Sarcopenia and gut microbiota alterations in patients with hematological diseases before and after hematopoietic stem cell transplantation

Objective: The aim of this study was to investigate the prevalence of sarcopenia(SP) and its relationship with gut microbiota alterations in patients with hematological diseases before and after hematopoietic stem cell transplantation(HSCT).Methods: A total of 108 patients with various hematological disorders were selected from Peking University People’s Hospital. SP was screened and diagnosed based on the 2019 Asian Sarcopenia Diagnosis Strategy. Physical measurements and fecal samples were collected, and 16S rRNA gene sequencing was conducted. Alpha and beta diversity analyses were performed to evaluate gut microbiota composition and diversity.Results: After HSCT, significant decreases in calf circumference and body mass index(BMI) were observed,accompanied by a decline in physical function. Gut microbiota analyses revealed significant differences in the relative abundance of Enterococcus, Bacteroides, Blautia and Dorea species before and after HSCT(P<0.05). Before HSCT, sarcopenic patients had lower Dorea levels and higher Phascolarctobacterium levels than non-sarcopenia patients(P<0.01). After HSCT, no significant differences in species abundance were observed. Alpha diversity analysis showed significant differences in species diversity among the groups, with the highest diversity in the postHSCT 90-day group and the lowest in the post-HSCT 30-day group. Beta diversity analysis revealed significant differences in species composition between pre-and post-HSCT time points but not between SP groups. Linear discriminant analysis effect size(LEfSe) identified Alistipes, Rikenellaceae, Alistipes putredinis, Prevotellaceae defectiva and Blautia coccoides as biomarkers for the pre-HSCT sarcopenia group. Functional predictions showed significant differences in anaerobic, biofilm-forming and oxidative stress-tolerant functions among the groups(P<0.05).Conclusions: This study demonstrated a significant decline in physical function after HSCT and identified potential gut microbiota biomarkers and functional alterations associated with SP in patients with hematological disorders. Further research is needed to explore the underlying mechanisms and potential therapeutic targets.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Cellular immunotherapy for hematological malignancy: recent progress and future perspectives

Advancements in the field of cellular immunotherapy have accelerated in recent years and have changed the treatment landscape for a variety of hematologic malignancies.Cellular immunotherapy strategies exploit the patient’s immune system to kill cancer cells.The successful use of CD19 chimeric antigen receptor(CAR)T-cells in treating B-cell malignancies is the paradigm of this revolution,and numerous ongoing studies are investigating and extending this approach to other malignancies.However,resistance to CAR-Tcell therapy and non-durable efficacy have prevented CAR-T-cells from becoming the ultimate therapy.Because natural killer(NK)cells play an essential role in antitumor immunity,adoptively transferred allogeneic NK and CAR-modified NK cell therapy has been attempted in certain disease subgroups.Allogenic hematopoietic stem cell transplantation(allo-HSCT)is the oldest form of cellular immunotherapy and the only curative option for hematologic malignancies.Historically,the breadth of application of allo-HSCT has been limited by a lack of identical sibling donors(ISDs).However,great strides have recently been made in the success of haploidentical allografts worldwide,which enable everyone to have a donor.Haploidentical donors can achieve comparable outcomes to those of ISDs and even better outcomes in certain circumstances because of a stronger graft vs.tumor effect.Currently,novel strategies such as CAR-T or NK-based immunotherapy can be applied as a complement to allo-HSCT for curative effects,particularly in refractory cases.Here,we introduce the developments in cellular immunotherapy in hematology.

