Advances in graft-versus-host disease prevention strategies: latest updates from the 2022 ASH annual meeting
Experimental Hematology & Oncology volume 12, Article number: 59 (2023)
This review summarizes the significant advancements in prophylaxis against graft-versus-host disease (GvHD) presented at the 2022 ASH Annual Meeting. The use of innovative agents and regimens, along with the conventional prophylactic approach of combining post-transplant cyclophosphamide and anti-thymocyte globulin, were discussed. The innovative agents and regimens highlighted in this review include abatacept, the first FDA-approved drug for acute GvHD prophylaxis; RGI-2001, which promotes the expansion of regulatory T cells; and cell therapies such as Orca-T and Orca-Q. These advancements provide promising strategies and options for GvHD prevention, offering hope for improved post-transplant patient outcomes in terms of survival rates.
To the editor
Hematopoietic stem cell transplantation (HSCT) can lead to a severe multisystem disorder known as graft-versus-host disease (GvHD), resulting in considerable morbidity and non-relapse mortality (NRM). We reviewed several latest reports on GvHD prophylaxis from the 2022 ASH Annual Meeting (ASH2022).
Novel agents and regimens
Abatacept (ABA), a CD28:CD80/86 co-stimulation blockade, has shown potential in controlling early T cell allo-proliferative escape, a major contributor to breakthrough acute GvHD (aGvHD) following calcineurin inhibitor/methotrexate (CNI/MTX) prophylaxis . ABA + CNI/MTX administration in recipients of 7/8 mismatched unrelated donor (MMUD) grafts, known to carry a higher risk of GvHD-related mortality, demonstrated comparable overall survival (OS) and recurrence-free survival (RFS) rates to those of 8/8 matched unrelated donor (MUD) recipients, thereby improving the risk/benefit ratio for MMUD HSCT . A real-world study further confirmed the finding in adult and pediatric patients . Moreover, ABA/Tacrolimus +- post-transplant cyclophosphamide (PTCy) demonstrates feasibility and promising outcomes with low GvHD rates in matched or mismatched donor peripheral blood stem cell transplantation (PBSCT) .
The augmentation of regulatory T cells (Tregs) has gained significant attention as an effective strategy for preventing GvHD while preserving the graft-versus-leukemia (GvL) effect. RGI-2001, a liposomal glycolipid, expands Tregs by activating invariant natural killer cells through CD1d receptor on antigen-presenting cells, thereby modulating GvHD pathogenesis. RGI-2001 administered intravenously with tacrolimus/MTX was effective in preventing aGvHD in individuals receiving grafts from peripheral blood stem cell (PBSC) and bone marrow sources, with a favorable safety profile. Promising results justify the planning of a phase 3 clinical trial to assess the efficacy of the regimen . Orca-T is an innovative immunotherapy with purified donor regulatory T cells to target alloreactive immune responses. Graft composition optimization in HLA-matched PBSCT has shown robust GvL and graft-versus-infection effects, while also reducing the incidence of GvHD and NRM . In the context of haplo-PBSCT, another cellular therapy, Orca-Q, has emerged as a potential prevention option. Administered with single-agent tacrolimus, Orca-Q shows low incidence and severity of GvHD, improved GvHD-free and relapse-free survival (GRFS) rates, and demonstrates clinical superiority even without the use of PTCy. However, the broad adoption of these cell therapies is hindered by the logistical challenge of timely vein-to-vein administration within a restricted 72-hour window, confining their implementation to the specialized institution  (Table 1).
PTCy and ATG combination prophylaxis
Combining anti-thymocyte globulin (ATG) and PTCy as prophylaxis against GvHD is a promising strategy, surpassing the limitations of individual administration. ATG-based regimens pose viral infection risks, while PTCy-based prophylaxis is less effective with PBSC grafts. A retrospective study  showed that incorporating ATG to the Clo-Baltimore (CloB) regimen with PTCy enhanced GRFS. Another study  indicated that a low-dose ATG (2.5 mg/kg)/PTCy (50 mg/kg) regimen holds promise for preventing GvHD following haplo-PBSCT, with a cumulative incidence of aGvHD observed at 30.7%.
Salas et al. conducted trials investigating the use of reduced-dose ATG in various transplantation settings. In Abstract 2127 , a comparison was made between two doses of ATG, specifically 4.5 mg/kg and 2 mg/kg, in the context of PBSCT from 10/10 MUD. The higher dose showed a decreased incidence of moderate/severe cGvHD, but was associated with an increased occurrence of infectious complications. Conversely, recipients of the reduced-dose ATG exhibited a trend towards improved 1-year OS. Another study focusing on haplo-PBSCT  also reported an increased risk of grade III-IV aGvHD with the administration of the reduced-dose ATG. These studies suggest that the use of low-dose ATG involves certain compromises in prevention efficacy.
Low-dose PTCy has been investigated in elderly patients and those with cardiac comorbidities undergoing haplo-PBSCT . The study suggested that reducing PTCy to 70 mg/kg combined with low-dose ATG is a secure and efficacious strategy, resulting in higher GRFS. Furthermore, the low-dose PTCy led to accelerated immune reconstitution, decreased cumulative incidence of bacteremia, BK-virus associated hemorrhagic cystitis, and cardiac complications, while the risk of aGvHD and cGvHD remained unaffected (Table 2).
The emergence of novel agents and regimens has expanded the donor pool and allowed the use of different graft sources, including mismatched donors and PBSC, to address patient needs while minimizing the risk of GvHD. For PTCy and ATG combination prophylaxis, future endeavors could focus on investigating lower-dose combination of these agents to achieve the dual goals of minimizing adverse events and maintaining prophylactic efficacy.
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The study is supported by the National Key R&D Program of China (2022YFC2502704), the National Natural Science Foundation of China (82070187) and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX23_3270).
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Chen, Y., Xu, Y. & Wu, D. Advances in graft-versus-host disease prevention strategies: latest updates from the 2022 ASH annual meeting. Exp Hematol Oncol 12, 59 (2023). https://doi.org/10.1186/s40164-023-00425-y
- Hematopoietic stem cell transplantation
- Graft-versus-host disease