Immunologic Recovery Following Consolidation with 90Yttrium Ibritumomab Tiuxetan (Zevalin®)-BEAM and Autologous Stem Cell Transplantation for Transformed B Cell Non-Hodkgin’s Lymphoma
Authors: Wondergem Marielle J , Westers Theresia M , Visser Otto , Zijlstra Josee M , Zweegman Sonja , Chamuleau Martine ED 
Published: October 2019

Abstract
Introduction
Autologous stem cell transplantation (AuSCT) is widely used in patients with histologic transformation of indolent lymphoma. Although probably superior to standard chemotherapy, there is still room for improvement. We are currently studying the effect of the addition of 90Yttrium ibritumomab tiuxetan (Zevalin) to BEAM conditioning followed by an AuSCT on survival in a prospective phase 2 trial. It is known that, after rituximab-BEAM-AuSCT, recovery of T cells occurs after 4 months and of B cells after 9 months, with normal levels only being reached after 1 and 2 years, respectively. (1,2) It is however unclear if, in patients uniformly pre-treated with rituximab-chemotherapy, followed by BEAM and AuSCT, the addition of Zevalin further hampers immune reconstitution.
Materials and methods
Patients (n=14) with histologically proven transformed lymphoma were included in this prospective phase 2 trial when conditioning for AuSCT was started. AuSCT was planned when CR or PR was reached after (re)induction containing a minimum of 6 courses of rituximab (375 mg/m2) and chemotherapy. Patients subsequently received pre-doses of rituximab on day -15 and -8 (250 mg/m2), Zevalin on day -8 (0.4 mCi/kg) and BEAM conditioning on day -7 to -1, followed by AuSCT at day 0.
Blood samples were taken before the first predose of rituximab (day -15,t=0) and 3-6, 12-18 and 24-30 months after AuSCT. Absolute neutrophils were counted and samples were analyzed for NK-, B- and T-cell subsets using multicolor flowcytometry. T cells were defined using CD3 combined with either CD4 or CD8. NK cells were defined as CD45+, CD3-, CD56+ and/or CD16+, B cells as CD45+, CD3-, CD19+, memory B cells CD19+,CD27+.
Recovery was defined as: Neutrophils > 0.5 x 109/l, CD19+ B cells >0,07 x 109/l (CD27+ B cells >0,03 x 109/l) CD4>0,4 x 109/l,CD8>0,13 x 109/l, NK cell > 0,08 x 109/l. (1,2)
All infections after neutrophil recovery following AuSCT were registered. IgG levels were measured at baseline and after 2 years.
Results
A median of 3 (range 1-4) measurements were obtained depending on length of follow up. The median follow up was 26 months (range 3-30 months). Median time to neutrophil recovery was 22 days after AuSCT (range 17-29 days). As expected, patients were already severely B-cell depleted at start of consolidation (t=0, figure 1).B cells started to appear after nine months and reached (low) normal values after 12-18 months. T cell and NK cell recovery started after 3 months and took one year to normalize. (figure 1)
All patients had IgG levels >5 g/l after AuSCT, without support.
Only three infectious episodes were reported in 14 patients. In one patient an episode of herpes simplex virus infection with diarrhea was reported two months after AuSCT. In another patient a pneumonia was diagnosed two months after recovery from AuSCT (cultures stayed negative). Both had enough neutrophils but B cells and CD4 cells were not yet recovered. Both patients recovered completely after antiviral and empirical antibiotic and antimycotic therapy, respectively. One patient developed a herpes zoster virus infection at 2 years after AuSCT, recovering completely after antiviral therapy.
Conclusion
Compared to figures reported in literature (1,2), the addition of Zevalin to consolidation with BEAM and AuSCT after (re)induction with R-chemotherapy does not seem to lead to an increase of infectious complications or delayed immune-reconstitution as analyzed by T cell, B cell and NK cell recovery.
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Figure 1 Figure 1.

Disclosures
Wondergem: spectrum pharmaceuticals: Research Funding. Visser:spectrum pharmaceuticals: Research Funding.