Lei Gao

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation, with cutaneous fibrosis representing a debilitating and treatment-resistant manifestation. We identified a hypoxia-driven inflammatory and fibrotic program in cGVHD skin mediated by a hypoxia-inducible factor 1α–phosphatidylinositol 3-kinase–interleukin-13 (HIF-1α–PI3Kδ–IL-13) signaling axis. Spatial transcriptomics, single-cell RNA sequencing, and multiplex immunofluorescence revealed stabilization of HIF-1α in epidermal cells in hypoxic regions. HIF-1α stabilization was accompanied by IL-13 production from PI3Kδ-activated T cells and macrophage-epidermal cross-talk, which together promoted fibrosis and the formation of tertiary lymphoid structure (TLS)–like aggregates. In human epidermal cell lines and induced pluripotent stem cell–derived skin organoids, IL-13 directly induced HIF-1α expression in keratinocytes under normoxic conditions. HIF-1α expression was further amplified in hypoxic conditions, driving profibrotic signaling. Pharmacologic inhibition of HIF-1α, PI3Kδ, or IL-13 reduced tissue hypoxia, disrupted TLS-like aggregates, and ameliorated disease in murine cGVHD models. These findings identify a targetable circuit linking hypoxia, type 2 inflammation, and immune-stromal dysfunction in cGVHD and provide a translational framework for treating fibrotic cGVHD and related immune-mediated fibrosing diseases.

PURPOSE: The aim of this open-label, multicenter, randomized controlled trial was to determine the efficacy and safety of sequential umbilical cord–derived mesenchymal stem cell (UC-MSC) infusion for graft-versus-host disease (GVHD) prevention within 3 months of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). METHODS: This open-label study evaluated UC-MSC infusion (administer 1 × 10 ⁶ /kg 4 hours before the commencement of day 0, once weekly for the first month after transplantation, once every 2 weeks for the second month, and once during the third month, totaling eight doses). The primary end point was the 2-year cumulative incidence of severe chronic GVHD (cGVHD). RESULTS: In the primary analysis, 192 qualified participants between age 18 and 60 years with haplo-HSCT in three transplant centers in China were enrolled and randomly assigned to the MSC and control groups. In the primary analysis, the estimated 2-year cumulative incidence of severe cGVHD and all grades of cGVHD was lower in the MSC group than in the control group ( P = .033 and P = .022). The cumulative incidence of grade 1 to 4, 2 to 4, and 3 to 4 acute GVHD (aGVHD) in patients in the MSC group significantly decreased (all P < .001). The 3-year GVHD-free and relapse-free survival (GRFS) rate in the MSC group was 62.4%, which was significantly higher than that in the control group (32.0%, hazard ratio [HR], 0.34, P < .001). MSC infusion did not influence the cumulative incidence of relapse ( P = .34) and nonrelapse mortality ( P = .45). CONCLUSION: Our findings suggest that sequential infusion of MSCs within 3 months after haplo-HSCT significantly reduced both the incidence and severity of cGVHD and aGVHD, manifesting as a better GRFS rate for patients.

In recent years, great progress has been made in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) treatment for hematological malignant diseases because of the advent of novel conditioning regimens, optimized graft manipulation, improved graft-versus-host disease (GVHD) prophylaxis, and advances in supportive care. Recent studies have shown very favorable outcomes in severe aplastic anemia (SAA) patients, with comparable outcomes to those of patients receiving immune suppressive therapy (IST) and allogeneic HSCT from a matched sibling donor (MSD) or matched unrelated donor (MUD). However, most of the previous studies relied on single-center data analyses, and the conditioning regimen, GVHD prophylaxis and supportive care used were relatively singular. We do not know whether there are differences in the survival of SAA patients after haplo-HSCT and MSD-HSCT under conditions involving different transplant centers, conditioning regimens and GVHD prophylaxis. This is a disease-specific, multicenter and retrospective study. We retrospectively studied 156 consecutive patients with SAA who underwent haplo-HSCT or MSD-HSCT at four transplant centers in China. The 5-year overall survival (OS) rate was 87.5% in the haplo-HSCT group and 89.7% in the MSD-HSCT group. The time to hematopoietic reconstitution, incidence of graft versus host disease, and infection and graft failure rates were not significantly different between the groups. Haplo-HSCT achieved outcomes comparable to those of MSD-HSCT for SAA patients. According to the nomogram score, we developed a SAA prognostic scoring system. Haplo-HSCT should be considered an effective alternative for patients with SAA without a matched sibling donor. The SAA transplant-specific prognostic scoring system proposed in this study can conveniently predict the OS for SAA patients following MSD-HSCT or haplo-HSCT.

