MRD-directed and risk-adapted individualized stratified treatment of AML

Measurable residual disease(MRD)has been widely recognized as a biomarker for deeply evaluating complete remission(CR),predicting relapse,guiding pre-emptive interventions,and serving as an endpoint surrogate for drug testing.However,despite the emergence of new technologies,there remains a lack of comprehensive understanding regarding the proper techniques,sample materials,and optimal time points for MRD assessment.In this review,we summarized the MRD methods,sample sources,and evaluation frequency according to the risk category of the European Leukemia Net(ELN)2022.Additionally,we emphasize the importance of properly utilizing and combining these technologies.We have also refined the flowchart outlining each time point for preemptive interventions and intervention paths.The evaluation of MRD in acute myeloid leukemia(AML)is sophisticated,clinically applicable,and technology-dependent,and necessitates standardized approaches and further research.

Low WT1 transcript levels at diagnosis predicted poor outcomes of acute myeloid leukemia patients with t(8;21) who received chemotherapy or allogeneic hematopoietic stem cell transplantation

Background:Acute myeloid leukemia(AML) with t(8;21) is a heterogeneous disease.Identifying AML patients with t(8;21) who have a poor prognosis despite achieving remission is important for determining the best subsequent therapy.This study aimed to evaluate the impact of Wilm tumor gene-1(WT1) transcript levels and cellular homolog of the viral oncogene v-KIT receptor tyrosine kinase(C-KIT) mutations at diagnosis,and RUNXTRUNX1T1 transcript levels after the second consolidation chemotherapy cycle on outcomes.Methods:Eighty-eight AML patients with t(8;21) who received chemotherapy only or allogeneic hematopoietic stem cell transplantation(allo-HSCT) were included.Patients who achieved remission,received two or more cycles of consolidation chemotherapy,and had a positive measureable residual disease(MRD) test result(defined as <3-log reduction in RUNX1-RUNX1T1 transcript levels compared to baseline) after 2-8 cycles of consolidation chemotherapy were recommended to receive allo-HSCT.Patients who had a negative MRD test result were recommended to receive further chemotherapy up to only 8 cycles.WT1 transcript levels and C-KIT mutations at diagnosis,and RUNX1-RUNX1T1 transcript levels after the second consolidation chemotherapy cycle were tested.Results:Patients who had a C-KIT mutation had significantly lower WTl transcript levels than patients who did not have a C-KIT mutation(6.7%± 10.6%vs.19.5%± 19.9%,P < 0.001).Low WTl transcript levels(<5.0%) but not C-KIT mutation at diagnosis,a positive MRD test result after the second cycle of consolidation chemotherapy,and receiving only chemotherapy were independently associated with high cumulative incidence of relapse in all patients(hazard ratio[HR]= 3.53,2.30,and 11.49;95%confidence interval[CI]1.64-7.62,1.82-7.56,and 4.43-29.82;P = 0.002,0.034,and <0.001,respectively);these conditions were also independently associated with low leukemia-free survival(HR =3.71,2.33,and 5.85;95%CI 1.82-7.56,1.17-4.64,and 2.75-12.44;P < 0.001,0.016,and <0.001,respectively) and overall survival(HR = 3.50,2.32,and 4.34;95%CI 1.56-7.82,1.09-4.97,and 1.98-9.53;P = 0.002,0.030,and <0.001,respectively) in all patients.Conclusions:Testing for WTl transcript levels at diagnosis in patients with AML and t(8;21) may predict outcomes in those who achieve remission.A randomized study is warranted to determine whether allo-HSCT can improve prognosis in these patients.

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.

Ethical review of off-label drugs during the COVID-19 pandemic

High-quality scientific research is very important in attempting to effectively control the coronavirus disease 2019(COVID-19)pandemic and ensure people’s health and safety.Chloroquine(CQ)and hydroxychloroquine(HCQ)have received much attention.This article comprehensively investigates the ethical review of off-label CQ and HCQ research during the COVID-19 pandemic with regard to strictly abiding by review standards,improving review efficiency,ensuring the rights and interests of subjects and that ethics committees conduct independent reviews,and achieving full ethics supervision of research conducted during an emergency.Research must be both rigorous and prudent to ensure the best outcome,with the maximization of benefits as the core principle.Standardization of the application,implementation and ethical review processes are needed to prevent unnecessary risk.

