Abatacept As Salvage Therapy for Graft-Versus-Host Disease in Allogenic Hematopoietic Stem Cell Transplantation : A Systematic Review

Abstract

Introduction Graft vs host disease (GVHD) is one of the major complications after allogenic - Hematopoietic stem cell transplantation (allo-HSCT). It has been reported in around 70 % of patients after allo-HSCT and leads to increased non-relapse mortality (NRM)/transplant-related mortality (TRM) and also contributes to impaired quality of life. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), expressed on the surface of regulatory T cells and activated conventional T cells play a role in inhibiting T cell activation by modulating the costimulatory CD28 signal. The CTLA4-Fc fusion proteins abatacept and belatacept lead to immunosuppression induced by blocking CD28-costimulation. CTLA4Ig (Abatacept) has recently been approved by US Food and Drug Administration for prophylaxis of acute GVHD following mismatched unrelated donor (URD) HSCT. Methods We performed a comprehensive literature search on PubMed and ClinicalTrials.gov. We used the MeSH terms for Abatacept and Stem Cell Transplantation and their associated keywords. The search yielded 153 articles. Screening and data extraction were done according to PRISMA guidelines. After excluding case reports, review articles, 4 clinical studies (n=236) were included. Results: The total number of patients tested in the Abatacept group was 193. (Table 1.) In a retrospective trial by Wertheimer T et al., patients with severe cGVHD receiving abataceptdid not need new immunosuppressive treatments (80%) within 3 months of starting abatacept therapy. Patients with lung involvement (n = 9) showed significant benefit with an overall response rate of 89% based on lung severity score (n = 6), and lung function as measured by FEV1. In the phase II trial by Watkins et al addition of T-cell co-stimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, lead to reduced aGVHD, and improved day +180 severe-aGVHD-free-survival. Incidence of grade 3-4 aGVHD in 8/8-HLA-matched URD, was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). Severe-aGVHD-free-survival (SGFS) was 93.2% (CNI/MTX + abatacept) versus 82% (CNI/MTX + placebo, P = .05). In the smaller 7/8-HLA-mismatched URD cohort, grade 3-4 aGVHD was 2.3% (CNI/MTX + abatacept), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), with improved SGFS (97.7% v 58.7%, P < .001). In retrospective study by Khandelwal, P, et al, addition of Abatacept to post-transplantation cyclophosphamide (PTCy) based haploidentical transplantation for patients with thalassemia major (TM, n=5) and sickle cell disease (SCD, n=5), showed that none of the patients in the abatacept group, had grades III-IV aGVHD by day +100 compared with 50% in the group with standard aGVHD prophylaxis (P = 0.001). Thalassemia-free survival after HSCT was 100% in the patients who received abatacept compared to 62.5% in the cohort with standard aGVHD prophylaxis at follow-up (P = 0.007) .In another study by Jaiswal, et al, patients with refractory aggressive B-cell lymphoma (R-ABCL) following autologous HSCT received CTLA4Ig-based reduced-intensity conditioning and sequential CTLA4Ig-primed donor lymphocyte infusions (DLIs) on days +7, +21, and +35. aGVHD was not seen in any patient and cGVHD was seen in 2 patients. 3 patients had disease-progression at 100 days, progression-free and GVHD-free survival at 2 years was 75%. Conclusion: This systematic review shows that abatacept could be a promising treatment option for GvHD after HSCT. Abatacept is a novel treatment modality to markedly reduce GVHD and infections and yet augment NK cell-mediated cytotoxicity following HSCT. The addition of abatacept to routine GVHD prophylaxis reduced the incidence of GVHD without impacting engraftment or survival. Additional randomized clinical trials are needed to establish the efficacy and safety of to prevent GVHD after HSCT with a larger number of patients to confirm these results.