Single-cell transcriptomic analysis identifies an immune-prone population in erythroid precursors during human ontogenesis.

Nonimmune cells can have immunomodulatory roles that contribute to healthy development. However, the molecular and cellular mechanisms underlying the immunomodulatory functions of erythroid cells during human ontogenesis remain elusive. Here, integrated, single-cell transcriptomic studies of erythroid cells from the human yolk sac, fetal liver, preterm umbilical cord blood (UCB), term UCB and adult bone marrow (BM) identified classical and immune subsets of erythroid precursors with divergent differentiation trajectories. Immune-erythroid cells were present from the yolk sac to the adult BM throughout human ontogenesis but failed to be generated in vitro from human embryonic stem cells. Compared with classical-erythroid precursors, these immune-erythroid cells possessed dual erythroid and immune regulatory networks, showed immunomodulatory functions and interacted more frequently with various innate and adaptive immune cells. Our findings provide important insights into the nature of immune-erythroid cells and their roles during development and diseases.

Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection.

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.

GSNOR overexpression enhances CAR-T cell stemness and anti-tumor function by enforcing mitochondrial fitness.

Chimeric antigen receptor-T (CAR-T) cell has been developed as a promising agent for patients with refractory or relapsed lymphoma and leukemia, but not all the recipients could achieve a long-lasting remission. The limited capacity of in vivo expansion and memory differentiation post activation is one of the major reasons for suboptimal CAR-T therapeutic efficiency. Nitric oxide (NO) plays multifaceted roles in mitochondrial dynamics and T cell activation, but its function on CAR-T cell persistence and anti-tumor efficacy remains unknown. Herein, we found the continuous signaling from CAR not only promotes excessive NO production, but also suppressed S-nitrosoglutathione reductase (GSNOR) expression in T cells, which collectively led to increased protein S-nitrosylation, resulting in impaired mitochondrial fitness and deficiency of T cell stemness. Intriguingly, enforced expression of GSNOR promoted memory differentiation of CAR-T cell after immune activation, rendered CAR-T better resistance to mitochondrial dysfunction, further enhanced CAR-T cell expansion and anti-tumor capacity in vitro and in a mouse tumor model. Thus, we revealed a critical role of NO in restricting CAR-T cell persistence and functionality, and defined that GSNOR overexpression may provide a solution to combat NO stress and render patients with more durable protection from CAR-T therapy.

Is Short-Course Antibiotic Therapy Suitable for Pseudomonas aeruginosa Bloodstream Infections in Onco-hematology Patients With Febrile Neutropenia? Results of a Multi-institutional Analysis.

BACKGROUND: Several studies have suggested that short-course antibiotic therapy was effective in Pseudomonas aeruginosa (PA) bloodstream infections (BSI) in immunocompetent patients. But similar studies in patients with hematological malignancies were rare. METHODS: This cohort study included onco-hematology patients at 2 hematology centers in China. Inverse probability of treatment weighting was used to balance the confounding factors. Multivariate regression model was used to evaluate the effect of short-course antibiotic therapy on clinical outcomes. RESULTS: In total, 434 patients met eligibility criteria (short-course, 7-11 days, n = 229; prolonged, 12-21 days, n = 205). In the weighted cohort, the univariate and multivariate analysis indicated that short course antibiotic therapy had similar outcomes to the prolonged course. The recurrent PA infection at any site or mortality within 30 days of completing therapy occurred in 8 (3.9%) patients in the short-course group and in 10 (4.9%) in the prolonged-course group (P = .979). The recurrent infection within 90 days occurred in 20 (9.8%) patients in the short-course group and in 13 (6.3%) patients in the prolonged-course group (P = .139), and the recurrent fever within 7 days occurred in 17 (8.3%) patients in the short-course group and in 15 (7.4%) in the prolonged-course group (P = .957). On average, patients who received short-course antibiotic therapy spent 3.3 fewer days in the hospital (P < .001). CONCLUSIONS: In the study, short-course therapy was non-inferior to prolonged-course therapy in terms of clinical outcomes. However, due to its biases and limitations, further prospective randomized controlled trials are needed to generalize our findings.

