Ibritumomab Tiuxetan (Zevalin) Followed by High-Dose Chemotherapy and Autologous Stem-Cell Transplantation Results in Improved Survival of Patients with Chemo-Refractory Non-Hodgkin’s Lymphoma Expected To Have Poor Outcome with Standard Pre-Transplant Conditioning.
Authors: Shimoni Avichai , Zwass Tsila , Oksman Yaacov , Hardan Izhar , Shem-Tov Noga , Yerushalmi Ronit , Avigdor Abraham , Ben-Bassat Isaac , Nagler Arnon 
Published: October 2019

Abstract
High-dose chemotherapy and autologous stem-cell transplantation (autoSCT) have an established therapeutic role in patients (pts) with chemosensitive relapse of aggressive lymphoma. However, autoSCT has only limited success when performed in refractory or progressive stage of the disease and in heavily pretreated or multiply relapsed pts. The expected long-term progression-free survival (PFS) in this setting is less than 20%. This study was designed to explore the safety and outcome following inclusion of Zevalin in the conditioning regimen given prior to autoSCT in pts with refractory lymphoma expected to have poor outcome with standard autoSCT. Pts with aggressive lymphoma were eligible for this study if they did not achieve CR with prior chemotherapy (either as initial treatment or after relapse) and had active disease by PET-CT. Unlike standard treatment with Zevalin, extensive marrow involvement and pancytopenia were not contraindications for therapy. The study uncluded 23 pts, median age 55 years (range, 35–66), a median of 12 months (5–129) from diagnosis. Histology was diffuse large cell (n=15), transformed low grade (n=7) and mantle cell lymphoma (n=1). Disease status was primary refractory disease (n=11) or refractory relapse (n=12). Fourteen pts had bulky disease at autoSCT. The median number of prior therapies was 3 (range, 1–6). Rituximab 250 mg/m2 followed by Zevalin 0.4 mCi/kg were given on day -14 and high-dose BEAM chemotherapy started on day -6. All pts engrafted in a median of 10 days after autoSCT (9–22). Zevalin had no impact on engraftment kinetics although 9 pts became neutropenic on or prior to the day of autoSCT, an uncommon occurrence with standard BEAM. There were no early infusion reactions associated with Zevalin. Two pts died of multi-organ toxicities early after SCT. One died from infection and one died of bronchiolitis obliterans (infection related) 4 and 5 months after SCT, respectively. The day100 rate of non-relapse mortality in these heavily pretreated pts with refractory lymphoma is 9% (95% CI, 2–33) and it seems there was no additional toxicity related to Zevalin. Overall, 21 pts are evaluable for response; 11 achieved CR, 9 achieved PR, 5 of whom converted to CR with additional radiation therapy to residual disease (overall 16 pts achieved CR), 1 pt did not respond. In all, seven pts relapsed or did not respond. The 1-year cumulative incidence of relapse is only 32% (95% CI, 17–60%). As expected in refractory disease, all relapses occurred within 6 months of autoSCT. With a median follow-up of 15 months (range, 4–25), 15 pts are alive. The estimated 1-year overall and progression-free survival were 59% (95% CI, 36–83%) and 49%, respectively, compared with less than 20% expected with standard autoSCT in this setting. In conclusion, inclusion of Zevalin in the conditioning regimen prior to autoSCT is relatively safe and may improve outcome in pts with refractory lymphoma. Although excess non-relapse mortality can not be ruled out, relapse rate was relatively low, resulting in improved PFS. Zevalin in combination with autoSCT merits further study in larger scale randomized studies. Moreover, standard risk pts with chemosensitive disease may also benefit from Zevalin followed by autoSCT combination.