Treatment patterns and a prognostic scoring system for elderly acute myeloid leukemia patients:a retrospective multicenter cohort study in China

Objective:Acute myeloid leukemia(AML)is primarily a malignant disorder affecting the elderly.We aimed to compare the outcomes of different treatment patterns in elderly AML patients and to propose a prognostic scoring system that could predict survival and aid therapeutic decisions.Methods:Patients aged≥60 years who had been diagnosed with AML at 7 hospitals in China were enrolled(n=228).Treatment patterns included standard chemotherapy,low intensity therapy,and best supportive care(BSC).Results:The early mortality rates were 31%,6.8%,and 6.3%for the BSC,low intensity therapy,and standard chemotherapy groups,respectively.The complete remission rate of the standard chemotherapy group was higher than that of the low intensity therapy group.The median overall survival(OS)was 561 days and 222 days for the standard chemotherapy and low intensity therapy groups,respectively,and were both longer than that of the BSC group(86 days).Based on multivariate analyses,we defined a prognostic scoring system that enabled classification of patients into 3 risk groups,in an attempt to predict the OS of patients receiving chemotherapies and low intensity therapies.Low and intermediate risk patients benefited more from standard chemotherapies than from low intensity therapies.However,the median OS was comparable between standard chemotherapies and low intensity therapies in high risk patients.Conclusions:Our prognostic scoring system could predict survival and help select appropriate therapies for elderly AML patients.Standard chemotherapy is important for elderly AML patients,particularly for those categorized into low and intermediate risk groups.

Lactate Decreases Bortezomib Sensitivity and Predicts Poor Clinical Outcomes of Multiple Myeloma

Objective:Metabolic disorders are regarded as hallmarks of multiple myeloma(MM)and are responsible for rapid cancer cell proliferation and tumor growth.However,the exact biological roles of metabolites in MM cells have not been fully explored.This study aimed to explore the feasibility and clinical significance of lactate for MM and investigate the molecular mechanism of lactic acid(Lac)in the proliferation of myeloma cells and cell sensitivity to bortezomib(BTZ).Methods:Metabolomic analysis of the serum was carried out to obtain metabolites expression and clinical characteristics in MM patients.The CCK8 assay and flow cytometry were used to detect cell proliferation,apoptosis,and cell cycle changes.Western blotting was used to detect the potential mechanism and apoptosis-and cycle-related protein changes.Results:Lactate was highly expressed in both the peripheral blood and bone marrow of MM patients.It was significantly correlated with Durie-Salmon Staging(DS Staging)and the International Staging System(ISS Staging)and the serum and urinary involved/uninvolved free light chain ratios.Patients with relatively high lactate levels had a poor treatment response.Moreover,in vitro experiments showed that Lac could promote the proliferation of tumor cells and decrease the proportion of G0/G1-phase cells,which was accompanied by an increased proportion of S-phase cells.In addition,Lac could decrease tumor sensitivity to BTZ by disrupting the expression of nuclear factor kappa B subunit 2(NFκB2)and Re1B.Conclusion:Metabolic changes are important in MM cell proliferation and treatment response;lactate could be used as a biomarker in MM and as a therapeutic target to overcome cell resistance to BTZ.

Advances and clinical applications of immune checkpoint inhibitors in hematological malignancies

Immune checkpoints are differentially expressed on various immune cells to regulate immune responses in tumor microenvironment.Tumor cells can activate the immune checkpoint pathway to establish an immunosuppressive tumor microenvironment and inhibit the anti-tumor immune response,which may lead to tumor progression by evading immune surveillance.Interrupting coinhibitory signaling pathways with immune checkpoint inhibitors(ICIs)could reinvigorate the anti-tumor immune response and promote immune-mediated eradication of tumor cells.As a milestone in tumor treatment,ICIs have been firstly used in solid tumors and subsequently expanded to hematological malignancies,which are in their infancy.Currently,immune checkpoints have been investigated as promising biomarkers and therapeutic targets in hematological malignancies,and novel immune checkpoints,such as signal regulatory proteinα(SIRPα)and tumor necrosis factor-alpha-inducible protein 8-like 2(TIPE2),are constantly being discovered.Numerous ICIs have received clinical approval for clinical application in the treatment of hematological malignancies,especially when used in combination with other strategies,including oncolytic viruses(OVs),neoantigen vaccines,bispecific antibodies(bsAb),bio-nanomaterials,tumor vaccines,and cytokine-induced killer(CIK)cells.Moreover,the proportion of individuals with hematological malignancies benefiting from ICIs remains lower than expected due to multiple mechanisms of drug resistance and immune-related adverse events(irAEs).Close monitoring and appropriate intervention are needed to mitigate irAEs while using ICIs.This review provided a comprehensive overview of immune checkpoints on different immune cells,the latest advances of ICIs and highlighted the clinical applications of immune checkpoints in hematological malignancies,including biomarkers,targets,combination of ICIs with other therapies,mechanisms of resistance to ICIs,and irAEs,which can provide novel insight into the future exploration of ICIs in tumor treatment.

Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia:a multicenter,randomized,open-label,phase 3 trial

Coinfusion of unrelated cord blood(UCB)units in haploidentical hematopoietic cell transplantation(haplo-HCT)(haplo-cord HCT)for hematopoietic malignancies showed promising results in previous reports,but the efficiency of haplo-cord HCT in acute myeloid leukemia(AML)still lacks sufficient evidence.This multicenter,randomized,phase 3 trial(ClinicalTrials.gov NCT03719534)aimed to assess the efficacy and safety of haplo-cord HCT in AML patients.A total of 268 eligible patients aged 18-60 years,diagnosed with measurable residual disease in AML(excluding acute promyelocytic leukemia),with available haploidentical donors and suitable for allotransplantation,were randomly allocated(1:1)to receive haplo-cord HCT(n=134)or haplo-HCT(n=134).The 3-year overall survival(OS)was the primary endpoint in this study.Overall median follow-up was 36.50 months(IQR 24.75-46.50).The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group(80.5%,95%confidence interval[CI]:73.7-87.9 vs.67.8%95%CI 60.0-76.5,p=0.013).Favorable progression-free survival(70.3%,95%CI 62.6-78.8 vs.57.6%,95%CI 49.6-67.0,p=0.012)and cumulative incidence of relapse(12.1%,95%CI 12.0-12.2 vs.30.3%,95%CI 30.1-30.4,p=0.024)were observed in haplo-cord HCT group.Grade 3-4 adverse events(AEs)within two years posttransplantation in the two groups were similar.Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery(p=0.026)and increased T-cell reconstitution in the early period posttransplantation.Haplo-cord HCT can improve OS in AML patients without excessive AEs,which may exert additional benefits for recipients of haplo-HCT.

Disease Risk Comorbidity Index for Patients Receiving Haploidentical Allogeneic Hematopoietic Transplantation

We aimed to develop a disease risk comorbidity index(DRCI)based on disease risk index(DRI)and Hematopoietic Cell Transplantation-Specific Comorbidity Index(HCT-CI)in patients receiving haploidentical hematopoietic stem cell transplantation(haplo-HSCT).We identified the prognostic factors of disease-free survival(DFS)in a training subset(n=593),then assigned a weighted score using these factors to the remaining patients(validation subset;n=296).The multivariable model identified two independent predictors of DFS:DRI and HCT-CI before transplantation.In this scoring system,we assigned a weighted score of 2 to very high-risk DRI,and assigned a weighted score of 1 to high-risk DRI and intermediate-and high-risk HCT-CI(i.e.,haplo-DRCI).In the validation cohort,the three-year DFS rate was 65.2%(95%confidence interval(CI),58.2%–72.2%),55.8%(95%CI,44.9%–66.7%),and 32.0%(95%CI,5.8%–58.2%)for the low-,intermediate-,and high-risk group,respectively(P=0.005).Haplo-DRCI can also predict DFS in disease-specific subgroups,particularly in acute leukemia patients.Increasing score was also significantly predictive of increased relapse,increased non-relapse mortality(NRM),decreased DFS,and decreased overall survival(OS)in an independent historical cohort(n=526).These data confirmed that haplo-DRCI could effectively risk stratify haplo-HSCT recipients and provide a tool to better predict who will best benefit from haplo-HSCT.

