Haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) is an alternative treatment method for severe aplastic anemia (SAA) patients lacking suitable identical donors and those who are refractory to immunosuppressive therapy (IST). The current study evaluated the feasibility of upfront haploidentical HSCT in SAA patients. We conducted a multicenter study based on a registry database. One hundred fifty-eight SAA patients who underwent upfront transplantation between June 2012 and September 2015 were enrolled. Eighty-nine patients had haploidentical donors (HIDs), and 69 had matched related donors (MRDs) for HSCT. The median times for myeloid engraftment in the HID and MRD cohorts were 12 (range, 9–20) and 11 (range, 8–19) days, with a cumulative incidence of 97.8 and 97.1% (P = 0.528), respectively. HID recipients had an increased cumulative incidence of grades II–IV acute graft-versus-host disease (aGVHD) (30.3 vs. 1.5%, P < 0.001), grades III–IV aGVHD (10.1 vs. 1.5%, P = 0.026), and chronic GVHD (cGVHD) (30.6 vs. 4.4%, P < 0.001) at 1 year but similar extensive cGVHD (3.4 vs. 0%, P = 0.426). The three-year estimated overall survival (OS) rates were 86.1 and 91.3% (P = 0.358), while the three-year estimated failure-free survival (FFS) rates were 85.0 and 89.8% (P = 0.413) in the HID and MRD cohorts, respectively. In multivariate analysis, survival outcome for the entire population was significantly adversely associated with increased transfusions and poor performance status pre-SCT. We did not observe differences in primary engraftment and survival outcomes by donor type. Haploidentical SCT as upfront therapy was an effective and safe option for SAA patients, with favorable outcomes in experienced centers.

To our knowledge, this study first demonstrated the prognostic significance and biological function of long noncoding RNA (lncRNA) small nucleolar RNA host gene 15 (SNHG15) in multiple myeloma (MM), and indicated a novel revelation on the effect of N6-methyladenosine (m6A)-regulated lncRNA on MM tumorigenicity. Moreover, the novel chromatin-regulatory mechanism of lncRNA by interacting with epigenetic modifiers including m6A demethylase ALKBH5 and H3K36me3 methyltransferase SETD2 in myeloma progression elucidated intricate mechanism of tumor pathogenesis.

Currently, the graft-versus-host disease (GVHD) prophylaxis consists of an immunosuppressive therapy mainly based on antithymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). GVHD remains a major complication and limitation to successful allogeneic haploidentical hematopoietic stem cell transplantation (haplo‐HSCT). We modified the ATG-based GVHD prophylaxis with the addition of basiliximab in the setting of haplo-HSCT and attempted to explore the appropriate dosages. We conducted a retrospective analysis of 239 patients with intermediate- or high-risk hematologic malignancies who received haplo-HSCT with unmanipulated peripheral blood stem cells combined or not with bone marrow. All patients received the same GVHD prophylaxis consisting of the combination of methotrexate, cyclosporine or tacrolimus, mycofenolate-mofetil, and basiliximab with different doses of ATG (5-9mg/kg). With a median time of 11 days (range, 7-40 days), the rate of neutrophil engraftment was 96.65%. The 100-day cumulative incidences (CIs) of grade II–IV and III–IV aGVHD were 15.8 ± 2.5% and 5.0 ± 1.5%, while the 2-year CIs of total cGVHD and extensive cGVHD were 9.8 ± 2.2% and 4.1 ± 1.5%, respectively. The 3-year CIs of treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) were 14.6 ± 2.6%, 28.1 ± 3.4%, 60.9 ± 3.4%, 57.3 ± 3.4%, respectively. Furthermore, the impact of the reduction of the ATG dose to 6 mg/kg or less in combination with basiliximab on GVHD prevention and transplant outcomes among patients was analyzed. Compared to higher dose of ATG(>6mg/kg), lower dose of ATG (≤6mg/kg) was associated with a significant reduced risk of CMV viremia (52.38% vs 79.35%, P<0.001), while the incidences of aGVHD and cGVHD were similar between the two dose levels. No significant effect was found with regard to the risk of relapse, TRM, and OS. ATG combined with basiliximab could prevent GVHD efficiently and safely. The optimal scheme of using this combined regimen of ATG and basiliximab is that administration of lower dose ATG (≤6mg/kg), which seems to be more appropriate for balancing infection control and GVHD prophylaxis.

Metabolic reprogramming is a key focus of targeted therapies in acute myeloid leukemia (AML). The mitochondrial sirtuin SIRT5 removes succinyl groups from specific lysines and impacts cell metabolism, but its role in AML tumorigenesis has not been extensively explored. A recent study highlighted that SIRT5 regulates AML cell activity by modulating glutamine metabolism, but its molecular targets in AML remain unclear. This study aims to identify the substrates of SIRT5 in AML. It was found that a total of 83 proteins with 121 lysine (K) residues showed increased succinylation after SIRT5 knockdown, as determined by succinylome analysis of MOLM-13 cells. SIRT5 was validated to interact with HADHA, a key molecule in the fatty acid oxidation pathway. Knockdown of SIRT5 resulted in hypersuccinylation and reduced enzymatic activity of HADHA. Mimetic mutations of lysine indicated that SIRT5 desuccinylates HADHA at K644. Inhibiting SIRT5 or HADHA increased sensitivity to venetoclax (VEN) in both VEN-sensitive and VEN-resistant cell lines. SIRT5 knockdown enhanced VEN-mediated suppression of mitochondrial metabolism and improved the survival of AML-transplanted NSG mice when combined with VEN. This study reveals the role of SIRT5 in AML metabolic regulation and provides valuable insights for developing SIRT5-targeted drugs and combination therapies with metabolic inhibitors.

