieved long-term remissions lasting 24 months, suggesting that the achievement of a CR may be used as a surrogate marker for achieving long-lasting remissions [31]. Using the reduced dose of 0.3 mci/kg, 90 Y-ibritumomab tiuxetan was investigated in 30 mildly thrombocytopenic (100,000 149,000 platelets/ l) patients with relapsed or refractory low-grade NHL [32]. Although estimated radiation rates were well below the study-defined maximums ( 2,000 cgy for uninvolved major organs and 300 cgy for red marrow), the ORR was 83% (CR rate, 37%) in the intent-to-treat population, and a median time to progression of 12.6 months was observed in the 25 responders [32]. Although a dose-reduction rule was included in the study profile, no patients required a reduction because no toxicity crossed the threshold of the protocol-defined limit. The safety data from the main 90 Y-ibritumomab tiuxetan clinical trials, which included 349 patients, were analyzed for FDA approval [11, 33]. Infusion reactions, an AE associated with rituximab, were typically grade 1 or 2. AEs were primarily hematologic in nature, with grade 2 neutropenia, thrombocytopenia, and anemia observed in 30%, 10%, and 3% of patients, respectively, following use of the 0.4 mci/kg dose, with nadirs occurring at 7 9 weeks [11, Contraindicated for use in pregnancy due to potential harm to the fetal thyroid gland Most common subsequent therapies are rituximab monotherapy, rituximab plus chemotherapy, and rarely stem cell transplantation Subsequent therapy has been well tolerated with good responses, including some patients with stem cell transplants 33]. However, only 7% of patients were hospitalized because of infection (3% with neutropenia), possibly reflecting the low incidence ( 1%) of mucositis associated with this regimen [11, 33]. Only 2% of patients experienced grade 3 or 4 bleeding events. The risk for hematologic toxicity was higher with higher baseline bone marrow involvement with NHL. It was concluded that the safety profile of single-dose 90 Y-ibritumomab tiuxetan RIT is appropriate in patients with relapsed NHL and 25% lymphoma marrow involvement, adequate marrow reserve, platelets 100,000/ l, and neutrophils 1,500/ l [11, 33]. Isolation and shielding are not necessary for patients treated with 90 Y-ibritumomab tiuxetan, although contact with the patient s bodily fluids should be avoided [11]. AEs such as hair loss, nausea and vomiting, cardiotoxicity, nephrotoxicity, and neurotoxicity, associated with systemic chemotherapies for the treatment of NHL, are not associated with RIT using 90 Y-ibritumomab tiuxetan [11]. Although patient management strategies differ depending on the properties attributed to the radiolabeled nucleotide, the efficacy of the two RIT agents remains consistent. The radioimmunoconjugate 131 I-tositumomab is indicated for the treatment of patients with relapsed or refractory lowgrade, follicular, or transformed NHL, including patients with rituximab-refractory NHL. A study of 131 I-tositumomab in 59 patients with relapsed or refractory B-cell NHL showed an ORR of 83% in patients with low-grade or

Gregory, Hohloch, Gisselbrecht 9 transformed NHL and 43% in patients with aggressive NHL [34]. The median progression-free survival (PFS) time was 12 months for responders and 20.3 months for complete responders. A further trial of tositumomab and 131 I-tositumomab in 40 patients with indolent (5%), follicular (70%), or transformed B-cell (25%) lymphoma, progressive after rituximab therapy, gave a confirmed ORR of 65% and CR rate of 38%, which were not significantly associated with prior response to rituximab [35]. After a median follow-up of 3.3 years, the median PFS time was 24.5 months for responders, compared with 10.4 months overall. Furthermore, the median PFS time was not reached for patients who experienced a CR. Although 50% of patients experienced transient grade 3 4 marrow toxicity, the regimen was generally well tolerated. A pivotal registration trial of 131 I-tositumomab in 60 heavily pretreated (but rituximab-naïve) patients with lowgrade (60%) or transformed (38%) lymphoma showed a response rate of 65% and an acceptable safety profile [36]. Compared with the last qualifying chemotherapy regimens, the comparator in this trial, 131 I-tositumomab, was associated with a significantly greater median duration of response (3.4 months versus 6.5 months; p.001), and in the small subset of patients with a CR (20%), the median duration of response had not been reached after a median follow-up of 47 months. In a trial of 131 I-tositumomab in patients with previously untreated FL, 95% of the patients responded to therapy, with a CR rate of 75% [37]. After a median follow-up of 8 years, the overall 8-year PFS rate was 50%, compared with 64% for patients who achieved a CR [38]. Hematologic toxicity was common in the study, but usually of moderate intensity [39]. RIT Consolidation After First Remission Recently, the European label for 90 Y ibritumomab tiuxetan was expanded to