Human Leukocyte Antigen-matched Sibling Donor Research Articles

Risk factors for positive post-transplantation measurable residual disease in patients with acute lymphoblastic leukemia.

The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 1683 ALL patients from Peking University People's Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis. Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity (P<0.001 for all). Disease status (complete remission 1 [CR1] vs. ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups (P=0.027; P=0.003; P=0.035; P=0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively (P<0.001). Multivariate analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival. Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.

Neurocognitive outcome in children with sickle cell disease after myeloimmunoablative conditioning and haploidentical hematopoietic stem cell transplantation: a non-randomized clinical trial.

Due to the risk of cerebral vascular injury, children and adolescents with high-risk sickle cell disease (SCD) experience neurocognitive decline over time. Haploidentical stem cell transplantation (HISCT) from human leukocyte antigen-matched sibling donors may slow or stop progression of neurocognitive changes. The study is to determine if HISCT can ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression, determine which specific areas of neurocognitive functioning are particularly vulnerable to SCD, and determine if there are age-related differences in neurocognitive functioning over time. We performed neurocognitive and neuroimaging in SCD recipients following HISCT. Children and adolescents with high-risk SCD who received parental HISCT utilizing CD34+ enrichment and mononuclear cell (T-cell) addback following myeloimmunoablative conditioning received cognitive evaluations and neuroimaging at three time points: pre-transplant, 1 and 2 years post-transplant. Nineteen participants (13.1 ± 1.2 years [3.3-20.0]) received HISCT. At 2 years post-transplant, neuroimaging and cognitive function were stable. Regarding age-related differences pre-transplantation, older children (≥13 years) had already experienced significant decreases in language functioning (p < 0.023), verbal intelligence quotient (p < 0.05), non-verbal intelligence quotient (p < 0.006), and processing speed (p < 0.05), but normalized post-HISCT in all categories. Thus, HISCT has the potential to ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression. Further studies are required to determine if neurocognitive performance remains stable beyond 2 years post-HISCT.Clinical trial registration: The study was conducted under an investigator IND (14359) (MSC) and registered at clinicaltrials.gov (NCT01461837).

The range of haploidentical transplant protocols in sickle cell disease: all haplos are not created equally.

The ideal curative therapy for sickle cell disease (SCD) must be applicable across all ages and include individuals with strokes and preexisting heart, lung, and kidney disease. Myeloablative, matched sibling donor hematopoietic stem cell transplant (HCT) for children with SCD has shown excellent outcomes over the past 3 decades but has been restricted due to the limited availability of a human leukocyte antigen-matched sibling donor (10%-15%) and increased treatment-related death in adults with myeloablative conditioning. To overcome these 2 significant barriers to curative therapy in SCD, related haploidentical HCT has become an active area of research. The use of related haploidentical donors (first- and second-degree relatives) increases the donor pool to at least 90% of those eligible across the life span. Importantly, most adults, even with strokes or significant comorbidities, can tolerate the nonmyeloablative conditioning regimen without treatment-related death. Since 2013, at least 3 related haploidentical HCT strategies have emerged as potential curative therapies for SCD: (1) a nonmyeloablative, T-cell replete, bone marrow transplant with thiotepa and posttransplant cyclophosphamide with a goal of complete donor chimerism; (2) a nonmyeloablative, in vivo T-cell depletion, using peripheral blood stem cells (PBSCs) with a goal of stable mixed donor-recipient chimerism; and (3) a myeloablative, ex vivo T-cell depletion using PBSCs and advanced-technology graft manipulation, with a goal of complete donor chimerism. We review the similarities, differences, outcomes, and gaps in knowledge with these 3 haploidentical HCT approaches for SCD.

Organ function indications and potential improvements following curative therapy for sickle cell disease.

