90Y Ibritumomab Tiuxetan Research Articles

86Y Based PET Radiopharmaceuticals: Radiochemistry and Biological Applications

Development of targeted radionuclide therapy with (90)Y labeled antibodies and peptides has gained momentum in the past decade due to the successes of (90)Y-ibritumomab tiuxetan and (90)Y-DOTA-Phe(1)-Tyr(3)-octreotide in treatment of cancer. (90)Y is a pure β(-)-emitter and cannot be imaged for patient-specific dosimetry which is essential for pre-therapeutic treatment planning and accurate absorbed dose estimation in individual patients to mitigate radiation related risks. This review article describes the utility of (86)Y, a positron emitter (33%) with a 14.7-h half-life that can be imaged by positron emission tomography and used as an isotopically matched surrogate radionuclide for (90)Y radiation doses estimations. This review discusses various aspects involved in the development of (86)Y labeled radiopharmaceuticals with the specific emphasis on the radiochemistry and biological applications with antibodies and peptides.

90Y-Ibritumomab tiuxetan, fludarabine, and TBI-based nonmyeloablative allogeneic transplantation conditioning for patients with persistent high-risk B-cell lymphoma

AbstractNonmyeloablative allogeneic transplantation (NMAT) infrequently cures active chemoresistant, bulky, or aggressive B-cell lymphoma (B-cell non-Hodgkin lymphoma [B-NHL]). We hypothesized that 90Y-ibritumomab tiuxetan–based NMAT would facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft. Forty high-risk B-NHL patients with persistent disease received 0.4 mCi/kg (maximum, 32 mCi/kg) 90Y-ibritumomab tiuxetan, fludarabine, and 2 Gy total body irradiation and matched-related (15) or unrelated (25) transplantation. Baseline features included: median age, 58 years (range, 29-69 years); median prior regimens, 6 (range, 3-12); chemosensitive disease, 6 (15%); bulk > 5 cm, 17 (range, 5.2-18.6 cm, 43%); diffuse large B-cell lymphoma, 14 (35%); and comorbidity score > zero, 34 (85%). Early responses were observed in 24 (60%, 14 complete remission/complete remission unconfirmed, 10 partial response) patients, including 17 of 29 (59%) with chemotherapy-resistant disease and 10 (59%) with bulk > 5 cm. The estimated 30-month survival, progression-free survival, and nonrelapse mortality were 54.1%, 31.1%, and 15.9%, respectively. Early response, baseline platelet counts over 25 000/μL, indolent histology, and related donors were associated with improved survival. The addition of 90Y-ibritumomab tiuxetan to NMAT is safe and yields early responses and prolonged disease control in some of the highest-risk B-NHL patients. This trial was registered at www.clinicaltrials.gov as #NCT00119392.

Matched-Cohort Analysis of Autologous Hematopoietic Cell Transplantation with Radioimmunotherapy versus Total Body Irradiation–Based Conditioning for Poor-Risk Diffuse Large Cell Lymphoma

We conducted a matched-cohort analysis of autologous transplant conditioning regimens for diffuse large cell lymphoma in 92 patients treated with either radioimmunotherapy (RIT) or total body irradiation (TBI)-based conditioning regimens. The RIT regimen consisted of 0.4 mCi/kg of (90)Y-ibritumomab tiuxetan plus BEAM (BCNU, etoposide, cytarabine, melphalan). The TBI-based regimen combined fractionated TBI at 1200 cGy, with etoposide and cyclophosphamide. Five factors were matched between 46 patient pairs: age at transplant ±5 years, disease status at salvage, number of prior regimens, year of diagnosis ±5 years, and year of transplantation ±5 years. Patients in the TBI group had higher rates of cardiac toxicity and mucositis, whereas Z-BEAM patients had a higher incidence of pulmonary toxicity. Overall survival at 4 years was 81.0% for the Z-BEAM and 52.7% for the TBI group (P = .01). The 4-year cumulative incidence of relapse/progression was 40.4% and 42.1% for Z-BEAM and TBI, respectively (P = .63). Nonrelapse mortality was superior in the Z-BEAM group: 0% compared with 15.8% for TBI at 4 years (P < .01). Our data demonstrate that RIT-based conditioning had a similar relapse incidence to TBI, with lower toxicity, resulting in improved overall survival, particularly in patients with ≥2 prior regimens.

Safety and Efficacy of Combination Therapy with Fludarabine, Mitoxantrone, and Rituximab Followed by Yttrium-90 Ibritumomab Tiuxetan and Maintenance Rituximab as Front-Line Therapy for Patients With Follicular or Marginal Zone Lymphoma

