Introduction
Graft-versus-host disease (GvHD) is a major problem in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). It is caused by immune reactions associated with donor T-cells toward dissimilar host histocompatibility antigens. To prevent GvHD, prophylaxis includes calcineurin inhibitor (CNI), methotrexate (MTX), and anti-lymphocyte antibodies. Treatment approaches have been developed to target donor T-cell activation, which is achieved through two stimulatory signals: the T-cell receptor (TCR) and co-stimulation. Administration of abatacept following transplantation has been reported to inhibit graft rejection and graft-versus- host-disease (GvHD) in mouse models associated with allogeneic hematopoietic stem cell transplant (HSCT). This strategy has recently been adopted in clinical practice for GvHD prevention in human allogeneic HSCT and offers a unique approach to optimizing GvHD prophylaxis following alternative donor HSCTs. When combined with calcineurin inhibitors and methotrexate, abatacept had shown to be safe and effective in preventing moderate to severe acute GvHD in myeloablative HSCT using human leukocyte antigen (HLA) unrelated donors. These observations have led to hypothesizing that even in the setting of increasing donor HLA disparity, abatacept when given with traditional GvHD prophylaxis does not worsen general outcomes. In addition, in limited studies, abatacept have being protective against the development of chronic GvHD through extended dosing and in the treatment of steroid-refractory chronic GvHD.
Clinical transition of abatacept in treatment of GvHD: initial studies
Koura et al. conducted a feasibility study in humans and documented promising results in using traditional GvHD prophylaxis with abatacept in 10 pediatric and adult patients with leukemia. Subjects were conditioned with either total body irradiation (TBI) (1200 cGy) or cyclophosphamide (Cy) (120 mg/kg). Cyclosporine was started 3 days prior to transplant, with doses titrated to maintain a trough level of 100 to 300 ng/mL and continued at full dose up to 100 days after the HSCT. Abatacept was given intravenously over 30 min and the median time to neutrophil engraftment was 16.5 days. No graft failures, no deaths due to infection, and no cases of transplant-associated mortality were recorded. Seven out of 10 patients survived to a median follow-up of 16 months. Keen et al. further observed that blocking co-stimulation could impact the activation and proliferation of CD4+ after transplantation. They concluded that using abatacept in treating aGvHD in individuals undertaking unrelated-donor HSCT was feasible and encouraging.
Extended studies: malignant
Watkins et al. conducted a Phase II Trial study to investigate the role of abatacept in reducing aGvHD after unrelated donor HSCT in malignant disorders. The study involved 142 patients with hematologic malignancies in two categories: a randomized, double-blind, placebo-controlled group and a single-arm group with 7/8-HLA-mismatched unrelated donor (MMUD). The primary endpoint was day 100 grade III-IV aGVHD, while the secondary endpoint was day 180 severe-aGvHD-free-survival (SGFS). In the MUD category, grades III and IV was 6.8% and 2.3%, respectively, and the SGFS was better (97.7% versus 58.7%; p value < 0.001). The MMUD/CNI/MTX and abatacept group had 30.2% non-White compared with 11.6% non-Whites in MUD/placebo patients, no difference in platelet engraftment or neutrophils, and a 57.9% (95% CI, 40.7-71.8) cumulative incidence of moderate to severe chronic GvHD. There were no significant differences between the two study groups in the day +180 cumulative incidence of Epstein-Barr virus or cytomegalovirus viremia. Qayed and colleagues found that risk of cGvHD was not reduced, and a multicenter, randomized controlled trial (ABA3, NCT04380740) will investigate whether an eight-dose regimen of abatacept (last dose at day 150) can prevent cGVHD. Kean et al. found that patients treated with standard of care aGvHD prophylaxis did better than those treated with CNI/MTX/ATG or post transplant cyclophosphamide. A meta-analysis reported that ATG treatment was correlated with a high incidence of EBV reactivation and did not appear to affect overall survival.
Extended studies: nonmalignant
HSCT is used to treat nonmalignant diseases affecting the lymphohematopoietic system, particularly sickle cell anemia, which is limited due to a lack of appropriate donors. Alternative donor transplants with abatacept have shown promising results in patients suffering from life-threatening nonmalignant hematologic diseases and lacking an HLA-matched sibling donor. The study compared the clinical outcomes of eight patients who received a standard GvHD prophylaxis with corticosteroids and 24 patients who received abatacept given at a dose of 10 mg/kg intravenously on days − 1, + 5, and +28 following stem cell infusion. The rate of aGvHD was 50%, with no difference in platelets and neutrophils engraftment between both groups. Overall survival at 1 year was 62.5%, with durable engraftment and improved survival. Jaiswal et al. reported their experience in severe aplastic anemia following HLA-mismatched haploidentical HSCT. Abatacept combined with PTCy and sirolimus may augment transplantation tolerance and reduce aGvHD in children with SAA, according to two studies. Jaiswal et al. and Chaudhury et al. reported their initial experience in an ongoing multicenter trial. All nine patients are still alive and free from disease at a median follow-up of 28 months.
Using abatacept to treat and prevent chronic GvHD
In a preclinical study, Via et al. showed that CTAL4Ig administered early can prevent the development of acute and chronic GvHD by inhibiting the activation of T-cells of the donor. However, delayed administration after the development of T-helper type 1 and 2 effector responses (day 7) had no impact on aGvHD. Koura and colleagues showed that abatacept treated patients had a profound decrease in absolute and relative percentage of CD4+ T but not CD8+ cells early after transplantation. However, by day 60 post-HSCT, these differences were no longer seen. The authors could not determine if this was due to a true difference in functional regulatory cells. Abatacept has been shown to reduce the incidence of chronic GvHD in SAA patients undergoing a haploidentical transplant and in SCD patients undergoing a matched unrelated or mismatch related HSCT. In a recent phase I clinical trial, abatacept was used to treat patients with steroid-refractory cGvHD and showed to be safe. In a retrospective study, 15 patients (median age of 49) who underwent HSCT and were analyzed reported an overall response rate of 40%, mostly in patients with lung GvHD (bronchiolitis obliterans syndrome). Abatacept also showed significant, durable clinical improvement as measured by an 89% improvement based on lung severity score or lung function.
Conclusion
Abatacept has evolved its role from the bench to the bedside in HSCT, demonstrating its potential to help alleviate negative impacts associated with HLA disparity in transplantation in both malignant and nonmalignant disorders.
In a recent registry study, increased incidence of GvHD and inferior outcomes in patients receiving haploidentical HSCT with PTCy, tacrolimus and mycophenolate mofetil for GvHD prevention was reported signaling a need for improvement. Several ongoing and previously completed clinical trials exist and are focusing on expanding and bridging the knowledge gap on this novel approach of using abata-cept in transplantation. However, there are some limitations to its effectiveness, such as its ability to prevent moderate to severe cGvHD. As successful studies in this novel approach increases, this will guarantee effective and prompt HSCTs are accessible to everyone, including populations tradition-ally lacking donors, such as patients with hemoglobinopathies.
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