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.

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.

Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation

Haploidentical stem cell transplantation(haplo-SCT)achieves superior or at least comparable clinical outcomes to HLA-matched sibling donor transplantation(MSDT)in treating hematological malignancies.To define the underlying regulatory dynamics,we analyzed time courses of leukemia burden and immune abundance of haplo-SCT or MSDT from multiple dimension.First,we employed two nonirradiated leukemia mouse models which carried human AML-ETO or MLL-AF9 fusion gene to establish haplo-identical and major histocompatibility(MHC)-matched transplantation models and investigated the immune cell dynamic response during leukemia development in vivo.We found that haplo-matching the MHCs of leukemia cells with recipient mouse T cells prolonged leukemic mice survival and reduced leukemia burden.The stronger graft-versus-leukemia activity in haplo-SCT group mainly induced by decreased apoptosis and increased cytotoxic cytokine secretion including tumor necrosis factor–α,interferon-γ,pore-forming proteins and CD107a secreted by T cells or natural killer cells.Furthermore,we conducted a prospective clinical trial which enrolled 135 patients with t(8;21)acute myeloid leukemia that displayed minimal residual disease before transplantation and underwent either haplo-SCT or MSDT.The results showed that the haplo-SCT slowed the kinetics of the leukemia burden in vivo and reduced the cumulative incidence of relapse compared with MSDT.Ex vivo experiments showed that,1 year after transplantation,cytotoxic T lymphocytes from the haplo-SCT group had higher cytotoxicity than those from the MSDT group during the same period.Our results unraveled the role of immune cells in superior antileukemia effects of haplo-SCT compared with MSDT.

Association of Persistent Minimal Residual Disease with Poor Outcomes of Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background: Several studies have shown that detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) is an independent prognostic factor. This study aimed to evaluate the significance of dynamic MRD pretransplantation on outcome of AML patients receiving allogeneic hematopoietic stem cell transplantation (allo?HSCT). Methods: We retrospectively analyzed 145 consecutive AML patients undergoing allo?HSCT in complete remission status between June 2013 and June 2016. MRD was determined with multiparameter flow cytometry after the first and second courses of chemotherapy and pre?HSCT. Results: In matched sibling donor transplantation (MSDT) settings, patients with positive MRD had higher cumulative incidence of relapse (CIR) than those without MRD after the first (32.3 ± 9.7% vs. 7.7 ± 3.1%, χ2 = 3.661, P = 0.055) or second course of chemotherapy (57.1 ± 3.6% vs. 12.5 ± 2.7%, χ2 = 8.759, P = 0.003) or pre?HSCT (50.0 ± 9.7% vs. 23.0 ± 3.2%, χ2 = 5.547, P = 0.019). In haploidentical SCT (haplo?SCT) settings, the MRD status at those timepoints had no significant impact on clinical outcomes. However, patients with persistent positive MRD from chemotherapy to pre?HSCT had higher CIR than those without persistent positive MRD both in MSDT and haplo?SCT settings. Patients with persistent positive MRD underwent MSDT had the highest relapse incidence, followed by those with persistent positive MRD underwent haplo?SCT, those without persistent MRD underwent haplo?SCT, and those without persistent MRD underwent MSDT (66.7 ± 9.2% vs. 38.5 ± 6.0% vs. 18.8 ± 8.7% vs. 12.0 ± 1.0%, χ2 = 20.763, P < 0.001). Multivariate analysis showed that persistent positive MRD before transplantation was associated with higher CIR (hazard ratio [HR] = 1.69, 95% confidence interval [CI]: 1.200–2.382, P = 0.003), worse leukemia?free survival (HR = 1.812, 95% CI: 1.168–2.812, P = 0.008), and overall survival (HR = 2.354, 95% CI: 1.528–3.627, P < 0.001). Conclusion: Our results suggest that persistent positive MRD before transplantation, rather than positive MRD at single timepoint, could predict poor outcome both in MSDT and haplo?SCT settings.

Haploidentical stem cell transplantation in patients with chronic myelomonocytic leukemia

Dear Editor,Chronic myelomonocytic leukemia (CMML) is a rare clonal hematological malignancy with both myelodysplastic and myeloproliferative features. Patients with CMML have a very poor prognosis。

A risk score system for stratifying the risk of relapse in B cell acute lymphocytic leukemia patients after allogenic stem cell transplantation