We conducted a single-institution phase II clinical trial evaluating the safety and efficacy of combination chemoimmunotherapy followed by radioimmunotherapy consolidation and rituximab maintenance as front-line treatment in indolent lymphomas. We enrolled 20 patients with intermediate- to high-risk follicular lymphoma and 2 patients with marginal zone lymphoma. Treatment consisted of 4-6 cycles of FM (fludarabine 25 mg/m(2) on days 1-3, mitoxantrone 12 mg/m(2) on day 1 of each 28-day cycle). The protocol was amended after enrolling the first 4 patients to include rituximab 375 mg/m(2) on day 1. After 6-8 weeks, responders received (90)Y-ibritumomab tiuxetan (Zevalin) followed by maintenance rituximab (375 mg/m(2) weekly × 4 doses, repeated every 6 months for 2 years). After R-FM, the overall response rate was 95% with a complete response rate (CR) of 45% (n = 10), a partial response (PR) rate of 50% (n = 11), and stable disease in 1 patient. Nineteen patients received (90)Y-ibritumomab tiuxetan with a 60% conversion rate of PR to CR, resulting in an improved CR of 79% (n = 15) and a PR of 21% (n = 4). Fifteen patients proceeded to rituximab maintenance resulting in 3 patients with PR converting to CR. At median follow-up of 49.6 months, median progression-free survival (PFS) was 47.2 months and median overall survival (OS) was not reached in an intent-to-treat analysis. The most common adverse effects were hematologic, with 2 patients experiencing treatment-related myelodysplastic syndrome (MDS), evolving to acute myelogenous leukemia (AML) in 1 patient. R-FM with (90)Y-ibritumomab tiuxetan consolidation and rituximab maintenance is well tolerated, improving CR rates and maintaining durable responses in patients with untreated indolent lymphomas.

Use of myeloablative Y90-ibritumomab tiuxetan in patients with high-risk CD20+ NHL not eligible for standard ASCT: Five-year results.

8019 Background: ASCT is the procedure of choice in poor risk NHL, however conditioning regimens is a challenging procedures because safely delivered only in younger and clinically fit patients, thus new approaches are suggested to enhance its applicability. To extend the probability of cure to pts not eligible to standard ASCT from 12/2003 to 7/2007, 60 high-risk CD20+ NHL pts have been included in a phase II study with myeloablative Y90-Ibritumomab Tiuxetan, supported by ASCT. Methods: CD20+ relapsed/refractory or newly diagnosed high-risk NHL adults defined by IPI>3 DLBCL, MCL or transformed BCL, with no upper limit of age not eligible to standard ASCT have been enrolled. Pts were required to collect ≥9 x 106 CD34+cells/kg. Y90-Ibritumomab Tiuxetan (0.8-1.2 mci/kg) was administered after rituximab based HDCT: DHAP x 3, CTX 5-7g/mq followed stem cells collection, Ara-C 12-24 g/mq with 2x106 CD34+ cells/kg support. To hasten hematopoietic recovery, each pt received two stem-cell autograft of 2x106 CD34+ cells/kg on day +7 and of ≥5x106 CD34+ cells/kg on day +14 from RIT. Rationale of the procedure have been published elsewhere (Devizzi: JCO 2008). Results: Characteristics: M/F: 38/22; median age 63 (26-76); median comorbidities: 2 (1-3); Stage III-IV: 54; BM+: 36; newly high-risk NHL: 20; relapsed/refractory DLBC: 5/7; relapsed FCL/MZL 16/6; relapsed MCL: 6; molecular probe: 47. All pts received PCR – autograft. Fifty-two pts reached CR (87%), 3 GPR (5%) 5 PD (8%). Grade 3-4 neutropenia and thrombocytopenia was 37% and 70% with a median duration of 2 and 4 days. Non hemathological toxicity was: 4 pneumonia (6%); 2 mycetoma (3%); 7 CMV/HVZ reactivations (11%); One death occurred one month after transplant for VOD. Four pts developed sMDS/AML. With a median follow-up of 57 months 36 pts are in CCR, 18 pts relapsed, and 43 pts are still alive; the 5-year PFS and OS are 60% and 72% respectively. Conclusions: High dose90Y ibritumomab tiuxetan is an innovative, highly effective and tolerable myeloablative regimen. The incidence of sMDS/AML is similar to that observed with standard CT-based conditioning. Its use is strongly suggested in pts not eligible for standard ASCT.

Addition of low-dose, involved-field external beam radiotherapy just prior to radioimmunotherapy for CD20+ lymphoma: “Priming” cell death pathways?

e18533 Background: Radioimmunotherapy is an effective and increasingly used option for patients with B-cell lymphomas. Particularly in the relapsed/refractory setting, patients may have sizable disease limited to one or a few sites. Many patients are heavily pretreated, with a subsequent downregulation of CD20 expression on the surface of lymphoma cells. Emerging evidence suggests a role for radiation to upregulate CD20 expression, which could sensitize the irradiated lymphoma cells to radioimmunotherapy. Methods: Between July 1, 2009, and December 31, 2010, we treated 13 patients with a combination of low-dose, involved-field radiotherapy (IFRT) and radioimmunotherapy (RIT) for relapsed/refractory B-cell lymphoma: 5 transformed, 4 follicular, 2 marginal zone, 1 CLL/SLL, and 1 lymphoplasmacytic. All received 4 Gy in 2 fractions IFRT to sites of active disease, 2.5 cm or larger. 131I-tositumomab was used in 8 patients and 90Y-ibritumomab tiuxetan in 5 patients. The median age of patients treated was 61 (38 – 82). The median size of persistent disease prior to treatment was 4.2 cm (2.5 – 19.5). Results: With a median follow-up of 14 months (6 – 21), 11/13 patients obtained a complete response to combined therapy and remain in remission at this time. No patients have failed within the IFRT fields. Two patients achieved a local CR but exhibited persistent disease outside the IFRT fields. All 13 patients tolerated combined IFRT and RIT very well with no toxicity from the addition of IFRT, and only transient grade 2-3 hematologic toxicity from the RIT. The progression-free survival (PFS) is 100% in patients achieving a CR and is 85% for all patients treated. Conclusions: The addition of IFRT to sites of active disease > 2.5 cm to RIT in patients with relapsed/refractory B-cell lymphomas is well-tolerated, adds no toxicity to that of RIT alone, and results in excellent PFS, particularly for patients who obtain a CR. As the only failures to therapy were outside of radiation portals, the addition of IFRT to sites of active disease may play an important role in improving PFS when added to RIT. Prospective studies are needed to further evaluate this novel combined therapeutic approach.

