Tiuxetan Research Articles

Efficacy of radioimmunotherapy-based conditioning with high-dose chemotherapy and autologous stem cell transplantation for transformed lymphoma.

8556 Background: Transformed non-Hodgkin lymphoma (TF NHL) has a poor prognosis with median survival of 7-20 months. Studies have suggested the benefit of HDC. The series by Eide showed 47%, 5yr OS in 47 pts treated with HDC and ASCT (Br J Hem 2011). Our multicenter experience with RIT plus HDC (Yttrium 90 ibritumomab tiuxetan plus BEAM; carmustine, etoposide, cytarabine, melphalan "ZBEAM") demonstrated the safety and efficacy of the regimen in diffuse large cell lymphoma (DLCL). Therefore, the regimen was explored in other subtypes of NHL. Herein we report the outcome of 57 pts with TF NHL treated with ZBEAM conditioning and ASCT at three centers (City of Hope USA n=20, VUMC the Netherlands n=31, Chaim Sheba Med Center, Israel n=6.) between 2003- 2011. Methods: Histological confirmation of transformation was defined as dx of DLCL in pts with either a prior history or concomitant dx of follicular NHL. Results: Median age at ASCT was 59.6 yrs (range 41-69). Median number of prior regimens 2 (range 1-6), all pts received rituximab in at least one regimen. Disease status at ASCT: 1st CR 29, 1stPR 7,1st rel 9, IF 5, 2nd CR 5, 2nd rel 1, >3CR 1. Median time from TF NHL dx to ASCT was 7.7 mo (range 2.8-116). Pts engrafted white cells at median of 12 days (range 8-33). Non relapse mortality was 3.5%. There were two second malignancies: 1 MDS and 1 SCC Skin. Median f/u for living pts was 29 mo (range 7-100). Two year PFS was 69.67% (95%CI 59.39 - 77.83) and OS 90.29% (95% CI: 79.63 - 95.52). On univariate analysis, number of prior regimens, time from TF NHL dx to ASCT and history of marrow involvement were not significant for PFS and OS. Disease status at ASCT was significant for PFS in 1st CR vs relapse disease ( p=0.03) The relapsed pts had a significant increase in risk of relapse/progression or death post ASCT compared to the 1CR patients. [HR = 2.9, (95% CI: 1.07 - 7.9)]. Conclusions: ZBEAM conditioning with ASCT is an active treatment for pts with TF NHL, and is particularly efficacious as consolidation for pts in 1st CR.

Consolidation treatment with Yttrium-90 ibritumomab tiuxetan after a new induction regimen in intermediate and high-risk follicular lymphoma patients according to the follicular lymphoma international prognostic index (FLIPI): A multicenter, prospective Phase II trial of Spanish Lymphoma Oncology Group

Consolidation treatment with Yttrium-90 ibritumomab tiuxetan after a new induction regimen in intermediate and high-risk follicular lymphoma patients according to the follicular lymphoma international prognostic index (FLIPI): A multicenter, prospective Phase II trial of Spanish Lymphoma Oncology Group

Abstract 5477: Engineered toxin body demonstrating CD20-specific binding and cell kill in B-cell non-Hodgkin's lymphoma cells.

Abstract Non-Hodgkin's lymphoma (NHL) offers an attractive area for therapeutic biologics. The most successful example of this targeted approach is rituximab, which is approved for front and second line therapy of NHL. Rituximab targets the CD20 antigen expressed on 90% of B-cell NHL cells. However, rituximab has limited direct cell-kill effects, acting instead primarily through indirect immune responses induced by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC). Direct-cell kill approaches to CD20 have been limited to radioimmunotherapy because CD20 does not efficiently internalize. Despite improved clinical efficacy seen over Rituximab with both 131 tositumomab and ibritumomab tiuxetan, challenges around the administration of radioimmunotherapies have severely curtailed therapeutic use. We have developed an engineered toxin body (ETB) comprising a CD20 scFv and a modified Shiga-like Toxin A (3F7) capable of specifically recognizing and killing CD20 expressing cells. Utilizing a flow cytometry based binding affinity assay, 3F7 demonstrated selective binding to CD20 positive Raji cells whereas no significant binding was observed in CD20 negative BC-1 cells. Further, direct competition of 3F7 binding to Raji cells was observed in the presence of rituximab or the parent monoclonal antibody. 3F7 demonstrated CD20-specific direct cell kill of Raji, Daudi and Ramos cells with minimal cell kill of CD20 negative BC-1 or Jurkat cells. Initial dose finding studies in mice found that a therapeutic dosing schedule was well tolerated. Raji xenograft studies in mice are ongoing. 3F7 is a novel therapeutic approach with direct cell-kill activity against CD20-expressing cells which could expand treatment options for B-cell lymphoma. Citation Format: Rachel Wirth, Sangeetha Rajagopalan, Erin Willert, William Null, Jennifer Erdman, Jen-Sing Liu, Jack P. Higgins. Engineered toxin body demonstrating CD20-specific binding and cell kill in B-cell non-Hodgkin's lymphoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5477. doi:10.1158/1538-7445.AM2013-5477

90Yttrium-Ibritumomab Tiuxetan Consolidation of First Remission in Advanced-Stage Follicular Non-Hodgkin Lymphoma: Updated Results After a Median Follow-Up of 7.3 Years From the International, Randomized, Phase III First-Line Indolent Trial

