ABSTRACT We conducted a phase I/II trial of high-dose 90 Y ibritumomab tiuxetan in combination with high-dose etoposide (VP16) 40-60 mg/kg (day-4) and cyclophosphamide (CY) 100 mg/kg (day-2) followed by ASCT in 31 patients with CD 20 + NHL. Patients underwent dosimetry (day -21) with 5 mCi 111 In-ibritumomab tiuxetan following 250mg/m 2 rituximab, followed a week later by 90 Y ibritumomab tiuxetan to deliver target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day-7 to estimated radiation dose and stem cells were re-infused when radiation dose was estimated to be 500/µl and platelet>20,000/µl was 10 days and 12 days, respectively. There were two deaths and 5 relapses. At a median follow-up of 22 months, the 2-year estimated overall survival and relapse-free survival are 92% and 78%, respectively. We conclude that high-dose

PURPOSE:To determine the maximum-tolerated radiation-absorbed dose (RAD) to critical organs delivered by yttrium-90 ((90)Y) ibritumomab tiuxetan in combination with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with autologous transplantation.PATIENTS AND METHODS:Eligible patients had relapsed or refractory CD20+ non-Hodgkin's lymphoma (NHL). Individualized (90)Y activities were based on dosimetry and were calculated to deliver cohort-defined RAD (1 to 17 Gy) to critical organs with three to six patients per cohort. The therapeutic dose of (90)Y ibritumomab tiuxetan was followed by high-dose BEAM and autologous transplantation.RESULTS:Forty-four patients were treated. Thirty percent of patients had achieved less than a partial remission to their most recent therapy and would not have been eligible for autologous transplantation at most centers. The toxicity profile was similar to that associated with high-dose BEAM chemotherapy. Two dose-limiting toxicities occurred at the 17 Gy dose level, which made 15 Gy the recommended maximum-tolerated RAD. Although eight patients received at least twice the conventional dose of 0.4 mCi/kg, a weight-based strategy at 0.8 mCi/kg would have resulted in a wide range of RAD; nearly 25% of patient cases would have received 17 Gy or more, and many would have received less than 10 Gy. With a median follow-up of 33 months for all patients, the estimated 3-year progression-free and overall survivals were 43% and 60%, respectively.CONCLUSION:Dose-escalated (90)Y ibritumomab tiuxetan may be safely combined with high-dose BEAM with autologous transplantation and has the potential to be more effective than standard-dose radioimmunotherapy. Careful dosimetry is required to avoid toxicity and undertreatment.

44 patients with relapsed or refractory CD20+ NHL were enrolled on a phase I trial of dose-escalated 90YZ followed by high-dose BEAM and autotransplant in which the 90YZ dose was patient-specific based on dosimetry. 90YZ doses were calculated to deliver cohort-defined radiation doses (100–1700 cGy) to critical organs (liver, lung or kidney) with 3–6 patients per cohort. On D-22, rituximab (R) 250 mg/m2 was infused followed by 111In Zevalin®. Imaging was performed immediately and at 4, 24, 72 and 144 hours; dosimetry was performed on D-15. On D-14, R was followed immediately by 90YZ at the cohort-prescribed dose. On D-6 through D-1, patients received high-dose BEAM. On D0, a minimum of 2.0 × 106 CD 34+ cells/kg was infused and G-CSF 5 μg/kg SQ daily begun. The median age was 54 (range: 25–73) years. NHL histologic subtypes were as follows: 16% mantle cell, 57% diffuse aggressive, 11% low-grade and 16% transformed. 43% had recieved 3 or more chemotherapy regimens, and 70% had received R either alone or in combination with chemotherapy. The toxicity profile was similar to that associated with high-dose BEAM. The most common grade III/IV toxicities were infection, fever, stomatitis, nausea, vomiting, diarrhea. One patient experienced transient veno-occlusive disease at the 700 cGy dose level. Two dose-limiting toxicities occurred at the 1700 cGy dose level: one patient with grade 4 stomatitis died of pneumonia and sepsis on D+10, and one patient experienced septic emboli to the lung on D+13. Engraftment occurred at a median of 10 days (range: 8–18 ) to granulocytes ≥ 500/μL, and 21 days (range: 11–40 days) to platelets ≥20,000/μL. One heavily pretreated patient developed MDS on D+291 and expired of sepsis on D+483. With a median follow-up of 21 months, the three year overall and progression-free survivals are 52% and 37%, respectively.