90Y-Ibritumomab Tiuxetan as Consolidation Therapy After Autologous Stem Cell Transplantation in Aggressive Non-Hodgkin Lymphoma

Targeted radioimmunotherapy with (90)Y-labeled ibritumomab tiuxetan is a novel therapeutic approach for CD20-positive relapsed or refractory non-Hodgkin lymphoma (NHL). Seven consecutive patients with CD20-positive aggressive NHL who did not fully respond to prior myeloablative chemotherapy were enrolled. A 14.8 MBq (0.4 mCi)/kg dose of (90)Y-ibritumomab tiuxetan was administered to all patients, and approximately 100 d afterward (18)F-FDG PET/CT was performed to assess response. PET/CT showed a complete response in 5 of 7 patients. Of the 2 nonresponsive patients, 1 showed persistent disease and the other progression. Toxicity included thrombocytopenia in all 7 patients and grade IV neutropenic fever in 1 patient. Despite the small series studied, we suggest that radioimmunotherapy is safe for consolidation in patients treated with high-dose chemotherapy for aggressive NHL and may provide clinical benefit in extensively pretreated patients.

Characterization of Geometric Uncertainties of a Dose Calibrator During Measurement of 90Y Activity

The performance and measurement of (90)Y with a dose calibrator has always been a key point of several international recommendations, specifically in the case of the radiopharmaceutical (90)Y-ibritumomab tiuxetan, among other applications, used in the treatment of non-Hodgkin lymphoma. The objective of the present work was to examine in detail some important sources of geometric errors that, if neglected, can lead to an increase in uncertainty about the measured activity of this β(-) emitter radionuclide. A CRC-15R dose calibrator was used to measure and quantify some of these sources, although the same methodology can easily be applied to any other similar equipment. The depth response along the main axis of the dose calibrator was carefully characterized, as well as syringe volume effects and source angular dependence. It was found that, if not taken properly into account, these issues can contribute to an increase in the activity uncertainty (e.g., 5.1% in the present example). This finding implies the possibility of easily reaching higher values than the internationally suggested 5% uncertainty in activity measurement for therapeutic purposes. These errors can be greatly reduced by previous characterization of the dose calibrator and careful implementation of the methodology for measurement.

Myeloablative doses of yttrium‐90‐ibritumomab tiuxetan and the risk of secondary myelodysplasia/acute myelogenous leukemia

Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter of concern, the authors evaluated the hematopoietic damage and incidence of secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) in patients who received myeloablative doses of the radiolabeled antibody yttrium-90 (⁹⁰Y)-ibritumomab tiuxetan. The occurrence of sMDS/AML was investigated prospectively in 53 elderly patients with non-Hodgkin lymphoma (NHL) who underwent an autograft after high-dose radioimmunotherapy (HD-RIT) myeloablative conditioning with ⁹⁰Y-ibritumomab tiuxetan. Bone marrow (BM) hematopoietic progenitors and telomere length (TL) also were investigated. At a median follow-up of 49 months, 4 patients developed sMDS/AML at 6 months, 12 months, 27 months, and 36 months after HD-RIT, and the 5-year cumulative incidence of sMDS/AML was 8.29%. A significant but transient decrease in BM granulocyte-macrophage progenitors was observed; whereas multilineage, erythroid, and fibroblast progenitors were unaffected. A significant and persistent shortening of BM TL also was detected. A matched-pair analysis comparing the study patients with 55 NHL patients who underwent autografts after chemotherapy-based myeloablative conditioning demonstrated a 8.05% 5-year cumulative incidence of sMDS/AML. HD-RIT for patients with NHL was associated with 1) limited toxicity on hematopoietic progenitors, 2) accelerated TL shortening, and 3) non-negligible incidence of sMDS/AML, which nevertheless was comparable to the incidence observed in a matched group of patients who received chemotherapy-based conditioning. Thus, in the current series of elderly patients with NHL, the development of sMDS/AML was not influenced substantially by HD-RIT.

Radioimmunotherapy in Non-Hodgkin Lymphoma: Opinions of Nuclear Medicine Physicians and Radiation Oncologists

