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.

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.

Single-cell immune landscape of measurable residual disease in acute myeloid leukemia

Measurable residual disease(MRD)is a powerful prognostic factor of relapse in acute myeloid leukemia(AML).We applied the single-cell RNA sequencing to bone marrow(BM)samples from patients with(n=20)and without(n=12)MRD after allogeneic hematopoietic stem cell transplantation.A comprehensive immune landscape with 184,231 cells was created.Compared with CD8+T cells enriched in the MRDnegative group(MRD‒_CD8),those enriched in the MRD-positive group(MRD+_CD8)showed lower expression levels of cytotoxicity-related genes.Three monocyte clusters(i.e.,MRD+_M)and three B-cell clusters(i.e.,MRD+_B)were enriched in the MRD-positive group.Conversion from an MRD-positive state to an MRD-negative state was accompanied by an increase in MRD‒_CD8 clusters and vice versa.MRDenriched cell clusters employed the macrophage migration inhibitory factor pathway to regulate MRD‒_CD8 clusters.These findings revealed the characteristics of the immune cell landscape in MRD positivity,which will allow for a better understanding of the immune mechanisms for MRD conversion.

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]).

异基因造血干细胞移植后腺病毒感染的临床特征分析

目的分析异基因造血干细胞移植(allo-HSCT)后人腺病毒(HAdV)感染患者的临床特征及预后。方法回顾性病例系列研究。收集2015年8月至2019年10月在北京大学人民医院血液科接受allo-HSCT后出现疑似感染症状但感染病原不明的2728例患者标本,采用荧光定量PCR法检测HAdV DNA,HAdV DNA检测阳性视为HAdV感染。分析HAdV感染患者临床表现,并根据患者年龄、移植类型、移植年份、随访时间采用巢式病例配对按1∶3匹配了未发生HAdV感染的患者作为对照组,采用Kaplan-Meier法分析并进行Log-rank检验,比较HAdV感染组和对照组的临床预后。结果共检测7119份标本,其中36例患者99例次HAdV DNA阳性。36例HAdV感染患者中22例发生HAdV血症;24例除HAdV感染外合并1种或多种其他病毒感染;19例(53%)有发热,25例(69%)有消化道症状,11例(31%)有呼吸道症状,9例(25%)有肝功能异常,6例(17%)有神经系统症状;23例同时发生2度及以上急性移植物抗宿主病;9例患者接受西多福韦抗病毒治疗,其中7例HAdV转阴,2例治疗无效。所有患者随访时间[M(Q_(1),Q_(3))]为496(216,940)d,Kaplan-Meier分析显示HAdV感染组5年总体生存率低于对照组(48.4%±9.2%比91.3%±3.5%;χ^(2)=65.03,P<0.001),移植后5年的非复发死亡率高于对照组(40.8%±8.8%比4.0%±2.0%;χ^(2)=34.17,P<0.001)。结论allo-HSCT后HAdV感染者以消化道、呼吸道症状为主,合并2度以上急性移植物抗宿主病的风险增加,HAdV感染患者总体生存差,非复发死亡率高。

Interferon-α salvage treatment is effective for patients with acute leukemia/myelodysplastic syndrome with unsatisfactory response to minimal residual disease-directed donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation

The efficacy of salvage interferon-α(IFN-α) treatment was investigated in patients with unsatisfactory response to minimal residual disease (MRD)-directed donor lymphocyte infusion (DLI)(n=24). Patients who did not become MRD-negative at 1 month after DLI were those with unsatisfactory response and were eligible to receive salvage IFN-α treatment within 3 months of DLI. Recombinant human IFN-α-2b injections were subcutaneously administered 2–3 times a week for 6 months. Nine (37.5%), 6 (25.0%), and 3 (12.5%) patients became MRD-negative at 1, 2, and>2 months after the salvage IFN-α treatment, respectively. Two-year cumulative incidences of relapse and non-relapse mortality were 35.9% and 8.3%, respectively. Two-year probabilities of event-free survival, disease-free survival, and overall survival were 51.6%, 54.3%, and 68.0%, respectively. Outcomes of patients subjected to salvage IFN-α treatment after DLI were significantly better than those with persistent MRD without IFN-α treatment. Moreover, clinical outcomes were comparable between the salvage DLI and IFN-α treatment groups. Thus, salvage IFN-α treatment may help improve the outcome of patients with unsatisfactory responses to MRD-directed DLI and could be a potential salvage treatment for these patients after allogeneic hematopoietic stem cell transplantation.