include consolidation therapy after remission induction in previously untreated patients with FL. The updated indication was based on new data from a randomized phase III study of consolidation with 90 Y-ibritumomab tiuxetan after first-line induction chemotherapy in patients with advanced-stage FL. Although many randomized controlled trials of rituximab added to chemotherapy in the treatment of NHL have since been published documenting superior outcomes associated with the addition of rituximab [40], this trial was designed prior to the widespread use of rituximab plus chemotherapy for FL. Therefore, patients generally received first-line induction chemotherapy without rituximab in most cases. Although a few patients did receive rituximab plus chemotherapy (15.6% in the control arm and 13.2% in the consolidation arm), the impact of consolidating more aggressive induction therapy (rituximab www.theoncologist.com plus chemotherapy) cannot currently be compared. However, follow-up is ongoing in these patients. Results from this trial showed a 2 years longer PFS duration and an unprecedented rate of conversion from partial response (PR) to CR as a result of consolidation with 90 Y-ibritumomab tiuxetan [41, 42]. Patients who had previously achieved a CR or PR following first-line induction therapy (n 409) were randomized to receive either consolidation (rituximab, 250 mg/m 2 on day 7 and day 0 plus 90 Y-ibritumomab tiuxetan, 14.8 MBq/kg on day 0; n 202) or no further therapy (n 207). A significantly prolonged PFS time was observed with consolidation than with control therapy (54 versus 14 months; p.0001), regardless of whether patients achieved a PR (29.6 versus 6.7 months; p.001) or CR/unconfirmed CR ( 67 versus 30.5 months; p.015) after induction treatment [42]. Of the patients who achieved a PR after induction treatment, 77% were converted to CR/unconfirmed CR after consolidation treatment, with a final CR rate of 87% [41]. Because the median OS duration for FL is typically 8 10 years [43, 44], it is not surprising that no significant difference in terms of OS has yet emerged between the two treatment groups. The tolerability profile was similar to that observed in the previous trials, with no unexpected toxicities [41]. Consolidation with 131 I-tositumomab therapy following CHOP chemotherapy was also studied in 60 patients with previously untreated advanced FL [45, 46]. With an ORR of 91%, including a 69% CR rate and a 57% conversion rate from non-cr following RIT, the estimated 5-year OS rate was 87%, whereas the estimated 5-year PFS rate was 67% [46]. In a further phase II study in 30 patients with previously untreated FL, CVP chemotherapy resulted in an ORR of 100% (CR rate, 50%), and following consolidation with 131 I-tositumomab RIT, a further 30% achieved a CR [47]. For further information regarding the use of RIT consolidation therapy, see Morschhauser et al. [48]. There is also significant clinical interest in the use of rituximab maintenance following induction therapy for FL. A recent meta-analysis regarding the use of rituximab maintenance for the treatment of patients with FL showed a survival benefit in patients with refractory or relapsed FL, although no clear benefit was observed in previously untreated patients [49]. Data from the Primary Rituximab and Maintenance (PRIMA) study, of first-line rituximab plus chemotherapy with or without rituximab maintenance in patients with advanced FL, are eagerly awaited to clarify this [50]. Once the role of rituximab maintenance has been ascertained, the potential use of rituximab maintenance following RIT consolidation should also be assessed. To date, one trial of 20 previously untreated patients with FL receiving chemotherapy and RIT induction with 90 Y-ibritu-

10 Radioimmunotherapy for NHL Patients momab tiuxetan followed by rituximab maintenance has shown encouraging response rates, although longer follow-up is needed to evaluate any survival benefit [51]. In order to learn more about real-life patients receiving RIT outside the clinical trial setting, the international RIT network was launched in 2006 to collect data from many countries. By January 2008, 579 patients had been entered [52]. As expected, the majority of patients in this database have FL (62%); however, patients with diffuse large B-cell lymphoma (15%) and mantle cell lymphoma (12%) are also receiving RIT in real-life clinical practice. We await further analyses of outcomes and toxicity with interest, because these will further help to guide new clinical trials and clinical practice. ADMINISTRATION OF RIT Prior to treatment with 90 Y-ibritumomab tiuxetan, patients receive rituximab as an unlabeled pretreatment antibody on day 1 of the therapeutic regimen. The use of rituximab as a pretreatment antibody increases radioantibody biodistribution by binding to the CD20 antigen on non-specific binding sites such as circulating and splenic B cells, thus enhancing tumor targeting [11]. As part of the RIT regimen in the U.S. and