Curative therapies for sickle cell disease include allogeneic hematopoietic stem cell transplantation (HSCT) and gene-modified autologous stem cell transplantation. HSCT has been used for 30 years with success measured by engraftment, symptom control, graft-vs-host disease (GVHD) risk, organ toxicity, and immune reconstitution. While human leukocyte antigen-matched sibling donor (MSD) transplants have excellent outcomes, alternate donor transplants (unrelated/haploidentical) are just beginning to overcome GVHD and engraftment hurdles to match MSD. Gene therapy, a newly developed treatment, is undergoing careful evaluation in many trials with varying approaches. The risk/benefit ratio to the patient in relation to outcomes, toxicities, and mortality risk drives eligibility for curative interventions. Consequently, eligibility criteria for MSD transplants can be less stringent, especially in the young. Posttransplant outcome analysis after the "cure" with respect to organ function recovery is essential. While established damage such as stroke is irreversible, transplant can help stabilize (pulmonary function), prevent further deterioration (stroke), improve (neurocognition), and protect unaffected organs. Tracking organ functions postintervention uniformly between clinical trials and for adequate duration is essential to answer safety and efficacy questions related to curative therapies. Age-appropriate application/outcome analyses of such therapies will be the ultimate goal in overcoming this disease.

Liver Transplantation from a Human Leukocyte Antigen-Matched Sibling Donor: Effectiveness of Direct-Acting Antiviral Therapy against Hepatitis C Virus Infection

Through living-donor liver transplantation (LDLT) from a human leukocyte antigen (HLA)-matched sibling donor, it may be possible to stop the use of immunosuppressants. It is possible that acute antibody-mediated rejection and chronic active antibody-mediated rejection through the positivity of donor-specific anti-HLA antibodies and/or T cell-mediated rejection may affect the prognosis of liver transplantation. The etiologies of liver diseases of the recipient may also affect the post-transplantation course. Herein, we report on the successful re-treatment with direct-acting antiviral (DAA) therapy against hepatitis C virus (HCV) infection in a patient who underwent a LDLT from HLA-matched sibling donor. After liver transplantation for HCV-related liver diseases, it is easy for HCV to re-infect the graft liver under a lack of immunosuppressants. DAA therapy against HCV re-infection immediately after transplantation should be commenced, and it is important to eradicate HCV for better prognosis of the recipients in LDLT for HCV-related liver diseases.

P1341: HAPLO-CORD VS HAPLOIDENTICAL TRANSPLANT IN 49 CHILDREN – A RETROSPECTIVE SINGLE CENTER ANALYSIS

Background: Haplo-cord transplantation means that umbilical cord blood grafts from unrelated donors are infused together with CD34+-selected cells selected from Haploidentical relatives, which avoids the delayed implantation and long initial hospital stay caused by umbilical cord blood transplantation, and provides an effective alternative for patients without suitable donors. Some studies showed that haplo-cord transplantation could lead to faster neutrophil recovery and lower incidence of chronic GVHD compared with haplo transplantation. In order to make full use of the advantages of easy access to grafts and possibly reducing the incidence of chronic GVHD, we have adopted haplo-cord program to some children lacking suitable donors, and reported the outcome of haplo-cord transplantation, comparing Virus reactivation,the incidence rate of acute and chronic GVHD, and 3-year overall survival rate with haplo-SCT. Aims: To compare the outcome of haplo-cord transplantation program with haplo transplantation. Methods: 35 children with Haplo-cord transplantation and 14 children with Haplo-SCT in our hospital were followed up between May 2017 and May 2021, the engraftment, immune reconstitution,Virus reactivation, incidence of GVHD and 3-year overall survival rate were observed. Results: The median time of neutrophil recovery in both groups was 13 days, and the cumulative recovery rate of neutrophils on the 30th day was 100%. By day 15,85.7% of the haplo-cord recipients had recovered neutrophil counts vs 92.7% of haplo recipients (P= 0.8). The median time of platelet recovery in both groups was 17 days, and no primary graft failure was observed in all patients. Secondary graft failure was documented in 5 haplo-cord recipients and 2 haplo recipients. 17 patients developed CMV-DNAemia in haplo-cord transplant and 9 in haplo patients. 31 cases had EB-DNAemia in haplo-cord vs 10 in haplo patients.By day 100, the cumulative incidence of acute GVHD in Haplo-cord patients was 25.7% vs 28.5% in haplo patients (P=1), and the cumulative incidence of grade 3-4 acute GVHD by day 100 was 11.4% vs 21.4% respectively (P = 0.65). There were no acute GVHD related deaths. Chronic GVHD was significantly reduced in haplo-cord with a cumulative incidence of 5.7% vs 28.6% in haplo patients by 1 year (P =0.04), but no extensive chronic GVHD was observed. The 3-year overall survival rate was 84.5% in haplo-cord transplant vs 74.3% in haplo transplant(P=0.98). Summary/Conclusion: Haplo-cord transplantation has high implantation rate and good long-term prognosis, and the incidence of chronic GVHD is significantly reduced, which provides an alternative for patients lacking Human leukocyte antigen-matched sibling donor and HLA-matched unrelated donor.

