Allogeneic hematopoietic stem cell transplantation (hereinafter referred to as transplantation) is the most effective and even the only curative approach for malignant hematologic diseases. Over the past decade, the cure rate for acute leukemia using transplants from HLA-matched sibling donors has reached 50%-75%. Although transplantation techniques have been continuously improving, the development of graft-versus-host disease (GVHD) after transplantation remains one of the most significant and severe complications, particularly acute GVHD (aGVHD). It reduces the success rate of transplantation and post-transplant disease-free survival, and is also one of the leading causes of non-relapse mortality (NRM). Acute GVHD typically occurs within the first 100 days post-transplant, with an incidence of 35% to 64%, and a mortality rate of 15% to 40% among allogeneic transplant recipients. Despite advances in transplantation techniques and GVHD prophylaxis in recent years, the incidence of acute GVHD remains as high as 30% to 60%, and treatment outcomes remain unsatisfactory. Among these, grade II acute GVHD, although less severe than grades III and IV, has a high incidence, a tendency to progress to severe GVHD, and often leads to long-term dependence on immunosuppressive therapy, imposing a heavy medical burden on patients.
Currently, the standard first-line therapy for grade II acute GVHD is systemic corticosteroids. However, approximately 40% of patients progress to severe (grade III-IV) acute GVHD, leading to a significant increase in non-relapse mortality (1-year overall mortality reaching 35.2%). Long-term high-dose corticosteroid therapy not only readily causes side effects such as infections and metabolic disorders, but also results in treatment failure or steroid dependence in up to 44.4% of patients. Nevertheless, there is currently no standard second-line treatment option for patients with steroid-refractory acute GVHD, and commonly used combination strategies lack robust evidence-based support. Therefore, there is an urgent need to explore more effective and safer early intervention strategies for the treatment of grade II acute GVHD.
In recent years, ruxolitinib (a JAK inhibitor) has brought new hope for the treatment of acute GVHD. Ruxolitinib is a selective JAK1/2 inhibitor that has been approved for the treatment of steroid-refractory acute GVHD. Studies have shown that in the early stage of GVHD, neutrophils migrate to mesenteric lymph nodes and promote disease progression, and ruxolitinib can effectively inhibit this process while reducing MHC-II expression, thereby blocking the early pathogenesis of GVHD. Furthermore, hyperactivation of the JAK-STAT signaling pathway exacerbates GVHD, and early intervention with ruxolitinib may prevent disease progression and reduce the need for second-line therapy. Additionally, ruxolitinib can enhance the therapeutic effect of corticosteroids on T cells by modulating the balance of apoptotic factors to overcome steroid resistance.
In summary, the occurrence of acute GVHD is one of the most important and severe complications after allogeneic hematopoietic stem cell transplantation, reducing transplant success rates and post-transplant disease-free survival. Grade II acute GVHD has a high incidence, a tendency to progress to severe disease, and long-term steroid dependence leads to complications such as infections and metabolic disorders, severely affecting patients' quality of life and transplant outcomes. Currently, approximately 40% of patients receiving standard first-line therapy (systemic corticosteroids) progress to grade III-IV aGVHD, and the rate of steroid resistance or dependence is as high as 44.4%. Therefore, more effective early intervention strategies are urgently needed for patients with grade II GVHD. We plan to conduct a prospective, randomized, single-arm study in patients undergoing allogeneic hematopoietic stem cell transplantation to explore a new treatment strategy for grade II acute GVHD. By introducing an innovative regimen of "ruxolitinib combined with corticosteroids", we aim to prospectively and randomly observe the therapeutic efficacy and safety of low-dose corticosteroids combined with ruxolitinib in patients with grade II acute GVHD, with the goal of improving the treatment response rates, reducing the dose and duration of corticosteroid use, and decreasing the risk of disease progression and long-term complications. This study is expected not only to improve the prognosis of patients with grade II acute GVHD and increase the success rate of transplantation, but also to drive innovative advances in the field of acute GVHD therapy.
