Yttrium-90 Ibritumomab Tiuxetan Is Feasible and Efficient in Unselected Patients. Definitive Results of a Large Retrospective Phase IV Study

In July 2004 in Europe, radioimmunotherapy (RIT) with Yttrium-90 Ibritumomab Tiuxetan ((90)Y-IT) obtained marketing authorization (MA) for follicular lymphoma (FL) in consolidation treatment in front line or relapse after rituximab treatment. Additional results also showed the potential interest of high-dose ((90)Y-IT) in monotherapy or in combination with intensive chemotherapy with autologous or allogeneic hematopoietic stem cell transplantation. Due to its particular toxicity profile (extended cytopenia and high rate of oral mucositis), the use of RIT in unselected patients is still debated. The aim of this retrospective cohort study was to evaluate the toxicity and efficacy of (90)Y-IT) in unselected consecutive adult patients treated for CD20+ B-type lymphoma.

Between January 2013 and December 2014, 102 patients at 25 Francophone centers were treated with at least one injection of (90)Y-IT. Median age was 62 years (range 32-87) and 36% were female. Sixty-one percent of patients had a low-grade B lymphoma. More than 80% of patients presented an advanced stage with bone marrow involvement in 25% of cases. ECOG performance status was <2 for 94 (92%) patients and 72 (78%) patients had a prognostic score >1. Nearly two thirds of diffuse large B-cell lymphomas (DLBCL) were GC-like. About half of the patients (51%) were treated with ((90)Y-IT) combined with high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine and melphalan) or BeEAM (bendamustine, etoposide, cytarabine and melphalan) followed by autologous stem cell transplantation (autoSCT). Median prior therapies was 1 (range 0-3). Eight (8%) patients were treated with ((90)Y-IT) combined with intensive chemotherapy (fludarabine, busulfan) and allogeneic stem cell transplantation (alloSCT): median prior therapies was 2 (range 1-4). Forty-two (41%) patients were treated with RIT in monotherapy: median prior therapies was 1 (range 0-3). Among the 42 patients treated with ((90)Y-IT) as consolidation, 6 (14%) did not receive chemotherapy before administration of RIT, 8 (19%) received R bendamustine, 12 (29%) RCHOP, 14 (33%) R DHAox and 2 (5%) received RFC regimen before RIT. The median time between diagnosis and first administration of ((90)Y-IT) was 22 months (range 1-281) and the median time between the last treatment received and the start of RIT regimen was 1 month (range 0-75).

In the autoSCT group, ((90)Y-IT) combined with BEAM or BeEAM, the post-RIT evaluation showed 45 (86%) complete responses (CR), 2 (4%) partial responses (PR), 4 (8%) stable disease (SD) and 1 (2%) progression (PG). The median time to onset of grade 3 or 4 anemia, thrombopenia and neutropenia was, respectively, 6 (range 1-90), 8 (range 3-90) and 10 days (range 6-90). Grade 3 or 4 oral mucositis occurred in 29 patients (56%). Interestingly, among patients treated with Z-Beam associated with amifostine (n=6), only one patient suffered from severe oral mucositis (17%). In the group of patients who underwent alloSCT, ((90)Y-IT) injection combined with fludarabine and busulfan, the post-RIT evaluation showed 4 (50%) CR, 1 (12.5%) PR, 1 (12.5%) SD and 2 (25%) PG. The median time to onset of grade 3 or 4 anemia, thrombopenia and neutropenia was, 12 (range 10-35), 15 (range 11-240) and 23 days (range 15-48), respectively. Severe oral mucositis (grade 3-4) occurred in 3 patients (37%). In the group of patients who underwent consolidation treatment, ((90)Y-IT) injection in monotherapy, the post-RIT evaluation showed 25 (60%) CR, 9 (21%) PR and 8 (19%) PG. The median time to onset of grade 3-4 anemia, thrombopenia and neutropenia was 70 (range 4-150), 80 (range 6-100) and 45 days (range 6-120), respectively. Grade 3/4 oral mucositis occurred in 1 patient (2%). The median follow-up time was 11 months (range 1-30). Median progression-free survival (PFS) and overall survival (OS) were 9 months (range 1-30) and 11 months (range 1-120), respectively.

These results confirmed, on a large retrospective series of unselected patients, the safety and efficacy of ((90)Y-IT) administered in monotherapy or in combination with intensive chemotherapy with autologous or allogeneic hematopoietic stem cell transplantation, without increased toxicity. For autologous bone marrow transplant, the use of amisfostine could lower the high-grade mucositis rate. However, further analysis of long-term outcome criteria such as PFS, OS and toxicities will be of interest in this series of patients.