Switzerland, a 5-mCi (185-MBq) injection of 111 In-labeled ibritumomab tiuxetan is administered prior to 90 Y-ibritumomab tiuxetan to assess biodistribution before the therapeutic dose. This occurs 4 hours after the 250-mg/m 2 infusion of rituximab. A visual evaluation of whole-body, planar-view, anterior, and posterior gamma images are then performed at 2 24 hours (scan 1) and 48 72 hours (scan 2) after injection of the imaging dose [11]. If there are any ambiguities, a third scan can be performed at 90 120 hours [23, 24, 53]. It is expected that, in the first scan, RIT will be easily detectable in the blood pool areas, but this will become less in later images. Low uptake is expected in the lungs, kidneys, and urinary bladder, with higher uptake expected in the normal liver and spleen [11]. Visualization of the tumor is not a criterion for proceeding to the active therapy, although if the images reveal altered biodistribution, the patient will not receive the therapeutic dose. Altered biodistribution includes a failure to visualize the blood pool on the first image, which possibly indicates rapid clearance of the radionuclide, or diffuse uptake in the normal lungs or kidneys becoming more intense in the liver on the second or third image [11]. Data from phase I and II clinical trials were used to determine the optimal therapeutic dose of 90 Y-ibritumomab tiuxetan, and the nonmyeloablative MTD was identified as 0.4 mci/kg (15 MBq/kg), to a maximum of 32 mci (1.2 GBq), in patients with baseline platelet counts 150,000/ l [11, 29]. The therapeutic dose is adjusted to 0.3 mci/kg (11 MBq/kg), to a maximum of 32 mci (1.2 GBq), for patients with mild thrombocytopenia at baseline (platelet count, 100,000 149,000/ l), because baseline thrombocytopenia indicates reduced marrow reserves and can indicate severe cytopenia [11, 29, 32, 54, 55]. Therapeutic injections of 90 Y-ibritumomab tiuxetan are administered on days 7 9 of the regimen, along with a second infusion of rituximab (250 mg/m 2 ) [11]. Dosimetry studies have been used to estimate the radiation-absorbed doses by individual organs, helping to determine whether a patient can be treated safely, and by the tumor, helping to predict the therapeutic value of RIT. Estimates of radiation-absorbed doses were obtained using blood sampling data and quantitative imaging with 111 Inibritumomab tiuxetan [11, 56 61]. These studies found that the estimated radiation-absorbed doses to normal organs are substantially below recognized upper safety limits ( 2,000 cgy for normal organs and 300 cgy for red marrow) and do not correlate with hematologic toxicity [60]. Therefore, dosimetric calculations are not mandatory for all patients [4]. SELECTING PATIENTS FOR RIT A number of clinical criteria should be considered when assessing the suitability of patients for RIT, which is critical to ensure that the efficacy and safety of RIT are optimized [62]. Prior hypersensitivities to murine antibodies or other components of the regimen, such as rituximab, yttrium chloride, or tositumomab, are contraindications for RIT, as are bone marrow transplants [4]. Although the use of RIT is also contraindicated in patients who have had prior stem cell transplants because of the higher increased risk for hematologic complications potentially associated with compromised bone marrow function, preliminary studies indicate that RIT at a reduced dose may be well tolerated with potential efficacy benefit for patients who relapse following stem cell transplants, although further study is needed to verify this [63 65]. Because of the risk for hematologic toxicity, RIT is also contraindicated in patients whose: platelet count is 100,000/ l and/or neutrophil count is 1.5 10 3 / l; bone marrow exhibits hypocellularity ( 15%), reduction in bone marrow precursors, or a history of failed stem cell collection; or lymphoma cells comprise 25% of the bone marrow [4, 62, 66]. However, patients with mild thrombocytopenia (platelet count, 100,000 149,000/ l) can receive a reduced dose of 90 Y- ibritumomab tiuxetan [33]. A recent meta-analysis demonstrated that the response rate, duration of response, and safety profile of 90 Y-ibritumomab tiuxetan in elderly patients ( 70 years) were similar to those of younger pa-

Gregory, Hohloch, Gisselbrecht 11 Patient selection checklist Patients should be considered for radioimmunotherapy (RIT) if they have one of the following: 1. Previously untreated follicular lymphoma (FL) after remission induction a 2. Relapsed or refractory low-grade FL 3. FL refractory to rituximab or prior chemotherapy or radiotherapy regimens The following patients are suitable for RIT: Adults ( 18 years), including the elderly Any weight, including obese patients Any performance status, including those with compromised performance status or high-risk International Prognostic Index Comorbidities: Charleston Score Any serum lactate dehydrogenase, including high levels No prior stem cell or bone marrow transplants No prior history of failed stem cell