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Abstract Background Severe pneumonia is one of the most important causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adenovirus (ADV) is a significant cause of severe viral pneumonia after allo-HSCT, and we aimed to identify the clinical manifestations, prognostic factors, and outcomes of ADV pneumonia after allo-HSCT. Methods Twenty-nine patients who underwent allo-HSCT at the Peking University Institute of Hematology and who experienced ADV pneumonia after allo-HSCT were enrolled in this study. The Kaplan–Meier method was used to estimate the probability of overall survival (OS). Potential prognostic factors for 100-day OS after ADV pneumonia were evaluated through univariate and multivariate Cox regression analyses. Results The incidence rate of ADV pneumonia after allo-HSCT was approximately 0.71%. The median time from allo-HSCT to the occurrence of ADV pneumonia was 99 days (range 17–609 days). The most common clinical manifestations were fever (86.2%), cough (34.5%) and dyspnea (31.0%). The 100-day probabilities of ADV-related mortality and OS were 40.4% (95% CI 21.1%-59.7%) and 40.5% (95% CI 25.2%-64.9%), respectively. Patients with low-level ADV DNAemia had lower ADV-related mortality and better OS than did those with high-level (≥ 106 copies/ml in plasma) ADV DNAemia. According to the multivariate analysis, high-level ADV DNAemia was the only risk factor for intensive care unit admission, invasive mechanical ventilation, ADV-related mortality, and OS after ADV pneumonia. Conclusions We first reported the prognostic factors and confirmed the poor outcomes of patients with ADV pneumonia after allo-HSCT. Patients with high-level ADV DNAemia should receive immediate and intensive therapy.

Abstract Background For patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD), effective second-line regimens are urgently needed. Mesenchymal stromal cells (MSCs) have been used as salvage regimens for SR-aGVHD in the past. However, clinical trials and an overall understanding of the molecular mechanisms of MSCs combined with basiliximab for SR-aGVHD are limited, especially in haploidentical haemopoietic stem cell transplantation (HID HSCT). Methods The primary endpoint of this multicentre, randomized, controlled trial was the 4-week complete response (CR) rate of SR-aGVHD. A total of 130 patients with SR-aGVHD were assigned in a 1:1 randomization schedule to the MSC group (receiving basiliximab plus MSCs) or control group (receiving basiliximab alone) (NCT04738981). Results Most enrolled patients (96.2%) received HID HSCT. The 4-week CR rate of SR-aGVHD in the MSC group was obviously better than that in the control group (83.1% vs. 55.4%, P = 0.001). However, for the overall response rates at week 4, the two groups were comparable. More patients in the control group used ≥ 6 doses of basiliximab (4.6% vs. 20%, P = 0.008). We collected blood samples from 19 consecutive patients and evaluated MSC-derived immunosuppressive cytokines, including HO1, GAL1, GAL9, TNFIA6, PGE2, PDL1, TGF-β and HGF. Compared to the levels before MSC infusion, the HO1 (P = 0.0072) and TGF-β (P = 0.0243) levels increased significantly 1 day after MSC infusion. At 7 days after MSC infusion, the levels of HO1, GAL1, TNFIA6 and TGF-β tended to increase; however, the differences were not statistically significant. Although the 52-week cumulative incidence of cGVHD in the MSC group was comparable to that in the control group, fewer patients in the MSC group developed cGVHD involving ≥3 organs (14.3% vs. 43.6%, P = 0.006). MSCs were well tolerated, no infusion-related adverse events (AEs) occurred and other AEs were also comparable between the two groups. However, patients with malignant haematological diseases in the MSC group had a higher 52-week disease-free survival rate than those in the control group (84.8% vs. 65.9%, P = 0.031). Conclusions For SR-aGVHD after allo-HSCT, especially HID HSCT, the combination of MSCs and basiliximab as the second-line therapy led to significantly better 4-week CR rates than basiliximab alone. The addition of MSCs not only did not increase toxicity but also provided a survival benefit.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT), as one of the life-saving treatments for severe aplastic anemia (SAA), is widely used because of its great donor availability. Over decades, granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG)-based protocol (the so-called Beijing Protocol) has achieved favorable engraftment and survival outcomes. In this study, we modified the conventional Beijing Protocol: the full-dose Cyclophosphamide (Cy) (200 mg/kg in total) was divided into 42.75 mg/kg Cy on day -5 to day -2 and Low dose post-transplant Cy (PTCy) (14.5 mg/kg on days +3 and +4), hoping to reduce the incidence of severe acute graft-versus-host disease (aGVHD) and to guarantee successful and stable engraftment. Here we retrospectively reported and analyzed the data of first 17 patients with SAA who had received haplo-HSCT using this novel regimen between August 2020 and August 2022. The median follow-up was 522 days (range, 138-859 days). No patient developed primary graft failure. Four (23.5%) patients developed grade II bladder toxicity, two (11.8%) patients developed grade II cardiotoxicity. All patients achieved neutrophil and platelet engraftment at median times of 12 days (range, 11–20 days) and14 days (range, 8-36 days). During our follow-up, no patients developed grade III-IV aGVHD. The cumulative incidence of grade II and grade I aGVHD at 100 days was 23.5% (95% CI, 6.8%-49.9%) and 47.1% (95% CI, 23.0%-72.2%). Three patients (17.6%) developed chronic GVHD of skin, mouth, and eyes and all of which were mild. All patients are alive by the end of the follow-up, with a failure-free survival of 100%, which was defined as survival without treatment failures, such as death, graft failure, or relapse rate. The rate of cytomegalovirus (CMV) reactivation was 82.4% (95% CI, 64.3%-100%). The rate of Epstein-Barr virus (EBV) reactivation was 17.6% (95% CI, 3.8%-43.4%). No CMV disease and post-transplantation lymphoproliferative disorder (PTLD) occurred among these patients. In conclusion, the encouraging results of prolonged survival outcomes and reduced incidence of GVHD suggest promising effect of this novel regimen in haplo-HSCT for patients with SAA. Larger-sample prospective clinical trials are needed to confirm the effectiveness of this regimen.

