Blinatumomab Is Well Tolerated Maintenance Therapy Following Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

Abstract

<h3>Background</h3> Patients (pts) with high-risk B-lineage acute lymphoblastic leukemia (ALL) have a high rate of relapse, even after allogeneic hematopoietic cell transplantation (HCT). In an effort to reduce the risk for relapse, we investigated the role of blinatumomab (Blin), a bi-specific T cell immunotherapy targeting CD19, as maintenance therapy following allogeneic HCT. We rationalized that this is an ideal agent with little cytotoxicity, and the potential to provide immune protection against disease relapse during the first year post HCT when GVL is still maturing. <h3>Methods</h3> Adult pts with B-ALL deemed high risk for relapse defined as disease stage beyond CR1, active disease including MRD, or presence of high risk molecular mutations or karyotype at time of HCT, or patients with evidence of MRD post HCT, were eligible for study enrollment; prior Blin treatment was allowed. Pts with active disease or GVHD requiring steroid therapy post HCT were excluded. Pts were scheduled to receive 4 cycles of Blin at 28 μg/24 hours over 4 weeks, with the first cycle to be administered within the first 3 months post HCT after count recovery; subsequent cycles at 6, 9, 12 months following HCT. <h3>Results</h3> 12 pts with median age 30 years (range, 21-65 years) were treated to date with characteristics and outcomes reported in Table 1. The median days to start of therapy post HCT was 84 (range, 38-105 days). There was no reported CRS, GVHD, graft failure, or grade 5 adverse events (AE). A cumulative 26 cycles of Blin were administered with 7 Blin-related grade 3 or 4 AEs reported (leukopenia n=4, transaminitis n=2, rash n=1). Grade 2 neurotoxicity was noted in 1 pt. Median follow up was 8.5 months post HCT (range 2-35 months). None of the 8 pts who were MRD negative post HCT have relapsed. We performed multiparametric flow cytometry studies on serial peripheral blood patient samples collected prospectively at multiple time points to measure T cell subsets, T-cell function and cell surface expression of various checkpoint inhibitors including PD1, TIGIT, Tim3, 2B4 and CD160. Samples were studied on an X-20 Fortessa, and the data analyzed using Kaluza software. The 4 pts who progressed on Blin maintenance had lower CD8 to CD4 ratio compared to non-progressors (45.75:42.01 vs 16.53:59.72) (Figure 1). Furthermore, compared to healthy controls, we observed higher levels of checkpoint molecules as multiple checkpoints per cell. PD1 and TIGIT upregulation and co-expression were more common in progressing patients compared to non-progressors (Figure 2). <h3>Conclusion</h3> We observed that Blin maintenance following allogeneic HCT for B-ALL is well tolerated, and encouraging for pts who are MRD negative post HCT. More pts need to be treated to confirm the efficacy of this approach.Strategies to increase CD8 levels and blockade against checkpoint inhibitors may overcome resistance to therapy.