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IntroductionThe prognosis of relapsed/refractory acute myeloid leukemia (r/rAML) is dismal, and allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potential cure. Combining anti-PD-1, hypomethylating agent (HMA), and CAG (cytarabine, aclarubicin/idarubicin, granulocyte colony-stimulating factor) regimen has showed primary efficacy in r/rAML. However, pre-transplant exposure to anti-PD-1 may lead to severe graft-versus-host disease (GVHD). This preliminary study aimed to evaluate the safety and efficacy of allo-HSCT in r/rAML patients receiving the anti-PD-1+HMA+CAG regimen.MethodsFifteen r/rAML patients (12 related haploidentical donors [HIDs], 2 matched siblings, 1 unrelated donor) received this regimen and subsequent peripheral blood HSCT.ResultsFour patients with HIDs received a GVHD prophylaxis regimen consisted of Anti-thymocyte globulin and a reduced-dose of post-transplant cyclophosphamide. The median follow-up was 20.9 months (range, 1.2-34.2). The cumulative incidences of acute GVHD grade 2-4 and grade 3-4 were 40% and 13.3%, respectively. The 2-year incidence of moderate-to-severe chronic GVHD, non-relapse mortality, and relapse were 10%, 22.3%, and 22.5%, respectively. The 2-year overall survival and GVHD-free/relapse-free survival rates were 54% and 48.6%, respectively. No death or relapse was observed in the PTCy group.ConclusionThe anti-PD-1+HMA+CAG regimen bridging to allo-HSCT for r/r AML was tolerable with promising efficacy. GVHD prophylaxis with PTCy for HID-HSCT showed preliminary survival advantage.

Background Cytomegalovirus (CMV) reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Pre-emptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard of care but it was associated with significant toxicity. The CMV antigen-specific cytotoxic T lymphocyte therapy was limited by the time-consuming manufacture process and relatively low success rate. More effective and safer approaches for the treatment of CMV reactivation after haploidentical SCT are in urgent need.Methods A single-arm, open-label, phase I clinical trial evaluating the safety and efficacy of CMV-targeting T cell receptor-engineered T (CMV-TCR-T) cell therapy as the first-line pre-emptive therapy for patients with CMV reactivation after haploidentical peripheral blood SCT (PBSCT) was conducted in the Chinese PLA General Hospital. Six patients with CMV reactivation after haploidentical SCT were adoptively transferred by one to three doses of SCT donors-derived CMV-TCR-T cells. This trial was a dose-escalation study with doses ranging from 1×103 CMV-TCR-T cells/kg body weight per dose to 5×105 CMV-TCR-T cells/kg per dose.Results Except for the grade 1 cytokine release syndrome observed in one patient and mild fever in two patients, no other adverse events were observed. Four patients had response within a month after CMV-TCR-T cell infusion without the administration of any antiviral agents. The other two patients who initially did not respond to CMV-TCR-T cell therapy had salvage ganciclovir and foscarnet administration and then had rapid CMV clearance. The CMV-TCR-T cells displayed overall robust expansion and persistence in the peripheral blood after infusion. The CMV-TCR-T cells were first detected in the peripheral blood of these patients 3–7 days after the first dose of CMV-TCR-T infusion, rapidly expanded and persisted for at least 1–4 months, providing long-term protection against CMV reactivation. In one patient, the CMV-TCR-T cells started to expand even when the anti-graft-versus-host disease reagents were still being used, further indicating the proliferation potential of CMV-TCR-T cells.Conclusions Our study first showed CMV-TCR-T cell as a highly feasible, safe and effective first-line pre-emptive treatment for CMV reactivation after haploidentical PBSCT.Trial registration number ClinicalTrials.gov Registry (NCT05140187).