Abstract. Background:. The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with high-risk (HR) T-cell acute lymphoblastic leukemia (T-ALL) in first complete remission (CR1) is still under evaluation. Moreover, relapse is the main factor affecting survival. This study aimed to explore the effect of allo-HSCT (especially haploidentical HSCT [haplo-HSCT]) on improving survival and reducing relapse for HR childhood T-ALL in CR1 and the prognostic factors of childhood T-ALL in order to identify who could benefit from HSCT. Methods:. A total of 74 newly diagnosed pediatric T-ALL patients between January 1, 2012 and June 30, 2018 were enrolled in this retrospective study. Patients were stratified into the low-risk chemotherapy cohort (n = 16), HR chemotherapy cohort (n = 31), and HR transplant cohort (n = 27). Characteristics, survival outcomes, and prognostic factors of all patients were then analyzed. Results:. Patient prognosis in the HR chemotherapy cohort was significantly worse than that in the low-risk chemotherapy cohort (5year overall survival [OS]: 58.5% vs. 100%, P = 0.003; 5-year event-free survival [EFS]: 54.1% vs. 83.4%, P = 0.010; 5-year cumulative incidence of relapse [CIR]: 45.2% vs. 6.3%, P = 0.011). In HR patients, allo-HSCT improved the 5-year EFS and CIR compared to that of chemotherapy (5-year EFS: 80.1% vs. 54.1%, P = 0.041; 5-year CIR: 11.6% vs. 45.2%, P = 0.006). The 5-year OS was higher in the HR transplant cohort than that in the HR chemotherapy cohort (81.0% vs. 58.5%, P = 0.084). Minimal residual disease re-emergence was an independent risk factor for 5-year OS, EFS, and CIR; age ≥10 years was an independent risk factor for OS and EFS; and high white blood cell count was an independent risk factor for EFS and CIR. Conclusion:. Allo-HSCT, especially haplo-HSCT, could effectively reduce relapse of children with HR T-ALL in CR1.