We conducted a phase 1/2 trial of high-dose 90Y-ibritumomab tiuxetan in combination with high-dose etoposide (VP-16) 40 to 60 mg/kg (day -4) and cyclophosphamide 100 mg/kg (day -2) followed by autologous stem cell transplantation (ASCT) in 31 patients with CD20+ non-Hodgkin lymphoma (NHL). Patients underwent dosimetry (day -21) with 5 mCi (185 MBq) 111In-ibritumomab tiuxetan following 250 mg/m2 rituximab, followed a week later by 90Y-ibritumomab tiuxetan to deliver a target dose of 1000 cGy to highest normal organ. Bone marrow biopsy was done on day -7 to estimate radiation dose and stem cells were reinfused when the radiation dose was estimated to be less than 5 cGy. The median 90Y-ibritumomab tiuxetan dose was 71.6 mCi (2649.2 MBq; range, 36.6-105 mCi; range, 1354.2-3885 MBq). Histology included follicular lymphoma (n = 12), diffuse large B-cell (n = 14), and mantle cell (n = 5). The median number of prior chemo-therapy treatments was 2. The treatment was well tolerated. The median times to reach an absolute neutrophil count greater than 500/microL and platelet count more than 20,000/microL were 10 days and 12 days, respectively. There were 2 deaths and 5 relapses. At a median follow-up of 22 months, the 2-year estimated overall survival and relapse-free survival rates are 92% and 78%, respectively. We conclude that high-dose 90Y-ibritumomab tiuxetan can be combined safely with high-dose etoposide and cyclophosphamide without an increase in transplant-related toxicity or delayed engraftment.

The ibritumomab tiuxetan therapeutic regimen consists of a dose of rituximab, 250 mg/m(2), followed by In-111-ibritumomab tiuxetan, for imaging, on day 1 and a dose of rituximab followed by Y-90-ibritumomab tiuxetan, for therapy, on day 7, 8, or 9. Treatment with the Food and Drug Administration-approved regimen also requires that scans be performed at 2-24 h and at 48-72 In after the In-111-ibritumomab tiuxetan, with an optional third scan at 90-120 h, to confirm appropriate biodistribution. In the clinical trials before the approval of the regimen, only 1 patient (of approximately 400) was not treated with Y-90-ibritumomab tiuxetan after imaging with In-111-ibritumomab tiuxetan, because of altered biodistribution. The Zevalin Imaging Registry was established by Biogen Idec Inc. to identify cases of potential altered biodistribution and to collect clinical information in cases in which the regimen was not completed after imaging. Methods: The registry surveyed treating physicians to verify completion of treatment with the ibritumomab tiuxetan therapeutic regimen in patients treated with In-111-ibritumomab tiuxetan between March 27, 2002, and March 31, 2003. Results: Survey data were collected on 953 of an estimated 1,144-1,192 patients in whom ibritumomab tiuxetan therapy was initiated (case capture rate of 80%-83%). Thirty-eight cases were reported in which a decision not to treat was made after imaging with In-111-ibritumomab tiuxetan (4.0% of all cases captured); 16 of these were for imaging reasons, and 22 were for medical reasons. Twelve of the 16 imaging cases met the criteria for altered biodistribution (1.3%). Of these 12 cases, 6 (0.6%) were suspected to be true altered biodistribution and 6 appeared to be due to the use of a procedure for radiolabeling In-111-ibritumomab tiuxetan that differed from that in the prescribing information. All cases of altered biodistribution were seen on the first image (2-24 h) after the administration of In-111-ibritumomab tiuxetan. The 22 cases in which decisions not to treat were made for medical reasons accounted for 2.3% of the cases. The majority of these cases (19/22) were in patients who had an expected biodistribution but had a rapid change in their clinical condition that precluded treatment. Conclusion: The rate of true altered biodistribution was 0.6% in the Zevalin Imaging Registry, which collected treatment decisions based on data from approximately 80% of all patients treated commercially in the first year after drug approval. All cases of altered biodistribution were apparent on the first image, obtained at 2-24 h after the administration of In-111-ibritumomab tiuxetan.