Refractory patients with favorable/intermediate-risk acute myeloid leukemia benefit from azacytidine maintenance therapy following allogeneic hematopoietic stem cell transplantation.

Recurrence following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the major cause of treatment failure in patients with myeloid malignancy. Azacytidine (AZA) maintenance is a promising therapy to prevent relapse and improve survival. We conducted a prospective, one-arm study involving 78 patients with myeloid malignancy at a high risk of recurrence who were enrolled between September 2019 and April 2022. Furthermore, 102 matched historical controls were selected using propensity score matching. With a median follow-up time of 19.6 (3.5-91.7) months, AZA maintenance therapy significantly improved relapse-free survival (RFS; log-rank test, p = 0.01). The AZA and control groups had a 1-year RFS of 87.7% (95% confidence interval [CI], 0.80-0.96) and 72.2% (95% CI, 0.64-0.82), respectively, with a hazard ratio (HR) of 0.21 (95% CI, 0.09-0. 47; p < 0.01). There were no grade 4 adverse effects or deaths related to AZA. Refractory patients with favorable/intermediate-risk acute myeloid leukemia (AML) benefited more from AZA maintenance therapy than those with adverse-risk AML according to the European Leukemia Net guidelines (RFS in favorable/intermediate-risk AML, HR = 0.29, 95% CI, 0.11-0.79; RFS in adverse-risk AML, HR = 0.57, 95% CI, 0.21-1.6; p for interaction = 0.03). Our findings suggest that AZA maintenance therapy following allo-HSCT was safe and could reduce the incidence of relapse, particularly for refractory patients with favorable/intermediate-risk AML.

Comparison of autologous, matched sibling, and alternative donor stem cell transplant outcomes for acute myeloid leukemia patients in first remission: A propensity score matching study.

Autologous hematopoietic stem cell transplantation (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and alternative donor HSCT (AD-HSCT) are viable post-remission treatment options for acute myeloid leukemia (AML). A total of 283 de novo favorable- and intermediate-risk AML patients, based on the ELN 2022 criteria, in first complete remission were initially included for propensity score matching. Following the matching process, 126 patients were selected for further analysis, with 42 patients in each of the auto-HSCT, MSD-HSCT, and AD-HSCT groups. Among the AD-HSCT group, 38 of 42 (90.5%) patients received haploidentical HSCT. In patients with persistent undetectable measurable residual disease (uMRD) before transplant (n = 83), overall survival (OS) was similar across the groups. However, auto-HSCT showed a trend of increased disease-free survival (DFS) compared to AD-HSCT (HR 2.85, P = 0.09), resulting in a 3-year DFS and OS of 79.1% and 82.8%, respectively. In the non-persistent uMRD group (n = 38), auto-HSCT exhibited a tendency to increase the risk of relapse, particularly when compared to AD-HSCT (HR 0.24, P = 0.07), but this did not result in inferior OS. The monthly direct medical cost per patient within the first 2 years after HSCT was significantly lower in auto-HSCT compared to MSD-HSCT (P = 0.015) and AD-HSCT (P < 0.001). Our results provide evidence for the use of auto-HSCT as a viable therapeutic option for favorable- and intermediate-risk de novo AML patients in first complete remission with persistent uMRD. Additionally, our findings demonstrated a notable cost advantage associated with auto-HSCT compared to MSD-HSCT and AD-HSCT.

Hematopoietic progenitor cell count as a potential quantitative marker in apheresis products during allogeneic stem cell transplantation.