Abstract The consensus recommendations in 2018 from The Chinese Society of Hematology (CSH) on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation (allo-HSCT) facilitated the standardization of clinical practices of allo-HSCT in China and progressive integration with the world. There have been new developments since the initial publication. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the consensus recommendations, which are summarized as follows: (1) there is a new algorithm for selecting appropriate donors for allo-HSCT candidates. Haploidentical donors (HIDs) are the preferred donor choice over matched sibling donors (MSDs) for patients with high-risk leukemia or elderly patients with young offspring donors in experienced centers. This replaces the previous algorithm for donor selection, which favored MSDs over HIDs. (2) Patients with refractory/relapsed lymphoblastic malignancies are now encouraged to undergo salvage treatment with novel immunotherapies prior to HSCT. (3) The consensus has been updated to reflect additional evidence for the application of allo-HSCT in specific groups of patients with hematological malignancies (intermediate-risk acute myeloid leukemia (AML), favorable-risk AML with positive minimal residual disease, and standard-risk acute lymphoblastic leukemia). (4) The consensus has been updated to reflect additional evidence for the application of HSCT in patients with nonmalignant diseases, such as severe aplastic anemia and inherited diseases. (5) The consensus has been updated to reflect additional evidence for the administration of anti-thymocyte globulin, granulocyte colony-stimulating factors and post-transplantation cyclophosphamide in HID-HSCT.

Abstract. Background:. There were few studies on real-world data about autologous hematopoietic stem cell transplantation (auto-HSCT) or allogeneic HSCT (allo-HSCT) in peripheral T-cell lymphoma (PTCL). This study aimed to investigate the clinical outcomes of patients who received auto-HSCT or allo-HSCT in China. Methods:. From July 2007 to June 2017, a total of 128 patients who received auto-HSCT (n = 72) or allo-HSCT (n = 56) at eight medical centers across China were included in this study. We retrospectively collected their demographic and clinical data and compared the clinical outcomes between groups. Results:. Patients receiving allo-HSCT were more likely to be diagnosed with stage III or IV disease (95% vs. 82%, P = 0.027), bone marrow involvement (42% vs. 15%, P = 0.001), chemotherapy-resistant disease (41% vs. 8%, P = 0.001), and progression disease (32% vs. 4%, P

Abstract. Background:. Bendamustine was approved in China on May 26th, 2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma (NHL). The current study was the registration trial and the first reported evaluation of the efficacy, safety, and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment. Methods:. This was a prospective, multicenter, open-label, single-arm, phase 3 study (NCT01596621; C18083/3076) with a 2-year follow-up period. Eligible patients received bendamustine hydrochloride 120 mg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles (and up to eight cycles). The primary endpoint was the overall response rate (ORR); and secondary endpoints were duration of response (DoR), progression-free survival (PFS), safety, and pharmacokinetics. Patients were classified according to their best overall response after initiation of therapy. Proportions of patients in each response category (complete response [CR], partial response [PR], stable disease, or progressive disease) were summarized along with a two-sided binomial exact 95% confidence intervals (CIs) for the ORR. Results:. A total of 102 patients were enrolled from 20 centers between August 6th, 2012, and June 18th, 2015. At the time of the primary analysis, the ORR was 73% (95% CI: 63%–81%) per Independent Review Committee (IRC) including 19% CR and 54% PR. With the follow-up period, the median DoR was 16.2 months by IRC and 13.4 months by investigator assessment; the median PFS was 18.6 months and 15.3 months, respectively. The most common non-hematologic adverse events (AEs) were gastrointestinal toxicity, pyrexia, and rash. Grade 3/4 neutropenia was reported in 76% of patients. Serious AEs were reported in 29 patients and five patients died during the study. Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities. Conclusion:. Bendamustine is an active and effective therapy in Chinese patients with relapsed, indolent B-cell NHL, with a comparable risk/benefit relationship to that reported in North American patients. Clinical trial registration:. ClinicalTrials.gov, No. NCT01596621; https://clinicaltrials.gov/ct2/show/NCT01596621