Pre-Transplant Platelet Refractoriness and Alternative Donors Are Associated With Cytomegalovirus Retinitis in Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia.

BackgroundCytomegalovirus retinitis is a severe, vision-threatening opportunistic infection in an immunodeficient population. Reports on cytomegalovirus retinitis in hematopoietic stem cell transplant recipients due to severe aplastic anemia have been scant. This study assessed the risk of cytomegalovirus retinitis in relation to the pre-transplant status of severe aplastic anemia patients.MethodsWe conducted a retrospective nested case-control study of cytomegalovirus retinitis among severe aplastic anemia patients receiving allogeneic hematopoietic stem cell transplants in a tertiary care institution that attends severe aplastic anemia patients from southern China from January 1, 2013 to December 31, 2018. Each cytomegalovirus retinitis case was matched with four controls without cytomegalovirus retinitis by age and gender. Thirteen pre-transplant parameters were chosen to compare the risk factor levels between the cases and controls. Multivariable logistic regressions were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs).ResultsA total of 361 severe aplastic anemia patients received hematopoietic stem cell transplants in the study period 2013–2018 in our medical institution, and 31 (8.58%) developed cytomegalovirus retinitis. Cytomegalovirus retinitis was diagnosed in the median of 148 days after transplantation. We confirmed platelet refractoriness more frequently in cases than in controls (p = 0.0005). Compared with human leukocyte antigen-matched sibling donors, alternative donors were significantly more prone to cytomegalovirus retinitis (p = 0.0009). After stepwise selection in multivariate logistic regression, platelet refractoriness (OR 5.41, 95% CI 1.98–15.39), haploidentical donor (OR 7.46, 95% CI 2.19–34.87), and unrelated donor (OR 8.38, 95% CI 2.30–41.34) were associated with an increased risk of cytomegalovirus retinitis.ConclusionsPre-transplant platelet refractoriness and alternative donors were significant predictors of cytomegalovirus retinitis in severe aplastic anemia recipients. These results highlight the importance of accounting for existing risks while developing prevention strategies and preemptive treatment for severe aplastic anemia recipients. We recommend that the platelet count be closely monitored and thrombopoietin be properly applied during the period when cytomegalovirus retinitis is prone to occur.

A retrospective comparative study of haplotype hematopoietic stem cell transplantation and human leukocyte antigen-matched sibling donor hematopoietic stem cell transplantation in the treatment of acute B-lymphocyte leukemia