BACKGROUND: The quality and quantity of hematopoietic stem cells in apheresis products are essential to the success of peripheral blood hematopoietic stem cell transplantation (PB-HSCT). While the flow cytometry measurement of CD34+ cells as a golden standard for stem cell count is labor and cost-intensive, hematopoietic progenitor cell number evaluated by XN Sysmex series automated hematology analyzers (XN-HPC) is suggested as a surrogate marker. MATERIALS AND METHODS: We evaluated the correlation and consistency of XN-HPC and CD34+ cell count in apheresis samples from both allogeneic donors and autologous patients during PB-HSCT. RESULTS: Good correlation and consistency were observed between XN-HPC and CD34+ cell counts in harvests collected from healthy donors (R = .852) rather than autologous patients (R = .375). Subgroup analysis showed that the correlation was especially poor when autologous patients used plerixafor as an additional mobilizer or were diagnosed with multiple myeloma (MM). In the setting of allogeneic transplantation, the correlation coefficients were even better in samples from non-first-round apheresis (R = .951), with high white blood cell (WBC) counts (R = .941), or having successful engraftment within 2 weeks (R = .895). ROC analysis suggested that an optimal XN-HPC count of 1127 × 106 /L best predicted a sufficient yield of CD34+ stem cells, with diagnostic sensitivity and specificity being 92% and 72%, respectively (AUC = 0.852). CONCLUSIONS: XN-HPC is a sufficient quantitative marker for stem cell assessment of harvest yield in allogeneic but not autologous HSCT.

WT1 gene mutations impact post-transplant relapse in myelodysplastic syndrome with excess blasts 2 patients.

Wilms tumor 1 (WT1) gene mutations are infrequent in myelodysplastic syndrome (MDS), but MDS with WT1 mutations (WT1mut) is considered high risk for acute myeloid leukemia (AML) transformation. The influence of WT1 mutations in patients with MDS after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. We performed a retrospective analysis of 136 MDS with excess blasts 2 (MDS-EB2) patients with available WT1 status who underwent their first allo-HSCT between 2017 and 2022 in our center. There were 20 (20/136, 15%) cases in the WT1mut group and 116 (116/136, 85%) cases in the WT1 wild-type (WT1wt) group. WT1mut patients had a higher 2-year cumulative incidence of relapse (CIR) than WT1wt cases (26.2% vs. 9.4%, p = 0.037) after allo-HSCT. Multivariate analysis of relapse showed that WT1 mutations (HR, 6.0; p = 0.002), TP53 mutations (HR, 4.2; p = 0.021), and ≥ 5% blasts in bone marrow (BM) at transplantation (HR, 6.6; p = 0.004) were independent risk factors for relapse. Patients were stratified into three groups according to the risk factors. Two-year CIR differed significantly in high-, intermediate-, and low-risk groups (31.8%, 11.6%, and 0%, respectively). Hence, WT1 mutations may be related to post-transplant relapse in patients with MDS-EB2, which warrants further study.

Prophylactic therapy using epigenetic agents for RUNX1::RUNXT1-positive high-risk AML after Allo-HSCT.

Disease recurrence is the leading cause of treatment failure in patients with RUNX1::RUNXT1-positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Post-transplant maintenance therapy, guided by monitoring minimal residual disease (MRD), is commonly administered; however, relapse rates remain high. This prospective study aimed to assess the effectiveness and safety of epigenetic agents as prophylactic therapy in patients with RUNX1::RUNXT1-positive AML. Thirty high-risk patients received prophylactic therapy (n = 17 and n = 13 in the chidamide and AZA groups, respectively) between January 2019 and July 2023. 34 high-risk patients who received preemptive treatment due to molecular relapse were included in the analysis. The two-year relapse-free survival (RFS) and overall survival (OS) were significantly higher in the prophylactic group compared to the preemptive group (82.82% vs. 51.38%, P = 0.014; 86.42% vs. 56.16%, P = 0.025, respectively); 2-year cumulative incidence of relapse rates were 13.8% and 36.40%, respectively (P = 0.037). In conclusion, prophylactic therapy with epigenetic agents may improve long-term prognosis and is well-tolerated in patients with RUNX1::RUNXT1-positive high-risk AML. Timely post-transplant prophylactic therapy may be more effective than preemptive therapy based on positive MRD results.

Combining serum microRNAs and machine learning algorithms for diagnosing infectious fever after HSCT.