Acute leukemia (AL) is a rare yet perilous malignancy. Currently, the primary treatment for AL involves combination chemotherapy as the cornerstone of comprehensive measures, alongside hematopoietic stem cell transplantation as a radical approach. However, despite these interventions, mortality rates remain high, particularly among refractory/recurrent patients or elderly individuals with a poor prognosis. Acetylation, a form of epigenetic regulation, has emerged as a promising therapeutic avenue for treating AL. Recent studies have highlighted the potential of acetylation regulation as a novel treatment pathway. Histone deacetylase inhibitors (HDACis) play a pivotal role in modulating the differentiation and development of tumor cells through diverse pathways, simultaneously impacting the maturation and function of lymphocytes. HDACis demonstrate promise in enhancing survival rates and achieving a complete response in both acute myeloid leukemia and acute T-lymphoblastic leukemia patients. This article provides a comprehensive review of the advancements in HDACi therapy for AL, shedding light on its potential implications for clinical practice.

Disclosures. No relevant conflicts of interest to declare.

Peroxisome proliferator-activated receptor alpha (PPARA) has been suggested as a therapeutic target for chronic lymphocytic leukemia (CLL). However, the underlying molecular mechanism remains largely unclear. In this study, we analyzed DNA next-generation sequencing (NGS) data and clinical information from 86 CLL patients to identify gene markers related to treatment-free survival (TFS) length. We then constructed a genetic network that includes CLL promoters, treatment targets, and TFS-related marker genes. To assess the significance of PPARA within the network, we utilized degree centrality (DC) and pathway enrichment score (EScore). Clinical and NGS data revealed 10 TFS length-related gene markers, including RPS15, FOXO1, FBXW7, KMT2A, NOTCH1, GNA12, EGR2, GNA13, KDM6A, and ATM. Through literature data mining, 83 genes were identified as CLL upstream promoters and treatment targets. Among them, PPARA exhibited a stronger connection to CLL and TFS-related gene markers, as evidenced by its ranking at No. 13 based on DC, compared to most of the other promoters (84). Additionally, PPARA co-functions with 70 out of 92 in-network genes in various functional pathways/gene groups related to CLL pathology, such as regulation of cell adhesion, inflammation, reactive oxygen species, and cell differentiation. Based on our findings, PPARA is considered one of the critical genes within a large genetic network that influences the prognosis and TFS of CLL through multiple pathogenic pathways.

To compare the outcomes of patients with hematological malignancies who received ATG-Fresenius (ATG-F) 20 mg/kg versus those who received ATG-Genzyme (ATG-G) 10 mg/kg in an unrelated donor hematopoietic stem cell transplantation (HSCT) procedure, a total of 186 patients who underwent their first allogeneic HSCT with an unrelated donor were retrospectively analyzed. One hundred and seven patients received ATG-F, and seventy-nine patients received ATG-G. Multivariate analysis showed that the type of ATG preparation had no effect on neutrophil engraftment (P = 0.61), cumulative incidence of relapse (P = 0.092), nonrelapse mortality (P = 0.44), grade II-IV acute graft-versus-host disease (GVHD) (P = 0.47), chronic GVHD (P = 0.29), overall survival (P = 0.795), recurrence-free survival (P = 0.945) or GVHD-free relapse-free survival (P = 0.082). ATG-G was associated with a lower risk of extensive chronic GVHD and a higher risk of cytomegaloviremia (P = 0.01 and HR = 0.41, P < 0.001 and HR = 4.244, respectively). The results of this study suggest that the preparation of rabbit ATG used for unrelated HSCT should be selected based on the incidence of extensive chronic GVHD of each center, and the posttransplant management strategy should be adjusted according to the ATG preparation.