90Y Zevalin was added to high-dose BEAM followed by autotransplant in 22 patients with relapsed or refractory CD20+ NHL with the goal of increasing progression-free and overall survival (PFS, OS). Cohorts of 3–6 patients were treated at doses calculated to result in increasing radiation exposure(100, 300, 500, 700 cGy) to the critical organ (liver, lung or kidney). On D -22, rituximab(R) 250 mg/m2 was administered followed by the imaging dose of 111In Zevalin (5 mCi). Imaging was performed immediately and at 4, 24, 72, and 144 hours post-injection; dosimetry was performed on D -15. On D -14, R at 250 mg/m2 was administered followed by 90Y Zevalin at a dose calculated to deliver the cohort-prescribed absorbed radiation dose to the critical organ. On D -6 through -1, patients received BEAM. On D 0, a minimum of 2.0 × 106 CD34+ cells/kg was infused and G-CSF 5 μg/kg SQ daily was begun. The median age was 53 (range: 25–72). 5 patients had mantle cell lymphoma, 9 had diffuse aggressive NHL, 4 had low grade NHL, and 4 had transformed NHL. The majority (55%) had received 3 or more treatment regimens. Prior therapy included R in half of all patients. 12 patients had never achieved a complete remission, and 8 had primary refractory disease. Toxicity was similar to that reported with BEAM alone and included a fall in DLCO for most patients with 1 patient experiencing a transient decline to below 50% of the predicted values corrected for hemoglobin. Grade III/IV toxicities included infection, fever, stomatitis, nausea, vomiting, diarrhea, hemorrhage, and edema. One patient at the 700 cGy level developed veno-occlusive disease which constituted a dose-limiting toxicity (maximum total bilirubin 10.4), necessitating the enrollment of 3 additional patients at that dose level. Ascites resolved by D +34, and total bilirubin was normal by D +60. At the 700 cGy level, administered radioactivities ranged from 0.27 to 0.73 mCi/kg (median: 0.37), and the total body dose from 43 to 12 cGy (median: 99 cGy). In all but one case, the critical organ was the liver. Engraftment by ABMTR criteria occurred at a median of 10 days (range: 8–18) for 1000 granulocytes and 21 days (range: 12–40) for platelet recovery to 20,000. With a median follow-up of 12 months, the OS is 60% at 3 years. PFS is 47% at both 2 and 3 years. Accrual continues at the 900 cGy dose level which is anticipated to require greater than the .4 mCi/kg dose of 90 Y Zevalin recommended for conventional treatment.

Twenty-eight patients with relapsed or refractory CD20+ NHL have been enrolled in an ongoing phase I trial of dose-escalated 90YZ followed by high-dose BEAM and autotransplant in which the 90YZ dose is patient-specific based on dosimetry. 90YZ doses are calculated to deliver cohort-defined radiation doses (100, 300, 500, ... cGy) to critical organs (liver, lung or kidney), with 3–6 patients per group. On D -22, rituximab (R) 250 mg/m2 is infused followed by the imaging dose of 111In Zevalin® (5 mCi). Imaging is performed immediately post-injection and at 4, 24, 72, and 144 hours; dosimetry is performed on D -15. On D -14, R 250 mg/m2 is administered followed immediately by 90YZ at the dose calculated to deliver the cohort-prescribed absorbed radiation dose to the critical organ. On D -6 through -1, patients receive high-dose BEAM. On D0, a minimum of 2.0 X 106 CD34+ cells/kg is infused and G-CSF 5 μg/kg SQ daily begun. The median age was 54 (range: 25–72) years. NHL histologic subtypes were as follows: mantle cell 5, diffuse aggressive 13, low grade 5, and transformed 5. Most had received 3 or more treatment regimens, including R. The toxicity profile was similar to that associated with high-dose BEAM and included a decrease in DLCO for most patients with one patient at the 500 cGy dose level experiencing a transient decline to below 50% of the predicted value corrected for hemoglobin. The most common grade III/IV toxicities were infection, fever, stomatitis, nausea, vomiting, diarrhea, hemorrhage, and edema. One patient experienced transient veno-occlusive disease at the 700 cGy dose level. Engraftment occurred at a median of 10 days (range:8–18) to granulocytes ≥ 500/μL, and 21 days (range:13–40days) to platelets ≥20,000/μL . With a median follow-up of one year, the 3 year overall and progression-free survivals are 60% and 50%, respectively.

Background: The yttrium 90 (90Y) ibritumomab tiuxetan (ZevalinÒ) therapeutic regimen consists of rituximab 250 mg/m2 on day 1 and 8, followed by indium 111 (111In) ibritumomab tiuxetan for imaging on Day 1 and 90Y ibritumomab tiuxetan for therapy on day 8. Indium 111 ibritumomab tiuxetan scans are performed as an added safety measure to ensure appropriate biodistribution of the radiolabeled antibody. Two scans are required at 2–24 hours and 48–72 hours, with an optional third scan performed at 90–120 hours after 111In ibritumomab tiuxetan. At the time of market launch, approximately 400 clinical trial patients had undergone 111In ibritumomab tiuxetan imaging (or full dosimetry) prior to receiving 90Y ibritumomab tiuxetan treatment and, of these, only 1 case did not receive treatment because of altered biodistribution. A Zevalin imaging registry was established by Biogen Idec to collect additional information on treatment decisions based on imaging results.

