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Abstract: Objectives: To explore the possible risk factors for the occurrence and mortality of thrombotic microangiopathy (TMA) with concomitant acute graft‐vs‐host disease (aGVHD) and to investigate outcomes and treatments of this disorder after allo‐HSCT. Methods: Fifty cases diagnosed with TMA with concomitant aGVHD and 150 controls were identified from a cohort composed of 3992 patients who underwent allo‐HSCT from 2008 to 2016. Results: Grade III‐IV aGVHD (P = .000), acute kidney injury (AKI) (P = .033), and hypertension (P = .028) were significant independent risk factors associated with the occurrence of TMA with concomitant aGVHD. A haptoglobin level below normal (P = .013), a maximum volume of diarrhea >2500 mL/d (P = .015), and bloody diarrhea (P = .049) were significant markers for death in both univariate and multivariate analyses. Patients diagnosed with TMA with concomitant aGVHD had a lower overall survival (OS), a higher non‐relapse mortality (NRM), but a lower risk of relapse. Conclusions: Thrombotic microangiopathy with concomitant aGVHD is a significant complication after allo‐HSCT, with a worse outcome, including significantly lower OS and higher NRM. There are specific risk factors associated with occurrence and mortality of this complication. [ABSTRACT FROM AUTHOR]

Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers. • PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, which can be restored by PPARδ overexpression. • Activation of PPARδ benefited the damaged BM EPCs from PGF patients or AML-CR patients. • Increased expression of NADPH oxidases (NOXs) may lead to elevated ROS level in BM EPCs. • Insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. [ABSTRACT FROM AUTHOR]

Introduction: Myeloid-derived suppressor cells (MDSCs) are proposed to control graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the definition of human MDSCs has not yet reached consensus, and the mechanism of MDSCs to control GVHD remains unclear. Methods: Immature myeloid cells (HLA-DR−/lowCD33+CD16−) were tested before and after granulocyte colony-stimulating factor (G-CSF) administration in healthy donor and isolated for suppression assays and co-culture with T cells in vitro. Isolated cells were infused in humanized mice for a xenogeneic model of acute GVHD. One hundred allo-HSCT recipients were enrolled prospectively to assess the role of HLA-DR−/lowCD33+CD16− cells in grafts on the occurrence of acute GVHD. Results: In the present study, G-CSF mobilized HLA-DR−/lowCD33+CD16− cells with immunosuppressive properties in donor peripheral blood. These cells contained more interleukin-10+ and transforming growth factor-beta (TGF-β)+ cells after G-CSF administration and inhibited the proliferation of autologous donor T cells in a TGF-β-dependent manner. Meanwhile, these immature myeloid cells promoted regulatory T cell expansion and induced Th2 differentiation. Importantly, these cells prevented acute GVHD in a humanized mouse model. Moreover, clinical cohort results showed that the number of HLA-DR−/lowCD33+CD16− cells in the donor graft was the only independent risk factor inversely correlated with the incidence of grade II–IV acute GVHD in the recipients (HR 0.388, 95% CI 0.158–0.954, p = 0.039). Conclusion: HLA-DR−/lowCD33+CD16− cells represent functional MDSCs that may control acute GVHD in allo-HSCT. [ABSTRACT FROM AUTHOR]

Prolonged isolated thrombocytopenia (PT) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether abnormalities of the bone marrow (BM) immune microenvironment are involved in the pathogenesis of PT remains unknown, however. Twenty patients with PT, 40 matched patients with good graft function (GGF) after allo-HSCT, and 20 healthy donors (HD) were enrolled in this nested case-control study. Th1, Th2, Tc1, Tc2, Th17, and Treg cells were analyzed by flow cytometry, and IFN-γ, IL-4, IL-17, IL-6, IL-21, and thrombopoietin levels in BM plasma were evaluated with a cytometric bead assay and ELISA. Relative to GGF patients and HD controls, PT patients had significantly higher proportions of Th1 and Tc1 cells, resulting in higher Th1/Th2 and Tc1/Tc2 ratios in the BM microenvironment. In addition, the excessive polarization of Th17 was observed in patients with PT. Changes in BM plasma cytokines were consistent with our cellular findings. These results suggest that dysregulated T cell responses in the BM microenvironment might play an important role in the pathogenesis of PT. [ABSTRACT FROM AUTHOR]