Updated results are presented after a median follow-up of 7.3 years from the phase III First-Line Indolent Trial of yttrium-90 ((90)Y) -ibritumomab tiuxetan in advanced-stage follicular lymphoma (FL) in first remission. Patients with CD20(+) stage III or IV FL with complete response (CR), unconfirmed CR (CRu), or partial response (PR) after first-line induction treatment were randomly assigned to (90)Y-ibritumomab consolidation therapy (rituximab 250 mg/m(2) days -7 and 0, then (90)Y-ibritumomab 14.8 MBq/kg day 0; maximum 1,184 MBq) or no further treatment (control). Primary end point was progression-free survival (PFS) from date of random assignment. For 409 patients available for analysis ((90)Y-ibritumomab, n = 207; control, n = 202), estimated 8-year overall PFS was 41% with (90)Y-ibritumomab versus 22% for control (hazard ratio [HR], 0.47; P < .001). For patients in CR/CRu after induction, 8-year PFS with (90)Y-ibritumomab was 48% versus 32% for control (HR, 0.61; P = .008), and for PR patients, it was 33% versus 10% (HR, 0.38; P < .001). For (90)Y-ibritumomab consolidation, median PFS was 4.1 years (v 1.1 years for control; P < .001). Median time to next treatment (TTNT) was 8.1 years for (90)Y-ibritumomab versus 3.0 years for control (P < .001) with approximately 80% response rates to second-line therapy in either arm, including autologous stem-cell transplantation. No unexpected toxicities emerged during long-term follow-up. Estimated between-group 8-year overall survival rates were similar. Annualized incidence rate of myelodysplastic syndrome/acute myeloblastic leukemia was 0.50% versus 0.07% in (90)Y-ibritumomab and control groups, respectively (P = .042). (90)Y-ibritumomab consolidation after achieving PR or CR/CRu to induction confers 3-year benefit in median PFS with durable 19% PFS advantage at 8 years and improves TTNT by 5.1 years for patients with advanced FL.

Phase I Study of a Modified Regimen of 90Yttrium–Ibritumomab Tiuxetan for Relapsed or Refractory Follicular or Transformed CD20+ Non-Hodgkin Lymphoma

Radioimmunotherapy capitalizes on the radiosensitivity of non-Hodgkin lymphoma (NHL) and the targeted nature of monoclonal antibodies. In an attempt to reverse bone marrow infiltration with B-cells and optimize the biodistribution of Yttrium-90 (⁹⁰Y)-ibritumomab tiuxetan, we conducted a phase I study combining a single course of ⁹⁰Y-ibritumomab tiuxetan after a 4-weekly course of rituximab in relapsed or refractory low-grade or transformed CD20+ B-cell NHLs with <25% marrow involvement. The 0.4 mCi/kg dose was associated with 80% grade-4 cytopenias. Dose escalation was held, and 6 patients were enrolled at a 0.3 mCi/kg cohort. As the 0.3 mCi/kg dose was well tolerated, the 0.4 mCi/kg cohort was expanded to 6 additional patients. In the expansion cohort, grade-4 cytopenia developed in 33%. Further dose escalation was held, and the maximum tolerated dose was determined at 0.4 mCi/kg. With this regimen, marrow involvement decreased in all patients with complete clearance in 50%. The overall response rate was 82%. With a median follow-up of 31.7 months, the median progression-free survival and time to next treatment were 12.3 and 10.9 months, respectively. Although this regimen was associated with a high response rate, the hematologic toxicity was higher than with the standard ⁹⁰Y-ibritumomab tiuxetan regimen.

Bulky Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma Treated with Yttrium-90 Ibritumomab Tiuxetan

An 84-year-old woman was admitted to our hospital with nonproductive cough and dyspnea on exertion. Computed tomography (CT) scan revealed extensive consolidation in the right lung. She was diagnosed with pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma using CT-guided lung biopsy. Her pulmonary images and respiratory symptoms did not improve two months after receiving 4 cycles of rituximab weekly; therefore, yttrium-90 ibritumomab tiuxetan was chosen as salvage therapy. The abnormal shadow on her pulmonary images was significantly reduced two months later, and she had no symptoms without nonhematological toxicities. She has had no progression for 18 months. Furthermore, radiation pneumonitis has not also been observed. We herein reported bulky pulmonary MALT lymphoma treated with yttrium-90 ibritumomab tiuxetan.

Upfront Consolidation Combining Yttrium-90 Ibritumomab Tiuxetan and High Dose Therapy with Stem-Cell Transplantation in Poor Risk Patients with Diffuse Large B-Cell Lymphoma

AbstractAbstract ▪812▪This icon denotes a clinically relevant abstract Background:High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is considered as a relevant option for upfront consolidation in patients with poor risk aggressive lymphomas (Fitoussi, hematologica 2011; 96(8):1136-1143). Adding Y90-Ibritumomab Tiuxetan to BEAM regimen would improve outcomes in relapse or refractory lymphomas. We evaluated the safety and efficacy of standard-dose Y90-Ibritumomab Tiuxetan combined with high-dose BEAM after first line induction treatment in patients under 65 years of age with poor prognosis diffuse large B-cell lymphoma (DLBCL). (clinicaltrials.gov: NCT00689169). Methods and Patients:Pathologically proven CD20+ DLBCL patients, 18–65 years of age, with IPI ≥ 2, in CR, CRu or PR according to the IWG 1999 criteria after rituximab-containing induction therapy were included. Patients received Rituximab 250 mg/m2 on d-21, Rituximab 250 mg/m2 followed by Y90-Ibritumomab Tiuxetan 0.4mCi/kg on d-14, BEAM started on d-7 followed by ASCT. FDG-PET scans evaluated using Juweid criteria were performed before transplant in all patients, but were not decisional. Patients were analyzed by immunochemistry for CD10, BCL6, MUM1 and BCL2 expression. End of treatment assessment was done at day 100 (D100). The primary end point was event-free survival (EFS) at 2 years. Results:Seventy five consecutive patients were enrolled from August 2007 to December 2008. Median age was 49 years (19–64) with 7 pts (9%) older than 60 years. The IPI score was 2 in 28 pts (37%) and >2 in 47 pts (63%), bulky disease ≥ 10 cm in 29 pts (39%) and mediastinal involvement in 20 pts (26%). Thirty six patients received 4 (14 pts) or 6 (22 pts) cycles of R-CHOP and 39 had 4 cycles of R-ACVBP as induction treatment. After induction, 63 patients (84%) were in CR or CRu and 12 (16%) were in PR, 21 pts (28%) presented with positive PET. Four pts progressed before they completed the treatment including 2 with positive PET. Median follow-up was 34 months for the 71 patients eligible for analysis. Median time to reach a neutrophil count > 500/μL and platelet count > 20 000/μL was 11 days. Neutropenic fever (100%) and mucositis (78%) occurred in most patients. Other adverse events (AE) were usually mild to moderate in severity. Twenty three AE were reported as serious, mostly infection (n=9). One of them was fatal due to septic shock. The 2-yr EFS and overall survival (OS) was 79% (95% CI: 67–88%) and 83% (95% CI: 70–88%) respectively. Fourteen pts relapsed including 9 before D100. The Overall Response Rate (CR+CRu+PR) was 83%, 59 patients (81%) achieved a CR/CRu, 2 pts were in PR. The 2-year DFS was 91% (95% CI: 80% – 96%). There were no differences in OS (p=0.9) and EFS (p=0.8) between patients in CR/Cru or in PR. Positive PET imaging before transplant did not predict treatment failure. Nineteen pts with positive PET after induction were consolidated with Y90-Ibritumomab Tiuxetan and BEAM, one died of sepsis, 18 achieved a CR/CRu and 3 relapsed at 9, 14 and 20 month. Mediastinal involvement, non-GCB phenotype and high BCL2 expression did not affect outcome. IPI score (2 v >2) and bulky disease at diagnosis appeared to be prognosis factors for OS: 96% v 75% (p = 0.02) and 91% v 70% (p=0.02) respectively, but not for EFS: 2 years EFS 89% v 73% (p = 0.09) and 84% v 70% (p=0.1) respectively. Conclusions:Adding Y90 Ibritumomab Tiuxetan to BEAM is safe without an increase in transplant-related toxicity. First line consolidation with Y90 Ibritumomab Tiuxetan and HDT induced high rates of EFS and OS in poor prognosis patients with DLBCL irrespectively of PET status after induction treatment and warrants randomized study. Disclosures:Gisselbrecht:roche: Consultancy, Research Funding; baxter: Research Funding.

