Quality-adjusted time without symptoms or toxicity analysis of haploidentical-related donor vs.identical sibling donor hematopoietic stem cell transplantation in acute myeloid leukemia

Objective:We aimed to compare the quality-adjusted time without symptoms or toxicity(Q-TWiST)in acute myeloid leukemia(AML)patients who received haploidentical-related donor(HID)and identical sibling donor(ISD)hematopoietic stem cell transplantation(HSCT).Methods:Five clinical health states were defined:toxicity(TOX),acute graft-versus-host disease(GVHD),chronic GVHD(cGVHD),time without symptoms and toxicity(TWiST)and relapse(REL).The equation used in this study was as follows:Q-TWiST=UTOX×TOX+UTWiST×TWiST+UREL×REL+UaGVHD×aGVHD+UcGVHD×cGVHD.Results:A total of 239 AML patients were enrolled.We established a mathematical model,i.e.,Q-TWiST HID HSCT>Q-TWiST ISD HSCT,to explore the range of utility coefficients satisfying the inequality.Based on the raw data,the utility coefficient is equivalent to the following inequality:10.57067UTOX-46.27733UREL+105.9374+3.388078UaGVHD-210.8198UcGVHD>0.The model showed that when UTOX,UREL,and UaGVHD were within the range of 0-1,as well as when UcGVHD was within the range of 0-0.569,the inequality Q-TWiST HID HSCT>Q-TWiST ISD HSCT was valid.According to the results of the ChiCTR1800016972 study,the median coefficients of TOX,acute GVHD(aGVHD),and cGVHD were 0.56(0.41-0.76),0.56(0.47-0.72),and 0.54(0.37-0.79),respectively.We selected a series of specific examples of the coefficients,i.e.,UTOX=0.5,UREL=0.05,UaGVHD-0.5,and UcGVHD-0.5.The Q-TWiST values of ISD and HID HSCT were 896 and 900 d,respectively(P=0.470).Conclusions:We first observed that Q-TWiST was comparable between AML patients receiving HID HSCT and those receiving ISD HSCT.

Advantageous tactics with certain probiotics for the treatment of graft-versus-host-disease after hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation(HSCT)becomes a standard form of cellular therapy for patients with malignant diseases.HSCT is the first-choice of immunotherapy,although HSCT can be associated with many complications such as graft-versus-host disease(GVHD)which is a major cause of morbidity and mortality after allogeneic HSCT.It has been shown that certain gut microbiota could exert protective and/or regenerative immunomodulatory effects by the production of short-chain fatty acids(SCFAs)such as butyrate in the experimental models of GVHD after allogeneic HSCT.Loss of gut commensal bacteria which can produce SCFAs may worsen dysbiosis,increasing the risk of GVHD.Expression of G-protein coupled receptors such as GPR41 seems to be upre-gulated in the presence of commensal bacteria,which might be associated with the biology of regulatory T cells(Tregs).Treg cells are a suppressive subset of CD4 positive T lymphocytes implicated in the prevention of GVHD after allogeneic HSCT.Here,we discuss the current findings of the relationship between the modification of gut microbiota and the GVHD-related immunity,which suggested that tactics with certain probiotics for the beneficial symbiosis in gut-immune axis might lead to the elevation of safety in the allogeneic HSCT.

Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities

As an important treatment for acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation(allo-HSCT) plays an important role in reducing relapse and improving long-term survival. With rapid advancements in basic research in molecular biology and immunology and with deepening understanding of the biological characteristics of hematopoietic stem cells, allo-HSCT has been widely applied in clinical practice. During allo-HSCT, preconditioning, the donor, and the source of stem cells can be tailored to the patient’s conditions, greatly broadening the indications for HSCT, with clear survival benefits. However, the risks associated with allo-HSCT remain high, i.e. hematopoietic reconstitution failure, delayed immune reconstitution, graft-versus-host disease, and posttransplant relapse, which are bottlenecks for further improvements in allo-HSCT efficacy and have become hot topics in the field of HSCT. Other bottlenecks recognized in the current treatment of individuals diagnosed with acute myeloid leukemia and subjected to allo-HSCT include the selection of the most appropriate conditioning regimen and post-transplantation management. In this paper, we reviewed the progress of relevant research regarding these aspects.