collection No prior hypersensitivities to murine antibodies or rituximab or yttrium chloride Platelet count 100,000/µl and/or neutrophil count 1.5 103/µl Bone marrow cellularity >15% Lymphoma cells comprising <25% of bone marrow a Approved in the European Union only Figure 2. Checklist for selecting patients for radioimmunotherapy. tients [67]. Therefore, elderly patients with comorbid conditions are ideal candidates for RIT. Indeed, in the RIT patient registry, the highest proportion of patients was in the 60- to 70-year age group, and 64 patients aged 70 years had received RIT. Response to 90 Y-ibritumomab tiuxetan has been observed in patients with both good and poor prognostic factors, and good candidates for treatment include patients with compromised performance status or high-risk International Prognostic Index, high tumor burden, high serum lactate dehydrogenase, and disease resistant to prior chemotherapy or radiotherapy regimens [30, 33, 62, 68]. Because bulky disease ( 10 cm) is less responsive to RIT, chemotherapy is often used to debulk the disease prior to treatment. Furthermore, obesity is not a contraindication. A checklist of factors to consider when selecting patients for RIT with 90 Y-ibritumomab tiuxetan is given in Figure 2. The Follicular Lymphoma International Prognostic Index (FLIPI) to define patients as low, intermediate, or high risk is outlined in Table 2 and is useful for evaluating patients and determining the most appropriate treatments [69]. FLIPI is widely used in the U.S. and Europe to guide Table 2. Follicular Lymphoma International Prognostic Index scores 68 Parameter High risk Low risk Age 60 years 60 years Ann Arbor stage III IV I II Hemoglobin level 120 g/l 120 g/l Number of modal sites 4 4 Serum lactate dehydrogenase level normal normal Three risk groups have been defined according to the number of parameters in the high-risk category that the patient falls into: low risk (0 1 adverse factor). intermediate risk (2 factors). poor risk ( 3 factors). treatment decisions, and patients in all risk categories could be suitable for RIT, although some patients may benefit more than others. Indeed, although all patients in the randomized phase III First-line Indolent Trial showed a PFS benefit with RIT consolidation regardless of FLIPI category, patients in the FLIPI intermediate-risk category expe- www.theoncologist.com

12 Radioimmunotherapy for NHL Patients Assess patient Fit patient Compromised patient Frail patient Organ function Functional status Life expectancy Comorbidities Risk for toxicity Organ function Functional status Life expectancy Comorbidities Risk for toxicity Organ function Functional status Life expectancy Comorbidities Risk for toxicity Aim for long-term remission and maximal CR rates Intensive induction therapy RIT consolidation (rituximab maintenance) rienced a significantly longer PFS time (53.9 versus 11.3 months; p.0001) [41]. INDIVIDUAL TREATMENT STRATEGIES FOR PATIENTS WITH ADVANCED FL Although a wide variety of patients are eligible for RIT with 90 Y-ibritumomab tiuxetan, different treatment strategies could be used to optimize results. Patients with a good performance/functional status, good organ function, good life expectancy, few comorbidities, high tumor burden, intermediate/high FLIPI score, and a low risk for toxicity can be classed as medically fit. It is feasible to aim to achieve a cure in such patients using a more aggressive therapeutic strategy that will maximize responses and minimize the level of residual disease. Therefore, it may be possible to treat such patients with an induction regimen consisting of high-dose immunochemotherapy followed by consolidation of remission with RIT, and then maintain the maximum response achieved with induction and consolidation with a rituximab maintenance regimen. Trials are currently under Aim to reduce tumor burden, maximize responses, and manage toxicity R-CHOP induction RIT consolidation Potentially - mini-chop/r-chop - rituximab maintenance - single-agent RIT CR, complete response; R-CHOP, rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone; RIT, radioimmunotherapy Figure 3. Algorithm for patient selection. Aim to control symptoms and manage toxicity Supportive chemotherapy Discuss nonchemotherapycontaining options with favorable tolerability way to evaluate such a regimen. However, preliminary data on such an approach were recently published by Jacobs et al. [70], with a three-cycle R-CHOP induction regimen followed by consolidation and four cycles of maintenance. The optimal maintenance schedule is still to be defined and the benefit of adding rituximab maintenance after a firstline rituximab-based combination is currently being investigated in a large phase III trial. Compromised patients can be classed as those with lower organ function and performance status, a medium life expectancy, more comorbidities, and a higher risk for toxicity. These patients would benefit from less intensive therapy aimed at reducing the burden of lymphoma, such as a regimen including induction treatment with R-CHOP immunochemotherapy (4 weeks of rituximab, 375 mg/m 2 weekly infusions, followed by three cycles of standard R-CHOP) and consolidation with RIT [71] or three cycles of standard R-CHOP before RIT, followed by four weekly 375-mg/m 2 rituximab treatments as consolidation therapy [70]. Frail patients, or those with severely compromised or-