Abstract. Background:. The impacts of previous cardio-cerebrovascular disease (pre-CCVD) on the outcomes of hematopoietic cell transplantation (HCT) are not well described. Patients with pre-CCVD may often be poor candidates for HCT. This study aimed to investigate the impact of pre-CCVD on transplant outcomes. Methods:. A retrospective study was conducted between patients with and without pre-CCVD who consecutively received allogeneic or autologous HCT between November 2013 and January 2020 with a matching of age and disease status. The cardiovascular complications and HCT outcomes of the two groups were evaluated and compared. The primary endpoints were post-transplant cardio-cerebrovascular disease (post-CCVD) and non-relapse mortality (NRM). We used a multivariable Cox proportional hazard model and the Fine-Gray competing risk regressions for analyses to estimate the hazard ratios (HRs). Results:. The outcomes of 23 HCT recipients with pre-CCVD were compared with those of 107 patients in the control group. No significant differences were noted in terms of engraftment, overall survival (OS) (67.00% vs. 67.90%, P = 0.983), or relapse (29.78% vs. 28.26%, P = 0.561) between the pre-CCVD group and the control group. The cumulative incidences of 2-year NRM were similar between patients with pre-CCVD and the controls (14.68% vs. 17.08%, P = 0.670). However, pre-CCVD was associated with an increased incidence of post-CCVD (HR: 12.50, 95% confidence interval [CI]: 3.88–40.30, P

Abstract Background Induction therapy for acute myeloid leukemia (AML) is an anthracycline-based chemotherapy regimen. However, many patients experience a relapse or exhibit refractory disease (R/R). There is an urgent need for more effective regimens to reverse anthracycline resistance in these patients. Methods In this paper, Twenty-seven R/R AML patients with anthracycline resistance consecutively received chidamide in combination with anthracycline-based regimen as salvage therapy at the Chinese PLA General Hospital. Results Of the 27 patients who had received one course of salvage therapy, 13 achieved a complete response and 1 achieved a partial response. We found that the HDAC3-AKT-P21-CDK2 signaling pathway was significantly upregulated in anthracycline-resistant AML cells compared to non-resistant cells. AML patients with higher levels of HDAC3 had lower event-free survival (EFS) and overall survival (OS) rates. Moreover, anthracycline-resistant AML cells are susceptible to chidamide, a histone deacetylase inhibitor which can inhibit cell proliferation, increase cell apoptosis and induce cell-cycle arrest in a time- and dose-dependent manner. Chidamide increases the sensitivity of anthracycline-resistant cells to anthracycline drugs, and these effects are associated with the inhibition of the HDAC3-AKT-P21-CDK2 signaling pathway. Conclusion Chidamide can increase anthracycline drug sensitivity by inhibiting HDAC3-AKT-P21-CDK2 signaling pathway, thus demonstrating the potential for application.

Abstract Human leukocyte antigen (HLA) haploidentical stem cell transplantation (haplo-SCT) as a postremission treatment for standard risk Philadelphia chromosome-negative acute lymphoblastic leukemia (SR Ph-ALL) in the first complete remission (CR1) has not been defined. In this multicenter, phase 3 study (NCT02042690), of the 131 consecutive Ph-ALL young adult patients (YA, aged 18–39 years) without high-risk features who achieved CR1, 114 patients without HLA-matched donors received consolidation with an adult chemotherapy regimen (n = 55) or haplo-SCT (n = 59). In the landmark analysis, haplo-SCT resulted in a lower 2-year cumulative incidence of relapse (CIR, 12.8% vs 46.7%, P = 0.0017) and superior 2-year leukemia-free survival (LFS, 80.9% vs 51.1%, P = 0.0116) and 2-year overall survival (OS, 91.2% vs 75.7 [64.8–93.2] %, P = 0.0408) than chemotherapy. In the time-dependent multivariate analysis with propensity score adjustment, postremission treatment (haplo-SCT vs chemotherapy) was an independent risk factor for the CIR (HR 0.195, 95% CI 0.076–0.499, P = 0.001), LFS (HR 0.297, 95% CI 0.131–0.675, P = 0.003), and OS (HR 0.346, 95% CI 0.140–0.853, P = 0.011). In all subgroups, CIR was lower in haplo-SCT. Myeloablative haplo-SCT with ATG+G-CSF might be one of the preferred therapies for YA patients with standard-risk Ph-ALL. Trial registration ClinicalTrials.gov . Registered on 23 January 2014, https://clinicaltrials.gov/ct2/show/NCT02042690