Infection post-hematopoietic stem cell transplantation (HSCT) is one of the main causes of patient mortality. Fever is the most crucial clinical symptom indicating infection. However, current microbial detection methods are limited. Therefore, timely diagnosis of infectious fever and administration of antimicrobial drugs can effectively reduce patient mortality. In this study, serum samples were collected from 181 patients with HSCT with or without infection, as well as the clinical information. And more than 80 infectious-related microRNAs in the serum were selected according to the bulk RNA-seq result and detected in the 345 time-pointed serum samples by Q-PCR. Unsupervised clustering result indicates a close association between these microRNAs expression and infection occurrence. Compared to the uninfected cohort, more than 10 serum microRNAs were identified as the combined diagnostic markers in one formula constructed by the Random Forest (RF) algorithms, with a diagnostic accuracy more than 0.90. Furthermore, correlations of serum microRNAs to immune cells, inflammatory factors, pathgens, infection tissue, and prognosis were analyzed in the infection cohort. Overall, this study demonstrates that the combination of serum microRNAs detection and machine learning algorithms holds promising potential in diagnosing infectious fever after HSCT.

Loss of Lkb1 in CD11c+ myeloid cells protects mice from diet-induced obesity while enhancing glucose intolerance and IL-17/IFN-γ imbalance.

Adipose tissue CD11c+ myeloid cell is an independent risk factor associated with obesity and metabolic disorders. However, the underlying molecular basis remains elusive. Here, we demonstrated that liver kinase B1 (Lkb1), a key bioenergetic sensor, is involved in CD11c+ cell-mediated immune responses in diet-induced obesity. Loss of Lkb1 in CD11c+ cells results in obesity resistance but lower glucose tolerance, which accompanies tissue-specific immune abnormalities. The accumulation and CD80's expression of Lkb1 deficient adipose-tissue specific dendritic cells but not macrophages is restrained. Additionally, the balance of IL-17A and IFN-γ remarkably tips towards the latter in fat T cells and CD11c- macrophages. Mechanistically, IFN-γ promotes apoptosis of preadipocytes and inhibits their adipogenesis while IL-17A promotes the adipogenesis in vitro, which might account in part for the fat gain resistant phenotype. In summary, these findings reveal that Lkb1 is essential for fat CD11c+ dendritic cells responding to HFD exposure and provides new insights into the IL-17A/IFN-γ balance in HFD-induced obesity.

Ceftazidime-avibactam in the treatment of bacteremia due to carbapenem-resistant gram-negative bacteria in hematological patients: Experience in a single center.

INTRODUCTION: Limited experience exists with ceftazidime-avibactam (CAZ-AVI) in treating bacteremia caused by carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) in hematological patients. METHODS: We performed a single-center, retrospective, observational study including patients who received CAZ-AVI for bacteremia due to CRE or CRPA between 2018 and 2022. The primary outcome was 30-day survival. We conducted a multivariable analysis to identify predictors of survival. RESULTS: 56 patients were included and 57 (41 CRE and 16 CRPA) strains were isolated. 35 strains produced carbapenemase, including 25 metallo-beta-lactamase (MBL) and 10 serine-beta-lactamase. 48 patients (85.7 %) received combination therapy. All patients with MBL-CRE bacteremia (n = 24) received combination therapy with aztreonam (AZT). The susceptibility rates to CAZ-AVI were only 26.8 % (11/41) in CRE and 80.0 % (8/10) in CRPA. The 30-day survival rates were 85.0 % (34/40) in the CRE group and 81.3 % (13/16) in the CRPA group. In patients with MBL-CRE bacteremia, the 30-day survival was as high as 91.7 % (22/24) due to combination with AZT. Ceftazidime did not influence the activity of aztreonam-avibactam against MBL-CRE in-vitro. Multivariable cox analysis revealed neutropenia >14 days (P = 0.002, HR: 34.483, 95%CI: 3.846-333.333) and a higher Pitt bacteremia score (P = 0.005, HR: 2.074, 95%CI: 1.253-3.436) were risk factors for 30-day survival. CONCLUSIONS: CAZ-AVI is highly effective in treating bacteremia due to CRPA and serine-beta-lactamase CRE. The combination of avibactam with AZT is highly effective in treating bacteremia due to AZT-resistant MBL producers.

Clinical Characteristics, Prognosis Factors and Metagenomic Next-Generation Sequencing Diagnosis of Mucormycosis in patients With Hematologic Diseases.