Predictive Value of Dynamic Peri-Transplantation MRD Assessed By MFC Either Alone or in Combination with Other Variables for Outcomes of Patients with T-Cell Acute Lymphoblastic Leukemia

We performed a retrospective analysis to investigate dynamic peri-hematopoieticstem cell transplantation(HSCT)minimal/measurable residual disease(MRD)on outcomes inpatients with T-cell acute lymphoblastic leukemia(T-ALL).A total of 271 patients were enrolledand classified into three groups:unchanged ncgative MRD pre-and post-HSCT group(group A),post-MRD non-increase group(group B),and post-MRD increase group(group C).The patientsin group B and group C experienced a higher cumulative incidence of relapse(CIR)(42%vs.71%vs.16%,P<0.001)and lower leukemia-free survival(LFS)(46%vs.21%vs.70%,P<0.001)andoverall survival(OS)(50%vs.28%vs.72%,P<0.001)than in group A,but there was no significantdifference in non-relapse mortality(NRM)among three groups(14%vs.12%vs.8%,P=0.752).Multivariate analysis showed that dynamic peri-HSCT MRD was associated with CIR(HR=2.392,95%CI,1.816-3.151,P<0.001),LFS(HR=1.964,95%CI,1.546-2.496,P<0.001)and os(HR=1.731,95%CI,1.348-2.222,P<0.001).We also established a risk scoring system based ondynamic peri-HSCT MRD combined with remission status pre-HSCT and onsct of chronic graft-versus-host disease(GVHD).This risk scoring system could better distinguish ClR(c=0.730)thanthat for pre-HSCT MRD(c=0.562),post-HSCT MRD(c=0.616)and pre-and post-MRD dynamics(c=0.648).Our results confirm the outcome predictive value of dynamic peri-HSCT MRD eitheralone or in combination with other variables for patients with T-ALL.

Demands and technical developments of clinical flow cytometry with emphasis in quantitative,spectral,and imaging capabilities

As the gold-standard method for single-cell analysis,flow cytometry enables high-throughput and multiple-parameter characterization of individual biological cells.This review highlights the demands for clinical flow cytometry in laboratory hematology(e.g.,diagnoses of minimal residual disease and various types of leukemia),summarizes state-of-the-art clinical flow cytometers(e.g.,FACSLyricTMby Becton Dickinson,DxFLEX by Beckman Coulter),then considers innovative technical improvements in flow cytometry(including quantitative,spectral,and imaging approaches)to address the limitations of clinical flow cytometry in hematology diagnosis.Finally,driven by these clinical demands,future developments in clinical flow cytometry are suggested.

Comparison of clinical features of nephrotic syndrome after haploidentical and matched donor hematopoietic stem cell transplantation

To the Editor:Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is one of the most effective options for hematological diseases.However,allo-HSCT treatment can cause serious complications.Post-transplant kidney damage is an important complication.In this study,we retrospectively analyzed the frequency of nephrotic syndrome(NS)after allo-HSCT and compared the frequency and clinical characteristics of NS between haploidentical donor(HID)and matched donor(MD)HSCT(including matched sibling donors[MSD]and unrelated donors[URD]).

The regulatory roles and clinical significance of glycolysis in tumor

Metabolic reprogramming has been demonstrated to have a significant impact on the biological behaviors of tumor cells,among which glycolysis is an important form.Recent research has revealed that the heightened glycolysis levels,the abnormal expression of glycolytic enzymes,and the accumulation of glycolytic products could regulate the growth,proliferation,invasion,and metastasis of tumor cells and provide a favorable microenvironment for tumor development and progression.Based on the distinctive glycolytic characteristics of tumor cells,novel imaging tests have been developed to evaluate tumor proliferation and metastasis.In addition,glycolytic enzymes have been found to serve as promising biomarkers in tumor,which could provide assistance in the early diagnosis and prognostic assessment of tumor patients.Numerous glycolytic enzymes have been identified as potential therapeutic targets for tumor treatment,and various small molecule inhibitors targeting glycolytic enzymes have been developed to inhibit tumor development and some of them are already applied in the clinic.In this review,we systematically summarized recent advances of the regulatory roles of glycolysis in tumor progression and highlighted the potential clinical significance of glycolytic enzymes and products as novel biomarkers and therapeutic targets in tumor treatment.