Haploidentical stem cell transplantation (HSCT) has become an alternative treatment option for patients with aplastic anemia (AA) without matched sibling donors or matched unrelated donors. Recently, post-transplantation cyclophosphamide (PTCy) and granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG) regimens have become the most common protocols used worldwide. In this retrospective study, we retrospectively reviewed and analyzed the clinical data of 130 AA patients who underwent haploidentical HSCT and received the modified PTCy (mPTCy) regimen (n = 55) or G-CSF/ATG regimen (n = 75) between January 2013 and June 2021 across 7 transplantation centers. Neutrophil engraftment was successful in all patients within 30 days in the G-CSF/ATG group. The cumulative neutrophil engraftment rate in the mPTCy group was 96.36% (95% confidence interval [CI], 94.57 to 97.57; P = .010). The median time to neutrophil engraftment in the G-CSF/ATG group was 10 days (range, 7 to 28 days), which was more rapid than that observed in the mPTCy group (P < .001). There was no significant difference in the incidence of graft-versus-host disease (GVHD) between the 2 groups. The cumulative incidence of grade II-IV acute GVHD was 18.40% (95% CI, 4.27% to 40.31%) in the mPTCy group and 19.32% (95% CI, 5.86% to 38.58%) in the G-CSF/ATG group, whereas the cumulative incidence of grade III-IV acute GVHD was 7.31% (95% CI, .09% to 37.48%) in the mPTCy group and 7.57% (95% CI, .20 to 34.19) in the G-CSF/ATG group. Similarly, there were no significant between-group differences in overall survival (OS), failure-free survival (FFS), and GVHD-free relapse-free survival (GRFS). The 2-year OS, FFS, and GRFS rates were 95.91% (95% CI, 84.59% to 98.96%), 92.25% (95% CI, 80.59% to 97.03%), and 86.68% (95% CI, 73.98% to 93.44%), respectively, in the mPTCy group and 86.67% (95% CI, 76.64% to 92.59%), 81.28% (95% CI, 70.45% to 88.46%), and 77.20% (95% CI, 65.89% to 85.16%), respectively, in the G-CSF/ATG group. Transplantation-related mortality (TRM) was significantly higher in the G-CSG/ATG group than in the mPTCy group (13.33% versus 1.96%; P = .022). In multivariate analysis, the use of a female donor, a higher Hematopoietic Cell Transplantation Comorbidity Index, and grade III-IV acute GVHD were associated with worse survival outcomes. The mPTCy and G-CSF/ATG regimens led to similar outcomes in AA patients, but quicker engraftment was observed with the ATG/G-CSF regimen, and a lower incidence of TRM was observed with the mPTCy regimen.

Background: Bloodstream infection (BSI) due to carbapenem-resistant organisms (CROs) has emerged as a worldwide problem associated with high mortality. This study aimed to evaluate the risk factors associated with mortality in HM patients with CROs BSI and to establish a scoring model for early mortality prediction. Methods: We conducted a retrospective cohort study at our hematological department from January 2018 to December 2021, including all HM patients with CROs BSI. The outcome measured was death within 30-day of BSI onset. Survivor and non-survivor subgroups were compared to identify predictors of mortality. Univariate and multivariate Cox regression analyses were used to identify prognostic risk factors and develop a nomogram. Results: In total, 150 HM patients were included in the study showing an overall 30-day mortality rate of 56%. Klebsiella pneumonia was the dominant episode. Cox regression analysis showed that pre-infection length of stay was > 14 days (score 41), Pitt score > 4 (score 100), mucositis (score 41), CAR (The ratio of C-reactive protein to albumin) > 8.8 (score 57), early definitive therapy (score 44), and long-duration (score 78) were positive independent risk predictors associated with 30-day mortality, all of which were selected into the nomogram. Furthermore, all patients were divided into the high-risk group (≥ 160 points) or the low-risk group based on the prediction score model. The mortality of the high-risk group was 8 times more than the low-risk group. Kaplan-Meier analysis showed that empirical polymyxin B therapy was associated with a lower 30-day mortality rate, which was identified as a good prognostic factor in the high-risk group. In comparison, empirical carbapenems and tigecycline were poor prognostic factors in a low-risk group. Conclusion: Our score model can accurately predict 30-day mortality in HM patients with CROs BSI. Early administration of CROs-targeted therapy in the high-risk group is strongly recommended to decrease mortality.