A Phase II Trial of ⁹⁰Y-Ibritumomab Tiuxetan-Based Reduced Intensity Allogeneic Peripheral Blood Stem Cell (PBSC) Transplantation for Relapsed CD20+ B-Cell Non-Hodgkins Lymphoma (NHL).

Reduced intensity allogeneic transplantation offers a potentially curative option to NHL patients with chemorefractory disease or relapse following autologous transplant. The efficacy of this approach relies on the development of a graft-vs-lymphoma (GVL) effect by establishment of donor chimerism. GVL, however, is most effective for NHL in settings of stable, chemoresponsive, and non-bulky disease. Anti-CD20 radioimmunotherapy (RIT) has been shown to be safe and effective in the treatment of B-NHL. This phase II clinical trial was designed to evaluate the safety and efficacy of administering ⁹⁰Y-Ibritumomab Tiuxetan (Zevalin, Biogen-Idec) as part of reduced intensity allogeneic stem cell transplantation in order to safely provide disease control prior to the establishment of a GVL-effect that could maintain the remissions. Fourteen patients with relapsed or refractory CD20+ NHL and evaluable disease, who had too high-risk lymphoma for a routine non-ablative transplant and were not eligible for a traditional myeloablative transplant were treated with 0.4 mCi/kg ⁹⁰Y-Ibritumomab Tiuxetan (maximum 32 mCi) on day −14, followed by fludarabine (30mg/m2 on days −7 to −5), 2 Gy TBI on day 0, and HLA-matched related (n=8) or unrelated (n=6) allogeneic PBSC transplantation. Cyclosporine and mycophenolate mofetil were employed for graft-vs-host disease (GVHD) prophylaxis. Patient characteristics included: median age=57y (range 33–69y), median # of prior regimens=6 (range 3–12), prior autologous transplant=5 (36%), chemoresistant=100%, median tumor bulk=3.7cm, elevated LDH=5 (36%), baseline cytopenia (ANC<1000, plts<100K)=7 (57%), and >25% marrow involvement with NHL=5 (ranging from 30–85% NHL involvement). Histologies included: mantle cell=5, diffuse large B-cell=4, follicular=3, small lymphocytic=1, hairy cell=1. There have been no non-relapse-related deaths in the first 100 days, no graft rejections or failures, and all patients achieved >80% donor CD3/CD33 chimerism by 28 days after transplant. No patients developed ≥ grade 3 acute GVHD, though 7 experienced grade 2 GVHD. Three patients died following progressive NHL and 2 died after day 100 from GVHD and infection-related complications. The median platelet and neutrophil nadirs were 9×10³/μL and 50/μL, respectively. Responses to date include 3 complete responses (CR), and 4 partial responses (PR), including 1 CR, 6 PR, 3 stable disease by 1 month after transplant. With a median follow up of surviving patients of 6 months (range <1–18 months), 9/14 (64%) are alive and 7/14 (50%) are alive and progression-free. This study shows that standard-dose ⁹⁰Y-Ibritumomab Tiuxetan can safely be delivered as part of reduced intensity allogeneic transplantation regardless of preexisting bone marrow involvement and cytopenias. One-month response data suggest that this strategy may also prove useful in early post-transplant disease control, though the ultimate impact on long-term disease-free survival remains to be determined.