BackgroundAMKL without DS is a rare but aggressive hematological malignant disease in children, and it is associated with inferior outcomes. Several researchers have regarded pediatric AMKL without DS as high-risk or at least intermediate-risk AML and proposed that upfront allogenic hematopoietic stem cell transplantation (HSCT) in first complete remission might improve long-term survival.Patients and methodWe conducted a retrospective study with twenty-five pediatric (< 14 years old) AMKL patients without DS who underwent haploidentical HSCT in the Peking University Institute of Hematology, Peking University People’s Hospital from July 2016 to July 2021. The diagnostic criteria of AMKL without DS were adapted from the FAB and WHO: ≥ 20% blasts in the bone marrow, and those blasts expressed at least one or more of the platelet glycoproteins: CD41, CD61, or CD42. AMKL with DS and therapy related AML was excluded. Children without a suitable closely HLA-matched related or unrelated donor (donors with more than nine out of 10 matching HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ loci), were eligible to receive haploidentical HSCT. Definition was adapted from international cooperation group. All statistical tests were conducted with SPSS v.24 and R v.3.6.3.ResultsThe 2-year OS was 54.5 ± 10.3%, and the EFS was 50.9 ± 10.2% in pediatric AMKL without DS undergoing haplo-HSCT. Statistically significantly better EFS was observed in patients with trisomy 19 than in patients without trisomy 19 (80 ± 12.6% and 33.3 ± 12.2%, respectively, P = 0.045), and OS was better in patients with trisomy 19 but with no statistical significance (P = 0.114). MRD negative pre-HSCT patients showed a better OS and EFS than those who were positive (P < 0.001 and P = 0.003, respectively). Eleven patients relapsed post HSCT. The median time to relapse post HSCT was 2.1 months (range: 1.0–14.4 months). The 2-year cumulative incidence of relapse (CIR) was 46.1 ± 11.6%. One patient developed bronchiolitis obliterans and respiratory failure and died at d + 98 post HSCT.ConclusionAMKL without DS is a rare but aggressive hematological malignant disease in children, and it is associated with inferior outcomes. Trisomy 19 and MRD negative pre-HSCT might contribute to a better EFS and OS. Our TRM was low, haplo-HSCT might be an option for high-risk AMKL without DS.

Measurable residual disease (MRD) positivity before haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an independent prognostic factor in determining outcomes in patients with B-cell acute lymphoblastic leukemia (ALL). In this study, we conducted a parallel comparison of the efficacy and safety in patients with suboptimal MRD response after reinduction who underwent haplo-HSCT after chimeric antigen receptor T-cell (CAR-T) therapy or chemotherapy. Forty B-cell ALL patients who relapsed after first-line chemotherapy and with an MRD ≥0.1% after reinduction were analyzed. The median pre-HSCT MRD in the CAR-T group (n = 26) was significantly lower than that in the chemotherapy group (n = 14) (0.009% vs. 0.3%, p = 0.006). The CAR-T group exhibited a trend toward improved 3-year leukemia-free survival and a significantly improved 3-year overall survival compared to the chemotherapy group [71.8% (95% confidence interval (CI): 53.9–89.6) vs. 44.4% (95% CI: 15.4–73.4), p = 0.19 and 84.6% (95% CI: 70.6–98.5) vs. 40.0% (95% CI: 12.7–67.2), p = 0.008; respectively]. Furthermore, no increased risk of graft-versus-host disease, treatment-related mortality, or infection was observed in the CAR-T group. Our study suggests that CAR-T therapy effectively eliminates pre-HSCT MRD, resulting in better survival in the context of haplo-HSCT.

Secondary poor graft function (sPGF) increases the risk of life-threatening complications after hematopoietic stem cell transplantation (HSCT). The incidence, clinical outcomes, and risk factors of sPGF have not been elucidated in haploidentical (haplo-) HSCT for acquired aplastic anemia (AA) patients. We retrospectively reviewed 423 consecutive AA patients who underwent haplo-HSCT between January 2006 and December 2020 and report a 3-year cumulative incidence of 4.62% (95% confidence interval [CI]: 3.92%-10.23%) of sPGF. While no primary PGF occurred. The median time to sPGF was 121 days (range 30-626 days) after transplantation. To clarify the risk factors for sPGF, 17 sPGF cases and 382 without PGF were further analyzed. Compared to patients without PGF, the 2-year overall survival was significantly poorer for sPGF patients (67.7% vs 90.8%, p =.002). Twelve sPGF patients were alive until the last follow-up, and 7 achieved transfusion independency. The multivariable analyses revealed that later neutrophil engraftment (OR 2.819, p=.049) and a history of refractory cytomegalovirus viremia (OR=7.038, p=.002) post-transplantation were associated with sPGF. There was weak evidence that a history of grade 3-4 acute graft-versus-host disease increased the risk of sPGF (p=.063). We advocated better post-transplantation strategies to balance the risk of immunosuppression and viral reactivation for haplo-HSCT in AA patients.