The Risk of Secondary Myelodysplastic Syndrome/Acute Leukemia and Second Malignancy Following Yttrium-90 Ibritumomab Tiuxetan: 10-Year Single-Institution Experience of 138 Consecutive Patients

Abstract 4876Here we report one single centre experience with 90Y Ibritumomab tiuxetan in order to investigate the incidence of treatment-related myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) or second malignancies after90Y Ibritumomab tiuxetan.From 2001 to 2012 a total of 138 patients received radioimmunotherapy (RIT) with 90Y ibritumomab tiuxetan at European Institute of Oncology; 35 patients had Diffuse Large B Cell Lymphoma (DLBCL), 8 Mantle Cell Lymphoma (MCL), 61 Follicular Lymphoma (FL), 4 transformed FL, 27 Marginal Zone Lymphoma (MZL), 1 transformed MZL, 1 lymphoplasmacytoid lymphoma and 1 Burkitt. At time of treatment patients had a median age of 63 years (range, 21–85), 67 female and 71 male. They had received a median of 3 prior therapies (range, 1–11), including Rituximab, Radiotherapy and High Dose-Chemotherapy. 90Y Ibritumomab Tiuxetan was administered at the activity of 14.8 MBq/kg in 98 patients, at 11.1 MBq/kg in 14 patients due to mild thrombocytopenia. Two patients had received 90Y Ibritumomab Tiuxetan at further relapse (respectively 14.8 MBq/kg and 11.1 MBq/kg). In an experimental program - where PBSC transplantation was performed - an activity of 30 MBq/kg was delivered in 4 patients, 45 MBq/kg in 6 patients and 56 MBq/kg in 16 patients. After RIT 65 patients underwent further treatments due to relapse or progression, 7 patients underwent SC mobilization – with successful collection in 4 patients - and autologous transplantation.With a median follow-up of 3 years (range 0–10.3), 2 patients developed MDS (they had received 30 and 45MBq/kg respectively) and 3 patients AML (2 patients had received 14.8 MBq/kg, 1 patient 56 MBq/kg), with an incidence of 3.6%. Events occurred at a median of 8 years (range, 6–10) after diagnosis of NHL and 3.8 years (range 2–5) after RIT. Multiple cytogenetic aberrations detected - principally involving chromosome 7 and 5 - time from diagnosis and previous treatments received, all support the correlation with previous CT as the result of cumulative damage rather than it being directly related to RIT. Finally 4 patients developed second malignancy with an incidence of 2.9%.CONCLUSION: RIT does not appear to significantly increase the risk of second malignancies. These data suggest that the damage that leads to the development of second malignancy is probably cumulative and multifactorial. The incidences of MDS, AML or second tumors after 90Y Ibritumomab tiuxetan are consistent with that expected if we consider the patients' treatment history. However a preliminary assessment of patient characteristics may help in identifying those most at risk: cytogenetic testing should be performed before RIT to verify pre-existing chromosomal abnormalities in heavily pretreated patients, in elderly patients and those previously exposed to alkylating agents or purine nucleoside analogs. Disclosures:No relevant conflicts of interest to declare.

High Incidence of tMDS in Elderly Lymphoma Patients Subjected to Radioimmunotherapy