Decitabine for Relapsed Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Relapse after allogeneic hematopoietic stem cell transplantation（allo-HSCT） remains a main question on treatment failure. Current strategies for management that usually include salvage chemotherapy, donor lymphocytic infusion and second transplantation. Our study assessed the efficacy of decitabine（DAC） for treating patients with acute lymphoblastic leukemia（ALL） who relapsed after allogeneic hematopoietic stem cell transplantation（allo-HSCT）. We retrospectively analyzed the outcomes of 12 patients with relapsed ALL after allo-HSCT who received DAC therapy. Nine patients received DAC combined with chemotherapy and donor stem cell infusion, and 3 patients received single-agent DAC. Ten of the 12 patients achieved complete remission（CR）, 1 achieved a partial remission（PR）, and 1 had no response（NR） after treatment at the latest follow-up（LFU）, the median survival was 11.2 months（range, 3.8–34, 7 months）. The 1-and 2-year overall survival（OS） rates were 50%（6/12） and 25%（3/12）, respectively. Five patients were still alive; 4 had maintained CR and 1 was alive with disease. Patients with Philadelphia chromosome-positive ALL had higher survival rate than patients with Philadelphia chromosome-negative ALL（57.1% vs. 20%）. No aggravated flares of graft-versus-host disease（GVHD） were observed during DAC treatment. Therefore, DAC may be a promising therapeutic agent for ALL recurrence after allo-HSCT.

Gut microbiome in allogeneic hematopoietic stem cell transplantation and specific changes associated with acute graft vs host disease

Allogeneic hematopoietic stem cell transplantation(aHSCT)is a standard validated therapy for patients suffering from malignant and nonmalignant hematological diseases.However,aHSCT procedures are limited by potentially life-threatening complications,and one of the most serious complications is acute graft-versus-host disease(GVHD).During the last decades,DNA sequencing technologies were used to investigate relationship between composition or function of the gut microbiome and disease states.Even if it remains unclear whether these microbiome alterations are causative or secondary to the presence of the disease,they may be useful for diagnosis,prevention and therapy in aHSCT recipients.Here,we summarized the most recent findings of the association between human gut microbiome changes and acute GVHD in patients receiving aHSCT.

Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation for Thymoma-associated Severe Aplastic Anemia: a Case Report

THYMOMA, a relatively rare epithelial neoplasm with unique clinical and pathologic features, is the most usual diagnosis for a mass located in the mediastinum. It is often associated withautoimmune disorders. The myastnema gravls ano pure red cell aplasia are the most common disorders, with the incidences of 40% and 5%, respectively, while the incidence of aplastic anemia is only about 0-1.4%. 1 Thymectomy is hard to perform on patients with severe aplastic anemia（SAA） due to severe pancytopenia.

Profiles of interferon-gamma and interleukin-2 in patients after allogeneic hematopoietic stem cell transplantation

