Subcutaneous Abatacept for Acute Graft-Versus-Host Disease Prophylaxis after Haploidentical Donor Hematopoietic Cell Transplantation: Efficacy, Safety, and Immunologic Effects
Authors: Ru Yuhua , Zhu Jinjin , Gong Huanle , Xu Mimi , Wang Ying , Miao Miao , Chen Suning , Zhang Xiang , Fan Yi , Xu Yang , Chen Jia , Wu Depei 
Published: December 2024

Background
Acute graft-versus-host disease (aGVHD) is a major complication after haploidentical hematopoietic cell transplant (haplo-HCT), which results in signifiantly worsened clinical conditions and a series of concerns followed by immunosuppressive therapies. Although emerging agents have been appouved for aGVHD treatment, the prophylaxis is hardly improved.
Methods
We performed a single-arm phase II trial of abatacept for aGVHD prevention during haplo-HCT to assess safety, efficacy, and immunologic effects. The inclusion criteria were: (1) Haplo-HCT candidates with available donor; (2) diagnosed as acute myeloid leukemia, acute lymphoblastic leukemia or myelodysplastic syndromes and in complete remission. For GVHD prophylaxis, in addition to conventional regimen (cyclosporine, short-term methotrexate, mycophenolate mofetil and rATG), all paticipants received subcutaneous abatacept (loading dose of 250 mg on day -1, and 125 mg on day +5, +14, +21, +28, +35, +42, +49, +56) post-HCT. The primary endpoint was grade 2-4 aGVHD within day +100, and the key secondary endpoints included grade 3-4 aGVHD within day +100, overt GVHD and relapse-free survival (GRFS), transplant related mortality (TRM) and relapse. A control cohort which consisted of patients with comparable baselines was set so as to assess the immunologic effects of abatacept intervention. Samples of the control cohort were obtained from our institutional biobank.
Results
Among 27 participants who were recruited in this trial, 24 participants receiving abatacept intervention were recognized as modified intent-to-treat (mITT) population. By day +100 post-HCT, only 2 patients developed grade 2-4 aGVHD, resulting in the incidence of 8.3% (95%CI 2.3%-25.9%). Notably, no grade 3-4 aGVHD were observed within day +100. With a median follow-up of 532 (IQR 468, 715) days in the mITT population, the TRM and relapse at 1 year were 9.1% (95% CI 8.7%-9.5%) and 4.3% (95%CI 4.2%-4.5%), respectively. The 1-year GRFS was 64.0% (95%CI 46.8%-87.6%), and both of overall survival and disease-free survival at 1 year were 90.9% (95% CI 79.7%-100.0%). Seven participants developed chronic GVHD, and the 1-year cumulative incidence was 29.2% (95% CI 11.0%-47.7%). Toxicities were generally mild, and CMV reactivation was the most frequent adverse event related to abatacept intervention. By the end of follow-up, 6 participants died including 2 from infection, 2 from disease relapse, 1 from cerebral hemorrhage, and 1 from thrombotic microangiopathy. All of these deaths were considered unrelated to abatacept intervention.
Flow cytometric analysis showed a rapid reconstitution of NK cells and a tardy recovery of CD4+ T cells. Compared to the control cohort, abatacept intervention led to decreased T cell activation and effector memory T cell differentiation (p&lt;0.001). No difference in dendritic cells was observed between the two cohorts.
Conclusions
We concluded that for haplo-HCT, employing abatacept in aGVHD prophylaxis was a promising approach which might decrease the risk of aGVHD occurrence and improve the survival. The safety profile was acceptable although the risk of viral reactivation should be noted. Randomized controlled trials are warranted to confirm our findings.