AbstractAbstract 4882 Background:Conventional therapies with cytotoxic agents for disseminated NHL are associated with a high risk of therapy related myeloid neoplasm (tMN). The latency period between exposure to this agents and development of tMN ranges from one to 10 years.Radioimmunotherapy (RIT) uses monoclonal antibodies, specifically binding to antigens of tumor cells, as a carrier for the radioisotope. The radiation is delivered not only to the antibody –bound tumor cell, but also neighboring cells. Methods:In the years 2005–2011 radioimmunotherapy with ibritumomab tiuxetan was used in 102 patients with FL (during consolidation therapy), MCL (as consolidation of the first-line treatment and after achieving PR in the first- or second-line therapy), DLBCL and MCL (in the HDT supported by auto-SCT). 5 patients (4,9%) ( 4 with MCL/ 1 with FL) subjected to RIT developed tMDS. All patients with MCL in previous treatment were exposed to alkylating agents, antymetabolites and inhibitors of II topoisomerase. All patients had hypoplastic bone marrow year after RIT. Results:Median time to diagnosis of tMDS after treatment with RIT was 2,3 years. 4/5 during 6 month transformed into tAML. In peripheral blood of all patients anemia, thrombocytopenia or pancytopenia was observed. All patient in histophatology had dysplastic changes in 3 hematopoetic lines with 5% blast cells, without elevated percentage of ring sideroblasts. Each patient had typical for tMDS complex abnormalities with monosomy of chromosome 5 or 7, or abnormalities of this chromosome [table 1]. Three of this patients was treated with azacitidine, one of this patients was prepared to RIC allo BMT but developed tAML and died during induction therapy. All patients received supportive care.Tab 1Cytogenetic changesP 143-44,XY,del(3)(p21),-5,-7[4]/43,sl,-12,add(21)(q22)[10]P 247,XX,+11,add(17)(q25)P 342-45,XY,del(3)(p21),-5,r(7)(p22p12),del(12)(p11p13),-15, +mar1,+ mar2 [25cp]P 445,XX,-7,-16,-19,+mar1,+mar2[6]P 545,X,-X,del(5)(p12p35),add(12)(p13) Conclusion:The development of secondary hematological malignancies (tMDS and tAML) after RIT is very closely related to the drugs applied in the induction treatment especially purine analogues. Higher incidence of tMDS in patients with MCL confirm the relationship of occurrence of secondary MDS and AML after radioimmunotherapy with the earlier use of purine analogs (fludarabine) and cumulative damage to bone marrow cells rather than exclusively associated with administration of RIT. Disclosures:No relevant conflicts of interest to declare.

Delayed Immune Reconstitution After Allogeneic Hematopoietic Cell Transplantation with Yttrium-90 Ibritumomab Tiuxetan-Based Reduced-Intensity Conditioning

AbstractAbstract 4482 Introduction:Allogeneic hematopoietic cell transplantation (HCT) following reduced-intensity conditioning (RIC) including radioimmunotherapy (RIT) with yttrium-90 ibritumomab tiuxetan is a potential salvage treatment for patients with advanced high-risk B-cell lymphoma. The influence of RIT combined with RIC on immune reconstitution after allogeneic HCT has not been evaluated. Methods:We compared data on immune reconstitution of 14 patients receiving allogeneic HCT after RIT-RIC at our institution from 2006 to 2008. Yttrium-90 ibritumomab tiuxetan as RIT and RIC with either fludarabine (30 mg/m2, day −8 to −4)/melphalan (140 mg/m2, day −3)/alemtuzumab (20 mg for related donors and 30 mg for unrelated donors, day −3 and −2) (n=7, FLU/MEL/AL-RIT group) or fludarabine (30 mg/m2, day −4 to −2)/2 Gy total body irradiation (day 0) (n=7, FLU/TBI-RIT group) were used. Immunosuppression consisted of cyclosporine A alone (FLU/MEL/AL-RIT group) or cyclosporine A combined with mycophenolate mofetil (FLU/TBI-RIT group). The results were compared to 14 patients in a concurrent control group with similar conditioning regimens without RIT (n=7, FLU/MEL (without alemtuzumab); n=7, FLU/TBI). Differences in engraftment and immune reconstitution were evaluated. Results:Diagnoses in the RIT groups were high-grade NHL (n=6), low-grade NHL (n=6) and CLL (n=2). In the control groups diagnoses were high-grade NHL (n=4), acute leukemia (n=6), MDS (n=1), multiple myeloma (n=1), Hodgkin’s lymphoma (n=1) and CLL (n=1). Neutrophil engraftment (>500/μl) was observed after a median of 20 days (range 13–26) in the FLU/MEL/AL-RIT-group compared to 15 days (range 11–21) in the control group (p=0.11). After a median of 13 days (range 7–17) and 12 days (range 8–27) neutrophil engraftment was noted in the FLU/TBI-RIT group and control group, respectively (p=0.40). Median time to thrombocyte engraftment (>20,000/μl) was 11 days (range 8–42) in the FLU/MEL/AL-RIT-group and 21 days (range 5–29) in the control group (p=0.81). After a median of 10 days (range 7–16) and 11 days (range 10–35) thrombocyte engraftment was noted in the FLU/TBI-RIT group and control group, respectively (p=0.23). Immune reconstitution in the four groups is shown in Table 1:FLU/MEL/AL-RITFLU/MELFLU/TBI-RITFLU/TBIdaycells/μl median (range)p=cells/μl median (range)p=CD3+ T-cells+10065 (38–201)239 (92–353)0.06405 (247–7452)483 (301–909)0.27+500820 (117–994)1409 (422–2532)0.13465 (261–4481)536 (10–2553)0.49CD3+4+ T-cells+10057 (22–81)73 (35–99)0.36189 (85–1105)251 (27–337)0.32+50090 (27–151)184 (72–366)0.22102 (42–951)186 (3–257)0.26CD3+8+ T-cells+10013 (4–126)139 (33–218)0.08214 (84–6181)251 (137–539)0.27+500240 (13–271)732 (72–1469)0.09100 (35–2917)215 (2–2062)0.67CD19+ B-cells+1000 (0–1)9 (0–190)0.202 (0–46)45 (4–155)0.07+50056 (3–891)174 (1–520)0.65140 (8–440)83 (5–851)0.60CD16+56+ NK-cells+10060 (39–1170)176 (112–1199)0.80153 (59–631)209 (39–435)1.00+500303 (77–837)275 (46–676)0.79269 (58–2102)81 (2–214)0.25Regeneration of CD3+8+ T-cells on day +100 and day +500 was significantly (p<0.10) reduced in the FLU/MEL/AL-RIT group compared to the FLU/MEL control group (p=0.08 and p=0.09) while no difference was observed between the FLU/TBI-RIT and the FLU/TBI group. No significant long-term difference in recovery of the CD19+ B-cells was observed although early B-cell levels on day +100 were reduced in the RIT groups. Conclusion:Not the use of yttrium-90 ibritumomab tiuxetan alone but its combination with alemtuzumab leads to a significantly slower immune reconstitution after allogeneic HCT. Disclosures:Off Label Use: Off-label conditioning regimen.

