Results of a Phase II Trial of Allogeneic Hematopoietic Stem Cell Transplantation Using 90Y-Ibritumomab Tiuxetan (Zevalin) in Combination With Fludarabine and Melphalan in Patients With High-Risk B-Cell Non-Hodgkin's Lymphoma

Allogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative for relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL). However, relapse remains a major cause of treatment failure. 90Y-Ibritumomab tiuxetan (Zevalin) is a radiolabeled anti-CD20 antibody which is safe and effective in multiple histo-logic subtypes of B-cell NHL and has been incorporated in transplant conditioning regimens. We conducted a phase II trial (NCT 00577278) of Zevalin in conjunction with fludarabine and melphalan in patients with high -risk B-NHL. We enrolled 41 patients, all of whom had either a fully matched sibling or 8/8 or 7/8 matched unrelated donor. All patients received tacrolimus and sirolimus with or without methotrexate for GVHD prophy-laxis. Two-year overall survival (OS) and progression-free survival (PFS) for all patients were 63% and 61%, respectively. The incidence of relapse at 2-year was 20%. Nonrelapse mortality at day + 100 and 1 year were 5% and 12%, respectively. The overall incidence of grade III-IV acute GVHD was 15% and extensive chronic GVHD was occurred in 44% of patients. On univariate analysis, histology (DLBCL vs. others) was negatively predictive for OS ( P = .0013) and PFS ( P = .0 0 04), while histology (DLBCL vs. others, P = .0128) predicted for relapse. PET positivity pre-HCT did not correlate with any of the efficacy endpoints. Addition of Zevalin to Flu/Mel was safe and effective in the overall cohort.Background: Allogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (B-cell NHL). However, relapse remains a major cause of treatment failure, especially in patients with either positron emission tomography (PET)-positive and/or chemoresistant disease prior to alloHCT. 90Y-ibritumomab tiuxetan (Zevalin) is a radiolabeled anti-CD20 antibody which is a safe and effective therapy in multiple histologic subtypes of B-cell NHL and has also been incorporated in both autologous HCT (autoHCT) and alloHCT conditioning regimens. Objectives: The purpose of this study was to evaluate the efficacy and confirm the safety of the radiolabeled anti-CD20 antibody ibritumomab tiuxetan (Zevalin) combined with the reduced intensity conditioning (RIC) regimen of fludarabine and melphalan (Flu/Mel) in patients with high-risk B-cell NHL. Study Design: We conducted a phase II trial ( NCT00577278 ) of Zevalin with Flu/Mel in patients with high-risk B-cell NHL. We enrolled 41 patients from October 2007 to April 2014, all of whom had either a fully matched sibling or 8/8 or 7/8 matched unrelated donor (MUD). Patients received 111 In-Zevalin (5.0 mCi) on day -21 pre-HCT, followed by 90Y-Zevalin (0.4 mCi/kg) on day -14. Fludarabine (25 mg/m2 daily) was given from days -9 to -5 and melphalan (140 mg/m2) was administered on day -4. All patients received rituximab 250 mg/m2 on day + 8 and an additional dose on either day + 1 or -21 depending on the baseline rituximab level. Patients with a low rituximab level were given rituximab on days -21 and -15. All patients received tacrolimus/sirolimus (T/S) with or without methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis starting on day -3, and stem cells were infused on day 0.Results: The 2-year overall survival (OS) and progression-free survival (PFS) for all patients were 63% and 61%, respectively. The incidence of relapse at 2 years was 20%. Nonrelapse mortality (NRM) at day + 100 and 1 year were 5% and 12%, respectively. The overall cumulative incidence of grade II-IV and III-IV acute GVHD (aGVHD) were 44% and 15%, respectively. Extensive chronic GVHD (cGVHD) occurred in 44% of patients. On univariate analysis, histology (diffuse large B cell lymphoma (DLBCL) vs. others) was negatively predictive for OS ( P = .0013) and PFS ( P = .0004), while histology (DLBCL vs. others, P = .0128) predicted for relapse. PET positivity pre-HCT did not correlate with any of the efficacy endpoints.Conclusion: Addition of Zevalin to Flu/Mel is safe and effective in high-risk NHL and met the prespecific endpoint. Results were suboptimal in patients with DLBCL.