Plerixafor-based mobilization and mononuclear cell counts in graft increased the risk of engraftment syndrome after autologous hematopoietic stem cell transplantation

Engraftment syndrome(ES)is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation(ASCT),and we aimed to evaluate the incidence and risk factors for ES patients receiving ASCT in the era of plerixafor-based mobilization.A total of 294 were enrolled,and 16.0%(n=47)experienced ES after ASCT.The main clinical manifestations were fever(100%),diarrhea(78.7%),skin rash(23.4%),and hypoxemia/pulmonary edema(12.8%).Plerixafor-based mobilization was associated with higher counts of CD3^(+)cells,CD4^(+)cells,and CD8^(+)cells in grafts.In univariate analysis of the total cohort,age≥60 years,receiving ASCT at complete remission(CR),higher number of mononuclear cell(MNC),CD3^(+)cell counts,CD4^(+)cells as well as CD8^(+)cells transfused and plerixafor-based mobilization were associated with ES after ASCT.Multivariate analysis showed that age≥60 years(P=0.0014),receiving ASCT at CR(P=0.002),and higher number of MNC transfused(P=0.026)were associated with ES in total cohort.In plasma cell disease subgroup,age≥60 years(P=0.013),plerixafor-based mobilization(P=0.036),and receiving ASCT at CR(P=0.002)were associated with ES.Patients with more risk factors had a higher risk of ES.The 1-year probabilities of relapse,non-relapse mortality,and survival were comparable between patients with and without ES.Thus,plerixafor-based mobilization may influence the composition of T lymphocytes in grafts and increase the risk of ES,particularly in patients with plasma cell disease.

Current situation and development of hematopoietic cell transplantation centers:A nationwide survey in China

To the Editor:Hematopoietic cell transplantation(HCT)is a vital modality to cure severe hematological disorders.[1]Global or regional summarized data of HCT are annually reported by the Chinese Blood and Marrow Transplantation Registry Group(CBMTRG),European Society for Blood and Marrow Transplantation(EBMT)and Center for International Blood and Marrow Transplant Research(CIBMTR).It is shown that the number of transplants is continuously increasing,particularly in China in recent years.[2]Since the donor accessibility is significantly addressed by the well-established protocol of haplo-identical HCT(haplo-HCT).

Haploidentical-versus identical-sibling transplant for high-risk pediatric AML:A multi-center study

Background:Human leukocyte antigen-identical sibling donor(ISD)-hematopoietic stem cell transplantation(SCT)is a potentially curative treatment for high-risk pediatric acute myeloid leukemia(AML).A haploidentical donor(HID)is readily available to almost all children.Previous studies have demonstrated that patients with HID-SCT had similar outcomes compared to ISD-SCT for pediatric and adult AML.However,the role of HID-SCT in high-risk pediatric AML is unclear.Methods:To compare the overall survival of high-risk AML children who underwent either HID-SCT or ISD-SCT,we analyzed 179 cases of high-risk AML patients under 18 years of age treated with either ISD-SCT(n=23)or HID-SCT(n=156).Granulocyte colony-stimulating factor plus anti-thymocyte globulin-based regimens were used for HID-SCT.We also analyzed the subgroup data of AML patients at first complete remission(CR1)before SCT with known cytogenetic risk.Results:The numbers of adverse cytogenetic risk recipients were 8(34.8%)and 13(18.8%)in the ISD-SCT group and the HID-SCT group,and the number of patients with disease status beyond CR1 were 6(26.1%)and 14(20.3%)in the two groups.The cumulative rates of grades II-IV acute graft-versus-host disease(GVHD)were 13.0%in the ISD-SCT group and 34.8%in the HID-SCT group(P=0.062),with a three-year cumulative rates of chronic GVHD at 14.1%and 34.9%,respectively(P=0.091).The relapse rate in the ISD-SCT group was significantly higher than that in the HID-SCT group(39.1%vs.16.4%,P=0.027);with non-relapse mortality at 0.0%and 10.6%(P=0.113),respectively.The three-year overall survival rates were 73.0%for the ISD-SCT group and 74.6%for the HID-SCT group(P=0.689).In subgroup analysis,the three-year relapse rate in the ISD-SCT group was higher than that in the HID-SCT group(50.0%vs.9.2%,P=0.001)and the three-year DFS in the ISD-SCT group(50.0%)was lower than that in the HID-SCT group(81.2%)(P=0.021).Conclusions:Unmanipulated HID-SCT achieved DFS and OS outcomes comparable to those of ISD-SCT for high-risk pediatric AML patients with potentially higher rate but manageable GVHD.