Modification of donor lymphocyte infusion: how to improve the outcome?

(HSCT),which has been acknowledged as a curative procedure,relapse of leukemia remains the leading cause of death following transplantation and is a disappointment to transplant physicians.Leukemic relapse occurs due to leukemia cell escape from immune-mediated killing (immune escape) by pre-transplantation conditioning and post-transplantation immune control.Immune exhaustion of donor T cells is one of the common causes of relapse,and donor lymphocyte infusions (DLIs) have the potential to reverse this immune exhaustion.Patients who are deemed eligible for intensive treatment at this point are offered either DLI or a second transplant.Contrary to the contemporary understanding,DLI results in the same response and survival obtained via a second transplant but with less toxicity (Kharfan- Dabaja et al.,2018).Starting in the mid-1990s,our group along with few others demonstrated the efficacy of DLI,which was initially confirmed by the Hadassah group in Jerusalem in the late 1980s.In the first four patients (with both acute and chronic leukemias) treated by us with DLI,the initial success rate was 100%,which encouraged us to pursue this treatment further.

Minimal residual disease-directed immunotherapy for high-risk myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation

The efficacy of minimal residual disease (MRD)-directed immunotherapy,including interferon-α (IFN-α) treatment and chemotherapy plus granulocyte colony-stimulating factor-primed donor leukocyte infusion (chemo-DLI),was investigated in patients with high-risk myelodysplastic syndrome (MDS) who were MRD-positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT).High-risk MDS patients who received non-T-cell-depleted allo-HSCT at the Peking University Institute of Hematology and were MRD-positive after ailo-HSCT were studied (n =47).The MRD-positive status was considered if leukemia-associated aberrant immune phenotypes or Wilms' tumor gene 1 expression is present in a single bone marrow sample.The cumulative incidence of the relapse and non-relapse mortality 2 years after immunotherapy were 14.5% and 21.4% (P=0.377)and 9.1% and 0.0% (P=0.985) for patients in the IFN-α and chemo-DLI groups,respectively.The probability of disease-free and overall survival 2 years after immunotherapy were 76.4% and 78.6% (P =0.891) and 84.3% and 84.6% (P=0.972) for patients in the IFN-α and chemo-DLI groups,respectively.Persistent MRD after immunotherapy was associated with poor survival.Thus,the MRD-directed immunotherapy was effective for patients with high-risk MDS who were MRD-positive after alIo-HSCT,and the efficacy was comparable between chemo-DLI and IFN-α treatment.

Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia

Chronic graft-versus-host disease(cGVHD)is a major complication following unmanipulated haploidentical hematopoietic stem cell transplantation(haplo-HSCT).We aimed to identify the risk factors for cGVHD in patients who underwent anti-thymocyte globulin-based haplo-HSCT for acute myeloid leukemia(n=280).The diagnosis of cGVHD was in accordance with the National Institutes of Health consensus criteria.A total of 169 patients suffered from cGVHD.The patients who had 3 loci mismatched had a higher 8-year incidence of cGVHD(total,66.0%vs.53.7%,P=0.031;moderate to severe,42.4%vs.30.1%,P=0.036)than the patients who had 1 to 2 loci mismatched.The patients who had maternal donors had a higher 8-year incidence of moderate to severe cGVHD(49.2%vs.32.9%,P=0.024)compared with the patients who had other donors.The patients who had grades III to IV acute GVHD(aGVHD)had higher 8-year incidence of cGVHD(total,88.0%vs.50.4%,P<0.001;moderate to severe,68.0%vs.27.0%,P<0.001)compared with the patients without aGVHD.In multivariate analysis,grades III to IV aGVHD was the only independent risk factor for cGVHD.Thus,further interventions should be considered in patients with severe aGVHD to prevent cGVHD.