Abstract. Background:. Allogeneic stem-cell transplantation (SCT) is a well-established immunotherapeutic strategy for multiple myeloma (MM) with a potent and often sustained graft-vs.-myeloma effect. This multicenter investigation aimed to analyze the complications and survival of haploidentical SCT in patients with MM, and compare the main outcomes with matched-related donors (MRDs). Methods:. Haploidentical and MRD SCT was identified from a cohort of 97 patients with MM who received a myeloablative transplantation in 13 hospitals from May 2001 to December 2017. A matched-pair analysis was designed. For each haplo recipient, the recipients were randomly selected from the MRD group and were matched according to the following criteria: year of the hematopoietic SCT (±2 years), disease status at transplantation, and the length of follow-up. Results:. Seventy cases received MRD and 27 received haploidentical transplantation. The two groups showed no significant differences regarding age, gender, cytogenetic risk, and diagnostic stage. The cumulative incidences of non-relapse mortality (NRM) at 1 and 3 years based on donor type were 20.5% (95% confidence interval [CI], 10.90–30.10%) and 24.2% (95% CI, 13.81–34.59%) for the MRD group and 16.80% (95% CI, 1.71–31.89%) and 28.70% (95% CI, 8.71–48.69%) for the haplo group, respectively. Cumulative incidence of NRM did not differ significantly between the two groups (χ2 = 0.031, P = 0.861). The cumulative incidences of progression-free survival (PFS) and 1 year and 3 years by type of donors were 59.8% (95% CI, 48.24–71.36%) and 45.4% (95% CI, 33.44–57.36%), and 65.6% (95% CI, 47.18–84.02%) and 26.8% (95% CI, 7.59–46. 01%) for MRD and haploidentical donor, respectively. Cumulative incidence of PFS did not differ significantly between the two groups (χ2 = 0.182, P = 0.670). In multivariate analyses, no statistically significant differences were observed between haploidentical and MRD for relapse, NRM, PFS, and overall survival. There were no statistically differences on main outcomes after haploidentical and MRD. Conclusion:. Haploidentical SCT could be performed safely and feasibly for patients with MM in need.

Background: Studies of haploidentical-related donor (HRD) stem cell transplantation using a combination of peripheral blood stem cells (PBSCs) and bone marrow as the graft have reported encouraging results for patients with hematological diseases. However, few studies specifically reported transplantation of only PBSCs from HRDs among patients with relapsed or refractory acute myeloid leukemia (AML). Here, the long-term outcomes and side effects of unmanipulated HRD PBSC transplantation (HRD-PBSCT) for relapsed/refractory AML were analyzed. Methods: We performed a retrospective analysis of the outcomes in relapsed/refractory AML patients who underwent PBSCT from HRDs (n = 36). Results: Thirty-one (86.1%) patients in the HRD-PBSCT group achieved platelet recovery. The cumulative incidence of acute graft-versus-host disease (aGVHD) in the HRD-PBSCT group was 40.00%, and the cumulative incidence of grades 2–4 aGVHD in this group was 13.33%. A total of 13 patients in the HRD-PBSCT group had recurrent disease at a median of 183 days after transplantation (range: 10–1700 days), reaching cumulative incidences of relapse of 50.28% at 5 years. On multivariate analysis, donor age and patient age >40 years were independent risk factors for inferior disease-free survival or overall survival (P < 0.05). The results of the present study demonstrate rapid and complete neutrophil engraftment, a low incidence of grade 2–4 aGVHD, and promising survival rates in patients after HRD-PBSCT. Thus, granulocyte colony-stimulating factor–primed PBSCs may be a reliable graft source in unmanipulated HRD-HSCT under myeloablative conditioning when no matched sibling donor is available. Conclusions: Our results support the feasibility, effectiveness, and tolerability of PBSCs as a graft source in unmanipulated HRD transplantation under myeloablative conditioning in patients with leukemia.