Gregory, Hohloch, Gisselbrecht 13 Figure 4. Patient X scans. Abbreviations: CT, computed tomography; LAD, lymphadenopathy; PET, positron emission tomography; RIT, radioimmunotherapy. gan function and performance status, low life expectancy, many comorbidities, and a high risk for toxicity, would be better suited to a more supportive regimen aimed at controlling symptoms. There are currently some preliminary data suggesting that another option to limit toxicity could be to treat with RIT alone, without induction chemotherapy, because RIT has a very manageable tolerability profile and is not associated with much of the toxicity attributed to the intensive chemotherapy regimen [72]. The overall aim of developing patient classifications in www.theoncologist.com

14 Radioimmunotherapy for NHL Patients this way is to enable physicians to make individualized and specific treatment decisions in an effort to optimize survival outcomes for all patients. For our suggested treatment algorithm for patient selection, see Figure 3. A randomized trial is warranted to thoroughly test these principles and elucidate the most appropriate therapeutic approaches for patients with advanced FL. Currently, a wide variety of trials of 90 Y-ibritumomab tiuxetan are either recruiting or ongoing, in a number of different patient groups and clinical settings. CASE STUDY Patient X had reported lymphadenopathy (LAD) since 1996, and recurrent biopsies revealed follicular hyperplasia and a virulent Epstein-Barr virus infection. In 2005, the patient developed night sweats and inguinal and axillary adenopathy. Extensive LAD of the neck, chest, abdomen, and pelvis showed bulky abdominal disease (5.2 8.3 cm) (Fig. 4). An axillary lymph node biopsy led to a diagnosis of grade 1 follicular NHL, and a bone marrow biopsy showed extensive (80%) infiltration. The patient was enrolled in the FavId vaccine trial (Favrille, Inc., San Diego, CA) and was randomized to receive 4 weeks of rituximab, 26 weeks of rest, and the patient s own vaccine versus the keyhole limpet hemocyanin vaccine. Following the 4 weeks of rituximab, the patient experienced very little decrease in adenopathy. Furthermore, progressive neck adenopathy was observed following the 26 weeks of rest. Repeat computed tomography (CT) scans 4 weeks postrituximab demonstrated progressive disease. The patient entered a second clinical trial for relapsed disease, receiving four cycles of rituximab-fludarabine/mitoxantrone therapy; a restaging CT scan following this showed a marked improvement. At this stage, the bone marrow biopsy was also negative. The patient was therefore eligible to receive 90 Y-ibritumomab tiuxetan consolidation therapy. Restaging positron emission tomography scans following consolidation therapy were negative. The patient remains in complete remission 2 years following 90 Y-ibritumomab tiuxetan consolidation. CONCLUSIONS The favorable efficacy and tolerability profile of RIT makes it a promising option for patients with relapsed FL and transformed NHL. Furthermore, the recent approval of 90 Y- ibritumomab tiuxetan for first-line consolidation treatment of FL gives another option for these patients. In light of these data, it seems reasonable to propose the use of 90 Y- ibritumomab tiuxetan consolidation therapy after first remission as part of a curative strategy in an effort to improve CR rates and potentially improve OS. Indeed, the recent European Society for Medical Oncology guidelines have recommended the use of 90 Y-ibritumomab tiuxetan in frontline consolidation regimens [73, 74]. Although the wide variability among patients with NHL can mean that identifying the most suitable therapy is sometimes difficult, the suggested treatment algorithm in this paper may aid in the appropriate selection of patients who could benefit from consolidation therapy with 90 Y-ibritumomab tiuxetan. It is interesting to note that recent guidelines on the use of RIT recommend that RIT be used for fit patients for whom a curative approach and significant improvement in OS are both a possibility [74, 75]. The use of RIT may provide benefit to a wide range of patients within a variety of treatment regimens, and the guidance provided in this review can aid physicians in appropriate patient selection for treatment with 90 Y-ibritumomab tiuxetan. AUTHOR CONTRIBUTIONS Conception/design: Stephanie A. Gregory, Karin Hohloch, Kensei Tobinai, Martin Dreyling Provision of study materials or patients: Stephanie A. Gregory, Christian Gisselbrecht Collection/assembly of data: Stephanie A. 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