目的探讨单倍型造血干细胞移植（haplo-HSCT）治疗移植前微小残留病（Pre-MRD）阳性急性B淋巴细胞白血病（B-ALL）是否较全相合同胞造血干细胞移植（MSDT）具有生存优势，以及该作用是否受Pre-MRD的影响。方法对2009年6月至2018年6月在北京大学血液病研究所接受异基因造血干细胞移植（allo-HSCT）的998例移植前处于完全缓解（CR）的B-ALL患者进行回顾性分析，其中haplo-HSCT组788例、MSDT组210例，移植前用多参数流式细胞术（MFC）检测MRD水平。结果①全部998例B-ALL患者中，997例获得持续的完全供者嵌合状态，移植后100 d中性粒细胞、血小板植入率分别为99.9％（997/998）、95.3％（951/998），Ⅱ～Ⅳ度急性移植物抗宿主病（GVHD）发生率为26.6％（95％CI 23.8％～29.4％），3年慢性GVHD累积发生率为49.1％（95％CI 45.7％～52.4％），移植后3年白血病累积复发率（CIR）为17.3％（95％CI 15.0％～19.7％），非复发死亡率（NRM）为13.8％（95％ CI 11.6％～16.0％），移植后3年无白血病生存（LFS）率、总生存（OS）率分别为69.1％（95％CI 66.1％～72.1％）、73.0％（95％CI 70.2％～75.8％）。②Pre-MRD阳性组（282例）患者移植后3年CIR高于Pre-MRD阴性组（716例）［31.6％（95％CI 25.8％～37.5％）对14.3％（95％CI 11.4％～17.2％），P<0.001］。③在Pre-MRD阳性组中，haplo-HSCT患者（219例）移植后3年CIR低于MSDT患者（63例）［27.2％（95％CI 21.0％～33.4％）对47.0％（95％CI 33.8％～60.2％），P＝0.002］。④全部998例患者按照Pre-MRD结果分为阴性组（716例）、<0.01％组（46例）、0.01％～<0.1％组（117组）、0.1％～<1％组（87例）、≥1％组（32例）；5组患者中，<0.01％组haplo-HSCT患者（40例）移植后3年CIR低于MSDT患者（6例）［10.0％（95％CI 0.4％～19.6％）对32.3％（95％CI 0％～69.9％），P＝0.017］，0.01％～<0.1％组haplo-HSCT患者（81例）移植后3年CIR也低于MSDT患者（36例）［20.4％（95％CI 10.4％～30.4％）对47.0％（95％CI 29.2％～64.8％），P＝0.004］；其他三组中，haplo-HSCT和MSDT患者移植后3年CIR差异无统计学意义。⑤在Pre-MRD<0.1％组（163例）中，haplo-HSCT患者（121例）移植后3年CIR低于MSDT患者（42例）［16.0％（95％CI 9.4％～22.7％）对40.5％（95％ CI 25.2％～55.8％），P<0.001］，3年LFS率、OS率均高于MSDT组［78.2％（95％CI 70.6％～85.8％）对47.6％（95％CI 32.2％～63.0％），P<0.001；80.5％（95％CI 73.1％～87.9％）对54.6％（95％CI 39.2％～70.0％），P<0.001］，两组3年NRM差异无统计学意义［5.8％（95％CI 1.6％～10.0％）对11.9％（95％CI 2.0％～21.8％），P＝0.188］。多因素分析显示，haplo-HSCT是Pre-MRD<0.1％组移植后低CIR（HR＝0.248，95％CI 0.131～0.472，P<0.001）、高LFS率（HR＝0.275，95％CI 0.157～0.483，P<0.001）和高OS率（HR＝0.286，95％CI 0.159～0.513，P<0.001）的独立影响因素。结论haplo-HSCT治疗Pre-MRD<0.1％的B-ALL患者较MSDT具有生存优势。

Primary graft failure following allogeneic hematopoietic stem cell transplantation: risk factors, treatment and outcomes

ABSTRACT Objectives Graft failure (GF) is an intractable complication of transplantation, which can severely affect the efficacy of the graft; however, the characteristics, incidence, and risk factors of primary GF have not been well described. This study aimed to analyze the risk factors and outcomes of primary GF to swiftly identify high-risk patients for GF. Methods We performed a case-control study with a case-control ratio of 1:4 with 869 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between January 2015 and December 2019 at our center. Results Nineteen (2.19%) patients experienced primary poor graft function (PGF), while eleven (1.27%) patients developed primary graft rejection (GR). Univariate and multivariate logistic analyses identified two independent risk factors for primary PGF: splenomegaly [P = 0.030; odds ratio (OR), 3.486; 95% confidence interval (CI), 1.139 to 13.109], and donor type [non-matched sibling donor (non-MSD)] (P = 0.018; OR, 4.475; 95% CI, 1.289 to 15.537). However, only donor type (non-MSD) was statistically significant (P = 0.020; OR, 19.432; 95% CI, 1.595 to 236.691) for primary GR. The overall survival was significantly lower in the primary PGF (P = 0.001) and GR group (P = 0.000), respectively, compared to the control group. Conclusion GF can significantly affect the overall survival of patients who underwent allo-HSCT, despite its considerably low incidence. A human leukocyte antigen-matched sibling donor should be the first choice for patients undergoing allo-HSCT for the prevention of GF. Moreover, splenomegaly is an independent risk factor for PGF, and caution must be exercised while treating such patients.