BACKGROUND Allogeneic hematopoietic stem cell transplantation(allo-HSCT)may be related to the occurrence of complications,including graft-versus-host disease(GvHD)and infections.The pathogenesis of acute GvHD is connected with T lymphocytes,which identify alloantigens on host's antigen-presenting cells,activate production of interferon-gamma(IFN-gamma)and interleukin-2(IL-2),and act on the immune effector cells and damage tissues and organs.AIM The aim of the study was to investigate and distinguish serum concentration profiles of IFN-gamma and IL-2 within a 30-d period after allo-HSCT.METHODS We enrolled 62 patients,i.e.,30(48%)male and 32(52%)female subjects[median age 49.5(19-68)years],after allo-HSCT from siblings(n=12)or unrelated donors(n=50)due to acute myeloid leukemia with myeloablative conditioning(n=26;42%)and with non-myeloablative conditioning(n=36;58%).All patients were given standard immunosuppressive therapy with cyclosporin-A and methotrexate and pre-transplant antithymocyte globulin in the unrelated setting.Blood samples were collected pre-transplant before and after(on day-1)the conditioning therapy and on days+2,+4,+6,+10,+20,and+30 after allo-HSCT.Serum levels of IL-2 and IFNgamma were determined using ELISA.RESULTS Patients were divided into four groups depending on the presence of acute GvHD and clinical manifestations of infection.Group I included patients with neither acute GvHD nor infections[n=15(24%)],group II consisted of patients with infections without acute GvHD[n=17(27%)],group III was comprised of patients with acute GvHD without infections[n=9(15%)],and group IV included patients with both acute GvHD and infections[n=21(34%)].IFN-gamma concentrations were higher in Group II than in other groups on days+20(P=0.014)and+30(P=0.008).Post-hoc tests showed lower concentrations of IFN-gamma on day+30 in groups I(P=0.039)and IV(P=0.017)compared to group II.The levels of IL-2 were mostly undetectable.CONCLUSION Serum levels of IFN-gamma following allo-HSCT progressively escalate.High serum levels of IFN-gamma are related to infectious complications rather than acute GvHD.Serum concentrations of IL-2 in most patients are undetectable.

Allogeneic hematopoietic stem cell transplantation in 24 patients with β-thalassemia major

Objective To investigate the effect of allgeneic hematopoietic stem cell transplantation ( allo - HSCT ) for β - thalassemia major. Methods Twenty - four β - thalassemia major patients with median age of 4 years ( range: 2 -15 years) ,18 boys and 6 girls,received al-

Azacitidine maintenance therapy for blastic plasmacytoid dendritic cell neoplasm allograft: A case report

BACKGROUND Blastic plasmacytoid dendritic cell neoplasm(BPDCN)is a rare,highly invasive malignant neoplasm.There is no universally accepted standard of care because of its rarity and the dearth of prospective research.It is still challenging for some patients to achieve persistent clinical remission or cure,despite the success of allogeneic hematopoietic stem cell transplantation(allo-HSCT),indicating that there is still a significant recurrence rate.We report a case of prevention of BPDCN allograft recurrence by azacitidine maintenance therapy and review the relevant literature.CASE SUMMARY We report a 41-year-old man with BPDCN who was admitted to hospital due to skin sclerosis for>5 mo’duration.BPDCN was diagnosed by combined clinical assessment and laboratory examinations.Following diagnosis,the patients underwent induction consolidation chemotherapy to achieve the first complete remission,followed by bridging allo-HSCT.Post-transplantation,azacitidine(75 mg/m2 for 7 d)was administered as maintenance therapy,with repeat administration every 4–6 wk and appropriate extension of the chemotherapy cycle.After 10 cycles,the patient has been disease free for 26 mo after transplantation.Regular assessments of bone marrow morphology,minimal residual disease,full donor chimerism,Epstein–Barr virus,and cytomegalovirus all yielded normal results with no abnormalities detected.CONCLUSION Azacitidine may be a safe and effective maintenance treatment for BPDCN following transplantation because there were no overt adverse events during the course of treatment.

Rare myeloid sarcoma/acute myeloid leukemia with adrenal mass after allogeneic mobilization peripheral blood stem cell transplantation

Myeloid sarcoma(MS)is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia(AML).This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission.A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010.After one month,bone marrow biopsy and aspiration confirmed the diagnosis of AML.Allogeneic mobilization peripheral blood stem cell transplantation was performed,with the sister of the patient as donor,after complete remission(CR)was achieved by chemotherapy.Five months after treatment,an adrenal mass was detected by positron emission tomography-computed tomography(PET-CT).Radiotherapy was performed for the localized mass after a multidisciplinary team(MDT)discussion.The patient is still alive as of May 2013,with no evidence of recurrent MS or leukemia.

