Anti-thymocyte globulin-resistant CD4+ memory T cells contribute to haplo-fever after allogeneic hematopoietic stem cell transplantation

Haplo-fever (HF) is a form of non-infectious fever that occurs shortly after haploidentical (HID) hematopoietic stem cell transplantation (HSCT). Its clinical significance, risk factors, and pathophysiology, particularly in the context of anti-thymocyte globulin (ATG)-based prophylaxis for graft-versus-host disease (GvHD), remain largely unknown. Here, we retrospectively analyzed clinical data from 143 consecutive HID HSCT recipients. Patients with HF exhibited a higher incidence of chronic GvHD, a lower risk of measurable residual disease recurrence, and improved event-free survival, particularly among those receiving ATG-based acute GvHD prophylaxis. Identified risk factors for HF included higher infused doses of CD34⁺ cells, mononucleated cells, CD3⁺ T cells, and CD4⁺ memory T cells. At 90 days post-transplant, patients with HF demonstrated elevated absolute numbers of CD4⁺ memory T cells and activated CD4⁺ and CD8⁺ T cells. RNA sequencing of peripheral blood CD3⁺ T cells at day 2 post-transplant revealed transcriptional signatures of T-cell activation and an abundance of activated CD4⁺ memory T cells as hallmarks of HF. Using multiple complementary approaches, we demonstrated the impact of HF on transplant outcomes, identified its risk factors, and elucidated the underlying cellular and molecular mechanisms.