Leukemia relapse is still the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B cell acute lymphoblastic leukemia (B-ALL). Relapsed patients with B-ALL after allo-HSCT have a very short median survival. Minimal residual disease (MRD) is predictive of forthcoming hematological relapse after hematopoietic stem cell transplantation (HSCT); furthermore, eliminating MRD effectively prevents relapse. Donor lymphoblastic infusion (DLI) is the main established approach to treat B-ALL with MRD after allo-HSCT. However, about one-third of patients with MRD are non-responsive to DLI and their prognosis worsens. Although donor-derived cluster of differentiation (CD)19-directed chimeric antigen receptor-modified (CAR) T cells (CART19s) can potentially cure leukemia, the efficiency and safety of infusions with these cells have not yet been investigated in patients with MRD after HSCT. Between September 2014 and February 2018, six patients each received one or more infusions of CART19s from HSCT donors. Five (83.33%) achieved MRD-negative remission, and one case was not responsive to the administration of CAR T cells. Three of the six patients are currently alive without leukemia. No patient developed acute graft-versus-host disease (aGVHD), and no patient died of cytokine release syndrome. Donor-derived CAR T cell infusions seem to be an effective and safe intervention for patients with MRD in B-ALL after allo-HSCT and for those who were not responsive to DLI. Keywords: Donor-derived CD19-targeted T cell infusion, Hematopoietic stem cell transplantation, B cell acute lymphoblastic leukemia, Minimal residual disease

G-CSF-mobilized peripheral blood (G-PB) harvest is the predominant graft for identical sibling donor and unrelated donor allogeneic hematopoietic stem cell transplantation (HSCT) recipients, but it was controversial in haploidentical related donor (HID) HSCT. In this registry study, we aimed to identify the efficacy of HID G-PB HSCT (HID-PBSCT) for acute leukemia (AL) patients in first complete remission (CR1). Also, we reported the outcomes for the use of G-PB grafts in comparison with the combination of G-BM and G-PB grafts in HID HSCT recipients. Sixty-seven AL patients in CR1 who received HID-PBSCT were recruited at Institute of Hematology, Peking University. Patients who received haploidentical HSCT using the combination of G-BM and G-PB harvests in the same period were enrolled as controls (n=392). The median time from HSCT to neutrophil and platelet engraftment was 12 days (range, 9–19 days) and 12 days (range, 8–171 days), respectively. The 28-day cumulative incidence of neutrophil and platelet engraftment after HSCT was 98.5% and 95.5%, respectively. The cumulative incidences of grade II–IV and grade III–IV acute graft-versus-host disease (GVHD) were 29.9% (95%CI 18.8–40.9%) and 7.5% (95%CI 1.1–13.8%), respectively. The cumulative incidences of total and moderate-severe chronic GVHD were 54.9% (95%CI 40.9–68.8%) and 17.4% (95%CI 6.7–28.0%), respectively. The cumulative incidences of relapse and non-relapse mortality were 13.9% (95%CI 5.4–22.5%) and 3.4% (95%CI 0–8.1%), respectively. The probabilities of overall survival (OS) and leukemia-free survival (LFS) were 84.7% (95%CI 74.7–94.7%) and 82.7% (95%CI 73.3–92.1%) respectively. Compared with the HID HSCT recipients using the combination of G-BM and G-PB grafts, the engraftments of neutrophil and platelet were both significantly faster for the G-PB group, and the other clinical outcomes were all comparable between the groups. In multivariate analysis, graft types did not influence the clinical outcomes. Overall, for the patients with AL CR1, G-PB graft could be considered an acceptable graft for HID HSCT recipients. This study was registered at https://clinicaltrials.gov as NCT03756675.

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used to treat malignant hematological neoplasms and non-malignant hematological disorders. Approximately, 5000 allo-HSCT procedures are performed in China annually. Substantial progress has been made in haploidentical HSCT (HID-HSCT), pre-transplantation risk stratification, and donor selection in allo-HSCT, especially after the establishment of the “Beijing Protocol” HID-HSCT system. Transplant indications for selected subgroups in low-risk leukemia or severe aplastic anemia (SAA) differ from those in the Western world. These unique systems developed by Chinese doctors may inspire the refining of global clinical practice. We reviewed the efficacy of allo-HSCT practice from available Chinese studies on behalf of the HSCT workgroup of the Chinese Society of Hematology, Chinese Medical Association and compared these studies to the consensus or guideline outside China. We summarized the consensus on routine practices of all-HSCT in China and focused on the recommendations of indications, conditioning regimen, and donor selection.