Optimized therapeutic strategy for patients with refractory or relapsed acutemyeloid leukemia:long-term clinical outcomes and health-related quality of life assessment

Background:Patients with refractory or relapsed acute myeloid leukemia(AML)have poor survival,necessitating the exploration of optimized therapeutic strategy.Here,we aimed to investigate clinical outcomes and health-related quality of life(HR-QoL)after total therapy,which included allogeneic hematopoietic stem cell transplantation(allo-HSCT),and prophylactic donor lymphocyte infusion(DLI)in the early phase after transplantation,followed bymultiplemeasurable residual disease(MRD)and graft-versus-host disease(GvHD)-guided DLIs.Methods:Consecutive patients who had refractory or relapsed AML and had received non-T-cell-depleted allo-HSCT at Peking University Institute of Hematology were included in the study.If the patients achieved complete remission at 30 days after transplantation and had no evidence of relapse,severe infection,organ failure,and active GvHD at the time of planned DLI,prophylactic DLI was administered at 30 days after transplantation for human leukocyte antigen(HLA)-matched related HSCT or at 45-60 days after transplantation for haploidentical or unrelated HSCT.Subsequently,multiple DLIs were administered based on MRD results and whether they developed GvHD after transplantation.Results:A total of 105 patients were eligible.Eighty-seven patients received prophylactic DLI(group B),while 18 did not receive prophylactic DLI(group A).Among 105 patients,the cumulative incidence of grade 2-4 acute GvHD and chronic GvHDwas 40.6%(95%confidence interval[CI]=30.6%-50.6%)and 73.3%(95%CI=67.4%-79.2%),respectively.The cumulative incidence of relapse(CIR),transplant-related mortality(TRM),and leukemia-free survival(LFS)at 5 years after transplantation were 31.5%(95%CI=21.9%-41.1%),22.1%(95%CI=11.3%-32.9%),and 46.4%(95%CI=36.8%-56.0%),respectively.In group B,the CIR,TRM,and LFS at 5 years after transplantation were 27.6%(95%CI=17.6%-37.6%),21.6%(95%CI=11.2%-32.0%),and 50.8%(95%CI=40.0%-61.6%),respectively.At the end of follow-up,48 patients survived,and more than 90%of survivors had satisfactory recoveries of HR-QoL.Conclusions:Our study indicated that total therapy is not only associated with decreased CIR,comparable TRM,and better long-term LFS,but also with satisfactoryHR-QoL for refractory or relapsed AML,compared with those of standard of care therapy reported previously.Therefore,total therapymay be an optimized therapeutic strategy for refractory or relapsed AML.