Breast and dorsal spine relapse of granulocytic sarcoma after allogeneic stem cell transplantation for acute myelomonocytic leukemia:A case report

BACKGROUND Granulocytic sarcoma(GS)is a rare malignant tumor,and relapse is even rarer in the breast and dorsal spine following allogeneic hematopoietic stem cell transplantation.Currently,a standard treatment regimen is not available.CASE SUMMARY A rare case of GS of the right breast and dorsal spine after complete remission of acute myelogenous leukemia is reported here.A 55-year-old female patient presented with a palpable,growing,painless lump as well as worsening dorsal compressive myelopathy.She had a history of acute myelomonocytic leukemia(AML M4)and achieved complete remission after chemotherapy following allogeneic hematopoietic stem cell transplantation.Imaging examinations showed the breast lump and C7-T1 epidural masses suspected of malignancy.Histologic results were compatible with GS in both the right breast and dorsal spine,which were considered extramedullary relapse of the AML treated 4 years earlier.CONCLUSION A rare case of GS relapse following allogeneic hematopoietic stem cell transplantation and guidelines for treatment are discussed.

Hemorrhagic cystitis following hematopoietic stem cell transplantation:incidence,risk factors and association with CMV reactivation and graft-versus-host disease

Background The definite pathogenesis of hemorrhagic cystitis （HC） after allogenic hematopoietic stem cell transplantation （allo-HSCT） has not been well elucidated. The role of cytomegalovirus （CMV） reactivation and graft-versus-host disease （GVHD） in the development of HC remains obscure. This study determined the incidence and risk factors for HC after alIo-HSCT and analyzed its association with CMV reactivation and GVHD. Methods We retrospectively studied 250 patients at high risk for CMV disease who underwent alIo-HSCT all based on busulfan/cyclophosphamide （BU/CY） myloablative regimens. The incidence, etiology, risk factors and clinical management of HC were investigated. Results HC developed within 180 days of transplant in 72 patients, with an overall incidence of 28.8% and an incidence of 12.6% in patients with HLA-matched related donors （MRD）, 34.38% in those with HLA-matched unrelated donors （MUD）, 49.45% in those with mismatched related donors （MMRD）. CMV-viremia significantly increased the incidence of later onset HC （LOHC）; however, only 9 out of 15 patients with CMV viruria actually developed LOHC. Multiple regression analysis identified grade II-IV acute GVHD （RR=2.75; 95% CI 1.63-4.66; P〈0.01） and grafts from MUD or MMRD （RR=2.60; 95% CI 1.52-5.20; P〈0.01） as independent risk factors for HC. Event sequence analysis indicated a majority of HC episodes began around GVHD initiation. Conclusions CMV-viremia is a high risk factor for LOHC. Our data also showed a correlation between acute GVHD and HC, which suggested that alloimmunity may be involved in the pathogenesis of HC.

Novel agents targeting leukemia cells and immune microenvironment for prevention and treatment of relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation

Relapse remains the worst life-threatening complications after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in patients with acute myeloid leukemia(AML),whose prognosis has been historically dismal.Given the rapid development of genomics and immunotherapies,the interference strategies for AML recurrence have been changing these years.More and more novel targeting agents that have received the U.S.Food and Drug Administration(FDA)approval for de novo AML treatment have been administrated in the salvage or maintenance therapy of post-HSCT relapse.Targeted strategies that regulate the immune microenvironment of and optimize the graft versus leukemia(GVL)effect of immune cells are gradually improved.Such agents not only have been proven to achieve clinical benefits from a single drug,but if combined with classic therapies,can significantly improve the poor prognosis of AML patients who relapse after allo-HSCT.This review will focus on currently available and promising upcoming agents and also discuss the challenges and limitations of targeted therapies in the allogeneic hematopoietic stem cell transplantation community.