Enhanced peripheral complement activation has long been considered as one of the major pathogenic elements of immune thrombocytopenia. A dysfunctional bone marrow microenvironment, especially with regards to mesenchymal stem cells, has been observed in patients with immune thrombocytopenia. However, the potential role of the complement system in the dysfunctional bone marrow microenvironment remains poorly understood. In this study, bone marrow samples from patients with immune thrombocytopenia were divided into two groups based on whether or not complement components were deposited on the surfaces of their mesenchymal stem cells. The mesenchymal cells from the group with complement deposition were less numerous, dysfunctional, had a reduced capacity to proliferate, and showed increased apoptosis as well as abnormal secretion of interleukin-1β and C-X-C motif chemokine ligand 12. In vitro treatment with all-trans retinoic acid increased the number and improved the function of the complement-positive bone marrow mesenchymal stem cells by upregulating DNA hypermethylation of the interleukin-1β promoter. In vivo studies showed that all-trans retinoic acid could rescue the impaired mesenchymal stem cells to support the thrombopoietic niche in both patients with immune thrombocytopenia and a murine model of this disease. Taken together, these results indicate that impairment of mesenchymal stem cells, mediated by the complement–interleukin-1β loop, plays a role in the pathogenesis of immune thrombocytopenia. All-trans retinoic acid represents a promising therapeutic approach in patients with immune thrombocytopenia through its effect of repairing mesenchymal stem cell impairment.

Prolonged isolated thrombocytopenia (PT) after allogeneic stem cell transplantation (allo-SCT) has a great impact on transplant outcome. In this study, we performed a retrospective analysis to investigate the association of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) with PT in 394 patients who underwent unmanipulated haploidentical blood and marrow transplantation (HBMT). For HLA antibody positive samples with a median fluorescent intensity (MFI) > 500, DSAs were further examined. A total of 390 patients (99.0%) achieved sustained myeloid engraftment. Of the 394 cases tested, 45 (11.4%) were DSA positive. The cumulative incidence of PT in this cohort of patients was 9.9 ± 1.5%. The incidence of PT was higher in patients with a MFI ≥ 1000 compared with those with a MFI

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT), as one of the life-saving treatments for severe aplastic anemia (SAA), is widely used because of its great donor availability. Over decades, granulocyte colony-stimulating factor (G-CSF)/antithymocyte globulin (ATG)-based protocol (the so-called Beijing Protocol) has achieved favorable engraftment and survival outcomes. In this study, we modified the conventional Beijing Protocol: the full-dose Cyclophosphamide (Cy) (200 mg/kg in total) was divided into 42.75 mg/kg Cy on day -5 to day -2 and Low dose post-transplant Cy (PTCy) (14.5 mg/kg on days +3 and +4), hoping to reduce the incidence of severe acute graft-versus-host disease (aGVHD) and to guarantee successful and stable engraftment. Here we retrospectively reported and analyzed the data of first 17 patients with SAA who had received haplo-HSCT using this novel regimen between August 2020 and August 2022. The median follow-up was 522 days (range, 138-859 days). No patient developed primary graft failure. Four (23.5%) patients developed grade II bladder toxicity, two (11.8%) patients developed grade II cardiotoxicity. All patients achieved neutrophil and platelet engraftment at median times of 12 days (range, 11–20 days) and14 days (range, 8-36 days). During our follow-up, no patients developed grade III-IV aGVHD. The cumulative incidence of grade II and grade I aGVHD at 100 days was 23.5% (95% CI, 6.8%-49.9%) and 47.1% (95% CI, 23.0%-72.2%). Three patients (17.6%) developed chronic GVHD of skin, mouth, and eyes and all of which were mild. All patients are alive by the end of the follow-up, with a failure-free survival of 100%, which was defined as survival without treatment failures, such as death, graft failure, or relapse rate. The rate of cytomegalovirus (CMV) reactivation was 82.4% (95% CI, 64.3%-100%). The rate of Epstein-Barr virus (EBV) reactivation was 17.6% (95% CI, 3.8%-43.4%). No CMV disease and post-transplantation lymphoproliferative disorder (PTLD) occurred among these patients. In conclusion, the encouraging results of prolonged survival outcomes and reduced incidence of GVHD suggest promising effect of this novel regimen in haplo-HSCT for patients with SAA. Larger-sample prospective clinical trials are needed to confirm the effectiveness of this regimen. [ABSTRACT FROM AUTHOR]