Phase I Trial of Combination Therapy with 90y Ibritumomab Tiuxetan and Gemcitabine in Patients with Non-Hodgkin's Lymphoma, Final Report.

AbstractAbstract 2753Y90-ibritumomab tiuxetan radioimmuotherapy (Y90-RIT) is an effective therapy against CD20+ lymphomas approved for use in patients (pts) with relapsed/refractory low grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL), as well as consolidation of first remission low grade NHL. Gemcitabine (Gem) also is active against NHL and is a potent radiation sensitizer. We conducted a phase I trial to assess the safety of concomitant administration of Y90-RIT and G in patients with NHL. Eligible pts had any histologic subtype of recurrent CD20+ NHL (not candidates for potentially curative options) and met standard Y90-RIT criteria: platelets 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to <25% of bone marrow and no prior bone marrow or stem cell transplant. Initially, nine pts in three cohorts were treated with 250 mg/m2 of Gem IV on days 1 and 8 of the Y90-RIT treatment program (rituximab + 111In-ibritumomab day 1 and rituximab + Y90 ibritumomab day 8), with Y90-RIT at 0.2, 0.3 or 0.4 mCi/kg respectively. We confirmed that a standard Y90-RIT dose of 0.4 mg/kg can be safely administered with Gem at 250 mg/m2. In subsequent cohorts, escalating doses of Gem were used according to a Bayesian based system. Response evaluation was by CT scan criteria (IWG JCO 1999). Between 2004–2012, twenty pts were treated (10 follicular (FL), 3 marginal zone (MZL), 7 diffuse large B-cell (DLBCL) lymphomas). Median age is 71.5 (range 55–82). The median number of prior treatments is 3 (range 1–6). Gem doses ranged from 250 mg/m2 to the maximum planned dose of 800 mg/m2 on days 1 and 8. One DLT occurred (thrombocytopenia) and MTD was not reached. Treatment-related toxicities consisted of grades 3 (N=11) and 4 (N = 2) neutropenia, grade 3 (N=11) leukopenia, grades 3 (N=14) and 4 (N=8) thrombocytopenia. One grade 3 infection occurred, unrelated to study drugs. All pts recovered counts to ≤ grade 1 by week 12. The only grade 3 non-hematologic toxicity was elevated bilirubin in 1 and increased GGT in 2 pts. Best responses seen include: 3 CR/CRu, 7 PR, 4 SD, 4 PD and 2 patients still in follow up. Median PFS for all patients is 192 days. Median PFS for all non-DLBCL histologies (10 FL and 3 MALT) is 202 days and for DLBCL is 77 days. Conclusion:Standard dose Y90-RIT combined with gemcitabine days 1 and 8 is safe and well-tolerated at doses up to 800 mg/m2 in pts with relapsed/refractory NHL. Further investigation with the established doses in non-DLBCL histologies is warranted. Disclosures:Borghaei:Biogen-IDEC: Research Funding. Off Label Use: 90Y Ibritumomab Tiuxetan in relapsed DLBCL. Schilder:Biogen-IDEC: Research Funding. Smith:Biogen-IDEC: Research Funding.

RIT with 90Y Ibritumomab Tiuxetan in Agressive Non-Hodgkin Lymphoma. Evaluation of Recent Outcomes in a Single Institution

Abstract 4883Diffuse Large B Cell (DLBC) and Mantle Cell Lymphoma (MCL), are two subtypes of aggressive non-Hodgkin lymphoma (A-NHL),that frequently present as advanced systemic disease limiting the use of involved field radiation. They are also predominant in advanced age population non suitable for intensive therapy such as stem cell transplantation. Their aggressive systemic behavior, confer high rates of relapse and short overall survival. The development of radioimmunotherapy brings a new therapeutic approach for both types of A-NHL. We present the results derived from a single-institute use of 90Y-Ibritumomab Tiuxetan (90Y-IT) (Zevalin®) in DLBC and MCL, both as consolidation therapy in first complete response (C-1CR) after chemoimmunotherapy and as second line treatment in relapsed disease (RD). Patients and Methods:we included 19 patients with A-NHL, 10 MCL and 9 DLBCL, treated with 90Y-IT according to a multidisciplinary clinical protocol, between September 2005 and February 2012. Inclusion criteria were: histological confirmed CD20+ MCL or DLBCL, with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, absolute platelet count (APC) ≥ 100 × 109/L, ≤ 25% bone marrow CD20+ lymphocytes, in Complete Remission (CR) after first line chemoimmunotherapy or with relapsed disease. All patients received two prior 250 mg/m2 Rituximab doses, followed by 0.4 mCi /kg IV 90Y-IT. Response was evaluated by PET/TC 12 weeks after treatment. Major endpoints were: objective response rate (ORR), overall survival (OS), progression free survival (PFS), and safety. Other clinical prognostic factors were taken into account upon their possible influence in treatment value. Results:18 of 19 patients treated with 90Y-IT completed follow-up and were taken into analysis, 10 MCL (52.6%) and 9 DLBCL (47.4%); M/F distribution 10/9 (73.6/26.4%); Overall ECOG 0–1 82.35%. Mean follow-up time: 46.8 months. 8 patients were treated as C-1CR, 4 MCL and 4 DLBCL. For MCL mean age was 66.9 (53–79) years. MIPI score distribution: 0–3 (70.0%), >3 (30.0%). Status before 90Y-IT was: C-1CR 3; relapsed in CR after chemotherapy 3; relapsed/refractory with active disease after chemotherapy (PR) 4. Previous chemotherapeutic schedules: ≤2 (50 %). Overall response (80.0%) 7 CR; 1 PR. Mean estimated OS since 90Y-IT: 57.0 months (52.4–61.6), median OS: 59 months (34.8–86.1) and mean PFS: 24.9 months (95% CI: 14.3–35.6); median PFS: 22 months (95% CI: 1.9–42.0). For DLBCL: mean age 53 (35–87) years. IPI-R score distribution: 0–2 (33.3%), >2 (66.7%). Status before 90Y-IT was: C-1CR 5; relapse/refractory with active disease after chemotherapy (PR) 4; Previous chemotherapeutic schedules ≤2 (77.8%). Overall responses (88.8%) 5 CR; 3 PR. Mean OS since 90Y-IT: 49.2 months (42.8–55.6); median OS: NR and mean PFS: 39 months (95% CI: 22.6–55.4). Until analysis 11 patients have relapsed (57.8%), 8 MCL (80%) and 3 DLBCL (37.5%). Four patients had died, 3 because of disease progression even after several chemotherapeutic treatments. In respect to safety: thrombocytopenia was the most frequent hematologic toxicity presented in 63.1%, grade 3–4 in 21%, with median time to presentation of 2.8 weeks and median time for recovery of 3 weeks. Neutropenia occurred in 52.6%, grade 3–4 in 21%, with median time for recovery of 2 weeks. 1 patient (5.2%) required red cell transfusion and 4 (21.5%) needed platelet transfusion. The most frequent non hematologic toxicity was asthenia. One MCL patient who relapsed 28 months and received 2 more chemotherapy schedules has been diagnosed, four years after 90Y-IT as lung carcinoma. Conclusions:90Y-IT is a safe and effective consolidation therapy in A-NHL, that allows sustained CR and extends PFS with a low toxicity profile. There are needed further studies to evaluate the impact of radioimmunotherapy in A-NHL.This worh has bee partially sponsored by a grant from FEHHA Disclosures:No relevant conflicts of interest to declare.