Background:For patients with B cell acute lymphocytic leukemia(B-ALL)who underwent allogeneic stem cell transplantation(allo-SCT),many variables have been demonstrated to be associated with leukemia relapse.In this study,we attempted to establish a risk score system to predict transplant outcomes more precisely in patients with B-ALL after allo-SCT.Methods:A total of 477 patients with B-ALL who underwent allo-SCT at Peking University People’s Hospital from December 2010 to December 2015 were enrolled in this retrospective study.We aimed to evaluate the factors associated with transplant outcomes after allo-SCT,and establish a risk score to identify patients with different probabilities of relapse.The univariate and multivariate analyses were performed with the Cox proportional hazards model with time-dependent variables.Results:All patients achieved neutrophil engraftment,and 95.4%of patients achieved platelet engraftment.The 5-year cumulative incidence of relapse(CIR),overall survival(OS),leukemia-free survival(LFS),and non-relapse mortality were 20.7%,70.4%,65.6%,and 13.9%,respectively.Multivariate analysis showed that patients with positive post-transplantation minimal residual disease(MRD),transplanted beyond the first complete remission(≥CR2),and without chronic graft-versus-host disease(cGVHD)had higher CIR(P<0.001,P=0.004,and P<0.001,respectively)and worse LFS(P<0.001,P=0.017,and P<0.001,respectively),and OS(P<0.001,P=0.009,and P<0.001,respectively)than patients without MRD after transplantation,transplanted in CR1,and with cGVHD.A risk score for predicting relapse was formulated with the three above variables.The 5-year relapse rates were 6.3%,16.6%,55.9%,and 81.8%for patients with scores of 0,1,2,and 3(P<0.001),respectively,while the 5-year LFS and OS values decreased with increasing risk score.Conclusion:This new risk score system might stratify patients with different risks of relapse,which could guide treatment.

Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation

Adoptive transfer of cytomegalovirus(CMV)-specific cytotoxic T lymphocytes(CMV-CTLs)from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation(allo-SCT),but the antiviral activity of CMV-CTL types has not been compared.To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs,we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models,compared the in vivo recovery of CMV-specific immunity,and analyzed the underlying mechanisms driving sustained antiviral immunity.The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion.The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups.A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups.Our clinical study,which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection,further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity.We observed strong expansion of CD8+tetramer+T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion,which were associated with a reduced or cleared viral load.Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.

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.

Pre-transplantation cytoreduction does not benefit advancedmyelodysplastic syndrome patients after myeloablative transplantation with grafts from family donors

Background:The role of pre-hematopoietic stem cell transplantation(HSCT)cytoreduction with either induction chemotherapy(IC)or hypomethylating agents(HMAs)in treating advanced myelodysplastic syndrome(MDS)remains debatable.We aimed to evaluate pre-HSCT strategies by comparing the endpoints related to disease control between advanced MDS patients with pre-HSCT cytoreduction and those with best supportive care.Methods:We described 228 consecutive advanced MDS patients who received HSCT from a haploidentical donor(HID,n=162)or matched related donor(MSD,n=66)with uniform myeloablative conditioning regimens between January 2015 and December 2018.Of these 228 patients,131(57.5%)were treated exclusively with pre-HSCT best supportive care(BSC),49(22.5%)were given HMA,and 48(21.1%)received both IC and HMA.Propensity score-matching analysis,multivariate analyses,and subgroup analyses were performed to elucidate the impact of pre-HSCT strategies on transplant outcomes.Results:The 3-year relapse-free survival(RFS)rates were 78.2% and 70.0% for the BSC and cytoreduction cohorts(P=0.189)and were 78.2%,66.7%,and 73.2% for the BSC,HMA,and HMA+IC groups,respectively(P=0.269).A propensity score-matching analysis confirmed that the 3-year RFS rates were 81.9%,87.5%,and 66.9% for BSC,cytoreduction complete remission(CR),and cytoreduction non-CRgroups,respectively(P=0.051).Multivariate analyses demonstrated that pre-HSCT cytoreduction,older patient age,monosomal karyotype,and interval between diagnosis and HSCT were poor prognostic factors for RFS.In the subgroup analyses,BSC was associated with longer RFS compared to cytoreduction among the younger patients,those with international prognostic scoring system intermediate-2/high risk at diagnosis,and those with intermediate/poor cytogenetics.Conclusions:Different pre-HSCT therapies did not yield discrepant post-HSCT outcomes.No benefit in terms of post-HSCT outcomes were correlated with pre-HSCT cytoreduction in advanced MDS even for cytoreduction CR patients.Early referral to HSCT is essential for advanced MDS patients.

Successful hematopoietic stem cell transplantation with haploidentical donors and non-irradiation conditioning in patients with Fanconi anemia

To the Editor:Allogeneic hematopoietic stem cell transplantation(HSCT)is the only curative option for bone marrow(BM)abnormalities in Fanconi anemia(FA).However,patients with FA cannot tolerate the toxicity of the therapeutic regimen for acquired aplastic anemia,which mainly contains 200 mg/kg cyclophosphamide(CTX),and low-dose CTX regimens are considered more suitable.Some centers have also added different doses of irradiation to the conditioning regimen.[1]Due to their side effects on growth and development and the possibility of developing a secondary malignant disease,some trials have replaced the irradiation with fludarabine.Moreover,data on transplants from haploidentical donors are scarce.