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.

Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy

Chimeric antigen receptor(CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia(ALL).Measurable/minimal residual disease(MRD)monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy.Common MRD detection methods include flow cytometry(FCM),polymerase chain reaction(PCR),and next-generation sequencing(NGS),and each method has advantages and limitations.It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse.Thus,how to perform prognostic evaluations,stratify risk based on MRD status,and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice.This review assesses the common and novel MRD assessment methods.In addition,we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation(allo-HSCT),as well as other therapeutic strategies to improve treatment effect.Furthermore,this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.

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]).

Embracing the age of artificial intelligence:paradigm shifts,opportunities,and challenges in the treatment of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is an important medical development in treating hematological disorders.However,the risk of acute graft-versus-host disease(a GVHD)severely limits its use.a GVHD is a severe and potentially fatal complication of alloHSCT that causes inflammation and tissue damage.It often targets the skin.

Revolutionizing genetic disease treatment: The case of exagamglogene autotemcel

Recent approval of exagamglogene autotemcel(exa-cel)on November 16,2023,in the United Kingdom,developed by Vertex Pharmaceuticals and CRISPR Therapeutics,represents the first cell-based therapy for treatment of sickle cell disease(SCD)with recurrent vaso-occlusive crises(VOCs)or transfusion-dependentβ-thalassemia(TDT)in patients aged 12 and above.Following suit,the US Food and Drug Administration authorized exa-cel for the same indications on December 8,2023.Exa-cel represents the first commercially approved CRISPR-based gene therapy,offering hope to approximately 25,000 eligible patients in the US and Europe.The significance of exa-cel extends beyond revolutionizing therapeutic intervention in genetic medicine;it also raises profound ethical considerations and societal implications related to genome manipulation.

Donor-Derived CD19-Targeted T Cell Infusion Eliminates B Cell Acute Lymphoblastic Leukemia Minimal Residual Disease with No Response to Donor Lymphocytes after Allogeneic Hematopoietic Stem Cell Transplantation

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 BALL 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.

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.

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.

Development of allogeneic hematopoietic stem cell transplantation in 2022:Regenerating“Groot”to heal the world

Allogeneic hematopoietic stem cell transplantation(allo-HSCT),the pioneer and mainstream form of cellular therapy,represents the only curative or preferred treatment for various malignant and nonmalignant disorders or facilitates organ transplantation by reconstituting the new blood and immune system of a patient with donor’s regenerative HSCs,similar to the comics character“Groot,”who has an incredible regeneration ability.The annual cases of allo-HSCT in China's Mainland increased from 10042 in 2020 to 12744 in 2021,suggesting that the negative impact of the severe acute respiratory syndrome coronavirus 2 pandemic might be eliminated,while Europe and North American registries reported 18796 and 8326 cases in 2020,respectively.1 In addition,cutting-edge progress in other cellular therapies,including chimeric antigen receptor T(CAR-T)cells,mesenchymal stromal cells,and specific cytotoxic T lymphocyte(CTL)cells,promotes the combination of allo-HSCT with these therapies to compose the new chapter“Strong Together,Guardians of Life”to save more patients worldwide.

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.

Repair of dysfunctional bone marrow endothelial cells alleviates aplastic anemia

Aplastic anemia(AA)is a life-threatening disease characterized by bone marrow(BM)failure and pancytopenia.As an important component of the BM microenvironment,endothelial cells(ECs)play a crucial role in supporting hematopoiesis and regulating immunity.However,whether impaired BM ECs are involved in the occurrence of AA and whether repairing BM ECs could improve hematopoiesis and immune status in AA remain unknown.In this study,a classical AA mouse model and VE-cadherin blocking antibody that could antagonize the function of ECs were used to validate the role of BM ECs in the occurrence of AA.Nacetyl-L-cysteine(NAC,a reactive oxygen species scavenger)or exogenous EC infusion was administered to AA mice.Furthermore,the frequency and functions of BM ECs from AA patients and healthy donors were evaluated.BM ECs from AA patients were treated with NAC in vitro,and then the functions of BM ECs were evaluated.We found that BM ECs were significantly decreased and damaged in AA mice.Hematopoietic failure and immune imbalance became more severe when the function of BM ECs was antagonized,whereas NAC or EC infusion improved hematopoietic and immunological status by repairing BM ECs in AA mice.Consistently,BM ECs in AA patients were decreased and dysfunctional.Furthermore,dysfunctional BM ECs in AA patients led to their impaired ability to support hematopoiesis and dysregulate T cell differentiation toward proinflammatory phenotypes,which could be repaired by NAC in vitro.The reactive oxygen species pathway was activated,and hematopoiesis-and immune-related signaling pathways were enriched in BM ECs of AA patients.In conclusion,our data indicate that dysfunctional BM ECs with impaired hematopoiesis-supporting and immunomodulatory abilities are involved in the occurrence of AA,suggesting that repairing dysfunctional BM ECs may be a potential therapeutic approach for AA patients.