• We report the incidence of acute pancreatitis (AP) after allo-HSCT. • We identify younger age, grades II to IV aGVHD, a history of DLI, and pre-existing gallstones as independent risk factors of post-transplant AP. • We describe the outcomes of patients with post-transplant AP. • We establish an exploratory risk score model to help risk stratification in such patients. Acute pancreatitis (AP) has been recognized as an uncommon yet potentially lethal complication after hematopoietic stem cell transplant (HSCT). This retrospective, nested, case-control study reviewed data from 5284 consecutive patients who underwent allogeneic (allo)-HSCT between 2009 and 2018 at a single center, identifying 40 patients (0.76%) with AP after allo-HSCT. The diagnosis and severity of AP were established and classified according to existing criteria. Younger age (P =.008), grades II to IV acute graft-versus-host disease (P =.010), a history of donor lymphocyte infusion (P =.033), and pre-existing gallstones (P =.003) were independent risk factors of AP after allo-HSCT. Post-transplant AP had a trend to negatively influence overall survival (OS) and nonrelapse mortality (NRM) (P =.063) for allo-HSCT recipients, but no significant difference was found. Patients with moderately severe and severe AP had significantly lower OS (P =.002) and higher NRM (P =.000) than other patients. Based on these findings, a risk score model was also established to predict the occurrence of AP. Our risk score model performed well in terms of discrimination when applied to derivation samples. Patients were classified into a low-risk group (0 to 1 point), a medium-risk group (2 to 3 points), and a high-risk group (4 points or more). Significant difference was observed in AP incidence among the 3 groups. The predictive tool explored by our study might contribute to target high-risk patients and guide personalized AP prevention in allo-HSCT recipients. [ABSTRACT FROM AUTHOR]

Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are at an increased risk of thrombotic complications, most of which are catheter-related and present a substantial challenge. The incidence of CRT varies considerably depending on clinical factors. However, the underlying pathogenesis and risk factors remain unclear. Methods We performed a retrospective nested case-control study in patients following allo-HSCT. Thrombotic episodes were diagnosed based on the clinical suspicion of the physician (pain, swelling, etc.) with subsequent CVC or PICC thrombosis confirmed via duplex ultrasound. Cases with CRT and controls were matched for time of HSCT, age at HSCT, donor source and type of insertion (CVCs or PICC). Results During the 8-year period, catheters were placed in 2896 patients, with a total of 40 patients (1.38%) developed CRT, among which 11 were associated with CVCs and 29 were associated with PICCs. The median duration from catheter insertion to thrombosis was 97 days. Despite reports of an association between thrombosis and infection, central line-associated bloodstream infection was comparable between groups. No significant differences were noted in terms of primary disease, donor type, conditioning regimen or catheter type between the cases and controls. A multivariate regression analysis identified high-dose corticosteroids as independent risk factors for the development of CRT. CRT seems to negatively affect prognosis in allo-HSCT patients. Conclusion In conclusion, we demonstrate that the use of high-dose corticosteroids is correlated with the onset of CRT. However, the efficacy and safety of thromboprophylaxis in this population require further investigation. [ABSTRACT FROM AUTHOR]

Poor graft function (PGF) is a severe complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The question of whether the bone marrow (BM) immune microenvironment is involved in the pathogenesis of PGF remains unresolved. In total, 10 patients with PGF, 30 matched patients with good graft function after allo-HSCT, and 15 healthy donors were enrolled in this nested case-control study. The Th1, Th2, Tc1, Tc2, and active phenotypes were analyzed by flow cytometry. IFN-γ and IL-4 levels in BM plasma were evaluated using cytometric beads assay. Relative to other subjects, patients with PGF had significantly higher proportions of stimulated CD4 + and CD8 + T cells that produced IFN-γ (Th1 and Tc1 cells) but notably decreased proportions of IL-4-producing T cells (Th2 and Tc2 cells), resulting in a shift of the IFN-γ/IL-4 ratio towards a type 1 response and an elevated percentage of activated CD8 + T cells. Changes in IFN-γ and IL-4 levels in BM plasma were consistent with the cellular results. Our results suggest that dysregulated T cell responses may contribute to the occurrence of PGF after HSCT. [ABSTRACT FROM AUTHOR]