Cedar Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCD

Cedar Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCD

A Qualitative Analysis of State Medicaid Coverage Benefits for Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Patients with Sickle Cell Disease (SCD)

Sickle cell disease (SCD) is the most common inherited hemoglobin disorder, affecting approximately 100,000 people in the United States. Allogeneic hematopoietic cell transplantation (alloHCT), also known as bone marrow transplant (BMT), is currently the only established curative option for SCD. However, alloHCT is an optional benefit under Medicaid. This study of alloHCT coverage for patients with SCD aims to understand the scope of state Medicaid coverage benefits and BMT financial coordinators’ experience working with their state Medicaid programs. States estimated to have more than 50 newborns diagnosed with SCD in 2016 and at least one active BMT Clinical Trials Network (1503 [STRIDE 2], NCT02766465) transplant center (TC) were eligible to participate in this study. Qualitative, semi-structured interviews 30 to 60 minutes in length were conducted with BMT financial coordinators via telephone between May and October 2019. A total of 10 BMT financial coordinators from 10 TCs representing eight states (Florida, Georgia, Illinois, Michigan, New York, Pennsylvania, Texas, and Virginia) participated in the semi-structured interviews. Coordinators in all of the included states reported that alloHCT in children with SCD with a human leukocyte antigen-matched sibling donor was covered by their state Medicaid programs. However, only two states (Florida and Texas) had legislative policies mandating coverage of routine medical costs for patients in clinical trials. TCs in two states (Illinois and Pennsylvania) reported accepting out-of-state Medicaid insurance, but only one state (Michigan) covered both travel and lodging for the patient and one caregiver. Four themes emerged when coordinators were asked about their perspectives and experiences working with their corresponding state Medicaid programs: (1) state Medicaid eligibility criteria based on disability were perceived as being restrictive, and Medicaid reimbursement rates were reported to be low; (2) Medicaid fee-for-service plans were perceived as being more comprehensive and easier to navigate compared to comprehensive managed care (CMC) plans; (3) there is a need to address caregiver and financial assistance beyond the health care costs; and (4) completing the insurance authorization process leading up to alloHCT is critical, including peer-to-peer reviews. There is limited legislative policy to help ensure access to clinical trials and provide out-of-state benefits and travel and lodging for Medicaid enrollees with SCD. These data provide insight into potential areas that could influence changes in policy to enhance access to curative therapy for SCD.

The Use of Post-transplantation Cyclophosphamide in Peripheral Blood HLA-matched Stem Cell Transplantation as Graft-versus-host Disease Prophylaxis in Patients With Malignant or Non-malignant Hematologic Disorders: A Single-center Experience of 52 Patients

IntroductionStudies addressing the utilization of post-transplant cyclophosphamide (CY) as graft-versus-host disease (GVHD) prophylaxis in allogeneic hemopoietic stem cell transplantation from matched sibling donors are limited and with controversial results. Chronic GVHD incidence necessitating systemic treatment is around 35% in peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen-matched sibling donors. Patients and MethodsIn this study, high-dose CY was added to PBSCT aiming to reduce the incidence of GVHD to reach a lower figure compared with standard GVHD prophylaxis. Fifty-two patients with either benign or malignant hematologic disorders who underwent stem cell transplantation at Nasser Institute Hospital in Egypt from November 2017 to October 2018 were enrolled in this study. Fifty patients had fully human leukocyte antigen-matched siblings, whereas the remaining 2 patients had 1 locus class I mismatched donors. Pre-transplant conditioning regimen was fludarabine and busulfan (FLU/BU) in malignant cases (73.1%) and FLU/CY in benign hematologic disorders (26.9%) and 1 patient with hypocellular myelodysplastic syndrome. For GVHD prophylaxis, CY was given at a dose of 50 mg/kg/day on days 3 and 4 post-transplantation, and cyclosporine (CSA) starting day 5 in 96.1% of patients. For the 1-locus mismatched patients, both CSA and mycophenolate mofetil were administered starting day 5. ResultsThe 1-year incidence of acute GVHD (aGVHD) was 15.3% and for chronic GVHD (cGVHD) was 13.4%. Historical data of GVHD prophylaxis at our center using CSA and methotrexate showed an incidence of 37% for aGVHD and 33.9% for cGVHD. ConclusionsPost-transplant CY GVHD prophylaxis led to significantly less aGVHD (P = .03) and cGVHD (P = .04).

Different Effects of Pre-transplantation Measurable Residual Disease on Outcomes According to Transplant Modality in Patients With Philadelphia Chromosome Positive ALL.