RIT with 90Y Ibritumomab Tiuxetan in Patients with Non-Hodgkin Lymphoma Over 65 Years.

Abstract 2742 Introduction:90Y Ibritumomab tiuxetan (90Y-IT) has become an efficient alternative to therapy in non-Hodgkin Lymphoma, mainly in elderly patients. The aim of this study is to analyse our updated information of patients treated with 90YIbritumomab/tiuxetan in a prospective study according clinical practice setting and to analyse treatment outcome. Subjects and Methods:39 non Hodgkin lymphoma patients were included in a clinical protocol conducted by a multidisciplinary team and treated in the same centre. According the inclusion criteria: patients over 65 years old diagnosed as CD20+ NHL with neutrophils ≥ 1,5 × 109/L, platelets ≥ 100 × 109/L, bone marrow lymphocytes CD20+ ≤ 25%. All patients received 0,3 or 0,4 mCi /kg IV (88%) of 90YIbritumomab/tiuxetan and response evaluation was performed 12 weeks after. Period of study: September 2005/July 2012. The 90Y-IT was administered as consolidation of first line therapy (Rituximab alone, R-COP, R-CHOP21) or in relapsed/refractory status. Endpoints:Objective response rate (ORR), time to relapse (PFS) overall survival (OS) and safety. Other clinical prognostic factors were observed to assess their possible influence upon treatment value. Results:Until May 2012, 39 patients had received treatment with 90YIbritumomab/tiuxetan and completed the evaluation protocol and were considered to analysis; M/F 18/21 mean age 72.8 years (65–87); ECOG 0–1 92.3%. According OMS classification: NHL-follicular 27 (69.2%), mantle cell Lymphoma 7 (17.9%), DLBCL 4 (10.3%) and 1MALT (2.6%). Score distribution: low risk 19 (48.7%), intermediate 12 (30.8.2%) and advanced 8 (20.5%). Previous therapy schedules ≤2 (66.7%), >2 (33.3%). The median follow-up time: 42.0 months (95% CI: 4.0; 62.0), mean PFS: 38.1 months (95% CI: 30.8; 45.4) median NR. 13 patients received 90Y-IT as consolidation of first line therapy (33.3%) and 26 relapsed/refractory (66.6%). ORR was 84.6 % CR: 29 (74.3%); PR 4 (10.2%) and 6 failures (15.4%) in relapsed/refractory disease. Mean estimated OS since 90Y-IT: 54.4 months (95% CI: 49.4; 59.3) and mean estimated OS since diagnosis 159 months. Median PFS was NR. The mean PFS for patients in consolidation therapy was 54.2 months (95% CI: 47.4; 61.1). Safety: thrombocytopenia being the most frequent, G3–4 (35.9%), median time to developed haematological toxicity: fourth week, and neutropenia G3–4 (41.0%), the median time to recover normal values was 4.2 and 2.6 weeks respectively. In 5 (12.9%) of patients red blood cell transfusion was required, and 10 platelet transfusions (25.6%). The most frequent non haematological toxicity was asthenia. One patient developed a severe mucositis. Four patients have concomitant associated tumours (colon, breast, lung and prostate) and two patients over 77 years developed a rectum carcinoma after 18 months of 90Y-IT and another prostate and renal tumour after 8 years. Comments:In our experience 90Y Ibritumomab tiuxetan is a safety and effective therapy in patients with NHL over 65 years. According to obtained PFS results, it seems like the use of this kind of therapy as used in early part of therapy offers good and maintained response rate with lower toxicity in this fragile population. The OS in this population was not inferior to observed in younger NHL patients. Disclosures:No relevant conflicts of interest to declare.

90-Yttrium Ibritumomab Tiuxetan (Zevalin) and BEAM Chemotherapy (Z-BEAM) Vs BEAM for Autologous Stem Cell Transplantation in Lymphoma: Toxicity and Long Term Outcome From a Retrospective Multicentric Study of 123 Patients.