INTRODUCTION: New diagnostic methods and antifungal strategies may improve prognosis of mucormycosis. We describe the diagnostic value of metagenomic next⁃generation sequencing (mNGS) and identify the prognostic factors of mucormycosis. METHODS: We conducted a retrospective study of hematologic patients suffered from mucormycosis and treated with monotherapy [amphotericin B (AmB) or posaconazole] or combination therapy (AmB and posaconazole). The primary outcome was 84-day all-cause mortality after diagnosis. RESULTS: Ninety-five patients were included, with "proven" (n = 27), "probable" (n = 16) mucormycosis confirmed by traditional diagnostic methods, and "possible" (n = 52) mucormycosis with positive mNGS results. The mortality rate at 84 days was 44.2%. Possible + mNGS patients and probable patients had similar diagnosis processes, overall survival rates (44.2% vs 50.0%, p = 0.685) and overall response rates to effective drugs (44.0% vs 37.5%, p = 0.647). Furthermore, the median diagnostic time was shorter in possible + mNGS patients than proven and probable patients (14 vs 26 days, p < 0.001). Combination therapy was associated with better survival compared to monotherapy at six weeks after treatment (78.8% vs 53.1%, p = 0.0075). Multivariate analysis showed that combination therapy was the protective factor (HR = 0.338, 95% CI: 0.162-0.703, p = 0.004), though diabetes (HR = 3.864, 95% CI: 1.897-7.874, p < 0.001) and hypoxemia (HR = 3.536, 95% CI: 1.874-6.673, p < 0.001) were risk factors for mortality. CONCLUSIONS: Mucormycosis is a life-threatening infection. Early management of diabetes and hypoxemia may improve the prognosis. Exploring effective diagnostic and treatment methods is important, and combination antifungal therapy seems to hold potential benefits.

Poor pretransplantation minimal residual disease clearance as an independent prognostic risk factor for survival in myelodysplastic syndrome with excess blasts: A multicenter, retrospective cohort study.

BACKGROUND: Minimal residual disease (MRD) is an important prognostic factor for survival in adults with acute leukemia. The role of pretransplantation MRD status in myelodysplastic syndrome with excess blasts (MDS-EB) is unknown. This study retrospectively analyzed the relationship between pretransplantation MRD status and long-term survival. MATERIALS AND METHODS: Patients with MDS-EB who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from March 5, 2005, to November 8, 2020, were included. The relationship between pretransplantation MRD status and long-term survival was analyzed using univariate and multivariate logistic regression models. RESULTS: Of 220 patients with MDS-EB who underwent allo-HSCT, 198 were eligible for inclusion in this multicenter, retrospective cohort study. Complete remission was attained in 121 (61.1%) patients, and 103 patients underwent detection of MRD pretransplantation, with 67 patients being MRD-positive and 36 patients being MRD-negative. The median follow-up time was 16 months, the median age was 41 years (6-65 years), and 58% of the patients were men. The 3-year disease-free survival (DFS) and overall survival (OS) probabilities for all patients were 70.1% and 72.9%, respectively. For patients in complete remission, the 3-year DFS and OS probabilities were 72.2% and 74.8%, respectively. Further analysis found that the 3-year DFS rates of MRD-negative and MRD-positive patients were 85.6% and 66.5% (p = .045), respectively, whereas the 3-year OS rates were 91.3% and 66.4% (p = .035), respectively. Univariate and multivariate analyses showed that poor pretransplantation MRD clearance was an independent prognostic risk factor for DFS and OS. CONCLUSION: Poor pretransplantation MRD clearance is an independent prognostic risk factor for long-term survival after allo-HSCT for patients with MDS-EB. PLAIN LANGUAGE SUMMARY: Poor minimal residual disease clearance pretransplanation is an independent prognostic risk factor for long-term survival after allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome with excess blasts.

Haematopoietic stem cell transplantation for hepatitis-associated aplastic anaemia and non-hepatitis-associated aplastic anaemia: A propensity score-matched analysis.

