Data_Sheet_1_Clinical Significance of Haplo-Fever and Cytokine Profiling After Graft Infusion in Allogeneic Stem Cell Transplantation From Haplo-Identical Donors.docx

Allogeneic stem cell transplantation from haplo-identical donors (haplo-HSCT) has become a well-established therapeutic option for hematological malignancies. The fever of unknown origin (haplo-fever) early after the infusion of T cell repleted graft, which returned to normal right after post-transplantation cyclophosphamide (PTCy), is a unique clinical feature in patients undergoing haplo-HSCT. In the current study, the characteristics of haplo-fever and cytokine profiles during haplo-fever were retrospectively analyzed in a cohort of 37 patients undergoing T cell repleted haplo-HSCT with PTCy as graft versus host disease (GvHD) prophylaxis. In total, 33 patients (89.2%) developed haplo-fever from day 0 to day +7. Patients with high peak temperatures tended to have a lower incidence of chronic GvHD (cGvHD) (p = 0.07), moderate to severe cGvHD (p = 0.08), and superior GvHD and relapse-free survival (GRFS, p = 0.04). During the haplo-fever, there were significant increases in multiple cytokines, such as interferon gamma, interleukin (IL) 6, IL2, IL2 receptor, IL8, IL10, IL17, and tumor necrosis factor (TNF). The increases in IL2 receptor (p = 0.037) and TNF (p < 0.001) on day +4 were correlated with the lower risk of cGvHD. Increased TNF > 1.8055-fold on day +4 was the best predictive threshold for cGvHD, and was correlated with a lower incidence of cGvHD (p < 0.001), moderate to severe cGvHD (p = 0.003), and superior GRFS (p < 0.001). These observations may reflect the early reactivation of donor T cells after haplo graft infusion, which would potentially be eliminated by PTCy. Further studies with larger independent cohorts of patients are warranted, to clarify the clinical significance of haplo-fever, and day +4 TNF as a potential biomarker to predict GvHD and GRFS.

来自半相合供者的异基因造血干细胞移植（haplo-HSCT）现已成为血液系统恶性肿瘤的成熟治疗手段。在输注T细胞富集移植物后早期出现的不明原因发热（haplo-fever），可在移植后环磷酰胺（PTCy）给药后迅速恢复正常，这是接受haplo-HSCT患者的独特临床特征。本研究对37例接受T细胞富集移植物haplo-HSCT、并以PTCy作为移植物抗宿主病（GvHD）预防手段的患者队列进行了回顾性分析，探讨了haplo-fever的临床特征及其发作期间的细胞因子谱。总计33例（89.2%）患者在移植后0天至+7天期间出现haplo-fever。体温峰值较高的患者，其慢性移植物抗宿主病（cGvHD）、中重度cGvHD的发生率更低，且无GVHD且无复发生存期（GRFS）更优（p值分别为0.07、0.08和0.04）。在haplo-fever发作期间，患者体内多种细胞因子水平显著升高，包括γ干扰素、白细胞介素（IL）6、IL2、IL2受体、IL8、IL10、IL17以及肿瘤坏死因子（TNF）。移植后第4天，IL2受体（p=0.037）与TNF（p<0.001）的水平升高与cGvHD风险降低相关。移植后第4天TNF水平较基线升高超过1.8055倍是预测cGvHD的最佳临界值，且该指标与cGvHD、中重度cGvHD发生率降低及GRFS更优显著相关（p值分别为<0.001、0.003和<0.001）。上述观察结果或许反映了半相合移植物输注后供者T细胞的早期活化，而该活化过程可被PTCy潜在清除。未来需开展更大规模的独立患者队列研究，以明确haplo-fever的临床意义，以及移植后第4天TNF水平作为预测GvHD及GRFS的潜在生物标志物的价值。