Current status and future perspective of natural killer cell therapy for cancer

Natural killer(NK)cells possess innate abilities to effectively eliminate cancer cells.However,because of difficulties of proliferation and easy to be induced dysfunction in the setting of cancer post NK cell therapy,the curative effect of NK cell infusion has been constrained and not been widely applicable in clinical practice.The rapid development of biotechnology has promoted the development of NK cell therapy for cancer treatment.In this review,we will provide a comprehensive analysis of the current status and future prospects of NK cell therapy for cancer,focusing on the biological characteristics of NK cells,as well as strategies to enhance their targeting capabilities and overcome tumor immune suppression within the microenvironment.

Bridging chimeric antigen receptor T-cell before transplantation improves prognosis of relapsed/refractory B-cell acute lymphoblastic leukemia

To the Editor:For recipients with relapsed/refractory(R/R)B-cell acute lymphoblastic leukemia(B-ALL),allogeneic hematopoietic stem cell transplantation(allo-HSCT)often fails to provide them with a satisfactory prognosis.The chimeric antigen receptor T(CAR-T)cells are proven to be safe and effective for these patients.[1]But there are few published studies assessing the advantages of CAR-T compared to traditional chemotherapy as a bridging treatment followed by HSCT.Consequently,we conducted this study to confirm whether children and young adult R/R B-ALL patients with CAR-T therapy could expect a better post-HSCT prognosis,compared to R/R patients only receiving traditional chemotherapy before transplantation.

More than two courses of pre-transplant consolidation therapy benefits patients with acute myeloid leukemia in the first complete remission who underwent human leukocyte antigen-matched sibling allografts:a multicenter study

Background:Although the need for consolidation chemotherapy after successful induction therapy is well established in patients with acute myeloid leukemia(AML)in first complete remission(CR1),the value of consolidation chemotherapy before allogeneic hematopoietic stem cell transplantation remains controversial.Methods:We retrospectively compared the effect of the number of pre-transplant consolidation chemotherapies on outcomes of human leukocyte antigen-matched sibling stem cell transplantation(MSDT)for patients with AML in CR1 in multicenters across China.In our study,we analyzed data of 373 AML patients in CR1 from three centers across China.Results:With a median follow-up of 969 days,patients with≥3 courses of consolidation chemotherapy had higher probabilities of leukemia-free survival(LFS)(85.6%vs.67.0%,P<0.001)and overall survival(89.2%vs.78.5%,P=0.007),and better cumulative incidences of relapse(10.5%vs.19.6%,P=0.020)and non-relapse mortality(4.2%vs.14.9%,P=0.001)than those with≤2 courses of consolidation chemotherapy.Pre-transplantation minimal residual disease-negative patients with AML in CR1 who received MSDT with≥3 courses of consolidation chemotherapy had a higher probability of LFS(85.9%vs.67.7%,P=0.003)and a lower cumulative incidence of relapse(9.6%vs.23.3%,P=0.013)than those with≤2 courses.Conclusion:Our results indicate that patients with AML in CR1 who received MSDT might benefit from pre-transplant consolidation chemotherapy.

Insights from TARGET-seq:Inflammation drives TP53-mediated clonal evolution

Approximately 10%–20%myeloproliferative neoplasms(MPNs)can progress into blast-phase MPNs,also termed secondary acute myeloid leukemias(sAMLs),presenting dismal prognoses.sAML exhibits a distinctive clinical and pathological profile compared to de novo AML,marked by a higher incidence of erythroid leukemias and reduced responsive to conventional chemotherapies,resulting in a median survival of approximately 6 months.TP53 alterations are prevalent adverse events in leukemic transformation(LT),occurring in around one-third of sAML subjects.