Despite approval by the Food and Drug Administration and consistent reports of the efficacy and safety of (90)Y-ibritumomab tiuxetan and (131)I-tositumomab, these therapies are infrequently used. This study investigates the opinions and patterns of the use of radioimmunotherapy by nuclear physicians, affiliated researchers, nuclear medicine technologists, and radiation oncologists and aims to identify possible barriers to the use of this promising therapy. An e-mail-based survey with 13 broad questions related to radioimmunotherapy was sent electronically to 13,221 Society of Nuclear Medicine members and radiation oncologists throughout the United States. Six hundred thirteen individuals (4.6%) responded to the electronic survey. Two hundred fifty-one responders (40.9%) had treated patients with non-Hodgkin lymphoma (NHL) with radioimmunotherapy in the last 24 mo. Of the responders, 29.5% used only (90)Y-ibritumomab tiuxetan, 7.6% used only (131)I-tositumomab, and 24.9% used both radiopharmaceuticals; 37.9% did not treat NHL with radioimmunotherapy. Most responders said their patients came from university hospitals (33.9%) or private offices (25.6%), and they mainly treated in a second-line (42.9%), third-line (35.6%), or consolidation (23.5%) setting. Major concerns were that referring oncologists and hematologists wanted to treat by themselves with nonradioactive compounds (mean ± SD, 3.418 ± 1.49) and that (90)Y-ibritumomab tiuxetan and (131)I-tositumomab were expensive (mean ± SD, 3.413 ± 1.35). Of the responders and involved physicians, 40.4% and 35.2%, respectively, did not know if their institution accepted Medicare patients for radioimmunotherapy. Almost 30% (29.6%) of the responders thought radioimmunotherapy would probably grow and 38.0% thought it would grow in importance in the future. Responders who did not administer radioimmunotherapy for NHL thought it took too much time to administer radioimmunotherapy (P < 0.01) and had concerns about the dosimetry procedure (P < 0.01) and radiation safety (P < 0.01). Individuals who perceived a negative future for radioimmunotherapy had significantly more concerns about the time-consuming administration process (P < 0.05) and the high cost of radioimmunotherapy (P < 0.05). Responders from academic centers had significantly fewer concerns about payment (P < 0.01), dosimetry (P < 0.01), and radiation safety (P < 0.01). Radioimmunotherapy was generally viewed positively by the surveyed population. However, limited referrals due to alternative nonradioactive therapies and logistic, educational, and economic concerns played an important role for subgroups in the perception of radioimmunotherapy for NHL.

90Y-ibritumomab tiuxetan followed by reduced-intensity conditioning and allo-SCT in patients with advanced follicular lymphoma

RIC HSCT is a potentially curative therapeutic option for patients with advanced FL but disease relapse remains the most common cause of failure. Radioimmunoconjugates administered prior to RIC allogeneic HSCT may enhance cytoreduction and allow more time for graft versus lymphoma effect to develop without the associated toxicity of a myeloablative HSCT. We performed a retrospective study to describe the outcomes of patients with relapsed, refractory or transformed FL who received 90Y ibritumomab tiuxetan followed by fludarabine and low-dose busulfan RIC allogeneic HSCT at the Dana-Farber Cancer Institute between 2006 and 2009, inclusively. Twelve patients were identified with a median age of 55 (40–66) years and a median number of lines of therapy of 5 (2–10). Two patients (17%) had transformed to a more aggressive histology and 5 (42%) had chemorefractory FL. Cumulative incidences of grade II–IV acute GVHD at 100 days were 17% (± 11%) and chronic GVHD at 12 months were 63% (±19%). Two-year non-relapse mortality was 18% (± 12%). Two-year OS and progression-free survival (PFS) were 83% (± 11%) and 74% (± 13%), respectively. This treatment is associated with favorable outcomes including acceptable rates of GVHD and relapse in advanced FL patients and warrants prospective studies.

Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients

AbstractRadioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) has achieved objective response rates in clinical trials comparable with standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, but is relatively underused in routine practice. In this article, we report our clinical experience in 142 consecutive patients who received iodine-131 rituximab radioimmunotherapy for low-grade, predominantly follicular, relapsed NHL. Objective response rates of 67%, with complete response (CR) in 50% and median overall survival of 32 months, matched the response rates in a phase 2 clinical trial of 131I-rituximab radioimmunotherapy and compares favorably with those reported for 131I-tositumomab or 90Y-ibritumomab tiuxetan. Progression-free survival was 18 months overall and 32 months in CR or CR-unconfirmed patients. Our patients comprised 107 (75%) follicular lymphoma, 21 (15%) small lymphocytic lymphoma, 6 (4%) mucosa-associated lymphoid tissue/marginal zone lymphoma, and 8 (6%) mantle-cell lymphoma, with median follow-up of 32 months and 8-year overall survival of 48%. Toxicity was limited to hematologic grade 4 neutropenia, occurring in 10% and thrombocytopenia in 6%. There were no episodes of bleeding or infection requiring hospital admission. Radioimmunotherapy with 131I-rituximab in routine clinical outpatient practice provides cost-effective, safe treatment of relapsed/refractory indolent NHL, with half of patients achieving durable, complete remission with potential for repeat radioimmunotherapy on relapse.

Retrospective web-based multicenter evaluation of 18F-FDG-PET and CT derived predictive factors

Summary Aim: Although predictive factors (PF) for conventional lymphoma therapy are established and frequently used in clinical practice and medical research, the PF for radioimmunotherapy (RIT) have not been fully defined until now. The aim of this multicenter evaluation is to prove the feasibility of the multicenter web-based data collection and to preliminary explore imaging findings and prediction of therapy response in patients with follicular lymphoma (FL) following radioimmuno therapy (RIT) with 90Y-ibritumomab tiuxetan. Patients, methods: We retrospectively analyzed and correlated clinical and imaging data (CT and FDG-PET) before and after RIT as documented by the RIT-Network. Evaluation of treatment response was done on both patient and lesion basis. Every measurable lesion was analyzed in terms of standardized uptake value (SUV), volume (CT and PET) and response. PF were identified using a uni- and multivariate model. A web-based system was used for the documentation and evaluation of clinical and imaging data. Results: 16 patients with at least one PET before and after RIT were eligible for analysis. Concerning response three months postRIT, 5 patients achieved a CR, 6 patients a PR and 4 patients remained with NC. A total of 159 lesions were measured (mean 10 ± 8). In the multivariate model the log lesion volume (p &lt; 0.0001), the total (p = 0.03) and maximum lesion volume (p = 0.05) were predictors for response (CR + PR). Concerning the lesional CR initial small lesion volume (p = 0.009) and its high metabolic activity (p = 0.01) were identified as predictors. The web-based system showed no major disturbances allowing secure data transfer and central image interpretation in a reasonable time. Conclusion: The use of a web-based multicenter archiving system for clinical and imaging data is technically feasible in a multicenter setting and allows a central analysis. This preliminary analysis suggests that FDG-PET may predict the likelihood of response to RIT.