We report updated time-to-event variables of a phase III randomized study comparing yttrium 90–labeled ibritumomab with rituximab standard therapy in 143 rituximab-naive patients with relapsed or refractory low-grade, follicular, or transformed CD20+ non-Hodgkin's lymphoma (NHL). Most patients (79%) had follicular lymphoma. Patients were randomized to receive a single intravenous (I.V.) dose of 90Y ibritumomab tiuxetan 0.4 mCi/kg (n = 73) or rituximab 375 mg/m2 I.V. weekly for 4 doses (n = 70). The radioimmunotherapy group was pretreated with 2 rituximab doses (250 mg/m2) to improve biodistribution and one dose of Indium 111-labeled ibritumomab tiuxetan for imaging. The overall response rate was 80% versus 56% (P = 0.002) and complete response (CR)/CR unconfirmed (CRu) rates were 34% for 90Y ibritumomab tiuxetan versus 20% for rituximab. With a median follow-up of 44 months, the data are mature as all ongoing patients in both groups exceeded the median Kaplan-Meier estimated time to progression (TTP), duration of response (DR), and time to next therapy. Although this study was not powered to detect differences in time-to-event variables, the results from this randomized trial demonstrate trends toward longer median TTP (15 vs. 10.2 months; >P = 0.07), DR (16.7 vs. 11.2 months; P = 0.44) and time to next therapy (21.1 vs. 13.8 months; P = 0.27) in follicular NHL patients treated with 90Y ibritumomab tiuxetan compared with the rituximab control arm. In patients achieving a CR/CRu, the median TTP was 24.7 months for patients treated with 90Y ibritumomab tiuxetan compared with 13.2 months for rituximab-treated patients (P = 0.41), and ongoing responses of > 5 years have been observed. These results confirm that 90Y ibritumomab tiuxetan produces high response rates and durable remissions in patients with previously treated low-grade, follicular, and transformed NHL.

Immunotherapy with the anti-CD20 monoclonal antibody rituximab has been shown in clinical trials to be effective in the treatment of both indolent and aggressive non-Hodgkin's lymphomas (NHL). Recent studies have demonstrated improved clinical benefit with extended dose and maintenance therapies in patients with indolent lymphomas and chronic lymphocytic leukemia. Rituximab's label was recently expanded to include treatment of bulky disease, retreatment of patients previously treated with rituximab, and an eight-week extended treatment schedule. Rituximab has also been effectively combined with chemotherapy, resulting in higher response rates and longer response durations in randomized trials in patients with aggressive lymphoma. Studies continue to evaluate and expand the role of rituximab in the treatment of NHL, including its use in combined immunotherapy approaches and autologous stem cell transplant as well as in the treatment of autoimmune disorders. Radioimmunotherapy with the rituximab and ibritumomab tiuxetan (Zevalin) regimen was recently approved for the treatment of relapsed or refractory low-grade, follicular or CD20+ transformed NHL, including rituximab refractory follicular NHL. The regimen is delivered on an outpatient basis over the course of a week. Studies are currently exploring sequential dose therapy, radioimmunotherapy with rituximab maintenance, and ibritumomab tiuxetan radioimmunotherapy as part of autologous stem cell transplant. Current understanding of the mechanisms of action of rituximab and the use of rituximab and ibritumomab tiuxetan in patients with indolent and aggressive NHL will be discussed.

Engineering antibodies with reduced immunogenicity and enhanced effector functions, and selecting antigen targets with the appropriate specificity, density, and/or functionality, have contributed to the recent clinical successes in using unconjugated "naked" antibody therapies of B-cell lymphoma (rituximab) and breast carcinoma (Herceptin). The non-overlapping toxicities of naked antibodies and chemotherapy, together with their potential synergy, which is based on unique and complementary mechanisms of action, have contributed to the creation of new standards of care in cancer therapy and management. Clinical trial results supporting these concepts are presented. Furthermore, the exquisite specificity of antibodies renders them ideal vehicles for selective delivery of toxic payloads such as drugs or radionuclides. Although successful in therapy of hematological cancers (Zevalin, Mylotarg), the broader application of these technologies to carcinomas still remains to be proven in clinical testing. Engineering of antibody constructs with optimal blood clearance and tumor-targeting kinetics, and selecting the radionuclide that may deliver sufficient radiation energy to kill the more radio-resistant carcinomas, are discussed. With the advent of genomics and proteomics, new membrane-associated tumor antigens are being discovered and will provide novel targets for future antibody therapy of cancer.