To validate the efficacy and safety of haematopoietic stem cell transplantation (HSCT) in hepatitis-associated aplastic anaemia (HAAA) patients, we reviewed 260 patients who underwent HSCT for acquired aplastic anaemia and eventually included 30 HAAA patients and 90 non-HAAA patients using propensity score matching. In the HAAA group, the estimated 5-year overall survival rate (75.8% vs. 86.5%, p = 0.409), failure-free survival (FFS) rate (74.0% vs. 83.2%, p = 0.485), graft-versus-host disease (GVHD)-free FFS rate (61.2% vs. 67.6%, p = 0.669) after HSCT were slightly lower but not statistically significant than those in the non-HAAA group. Both groups did not significantly differ in engraftment, post-transplant severe infection, cytomegalovirus (CMV) or Epstein-Barr virus viraemia, or GVHD incidences. The patterns of immune reconstitution were broadly consistent between the two groups. When stratifying HAAA patients according to donor type, no significant differences in survival, transplant-related mortality, or GVHD cumulative incidences were observed. CMV viraemia (68.7% vs 8.3%, p = 0.009) occurred more commonly in haploidentical donor (HID) transplants than in matched sibling donor transplants. However, early CMV disease incidence (5.6% vs. 0.0%, p = 1.000) was low. Overall, the post-transplant outcomes of HAAA patients were comparable to those of non-HAAA patients after balancing potential confounders, and HID-HSCT can offer an alternative curative option for HAAA.

Outcomes of allogeneic or autologous stem cell transplantation followed by maintenance chemotherapy in adult patient with B-ALL in CR1 with no detectable minimal residual disease.

Autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for B-cell acute lymphoblastic leukaemia (B-ALL) has been rigorously debated in recent years. We retrospectively analysed the outcomes of 355 adult patients with B-ALL in first complete remission who had received auto-HSCT or allogeneic HSCT (allo-HSCT) in our centre. The treatment efficacy was evaluated from a model stratified on the risk classification and minimal residue disease (MRD) status after three chemotherapy cycles. Auto-HSCT demonstrated comparable 3-year overall survival (OS) (72.7% vs. 68.5%, p = 0.441) and leukaemia-free survival rates (62.8% vs. 56.1%, p = 0.383) compared to allo-HSCT for patients with negative MRD, while the advantage of lower non-relapse mortality (1.5% vs. 25.1%, p < 0.001) was offset by a higher cumulative incidence of relapse (CIR) rates (35.7% vs. 18.9%, p = 0.018), especially in high-risk patients. For patients at high risk and with positive MRD, there was a lower trend of 3-year OS (50.0% vs. 66.0%, p = 0.078) and significantly higher CIR rates (71.4% vs. 39.1%, p = 0.018) in auto-HSCT. However, no significant interaction was observed in the tests. In conclusion, auto-HSCT appears to be an attractive treatment for patients with negative MRD after three chemotherapy cycles. For MRD-positive patients, allo-HSCT may be a more effective treatment.

Radiation-induced bystander effects impair transplanted human hematopoietic stem cells via oxidative DNA damage.

Total body irradiation (TBI) is commonly used in host conditioning regimens for human hematopoietic stem cell (HSC) transplantation to treat various hematological disorders. Exposure to TBI not only induces acute myelosuppression and immunosuppression, but also injures the various components of the HSC niche in recipients. Our previous study demonstrated that radiation-induced bystander effects (RIBE) of irradiated recipients decreased the long-term repopulating ability of transplanted mouse HSCs. However, RIBE on transplanted human HSCs have not been studied. Here, we report that RIBE impaired the long-term hematopoietic reconstitution of human HSCs as well as the colony-forming ability of human hematopoietic progenitor cells (HPCs). Our further analyses revealed that the RIBE-affected human hematopoietic cells showed enhanced DNA damage responses, cell-cycle arrest, and p53-dependent apoptosis, mainly because of oxidative stress. Moreover, multiple antioxidants could mitigate these bystander effects, though at different efficacies in vitro and in vivo. Taken together, these findings suggest that RIBE impair human HSCs and HPCs by oxidative DNA damage. This study provides definitive evidence for RIBE on transplanted human HSCs and further justifies the necessity of conducting clinical trials to evaluate different antioxidants to improve the efficacy of HSC transplantation for the patients with hematological or nonhematological disorders.

Efficacy of venetoclax combined with decitabine conditioning regimen for allogeneic hematopoietic stem cell transplantation in high-risk and elderly patients with myeloid neoplasms.