AbstractAbstract 2726 Background.There is a need for improving conditioning regimens in poor risk Non Hodgkin Lymphoma (NHL) patients (pts) eligible for autologous stem cell transplantation (ASCT). Incorporating radioimmunotherapy in the conditioning is an option. Bexxar-BEAM does not appear to be superior to BEAM in relapsed Diffuse Large B –cell lymphoma (DLBCL). The benefic risk ratio of 90-yttrium ibritumomab tiuxetan (Zevalin) BEAM remains to be established. Aims and methods.We analyzed retrospectively the efficacy and the toxicity of Zevalin combined with BEAM chemotherapy (Z-BEAM) compared with BEAM alone followed by ASCT. From January 2000 to November 2004 (BEAM group) and from June 2005 to December 2011 (Z-BEAM group), 55 and 68 pts respectively were treated in 6 French centers (male n=78, female n=45). Zevalin was administered on day-14 prior to ASCT with standard dose of 0.4 mci/kg (n=32) or 0.3 mci/kg (n=36) chosen according to bone marrow reserve. The efficacy and toxicity were compared between the two groups. Results.The study included 123 pts (median age: 53 years old; range 21–69) with different histological subtypes (58 DLBCL, 19 Mantle cell lymphomas, 37 follicular lymphoma, 3 marginal zone lymphoma, 4 MALT lymphoma and 2 B-lymphocytic lymphoma). Fifty-four pts were treated in first line (20 in the Z-BEAM group and 34 in the BEAM group) and 69 pts in second line (Z-BEAM, n=48; BEAM, n=21). The median time to platelets engraftment (>20000/mm3) was 9 days and 10 days in the Z-BEAM and BEAM group respectively (p=0.334), and the median time to neutrophil engraftment (>500/mm3) was 11 days and 12 days respectively (P=0.117). Grade 3/4 infectious events were more frequent in the Z-BEAM group (80.9%) than in the BEAM group (56.4%), p=0.0001. Grade 3/4 mucositis were observed in 42.6% in the Z-BEAM group Vs 12.7% in the BEAM group (p<0.0001). Admissions to intensive care unit were more frequent in the Z-BEAM group (20.6%) than in the BEAM group (7.3%), p=0.038. Transplant-related mortality (TRM) occurred in six (8.8%) patients in the Z-BEAM group and only one patient (1.8%) in the BEAM group (P=0.071). Median follow up was 73 months in the BEAM group (range 3.1–141 months) and 31 months in the Z-BEAM group (1.4–80.9 months). The 3-years OS is 80% (95%CI, 69–89%) and 78.1% (95%CI, 64.5–88%) in the Z-BEAM and the BEAM group respectively (P=0.864), and 3-years PFS was 65% (95%CI, 56–79%) and 63.4% (95%CI, 51–77%) respectively (P=0.539). Outcome was not statically different with Age (>60 y.o), histological subtype, first line treatment Vs second line, or IPI (0–1 Vs 2–3). In a subset analysis of the Z-BEAM group, female gender was associated with worse outcome; 3 years-OS was 69% (95%CI, 48–85%) in female and 93% (95%CI, 79–98%) in male (p=0.042); 3 years-PFS was 54% (95%CI, 34–73%) in female and 81% (95%CI, 65–91%) in male (p=0.032). Those results may be linked to a higher TRM, 23.1% Vs 0% (P=0.002), more respiratory complications 23.1% Vs 4.8 % ( P=0.047) and more admissions to intensive care unit 46,1% Vs 2 % (P< 0.0001) in female than in male group respectively. Conclusions.Z-BEAM is possibly as effective as BEAM alone as a conditioning regimen for ASCT with an increased toxicity. Surprisingly, our series report for the first time an increased toxicity and TRM in female. A longer follow up is needed to asses this results. Disclosures:No relevant conflicts of interest to declare.

Monte Carlo Modeling of the Metastatic Formation of a Patient Treated With a Single Dose of Ibritumomab Tiuxetan: The Case for Radionuclide Combinations of Different Path Lengths

Radionuclides deposit energy over a known range, relative to their mean energy emission spectrum. Therefore, radionuclides with different path lengths will maximally sterilize tumor spheroids of various sizes. To date, there has been no clinical correlate of this concept. The purpose of this project is to measure the metastatic formation mass of a patient with NHL treated with a single instillation of ibritumomab tiuxetan and compare the result to an accepted metastatic formation model. This information will help elucidate the impact of therapy with radionuclides of a known path length.

O1-045 - Clinical Outcome of Radioimmunotherapy with ASCT (Z-Leed) for Relapsed and Refractory B-Cell Lymphoma

ABSTRACT Background Rarioimmunotherapy (RIT) with 90-yttrium ibritumomab tiuxetan (90Y-IT) is known to be an effective approach for treatment of NHL, because lymphoma is highly radiosensitive, however, 3-year progression-free survival in our department is 39.1% (overall survival is 79.9%), which is not sufficient considering the cost-effectiveness. Consolidation therapy with RIT is another attractive approach; however, bone marrow suppression is a major and life-threatening issue for especially aged patients. In view of these findings, we employed RIT (90Y-IT) followed by HDT (LEED) in patients with relapsed and refractory B-cell lymphoma. In this report, we tried to evaluate the safety and efficacy of RIT using ibritumomab tiuxetan (Zevalin) combined with high-dose LEED chemotherapy and ASCT (Z-LEED) in refractory/relapsed B-cell lymphoma. Patients and methods Eight patients with relapsed or refractory B-cell lymphoma (three mantle cell lymphoma patients and five grade III FL/DLBCL patients) were treated with Z-LEED. After PBSC mobilization and harvesting, the minimum target dose of CD34+ cells (2 × 106/kg) was stored. Patients were 111In ibritumobab tiuxetan (185 MBq IV) on day 1, followed by 90Y-IT (14.8 MBq/kg IV] administration on day 8 after rituximab. Then high-dose chemotherapy was delivered using the LEED (500 mg/m2 etoposide on day 4, 3, and 2; 60 mg/m2 cyclophosphamide on day 4 and 3; 130 mg/m2 mephalan on day 1; and 40 mg/m2 dexamethasone on day 4, 3, 2 and 1). Results Two patients had received more than three prior treatments, and three had chemotherapy-resistant disease. There were no therapy-related deaths. While one patient with conventionally measurable disease at the time of treatment, the respective complete and overall response rates were 100%. Seven patients remain CR at 2–27 months from transplantation and 8–102 months from diagnosis. One patient relapsed after 4 months from transplantation. Conclusion ibritumomab tiuxetan combined with LEED high-dose chemotherapy is safe and possibly effective as a conditioning regimen for ASCT.