Radioimmunotherapy of solid tumors: searching for the right target.

Radioimmunotherapy of solid tumors remains a challenge despite the tremendous success of ⁹⁰Y ibritumomab tiuxetan (Zevalin) and ¹³¹I Tositumomab (Bexxar) in treating non-Hodgkin's lymphoma. For a variety of reasons, clinical trials of radiolabeled antibodies against solid tumors have not led to responses equivalent to those seen against lymphoma. In contrast, promising responses have been observed with unlabeled antibodies that target solid tumor receptors associated with cellular signaling pathways. These observations suggest that anti-tumor efficacy of the carrier antibody might be critical to achieving clinical responses. Here, we review and compare tumor antigens targeted by radiolabeled antibodies and unlabeled antibodies used in immunotherapy. The review shows that the trend for radiolabeled antibodies under pre-clinical development is to also target antigens associated with signaling pathways that are essential for the growth and survival of the tumor.

90Y-ibritumomab tiuxetan (Zevalin) in heavily pretreated patients with mucosa associated lymphoid tissue lymphoma

Radioimmunotherapy using 90Y-ibritumomab tiuxetan has predominantly been used in patients with follicular lymphoma, but little is known about its activity in patients with extranodal marginal zone lymphoma of the mucosa associated lymphoid tissue (MALT). A total of six patients progressing/relapsing following conventional therapy for MALT lymphoma were treated with 90Y-ibritumomab tiuxetan at our institution. Two patients had gastric MALT lymphoma, one suffered from orbital MALT lymphoma, and two had cutaneous MALT lymphoma, while one patient had a widely disseminated lymphoma involving the stomach, lungs, lymph nodes, and salivary glands. All patients were at least in third relapse following various forms of therapy including Helicobacter pylori-eradication, radiation, chemotherapy, and application of rituximab. Following two doses of rituximab at 250 mg/m2 at an interval of 1 week, 90Y-ibritumomab tiuxetan was given immediately at a dose of 0.4 mCi/kg body weight. Treatment was well tolerated apart from one episode of pneumonia requiring hospitalization. Four patients developed a complete remission (ongoing now for 4, 16, 23, and 24 months), one patient had a partial response lasting for 5 months, and one patient had stable disease for 13 months. After a follow-up of 9–29 months, all patients are alive. Application of 90Y-ibritumomab tiuxetan is active and safe in heavily pretreated patients with MALT lymphoma.

Predicting Hematologic Toxicity in Patients Undergoing Radioimmunotherapy with 90Y-Ibritumomab Tiuxetan or 131I-Tositumomab

This study aimed at identifying clinical factors for predicting hematologic toxicity after radioimmunotherapy with (90)Y-ibritumomab tiuxetan or (131)I-tositumomab in clinical practice. Hematologic data were available from 14 non-Hodgkin lymphoma patients treated with (90)Y-ibritumomab tiuxetan and 18 who received (131)I-tositumomab. The percentage baseline at nadir and 4 wk post nadir and the time to nadir were selected as the toxicity indicators for both platelets and neutrophils. Multiple linear regression analysis was performed to identify significant predictors (P < 0.05) of each indicator. For both platelets and neutrophils, pooled and separate analyses of (90)Y-ibritumomab tiuxetan and (131)I-tositumomab data yielded the time elapsed since the last chemotherapy as the only significant predictor of the percentage baseline at nadir. The extent of bone marrow involvement was not a significant factor in this study, possibly because of the short time elapsed since the last chemotherapy of the 7 patients with bone marrow involvement. Because both treatments were designed to deliver a comparable bone marrow dose, this factor also was not significant. None of the 14 factors considered was predictive of the time to nadir. The R(2) value for the model predicting percentage baseline at nadir was 0.60 for platelets and 0.40 for neutrophils. This model predicted the platelet and neutrophil toxicity grade to within ±1 for 28 and 30 of the 32 patients, respectively. For the 7 patients predicted with grade I thrombocytopenia, 6 of whom had actual grade I-II, dosing might be increased to improve treatment efficacy. The elapsed time since the last chemotherapy can be used to predict hematologic toxicity and customize the current dosing method in radioimmunotherapy.