This prospective clinical investigation focused on the addition of venetoclax and decitabine to myeloablative conditioning regimens, targeting high-risk and elderly individuals undergoing allogeneic hematopoietic stem cell transplantation. In total, 19 patients were enrolled in the trial between December 2021 and February 2023, and their progress was monitored for a median follow-up period of 258 days, ranging from 35 to 544 days. In the initial regimen (n=11), venetoclax was administered at a dosage of 400 mg per day from day -14 to day -1, while in the modified regimen (n=8), it was administered from day -14 to day -5. Decitabine was orally administered at a dosage of 20mg/m2/day from day -7 to day -3. Grade 3/4 adverse events observed included hematological events, hypertension, infections, allergy, and increased amylase. In the entire cohort, the overall survival (OS) and relapse-free survival (RFS) rates at 6 months were 63% (95% CI, 45-89) and 63% (95% CI, 45-89), respectively. The non-relapse mortality (NRM) rate at 6 months was 37% (95% CI, 16-58), while the cumulative incidence of relapse (CIR) was 0. However, the incidence of grade II-IV acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD within 100 days was found to be 31% (95% CI, 12-53) and 26% (95% CI, 9-47), respectively. These rates indicate a relatively high occurrence, making it less suitable to administer the regimen to elderly patients. Therefore, further high-quality studies are required to enhance the conditioning regimen specifically for high-risk and elderly patients diagnosed with myeloid neoplasms. Clinical trial registration: ChiCTR2100050272.

Herombopag promotes platelet engraftment and decreases platelet transfusion after allogeneic hematopoietic stem cell transplantation.

The delayed platelet engraftment associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common complication and often results in increased transplant-related complications. A single-center, prospective, investigator-initiated pilot study was conducted to explore whether herombopag, a second generation thrombopoietin-receptor agonist, would promote platelet engraftment after allo-HSCT. Between 2/2022 and 06/2022, 17 individuals (median age 39; range 15-58 years) with hematological malignancies were enrolled. Herombopag was given for a median of 22 (range 14-61) days at a dose of 7.5 mg/d. The median time to neutrophil >500/µl was 11 (range 9-19) days. The median time to platelet >20 000/µl and >50 000/µl was 13 (range 8-22), and 20 (range 14-45) days, respectively. Compared with historical controls, the cumulative incidence of platelet engraftment after HSCT was significantly higher in the herombopag group (>20 000/µl at day +21, 88% vs 65%, p = .003; >50 000/µl at day +30, 65% vs. 43%, p = .001). Herombopag also reduced the units of platelet transfusion within 30 days post-SCT (3.6 ± 2.5 vs. 5.4 ± 3.2 U, p = .01). In conclusion, it seems likely that herombopag could enhance platelet engraftment after allo-HSCT.

The Composite Immune Risk Score predicts overall survival after allogeneic hematopoietic stem cell transplantation: A retrospective analysis of 1838 cases.

There has been little consensus on how to quantitatively assess immune reconstitution after hematopoietic stem cell transplantation (HSCT) as part of the standard of care. We retrospectively analyzed 11 150 post-transplant immune profiles of 1945 patients who underwent HSCT between 2012 and 2020. 1838 (94.5%) of the cases were allogeneic HSCT. Using the training set of patients (n = 729), we identified a composite immune signature (integrating neutrophil, total lymphocyte, natural killer, total T, CD4+ T, and B cell counts in the peripheral blood) during days 91-180 after allogeneic HSCT that was predictive of early mortality and moreover simplified it into a formula for a Composite Immune Risk Score. When we verified the Composite Immune Risk Score in the validation (n = 284) and test (n = 391) sets of patients, a high score value was found to be associated with hazard ratios (HR) of 3.64 (95% C.I. 1.55-8.51; p = .0014) and 2.44 (95% C.I., 1.22-4.87; p = .0087), respectively, for early mortality. In multivariate analysis, a high Composite Immune Risk Score during days 91-180 remained an independent risk factor for early mortality after allogeneic HSCT (HR, 1.80; 95% C.I., 1.28-2.55; p = .00085). In conclusion, the Composite Immune Risk Score is easy to compute and could identify the high-risk patients of allogeneic HSCT who require targeted effort for prevention and control of infection.