Objective: Peripheral T-cell lymphomas (PTCLs) confer dismal prognosis and no consensus has been established on the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to its rarity and heterogeneity. The purpose was to review key points of allo-HSCT for PTCLs, including indication, times of transplantation, conditioning regimen, graft versus host disease prophylaxis, and treatment of relapse. Data Sources: A comprehensive search in PubMed and Cochrane up to February 28, 2018, with the keywords “Peripheral”, “T”, “Lymphoma”, and “Transplantation” was done. Study Selection: Relevant articles including HSCT for PTCLs were carefully reviewed. Results: Promising data have been reported from advances in transplant technology and more and more PTCLs patients with poor prognosis could benefit from allo-HSCT. Conclusion: Allo-HSCT is a useful choice for patients with refractory/relapsed PTCLs or high-risk new diagnosed PTCLs.

Objective: The objective of this study was to investigate resting-state functional connectivity (FC) differences in insular sub-regions during the interictal phase in patients with migraine without aura (MWoA).Methods: Forty-nine MWoA patients (MWoA group) and 48 healthy individuals (healthy control group) were recruited for this study. All of the subjects underwent neurological examination and magnetic resonance imaging (MRI). The MRI data were processed using Brat 1.0 software to obtain a whole-brain FC diagram and using Rest 1.8 software to obtain the FC z-score of the sub-regions of both insulas (six sub-regions on each side). Therefore, there were a total of 12 regions of interest (ROIs) that were used as seed points for the statistical analysis.Results: There was abnormal FC between the insular sub-regions and multiple brain regions in the MWoA patients compared with the healthy control group, and a clear laterality was also observed. In addition, the FC z-score of certain sub-regions was negatively correlated with the disease duration.Conclusion: Different insular sub-regions are functionally associated with different regions of the brain and therefore have different functions. In MWoA, the FC between the insular sub-regions and other brain regions was mostly reduced, while a small amount was increased; additionally, the FC may be ipsilateral with a right-side advantage. Variations in the FC of insular sub-regions can be observed as an important indicator of MWoA.

Objective: Angiotensin II type-1 receptor antibodies (AT1R-Ab) and endothelin-1 type-A receptor antibodies (ETAR-Ab) are non-human leukocyte antigen (HLA) antibodies that can elicit adverse effects on kidney transplantation (KT) outcomes. We investigated the correlation between levels of AT1R-Ab and ETAR-Ab and postoperative outcomes in KT recipients. Methods: Pre-KT and post-KT serum from 79 patients was collected. Post-KT serum was collected within 1 year after KT or simultaneously as the biopsy. Levels of AT1R-Ab and ETAR-Ab were measured using enzyme-linked immunosorbent assay kits. AT1R-Ab >17.0 U/mL and ETAR-Ab >10.0 U/mL was considered to denote positivity according to manufacturer recommendations. We measured donor-specific antibodies against human leukocyte antigens (HLA-DSA) levels using LABScreen™ single-antigen kits. Results: Seventy-nine (54 men, 25 women) formed the study cohort. Seven (8.7%) patients were positive for AT1R-Ab, 25 (31.6%) patients were positive for both AT1R-Ab and ETAR-Ab, and 47 (59.5%) were negative for both antibodies at all time points. No patients died during the study period. Patients with both AT1R-Ab and ETAR-Ab were associated with a higher prevalence of antibody-mediated rejection (AMR) and lower estimated glomerular filtration rate, but not allograft loss or delayed graft function. AT1R-Ab were associated with T-cell-mediated rejection, but the association was not significant. HLA-DSA were associated significantly with a higher creatinine level in serum at 12 months and 24 months in patients with AT1R-Ab and/or ETAR-Ab. Conclusions: AT1R-Ab, ETAR-Ab, and HLA-DSA were associated with a higher prevalence of AMR and decline in graft function. Measurement of levels of AT1R-Ab and ETAR-Ab in KT patients may be useful for stratification of immunological risk and identification of patients at a high risk of adverse graft outcome. [ABSTRACT FROM AUTHOR]