Second unmanipulated allogeneic transplantation could be used as a salvage option for patients with relapsed acute leukemia post-chemotherapy plus modified donor lymphocyte infusion

Relapse is the main problem after allogeneic hematopoietic stem cell transplantation(allo-HSCT).The outcome of a second allo-HSCT(HSCT2)for relapse post-HSCT has shown promising results in some previous studies.However,little is known about the efficacy of HSCT2 in patients with relapsed/refractory acute leukemia(AL)post-chemotherapy plus modified donor lymphocyte infusion(post-Chemo+m-DLI)after the first allo-HSCT(HSCT1).Therefore,we retrospectively analyzed the efficacy of HSCT2 in 28 patients with relapsed/refractory AL post-Chemo+m-DLI in our center.With a median follow-up of 918(457–1732)days,26 patients(92.9%)achieved complete remission,and 2 patients exhibited persistent disease.The probabilities of overall survival(OS)and disease-free survival(DFS)1 year after HSCT2 were 25.0%and 21.4%,respectively.The cumulative incidences of nonrelapse mortality on day 100 and at 1 year post-HSCT2 were 7.1%±4.9%and 25.0%±8.4%.The cumulative incidences of relapse were 50.0%±9.8%and 53.5%±9.9%at 1 and 2 years post-HSCT2,respectively.Risk stratification prior to HSCT1 and percentage of blasts before HSCT2 were independent risk factors for OS post-HSCT2,and relapse within 6 months post-HSCT1 was an independent risk factor for DFS and relapse post-HSCT2.Our findings suggest that HSCT2 could be a salvage option for patients with relapsed AL post-Chemo+m-DLI.

Positive stool culture could predict the clinical outcomes of haploidentical hematopoietic stem cell transplantation

We aimed to identify the effect of positive stool cultures (PSCs) on the clinical outcomes of patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT)(n = 332). PSCs were observed in 61 patients (PSC group, 18.4%). Enterobacteriaceae in stool specimens was associated with a higher risk of bloodstream infection, and Candida in stool specimens was related to a higher risk of platelet engraftment failure. The cumulative incidence of infection-related mortality 1 year after haplo-HSCT in the PSC group was higher than that of the patients who showed persistently negative stool cultures (NSC group;19.2% vs. 8.9%, P = 0.017). The probabilities of overall survival (71.4% vs. 83.8%, P = 0.031) and disease-free survival (69.6% vs. 81.0%, P = 0.048) 1 year after haplo-HSCT for the PSC group were significantly lower than those for the NSC group, particularly for patients who had Candida in their stool specimens. In multivariate analysis, Candida in stool specimens significantly increased the risk of mortality and was associated with poorer survival. Our results showed that PSC influenced the clinical outcomes after haplo-HSCT, particularly those who had Candida in their stool specimens .

Influence of the degree of donor bone marrow hyperplasia on patient clinical outcomes after allogeneic hematopoietic stem cell transplantation

This study evaluated the influence of the degree of donor bone marrow(BM)hyperplasia on patient clinical outcomes after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Twelve patients received allo-HSCT from hypoplastic BM donors between January 2010 and December 2017.Forty-eight patients whose donors demonstrated BM hyperplasia were selected using a propensity score matching method(1:4).Primary graft failure including poor graft function and graft rejection did not occur in two groups.In BM hypoplasia and hyperplasia groups,the cumulative incidence(CI)of neutrophil engraftment at day 28(91.7%vs.93.8%,P=0.75),platelet engraftment at day 150(83.3%vs.93.8%,P=0.48),the median time to myeloid engraftment(14 days vs.14 days,P=0.85)and platelet engraftment(14 days vs.14 days,P=0.85)were comparable.The 3-year progression-free survival,overall survival,CI of non-relapse mortality and relapse were 67.8%vs.71.7%(P=0.98),69.8%vs.77.8%(P=0.69),18.5%vs.13.6%(P=0.66),and 10.2%vs.10.4%(P=0.82),respectively.In multivariate analysis,donor BM hypoplasia did not affect patient clinical outcomes after allo-HSCT.If patients have no other suitable donor,a donor with BM hypoplasia can be used for patients receiving allo-HSCT if the donor Complete Blood Count and other examinations are normal.