HLA-mismatched/haploidentical hematopoietic stem cell transplantation： a field in which Chinese doctors are making great contributions

Allogeneic hematopoietic stem cell transplantation .（allo-HSCT） is one of the best, or even the only,option for the cure of leukemia, especially for patients with high risk factors . However, it is limited by the shortage of suitable donors, because only 25%-30% patients can find a human leukocyte antigen （HLA）-identical sibling donor. Although much progress has been made in finding a suitable unrelated donor or unrelated cord blood （uCB） due to the expansion of the worldwide unrelated donor program,

Clinical and serological characterization of autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation

Background Autoimmune hemolytic anemia （AIHA） is an uncommon complication of allogeneic hematopoietic stem cell transplantation （allo-HSCT） which has only been reported in a few cases.We here aimed to explore its mechanism.Methods We retrospectively analyzed 296 patients who underwent allo-HSCT in our center from July 2010 to July 2012.Clinical manifestations were carefully reviewed and the response to currently available treatment approaches were evaluated.The survival and risk factors of AIHA patients after allo-HSCT were further analyzed.Results Twelve patients were diagnosed with AIHA at a median time of 100 days （15-720 days） after allo-HSCT.The incidence of AIHA after allo-HSCT was 4.1％.IgG antibody were detected in ten patients and IgM antibody in two patients.The two cold antibody AIHA patients had a better response to steroid corticoid only treatment and the ten warm antibody AIHA patients responded to corticosteroid treatment and adjustment of immunosuppressant therapy.Rituximab was shown to be effective for AIHA patients who failed conventional therapy.Survival analysis showed that the combination of AIHA in allo-HSCT patients hinted at poor survival.Cytomegalovirus （CMV） infection,graft-versus-host disease （GVHD） and histocompatibility leukocyte antigen （HLA） mismatch seemed to increase the risk of developing AIHA.Conclusions Patients who develop AIHA after allo-HSCT have poor survival compared to non-AIHA patients.Possible risk factors of AIHA are CMV infection,GVHD,and HLA mismatch.Rituximab is likely to be the effective treatment choice for the refractory patients.

Risk factors for bronchiolitis obliterans syndrome in allogeneic hematopoietic stem cell transplantation

Background The occurrence of bronchiolitis obliterans syndrome （BOS） after allogeneic hematopoietic stem cell transplantation （alIo-HSCT） is rare but severe. We examine the role of pre-HSCT chemotherapeutic exposure, pre-HSCT comorbidities, and transplant-related complications in the development of BOS after alIo-HSCT. Methods A nested case-control study was designed. Cases with BOS and controls matched for the year of alIo-HSCT and length of the follow-up were identified from a cohort of 1646 patients who underwent alIo-HSCT for treatment of hematologic malignancies between 2006 and 2011. Antithymocyte globulin was used in the partial matched related and unrelated matched donor HSCT, or patients with severe aplastic anemia. Results Thirty-six patients suffered from BOS; the mean age at the time of presentation was （32.7±2.4） years, and the mean time to presentation was （474±350） days post-HSCT. A pre-HSCT cyclophosphamide dose of 〉3.2 g/m2 （OR=8.74, P=0.025）, chronic graft-versus-host disease （moderate to severe） （OR=12.02, P=0.000）, and conditioning regimens without antithymocyte globulin （OR=2.79, P=0.031） were independently associated with BOS. Conclusions We found that higher pre-HSCT cyclophosphamide exposure, a conditioning regimen without antithymocyte globulin, and moderate to severe chronic graft-versus-host disease are significantly and independently associated with BOS. Based on these results, we can identify patients who are at a higher risk of developing BOS after alIo-HSCT, select a more appropriate therapeutic strategy, and improve the outcome of HSCT recipients.

Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation(alloHSCT)is a life-saving procedure used for the treatment of selected hematological malignancies,inborn errors of metabolism,and bone marrow failures.The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection.However,recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions.Accordingly,neutrophils are emerging as highly versatile cells that are able to acquire different,often opposite,functional capacities depending on the microenvironment and their differentiation status.Herein,we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT,from the hematopoietic stem cell(HSC)mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion.We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versushost disease(GVHD)prophylaxis.Finally,the potential involvement of neutrophils in alloHSCT-related complications,such as transplant-associated thrombotic microangiopathy(TA-TMA),acute and chronic GVHD,and cytomegalovirus(CMV)reactivation,is also discussed.Based on the data reviewed herein,the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role.However,much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT.