Background: Donor-specific HLA antibodies are important risk factors in antibody-mediated rejection and graft loss after renal transplantation and are associated with higher rejection rates and lower graft survival. Most de novo donor specific antibodies (dnDSA) after renal transplantation are directed toward donor HLA-DQ antigens. An HLA-DQ antigen is a heterodimer consisting of an alpha and beta chain. Traditionally, HLA-DQAl typing has not been part of pretransplant evaluation. Therefore, DQ alpha proteins are not usually considered in the interpretation of HLA-DQ antibody reactions. Methods: The renal transplant recipient had a 0% panel reactive antibody pretransplant. Two years after transplantation, he developed symptoms of abdominal distension and bilateral lower extremity edema. Histopathological findings on renal puncture biopsy showed a combination of T-cell-mediated acute rejection type ILA and antibody-mediated rejection with a trend toward chronicity in the transplanted kidney. DSAs were investigated by HLA-I (HLA-AR) and HLA-Il (HLA-DRBI/DQAl/DQB 1) single antigen bead (SAB) assay. HLA typing was performed to explain the antibody reactivity patterns by PCR-SSO and Sequencing-based typing (SBT). HLA-Matchmaker analysis was performed to identify eplets that explain antibody reactivity patterns, Results: HLA-II SAB analysis of the patient's serum at the time of rejection showed positive reactions with all DQB1*03:03-carrying beads with high mean fluorescence intensity (MFI). However, DQB1 *03:03 was not a dnDSA antigen. High-resolution HLA typing revealed that HLA-DQAl *05:01 and DQAl *03:02 were mismatched donor antigens. HLA Matchmaker analysis demonstrated reactivity toward 13OR and 116 V eplet on DQAl and DQB1. Conclusions: Antibodies specific to DQα chains after renal transplantation were highlighted. [ABSTRACT FROM AUTHOR]

Background Complement-binding donor-specific human leukocyte antigen (HLA) antibodies in kidney recipients have been associated with a higher risk of allograft rejection and loss. The objective of this meta-analysis was to investigate the correlation between C1q-binding donor-specific antibodies (DSAs) and clinical outcomes in kidney transplantation (KT) recipients. Methods We conducted systematic searches in the PubMed, EMBASE, and the Cochrane Library databases to identify all studies since inception to August 2021 that compared clinical outcomes between C1q + DSA and C1q-DSA patients who underwent KT. Data were independently extracted by two reviewers who assessed the risk of bias. Data were summarized with fixed effects or random effects models according to heterogeneity. We assessed clinical outcomes including graft loss, rejection, delayed graft function (DGF), and all-cause patient death. Results Twenty-six studies with a total of 1337 patients were included: 485 with C1q-binding DSAs, and 850 without C1q-binding DSAs. Compared with the C1q-DSA group, the C1q + DSA group had significant increases in antibody-mediated rejection (AMR) (relative risk [RR] = 2.09, 95% confidence interval [CI], 1.53–2.86; P < 0.00001), graft loss (RR = 2.40, 95% CI, 1.66–3.47; P < 0.00001), and death (RR = 3.13, 95% CI, 1.06–9.23; P = 0.04). The C1q + DSA and C1q-DSA groups did not show significant differences in T-cell-mediated rejection, acute rejection, acute cellular rejection, mixed rejection, or DGF. Conclusion The findings of this systematic review suggest that C1q + DSA KT have a higher risk of AMR, graft loss, and death compared with C1q-DSA patients. Monitoring C1q-binding DSAs allows risk stratification of recipients and guides physician management. [ABSTRACT FROM AUTHOR]