Machine learning algorithm as a prognostic tool for Epstein-Barr virus reactivation after haploidentical hematopoietic stem cell transplantation

Epstein-Barr virus(EBV)reactivation is one of the most important infections after hematopoietic stem cell transplantation(HSCT)using haplo-identical related donors(HID).We aimed to establish a comprehensive model with machine learning,which could predict EBV reactivation after HID HSCT with anti-thymocyte globulin(ATG)for graft-versus-host disease(GVHD)prophylaxis.We enrolled 470 consecutive acute leukemia patients,60%of them(n=282)randomly selected as a training cohort,the remaining 40%(n=188)as a validation cohort.The equation was as follows:Probability(EBV reactivation)=1/1+exp(−Y),where Y=0.0250×(age)–0.3614×(gender)+0.0668×(underlying disease)–0.6297×(disease status before HSCT)–0.0726×(disease risk index)–0.0118×(hematopoietic cell transplantation-specific comorbidity index[HCT-CI]score)+1.2037×(human leukocyte antigen disparity)+0.5347×(EBV serostatus)+0.1605×(conditioning regimen)–0.2270×(donor/recipient gender matched)+0.2304×(donor/recipient relation)–0.0170×(mononuclear cell counts in graft)+0.0395×(CD34+cell count in graft)–2.4510.The threshold of probability was 0.4623,which separated patients into low-and high-risk groups.The 1-year cumulative incidence of EBV reactivation in the low-and high-risk groups was 11.0%versus 24.5%(P<.001),10.7%versus 19.3%(P=.046),and 11.4%versus 31.6%(P=.001),respectively,in total,training and validation cohorts.The model could also predict relapse and survival after HID HSCT.We established a comprehensive model that could predict EBV reactivation in HID HSCT recipients using ATG for GVHD prophylaxis.

Expanded clinical-grade NK cells exhibit stronger effects than primary NK cells against HCMV infection

Cytomegalovirus (CMV) reactivation remains a common complication and leads to high mortality in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Early natural killer (NK) cell reconstitution may protect against the development of human CMV (HCMV) infection post-HSCT. Our previous data showed that ex vivo mbIL21/4-1BBL-expanded NK cells exhibited high cytotoxicity against leukemia cells. Nevertheless, whether expanded NK cells have stronger anti-HCMV function is unknown. Herein, we compared the anti-HCMV functions of ex vivo expanded NK cells and primary NK cells. Expanded NK cells showed higher expression of activating receptors, chemokine receptors and adhesion molecules;stronger cytotoxicity against HCMV-infected fibroblasts;and better inhibition of HCMV propagation in vitro than primary NK cells. In HCMV-infected humanized mice, expanded NK cell infusion resulted in higher NK cell persistence and more effective tissue HCMV elimination than primary NK cell infusion. A clinical cohort of 20 post-HSCT patients who underwent adoptive NK cell infusion had a significantly lower cumulative incidence of HCMV infection (HR = 0.54, 95% CI = 0.32–0.93, p = 0.042) and refractory HCMV infection (HR = 0.34, 95% CI = 0.18–0.65, p = 0.009) than controls and better NK cell reconstitution on day 30 post NK cell infusion. In conclusion, expanded NK cells exhibit stronger effects than primary NK cells against HCMV infection both in vivo and in vitro.

Chidamide-BEAC plus autologous stem cell transplantation in high-risk non-Hodgkin lymphoma:a phase II clinical trial

To the Editor:Non-Hodgkin lymphoma(NHL)is a common type of hematological malignancy.Although the development of targeted therapies has improved the survival of patients with aggressive NHL,autologous hematopoietic stem cell transplantation(HSCT)remains indispensable.There is no standard conditioning regimen for autologous stem cell transplantation(ASCT).

Novel microfluidic device for measurable residual disease detection in acute leukemia

Relapse is the most important cause of treatment failure in acute leukemia(AL).Thus,how to predict relapse is critical for improving the survival of patients with AL.Measurable residual diseases(MRDs;previously termed minimal resid-ual diseases),refering to the presence of remaining leukemia cells after the declaration of complete remission(CF)detected by morphological analysis,is the most important biomarker forrelapseprediction.'Several methods,including multiparameter flow cytometry(MFC),real-time quantitative polymerase dhain reaction(qPCR),digital PCR(dPCR),and next-generation sequencing(NGS),are used to monitor MRD after treatment,reaching a sensitvityof 10^(-4)to 10^(-6).