Y-90-Ibritumomab Tiuxetan, Fluadarabine and TBI Based Non-Myeloablative Allogeneic Transplant Conditioning for High-Risk B-Cell Lymphoma

AbstractAbstract 33 Purpose:Non-myeloablative allogeneic transplantation (NMAT) can provide prolonged remissions in patients with advanced B-cell lymphoma (B-NHL) via the graft versus lymphoma (GVL) effect, though inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy (RIT) can safely induce responses in B-NHL with little non-hematologic toxicity. We hypothesized that 90Y-ibritumomab tiuxetan-based NMAT would safely facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft which would also abrogate the hematologic toxicity of the RIT. Patients and Methods:Forty patients with relapsed, high-risk B-NHL and persistent disease who were not deemed appropriate for standard NMAT due to disease factors and not considered appropriate for myeloablative transplant due to age, pretreatment, or co-morbidities were enrolled in this phase II trial. Conditioning included 0.4 mCi/kg (max 32mCi) 90Y-ibritumomab tiuxetan (day-14), fludarabine (days -7 to -5) and 2 Gy total body irradiation (day 0) followed by transplantation from matched related (n=15) or unrelated (n=25) donors along with post-grafting immunosuppression with cyclosporine and mycophenolate mofetil. Baseline features included: median age = 58 years (range 29–69 years), median prior regimens = 6 (range 3 to 12), chemosensitive disease = 6 (15%), CR pretransplant = 0 (0%), bulk >5 cm = 17 (range 5.2–18.6cm, 43%), >25% bone marrow involvement with B-NHL = 10 (25%, range of marrow involvement 40–95%), comorbidity score ≥1 = 35 (85%), median comorbiditiy score 3 (range 0–10), pretransplant IPI ≥3=21 (53%). Histologies included: DLBCL (14, including 6 that had transformed from indolent disease), CLL/SLL (10), mantle cell lymphoma (8), FL (6), hairy cell leukemia (1), and marginal zone lymphoma (1). Results:Early objective responses attributable to the conditioning regimen at 1 and 3 months were observed in 19 (48%, 3 CR/CRU, 16 PR) and 24 (60%, 13 CR/CRU, 11 PR) patients, respectively, including 17 (59%) objective responses in the 29 patients with known chemoresistant disease and 10 (59%) of 17 with bulk > 5cm. In total, 33 (83%) patients experienced reduction in the measurable disease burden by day 84. The estimated OS and PFS at 30 months were 54.1%, and 31.1%, respectively. The regimen was well tolerated and all patients experienced sustained engraftment with no graft rejection. The neutrophil and platelet nadirs were 50/μ L and 12,000/μ L and occurred a median of 12 and 8 days after transplant, respectively. The median duration of neutropenia <500/μ L was 11 days and thrombocytopenia < 50,000/μ L was 8 days. Grade III acute GVHD occurred in 4 patients (10%) but none had grade IV. Chronic extensive GVHD occurred in 8 patients (20%). Non-relapse mortality at 100 days and 30 months were 2.5% and 15.9%, respectively. Multivariable analysis identified early response (p<0.001), baseline platelet counts >25,000/μ L (p=0.002), indolent histology (p<0.001), and related donors (p=0.04) as associated with improved survival. Conclusions:The addition of 90Y-ibritumomab tiuxetan to NMAT is safe, feasible, and can be readily employed yielding early responses and prolonged disease control in a subset of the highest risk B-NHL patients. Disclosures:Gopal:Biogen-Idec: Research Funding. Off Label Use: Zevalin for transplant conditioning. Maloney:Spectrum: Consultancy, Honoraria; Genetech: Consultancy, Honoraria.

90Y-Ibritumomab Tiuxetan Followed by Rituximab Is a Safe Treatment Option for Relapsed or Refractory Diffuse Large B-Cell Non-Hodgkin s Lymphoma

AbstractAbstract 2866 Introduction:Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy and is generally responsive to anthracycline-containing chemotherapy. However, 60% of patients (pts) will relapse after their first line treatment. At the time of relapse the only curative approach includes the use of a stem cell transplant (SCT). The incidence of DLBCL increases with age which creates a subset of pts who are not candidates for first line anthracycline-based chemotherapy, and a large subset of pts who are not candidates for SCT due to advanced age and/or co-morbidities. Thus, there is a significant unmet need for therapies with a low toxicity profile in elderly or medically unfit pts with DLBCL. 90Y-ibritumomab tiuxetan (90Y-IT) is an anti-CD20 murine antibody linked with a beta-emitting isotope approved for use in indolent lymphoma. Maintenance rituximab (R) has been reported to increase response rates and prolong remission duration in some lymphomas. We performed a phase II multicenter clinical trial to examine the efficacy of 90Y-IT induction followed by maintenance R in pts with DLBCL. Patients and Methods:Eligible pts were either intolerant of anthracycline-based chemotherapy or had relapsed or refractory CD20+ DLBCL with measurable disease. Pts had to be ineligible for SCT for reasons other than failure to harvest stem cells. Bone marrow involvement by lymphoma of less than 25% based on bilateral bone marrow aspirate and biopsy was required. R 250 mg/m2 was administered IV immediately followed by 111In-ibritumomab tiuxetan. Nuclear scans were performed at 24 and 48 hours to insure there was no altered biodistribution. On day 8 a second infusion of R 250 mg/m2 followed by 0.4 mCi/kg (for pts with a baseline platelet count >150,000/mm3) or 0.3 mCi/kg 90Y-IT (for pts with a baseline platelet count 100,000-149,000/mm3) was given. Pts with multiple extranodal sites or prior bone marrow involvement received CNS prophylaxis with intrathecal methotrexate or cytarabine. Maintenance R 375 mg/m2 was given on weeks 3–6, then weekly × 4 every 6 months × 4 cycles or until progression. Results:Between 10/2003 and 9/2009, 25 pts have been treated. During the course of the study, the ownership of the therapeutic agent changed three times and therefore enrollment was interrupted on two occasions. The median age of pts was 79 (range 45–91), 36% pts had a sIPI score 3 or more. The median number of prior regimens is 2 [0-5]. The 90Y-IT treatment regimen produced an overall response rate of 36% [9 pts] with 28% CR [7 pts]. To date, the mean OS is 18 months (median 8.1 months) with a median follow-up of 11.2 months. Among responding pts, the median OS has not been reached with a median follow-up of over 26.2 [0.1-71.4] months. Thirteen pts died within the first year, 6 patients (24%) continue to be in remission greater than 18 months, and 4 patients (16%) remain in long-term remission [39.9-71.4 months]. The most frequently observed toxicity was hematologic. Eleven percent of pts had grade 4 neutropenia with only one patient experiencing febrile neutropenia, and 16% of pts experienced grade 4 thrombocytopenia. There were no unexpected non-hematologic toxicities except for 1 patient that experienced extravasation. One late-occurring case of MDS/AML was reported that is possibly related to the study regimen, and one case of adenocarcinoma of the GI tract that is likely unrelated. Of note, none of the pts that progressed on the chemotherapy preceding this study achieved a response to the study regimen. Conclusions:The 90Y-IT treatment regimen has an acceptable toxicity profile in elderly or heavily pretreated pts with DLBCL. The two week outpatient 90Y-IT infusion produces response rates and durations similar to that of more prolonged cytotoxic chemotherapy regimens. Progression on previous chemotherapy predicts for poor response to 90Y-IT. Treatment with 90Y-IT can provide durable remission to a select subset of pts who are not candidates for SCT, or intensive anthracycline based chemotherapy. Disclosures:Off Label Use: We are describing a phase II study of the use of 90Y-Ibritumomab Tiuxetan for treatment of diffuse large B-cell lymphoma. Current FDA approved use of 90Y-Ibritumomab Tiuxetan includes relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) or previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy. Joyce:Spectrum Pharmaceuticals, Inc.: Research Funding; Cell Therapeutics Inc: Research Funding; Biogen Idec: Research Funding.