Risk factors associated with hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation

Hemorrhagic cystitis(HC)is a common complication of allogeneic hematopoietic stem cell transplantation(HSCT).The incidence is about 7%to 68%,and some patients have to suffer a long period of frequent,urgent,and painful urination,which brings great pain.This study aimed to analyze risk factors of HC and its effect on patient survival.We collected the medical records of 859 patients who underwent HSCT at our hospital between August 2016 and August 2020.Patients with and without HC were matched using propensity score matching at a 1:1 ratio based on sex,age,and diagnosis,and logistic regression analyses were used to identify factors associated with HC.We used Kaplan–Meier curves to analyze the survival rates of patients in the HC and non-HC groups.We also analyzed the relationship between BK viral load and the occurrence of HC using receiver operating characteristic curve(ROC)analysis.After propensity score matching,there were 131 patients each in the HC and non-HC groups.In the HC group,89 patients(67.9%)had mild HC(stage II°)and 43(32.1%)had severe HC(stage III–IV).The median interval between stem cell transplantation and HC development was 31(3–244)days.Univariate analysis indicated that donor age,hematopoietic stem cell source,HLA,acute graft-versus-host disease,busulfan,anti-thymocyte globulin(ATG),total body irradiation,cytomegalovirus(CMV)(urine),and BK polyomavirus(BKV)(urine)were significantly associated with HC.ATG,CMV(urine),and BKV(urine)were independent risk factors for HC based on the multivariate analysis.The Kaplan–Meier survival analysis showed no significant difference between the HC and non-HC groups(P=0.14).The 1-and 2-year survival rates in the HC group were 78.4%and 69.6%,respectively,and the corresponding rates in the non-HC group were 84.4%and 80.7%,respectively.ROC analysis indicated that a urine BKV load of 1×10^(7) copies/mL was able to stratify the risk of HC.In conclusion,when the BKV load is>1×10^(7),we needtobe aware of the potential for the development of HC.

Ex vivo expansion of regulatory T cells for clinical applications against graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

Objective To review the characteristics of regulatory T cells （Tregs） and ex vivo expansion of Tregs for treatment of graftversus-host disease （GVHD）.Data sources The data used in this review were retrieved from PubMed （1970-2013）.The terms ＂ex vivo expansion＂,＂regulatory T cell＂,and ＂graft-versus-host disease＂ were used for literature search.Study selection The publications about the characteristics of Tregs,ex vivo expansion of Tregs and clinical applications of Tregs against GVHD were identified,retrieved and reviewed.Results Tregs can be classified as natural Tregs （nTregs） and induced Tregs （iTregs）.Both subsets share most Treg features.Given their immunosuppressive property,Tregs have been tested for their capability of preventing GVHD.The bottleneck of Treg therapy is the limited numbers of naturally existing Tregs.To solve this problem,ex vivo expansion of nTregs or iTregs has been executed.The initial data indicate Treg therapy is effective in reducing GVHD without compromising graft-versus-leukemia （GVL）.Conclusion Ex vivo expansion of Tregs is a reliable way to prepare sufficient number of Tregs for management of GVHD.

Immune-mediated neuromuscular complications after haploidendtical hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation （Allo-HSCT） is associated with neuromuscluar complications in fewer than 5% of patients.1 The most common causes are associated with the toxicity of the conditioning regimen,infections,bleeding,and malignant disease relapse.Allo-HSCT related neuromuscular complications can also be caused by immune-mediated mechanisms,which are usually present in the form of myositis/polymyositis or demyelinating polyneuropathy.Keywords：allogeneic hematopoietic stem cell transplantation; immune mediated; chronic demyelinating polyneuropathy;steroid myopathy