Ibritumomab Tiuxetan (Zevalin) in the Conditioning Regimen for Autologous and Reduced-Intensity Allogeneic Stem-Cell Transplantation in Patients with Chemo-Refractory Non-Hodgkin’s Lymphoma.
Authors: Shimoni Avichai , Zwas Tsila , Oksman Yaacov , Hardan Izhar , Shem-Tov Noga , Yerushalmi Ronit , Avigdor Abraham , Ben-Bassat Isacc , Nagler Arnon 
Published: April 2020

Abstract
High-dose chemotherapy and autologous stem cell transplantation (SCT) has an established curative role in the treatment of patients (pts) with first chemosensitive relapse of aggressive lymphoma. However, autologous SCT has only limited success when performed at refractory or progressive stage of the disease and the expected 1-year disease-free survival (DFS) in this setting is less than 20%. Allogeneic SCT may offer some advantage by providing graft-versus-lymphoma effect, but outcome is still poor in refractory disease. This study was designed to explore the inclusion of Zevalin in the conditioning regimens given prior to autologous and reduced-intensity allogeneic SCT in pts with refractory lymphoma. Pts with chemosensitive first relapse or in any CR were not included. Bone marrow involvement and pancytopenia were not considered contraindications for treatment and dosimetry was not used. The study included 21 pts, median age 56 years (35–66). Histology was diffuse large B-cell (n=10), transformed low-grade (n=7), mantle cell (n=3), and follicular lymphoma (n=1). Disease status at SCT was primary refractory (n=8) and refractory relapse (n=13) and 12 pts had bulky disease at SCT. The median number of prior therapies was 3 (1–6), and 2 recipients of allogeneic SCT had a prior autologous SCT. Fourteen pts had autologous SCT and 7 had allogeneic (matched sibling-2, 1-Ag mismatched related-2, matched unrelated-3). Rituximab 250 mg/m2 followed by Zevalin 0.4 mCi/kg (max. 32 mCi) were given on day -14. Chemotherapy was started on day -6; standard BEAM prior to autologous SCT and the combination of fludarabine and intravenous busulfan (6.4 mg/kg) or melphalan (140 mg/m2) prior to allogeneic SCT. All pts engrafted with a median of 10 days (9–11) and 13 days (10–15) after autologous and allogeneic SCT, respectively. There were no early infusion reactions associated with Zevalin. Nine pts had neutropenia prior to day 0, an uncommon occurrence in similar non-Zevalin containing regimens. Fourteen pts achieved CR (3 after additional radiotherapy after SCT), 2 achieved PR and 5 are not evaluable (3 early death, 2 too early after SCT). With a median follow-up of 8 months (1–14), 15 pts are alive with an estimated 1-year overall survival of 63% (38–87), 75% after autologous and 44% after allogeneic SCT (p=NS). The 1-year DFS is 44% (13–77) after both autologous and allogeneic SCT. Only 3 pts progressed so far (the 2 with PR after SCT, and one who initially achieved CR). The 1-year cumulative incidence of relapse is only 27% (10–79). The cumulative incidence of non-relapse mortality was 21% (9–51), 14% after autologous and 36% after allogeneic SCT (p=NS). Three pts died of multi-organ toxicities (2 autologous, 1 allogeneic SCT recipients), one died of acute GVHD, and one of a late infection. These rates can be expected in a series of heavily pretreated pts with refractory lymphoma and there was no additional toxicity related to the inclusion of Zevalin in conditioning. In conclusion, the inclusion of Zevalin in the conditioning regimens given prior to autologous and reduced-intensity allogeneic SCT may reduce the risk of post SCT relapse and improve the poor outcome of pts with chemo-refractory lymphoma after SCT with standard regimens. This observation merits further study in larger comparative studies.