The Risk of Secondary Myelodysplastic Syndrome/Acute Leukemia Following High-Dose Yttrium-90 Ibritumomab Tiuxetan Is Analogous to That Observed Following High-Dose Chemotherapy: a Matched-Pair Analysis In Non-Hodgkin Lymphoma Patients.

AbstractAbstract 1289 Introduction:Myeloablative doses of Yttrium-90 (90Y)-Ibritumomab Tiuxetan combined with tandem autologous peripheral blood stem cell (PBSC) support can be safely administered to patients aged up to 76 years (Devizzi L et al, J Clin Oncol 2008). Whether marrow exposure to myeloablative doses of radiolabelled antibodies (hd-radio-immunotherapy) could increase the risk of secondary myelodysplastic syndrome and acute leukemia (sMDS/AL) remains a matter of concern. Therefore, we prospectively investigated by means of a longitudinal study the incidence of sMDS/AL in a cohort of high-risk non-Hodgkin lymphoma (NHL) patients receiving hd-radio-immunotherapy. The cumulative incidence of sMDS/AL in the study group was compared with that observed in a historical group of patients autografted following chemotherapy-based myeloablative conditioning. Additionally, to further investigate marrow damage induced by hd-radio-immunotherapy, hematopoietic and stromal progenitors, as well as telomere length (TL) were assessed. Patients and Methods:From July 2004 through December 2007, 53 relapsed/refractory (n= 36) or de novo high-risk (n= 17) NHL patients (median age, 64 years; range, 26 – 76 years) received a high-dose sequential (HDS) chemotherapy program, including a myeloablative phase with 90Y-Ibritumomab Tiuxetan (1.2 mCi/kg body weight). Patients were monitored for frequency of colony-forming cells (CFCs), cytogenetic and TL analysis. Bone marrow (BM) samples were collected prior to hd-radio-immunotherapy, every six months for two years and annually thereafter. The study was approved by the Institutional Ethical Committee and written informed consent was obtained from each patient. The study group included 29 patients with aggressive lymphoma (diffuse large B-cell lymphoma, n = 19; mantle cell lymphoma, n = 8; Richter syndrome, n = 2) and 24 with indolent NHL subtypes (follicular lymphoma, n = 20; marginal zone lymphoma, n = 3; lymphocytic lymphoma, n = 1). Thirty patients were relapsed after one (n=15) or more (n=15) previous chemotherapy regimens, 6 patients were refractory and 17 patients were previously untreated with high-risk prognostic index. Pre-exposure to alkylating agent involved 68% of the patients. A historical group of 55 NHL patients who received an analogous HDS program with final chemotherapy-based autografting was used as control group. Study and control groups were pair-matched for age, gender, histological subtype, disease status at transplant and type of grafted PBSC. Results:At a median follow-up of 49 months (range, 32 – 74), 4 out of 53 patients of the study group developed sMDS/AL at 6, 12, 27 and 36 months from transplant. According to WHO criteria, refractory anemia with excess of blasts 1 (RAEB-1) was diagnosed in one patient, whereas refractory cytopenia with unilineage dysplasia (RCUD) was diagnosed in the other three cases, with acute leukemia transformation being observed in two patients at 12 and 18 months after initial detection of abnormal cytogenetics, respectively. The cumulative incidence of sMDS/AL resulted of 8.29% at 5-years. An analogous 5-year cumulative incidence of 8.05% was observed in the historical control group autografted following a chemotherapy-based conditioning. Radioimmunotherapy-treated patients showed a significant but transient decrease in granulocyte-macrophage colony forming unit (CFU-GM) at 6 months after transplant, with recovery to baseline values at 12 months. Multilineage colony-forming units (CFU-Mix), erythroid burst-forming units (BFU-E) and fibroblast CFU (CFU-F) were not show significantly affected over time. In contrast, a progressive and significant decrease in BM TL was evident from 12 months after transplant. Conclusion:In our series of elderly NHL patients receiving hd-radio-immunotherapy, the incidence of sMDS/AL was found increased compared to recently reported series of younger lymphoma patients receiving chemotherapy-based conditioning. However, the increased risk of sMDS/AL was not associated with the type of myeloablative conditioning, i.e. chemotherapy vs radio-immunotherapy. Other factors may have favored the development of sMDS/AL, including advanced age at transplant, extensive pre-transplant therapy and type of reinfused PBSC. The observed progressive TL loss gives support to the concept that TL loss might be involved in sMDS/AL development. Disclosures:No relevant conflicts of interest to declare.

