Mismatch in Sirpα, a Regulatory Protein in Innate Immunity, Is Associated with Outcomes of Allogeneic Stem Cell Transplantation for Lymphoid Malignancies
Authors: Saliba Rima M. , Greenbaum Uri , Ma Qing , Srour Samer A. , Rondon Gabriela , Shpall Elizabeth J. , Cao Kai , Champlin Richard E. , Zou Jun 
Published: November 2021

Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with hematologic malignancies. It is conventionally believed that alloreactivity is initiated by T-cells recognizing the non-self HLA molecules on the graft. Cells from the innate immune system, such as macrophages and monocytes, are induced by nonspecific "danger" molecules released from damaged tissue. Recent studies revealed that the innate immune system could distinguish the non-self graft and subsequently prime the adaptive immune system to advance the allorecognition process. Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily receptor that is expressed on macrophages and myeloid cells. The interaction between SIRPα and its ubiquitously expressed ligand, CD47, suppresses the macrophages phagocytic function. It has been demonstrated that recipient's monocytes detect polymorphism in SIRPα, and mismatches of SIRPα between donor and recipient can regulate the allorecognition response in the murine model. Our group has recently investigated the role of SIRPα variant mismatch in recipients of allo-HSCT from an HLA-matched related donor for treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We found that donor/recipient SIRPα mismatch was commonly detected in 39% of transplant pairs, and the presence of the mismatch was significantly associated with an increase rate of chronic graft-versus-host disease (cGvHD) and a lower rate of early relapse. We hypothesized that comparable effects could be occurring in recipients of allo-HSCT for treatment of lymphoid malignancies. We tested our hypothesis in a cohort of patients who received an allo-HSCT from an HLA matched-related donor at our institution between January 2008 and December 2018 for the treatment of lymphoid malignancies. Only patients who received a peripheral blood stem cell graft and tacrolimus/methotrexate for GvHD prophylaxis were eligible for the study. A total of 313 patients met the eligibility criteria including 310 (99%) who engrafted and 3 (1%) who died early before engraftment. The risk of early death was not associated with SIRPα mismatch variant. Only patients who engrafted (N=310) were included in subsequent analyses. Among these, 42% (N=130) of donor/recipient pairs were SIRPα mismatched. The majority of patients were treated for acute lymphoblastic leukemia (N=115, 37%) or non-Hodgkin's lymphoma (NHL) (N=114, 37%), followed by chronic lymphoblastic leukemia (N=59, 19%), and Hodgkin's lymphoma (N=22, 7%). Most (N=259, 84%) of patients had chemo-sensitive disease. The median age at transplant was 51 (range: 18-72) years, and 64% of patients were female. The median age of donors was 50 (range: 18-79) years and 53% were male. Conditioning regimens were myeloablative in 52% of cases. Outcomes were evaluated accounting for competing risks. The median follow-up in surviving patients was 74 (range: 3-124) months. A total of 99, 84, 108, and 51 patients experienced grade 2-4 acute GvHD, cGvHD requiring systemic immunosuppressive therapy, disease progression, and non-relapse mortality (NRM), respectively. Multivariate analyses showed that SIRPα mismatch was associated with a significantly higher rate (hazard ratio [HR]=1.9, P=.005) of cGvHD requiring systemic immunosuppressive therapy, and a lower rate (HR=.5, P=.004) of disease progression. Notably, the increased rate of cGVHD was consistent across the 4 lymphoid malignancies evaluated, yet the lower rate of relapse was observed in all diagnoses except NHL. There was no significant impact of SIRPα mismatch on grade 2-4 acute GvHD (HR=1.2, P=.3) or on NRM (HR=0.7, P=.3). Consistent with our preceding study in the AML/MDS cohort, the mismatch in SIRPα, a regulatory protein in innate immunity, is associated with a higher rate of cGvHD and relapse protection in patients who underwent allo-HSCT for lymphoid malignancies. The results of this study could be clinically important in donor selection and provide insight into the underlying role of innate immunity in allo-HSCT.

Disclosures
Shpall: Adaptimmune: Consultancy; Takeda: Patents & Royalties; Novartis: Consultancy; Magenta: Honoraria; Navan: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Magenta: Consultancy; Axio: Consultancy; Affimed: Patents & Royalties; Novartis: Honoraria.