Low-Dose ATG/PTCy Plus Ivarmacitinib for aGVHD Prevention in Haplo-PBSCT From Parous Female Donors

Overview

Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), significantly affecting survival and quality of life. Acute GVHD (aGVHD) typically occurs within 100 days post-transplant, commonly involving skin, gastrointestinal tract, and liver. Chronic GVHD (cGVHD) can appear months to years later. Despite prophylaxis with calcineurin inhibitors (e.g., cyclosporine or tacrolimus), methotrexate, mycophenolate mofetil, and post-transplant cyclophosphamide (PTCy), patients receiving haploidentical transplantation from parous female donors remain at high risk for moderate-to-severe aGVHD. JAK1-dependent cytokine signaling (IL-6, IFN-γ) is central to GVHD pathogenesis. Selective JAK1 inhibition may attenuate T cell-mediated inflammation while preserving hematopoiesis. Ivarmacitinib (SHR0302) is a highly selective oral JAK1 inhibitor, showing favorable safety and preliminary efficacy in autoimmune and GVHD settings, making it a candidate for early GVHD prophylaxis.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative approach for various hematologic malignancies, marrow failure syndromes, and selected genetic disorders. Despite advances in donor selection, including unrelated, haploidentical, and peripheral blood stem cell (PBSC) sources, graft-versus-host disease (GVHD) continues to be the most common and clinically significant complication, adversely affecting both short- and long-term outcomes. Acute GVHD (aGVHD) typically occurs within the first 100 days post-transplant, primarily involving the skin, gastrointestinal tract, and liver, whereas chronic GVHD (cGVHD) may develop months to years later, often affecting multiple organs. Over the past decades, GVHD prophylaxis has evolved from calcineurin inhibitors (cyclosporine, tacrolimus) combined with methotrexate or mycophenolate mofetil to more targeted strategies. In haploidentical transplantation, post-transplant cyclophosphamide (PTCy) has markedly reduced the incidence of both acute and chronic GVHD. However, moderate-to-severe GVHD still occurs in a subset of recipients, highlighting the need for enhanced prophylactic strategies. Low-dose anti-thymocyte globulin (ATG) combined with PTCy has emerged as a promising regimen, with systematic reviews demonstrating significant reductions in grade II-IV aGVHD and cGVHD without increasing relapse risk, thereby improving GVHD-free survival. Notably, recipients of haploidentical transplants from parous female donors constitute a high-risk population. Prior studies indicate that such recipients exhibit substantially elevated rates of grade II-IV aGVHD and moderate-to-severe cGVHD compared with recipients from nulliparous female or male donors. For instance, retrospective analyses reported grade III-IV aGVHD incidence of 55.3% and extensive cGVHD of 64.3% in recipients from parous female donors, significantly higher than in recipients from male donors, emphasizing the need for additional prophylactic interventions in this group. Mechanistically, the JAK-STAT signaling pathway plays a central role in GVHD pathogenesis. Alloreactive donor T cells release proinflammatory cytokines such as IFN-γ, IL-6, and TNF-α, leading to tissue injury. JAK1 mediates critical signaling for IL-6 and IFN-γ, suggesting that selective JAK1 inhibition may attenuate pathogenic T cell responses while preserving hematopoiesis. JAK inhibitors such as ruxolitinib and baricitinib have demonstrated efficacy in steroid-refractory GVHD, and highly selective JAK1 inhibitors like itacitinib have shown promising results in early-phase studies, reducing both acute and chronic GVHD incidences with minimal myelosuppression. Ivarmacitinib (SHR0302), a novel, orally bioavailable, highly selective JAK1 inhibitor developed in China, exhibits potent JAK1 blockade with limited JAK2 inhibition, theoretically minimizing hematopoietic toxicity. Preclinical models show SHR0302 prevents and mitigates aGVHD without impairing graft-versus-leukemia effects. Early-phase clinical studies in cGVHD patients indicate favorable safety and high response rates, supporting its potential application for aGVHD prophylaxis. In summary, combining high-selectivity JAK1 inhibition with the established low-dose ATG/PTCy regimen offers a mechanistically rational strategy to further reduce GVHD risk in high-risk haploidentical PBSC recipients from parous female donors. This approach is expected to lower the incidence of acute GVHD without significantly increasing infection or relapse risk, improve long-term GVHD outcomes, and enhance overall survival and quality of life for these high-risk transplant recipients.