90Y-Ibritumomab Tiuxetan (Zevalin®) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin's Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients

AbstractAbstract 594The FIT trial was conducted to evaluate the safety and efficacy of 90Y-ibritumomab tiuxetan (0.4 mCi/kg; maximum dose 32 mCi) when used as consolidation of first complete or partial remission in patients with previously untreated, advanced-stage follicular lymphoma (FL). Patients were randomly assigned to either 90Y-ibritumomab treatment (n = 207) or observation (n = 202) within 3 months (mo) of completing initial induction therapy (chemotherapy only: 86%; rituximab in combination with chemotherapy: 14%). Response status prior to randomization did not differ between the groups: 52% complete response (CR)/CR unconfirmed (CRu) to induction therapy and 48% partial response (PR) in the 90Y-ibritumomab arm vs 53% CR/CRu and 44% PR in the control arm. The primary endpoint was progression-free survival (PFS) of the intent-to-treat (ITT) population. Results from the first extended follow-up after a median of 3.5 years revealed a significant improvement in PFS from the time of randomization with 90Y-ibritumomab consolidation compared with control (36.5 vs 13.3 mo, respectively; P < 0.0001; Morschhauser et al. JCO. 2008; 26:5156-5164). Here we report a median follow-up of 66.2 mo (5.5 years). Five-year PFS was 47% in the 90Y-ibritumomab group and 29% in the control group (hazard ratio (HR) = 0.51, 95% CI 0.39–0.65; P < 0.0001). Median PFS in the 90Y-ibritumomab group was 49 mo vs 14 mo in the control group. In patients achieving a CR/CRu after induction, 5-year PFS was 57% in the 90Y-ibritumomab group, and the median had not yet been reached at 92 months, compared with a 43% 5-year PFS in the control group and a median of 31 mo (HR = 0.61, 95% CI 0.42–0.89). For patients in PR after induction, the 5-year PFS was 38% in the 90Y-ibritumomab group with a median PFS of 30 mo vs 14% in the control group with a median PFS of 6 mo (HR = 0.38, 95% CI 0.27–0.53). Patients who had received rituximab as part of induction treatment had a 5-year PFS of 64% in the 90Y-ibritumomab group and 48% in the control group (HR = 0.66, 95% CI 0.30–1.47). For all patients, time to next treatment (as calculated from the date of randomization) differed significantly between both groups; median not reached at 99 mo in the 90Y-ibritumomab group vs 35 mo in the control group (P < 0.0001). The majority of patients received rituximab-containing regimens when treated after progression (63/82 [77%] in the 90Y-ibritumomab group and 102/122 [84%] in the control group). Overall response rate to second-line treatment was 79% in the 90Y-ibritumomab group (57% CR/CRu and 22% PR) vs 78% in the control arm (59% CR/CRu, 19% PR). Five-year overall survival was not significantly different between the groups; 93% and 89% in the 90Y-ibritumomab and control groups, respectively (P = 0.561). To date, 40 patients have died; 18 in the 90Y-ibritumomab group and 22 in the control group. Secondary malignancies were diagnosed in 16 patients in the 90Y-ibritumomab arm vs 9 patients in the control arm (P = 0.19). There were 6 (3%) cases of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) in the 90Y-ibritumomab arm vs 1 MDS in the control arm (P = 0.063). In conclusion, this extended follow-up of the FIT trial confirms the benefit of 90Y-ibritumomab consolidation with a nearly 3 year advantage in median PFS. A significant 5-year PFS improvement was confirmed for patients with a CR/CRu or a PR after induction. Effective rescue treatment with rituximab-containing regimens may explain the observed no difference in overall survival between both patient groups who were – for the greater part – rituximab-naïve. Disclosures:Hagenbeek:Roche Global Advisory Board: Consultancy. Radford:Schering (May 2009): Honoraria, Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche Italy: Membership on an entity's Board of Directors or advisory committees; Celgene Italy: Membership on an entity's Board of Directors or advisory committees. Soubeyran:Roche: Honoraria, Research Funding; Cephalon: Research Funding. Bischof Delaloye:Expert Statement (questions of reimbursement in Switzerland): Honoraria. Morschhauser:Roche: Honoraria, Paid expert testimony within the past 2 years; Bayer: Honoraria.