JS3-5 - Efficacy of Radioimmunotherapy for Malignant Lymphoma; Further Possibility of Molecular Targeted Radionuclide Therapy in Oncology

ABSTRACT A recent advance in radiation oncology depends on a remarkable progress in external radiotherapy (RT) techniques including stereotactic irradiation (STI), three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and image-guided radiation therapy (IGRT). Precise RT planning and positioning has often been carried out with an error of ±1 mm for some patients; however, the accuracy is not enough for molecular targeting. Molecular imaging has been utilized for IGRT planning recently and is expected to develop molecular targeted radiotherapy. But, the majority of the imaging for clinical use is 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT, and it is actually difficult to delineate molecular target precisely using IGRT. Combination of external RT and molecular targeted agents appears to be reasonable compared with molecular targeted external RT. Radionuclide therapy is achieved by using radioisotopes (iodine-131, strontium-89, yttrium-90, etc.) that usually emit beta particles for selective delivery of radiation to target tumor cells or organs, but not always to molecules. Radioimmunotherapy is a type of radionuclide therapy that combines monoclonal antibody treatment and radiation therapy. An yttrium-90-labeled CD20-directed antibody (ibritumomab tiuxetan) is used for some types of B-cell non-Hodgkin lymphoma (follicular lymphoma, mantle cell lymphoma, etc.) The antibody binds to the CD20 antigen on the surface of B-cell lymphoma cells specifically and the radiation emitted from the radioactive isotope damages or kills the lymphoma cells and some nearby, and has often showed promising results for patients with relapsed or refractory lymphoma. This treatment is a typical radioimmunotherapy and sometimes classified as a molecular targeted radiotherapy. Further possibility of molecular targeted radionuclide therapy will be promising.

Unsuspected Pneumonia Detected by Increased Lung Uptake on 111In-Ibritumomab Tiuxetan Scan

99Y-ibritumomab tiuxetan (Zevalin) is a CD20-targeted radioimmunotherapy for the treatment of B-cell non-Hodgkin lymphoma approved by the FDA in 2002. The acquisition of an 111In ibritumomab tiuxetan scan (bioscan) to confirm normal biodistribution before treatment with 99Y-ibritumomab tiuxetan was initially required in the United States until November 2011. This is the first documented example of abnormal biodistribution due to unsuspected pneumonia detected by increased lung uptake on the bioscan. The pneumonia was treated and resolved before 99Y Zevalin, avoiding potential harm and indicating that a screening chest x-ray may be appropriate when a bioscan is not performed.

Phase II Study of Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Immunochemotherapy Followed by Yttrium-90–Ibritumomab Tiuxetan in Untreated Mantle-Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499

To test the hypothesis that consolidation therapy with yttrium-90 ((90)Y) -ibritumomab tiuxetan after brief initial therapy with four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated mantle-cell lymphoma would be a well-tolerated regimen that would improve outcomes compared with historical R-CHOP data. Patients ≥ 18 years old with histologically confirmed mantle-cell lymphoma expressing CD20 and cyclin D1 who had not received any previous therapy and had an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were eligible. The study enrolled and treated 57 patients, of whom 56 patients were eligible. Fifty-two patients (50 eligible patients) received (90)Y-ibritumomab tiuxetan. The study design required 52 eligible patients to detect a 50% improvement in the median time to treatment failure (TTF) compared with that reported for six cycles of R-CHOP. With 56 analyzed patients (median age, 60 years; men, 73%), the overall response rate was 82% (55% complete response/complete response-unconfirmed). With a median follow-up of 72 months, the median TTF was 34.2 months. The median overall survival (OS) has not been reached, with an estimated 5-year OS of 73% (79% for patients ≤ age 65 years v 62% for patients > age 65 years; P = .08 [log-rank test]). There were no unexpected toxicities. R-CHOP given for four cycles followed by (90)Y-ibritumomab tiuxetan compared favorably with historical results with six cycles of R-CHOP in patients with previously untreated mantle-cell lymphoma. This regimen was well tolerated and should be applicable to most patients with this disease.

Efficacy and safety of yttrium-90 ibritumomab tiuxetan in Japanese patients with non-Hodgkin lymphoma

The aim of this study was to evaluate the efficacy and side effects of radioimmunotherapies with Zevalin(®) (RIT-Z) in Japanese patients with low-grade B-cell non-Hodgkin lymphoma (NHL). Sixty-two patients with NHL were enrolled. Based on histology, 49 of the patients had follicular lymphoma and 23 had other lesions. The response was assessed at 8-12 weeks after RIT-Z injection with PET/CT. The overall response rate was 85 %. Thirty-seven (60 %) patients achieved complete remission, 16 (26 %) had partial remission, 4 (6 %) had stable disease, and 5 (8 %) had progressive disease. There was a significant correlation between the response to RIT-Z, frequency of chemotherapy, and history of prior treatment with fludarabine. There was no significant difference in efficacy according to lymphoma type, years since last chemotherapy, patient age, or disease stage at RIT-Z. Thrombocytopenia of grade 4 was significantly correlated with disease stage at RIT-Z and history of prior treatment with fludarabine. There was also no significant correlation between hematotoxicity and lymphoma type, frequency of chemotherapy, years since last chemotherapy, patient age, or history of bone marrow transplant. Anemia was significantly correlated with frequency of chemotherapy, history of bone marrow transplant, and history of prior treatment with fludarabine. The response rate was high, and we were able to decrease the hematologic side effects by using RIT-Z earlier.