Background: This study compared the effects of pre-transplantation measurable residual disease (pre-MRD) on outcomes in Philadelphia chromosome (Ph)-positive ALL patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical SCT (haplo-SCT).Methods: A retrospective study (n = 202) was performed. MRD was detected by RT-PCR and multiparameter flow cytometry.Results: In the total patient group, patients with positive pre-MRD had a higher 4-year cumulative incidence of relapse (CIR) than that in patients with negative pre-MRD (26.1% vs. 12.1%, P = 0.009); however, the cumulative incidence of non-relapse mortality (NRM) (7.4% vs. 15.9%, P = 0.148), probability of leukemia-free survival (LFS) (66.3% vs. 71.4%, P = 0.480), and overall survival (OS) (68.8% vs. 76.5%, P = 0.322) were comparable. In the MSDT group, patients with positive pre-MRD had increased 4-year CIR (56.4% vs. 13.8%, P < 0.001) and decreased 4-year LFS (35.9% vs. 71.0%, P = 0.024) and OS (35.9% vs. 77.6%, P = 0.011) compared with those with negative pre-MRD. In haplo-SCT settings, the 4-year CIR (14.8% vs. 10.7%, P = 0.297), NRM (7.3% vs. 16.3%, P = 0.187) and the 4-year probability of OS (77.7% vs. 72.3%, P = 0.804) and LFS (80.5% vs. 75.7%, P = 0.660) were comparable between pre-MRD positive and negative groups. In subgroup patients with positive pre-MRD, haplo-SCT had a lower 4-year CIR (14.8% vs. 56.4%, P = 0.021) and a higher 4-year LFS (77.7% vs. 35.9%, P = 0.036) and OS (80.5% vs. 35.9%, P = 0.027) than those of MSDT. Multivariate analysis showed that haplo-SCT was associated with lower CIR (HR, 0.288; P = 0.031), superior LFS (HR, 0.283; P = 0.019) and OS (HR, 0.252; P = 0.013) in cases with a positive pre-MRD subgroup.Conclusions: Our results indicate that the effects of positive pre-MRD on the outcomes of patients with Ph-positive ALL are different according to transplant modality. For Ph-positive cases with positive pre-MRD, haplo-SCT might have strong graft-vs.-leukemia (GVL) effects.

Which donor is better when a matched donor is not available domestically? Comparison of outcomes of allogeneic stem cell transplantation with haploidentical and international donors in a homogenous ethnic population

A substantial proportion of patients requiring allogeneic stem cell transplantation (alloSCT) do not have a human leukocyte antigen-matched sibling donor and need an alternative donor. In this multicenter retrospective study, we compared the outcomes of 176 patients with myelodysplastic syndrome and acute leukemia undergoing alloSCT from haploidentical (n = 121) and international (n = 55) donors between 2002 and 2016. For recipients of haploidentical and international donors, the 2-year overall survival rates were 33.4% and 35.3%, respectively (P = 0.347), and relapse-free survival rates were 31.7% and 34.4% (P = 0.264), respectively. In addition, there were no significant differences in the cumulative incidences of acute and chronic graft versus host disease or incidences of infection within 30 days (all P > 0.05). Similarly, there were no significant differences in these measures for acute leukemia patients (n = 143; all P > 0.05). A multivariate analysis revealed that the donor type was not an independent prognostic or predictive factor. These data suggest that both haploidentical and international donors are feasible alternative sources for alloSCT when a matched donor is not available domestically.

Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry: a retrospective and prospective analysis

BackgroundThis study compared the effects of pre-transplantation minimal residual disease (pre-MRD) on outcomes in AML patients who underwent human leukocyte antigen-matched sibling donor transplantation (MSDT) or who received unmanipulated haploidentical allografts.MethodsA retrospective study (n = 339) and a prospective study (n = 340) were performed. MRD was determined using multiparameter flow cytometry.ResultsEither after retrospective or prospective analysis, patients with negative pre-MRD (pre-MRDneg) had a lower incidence of relapse than those with positive pre-MRD (pre-MRDpos) in MSDT settings (P < 0.001 for all), but relapse was comparable in Haplo-SCT settings for patients with pre-MRDneg versus pre-MRDpos (P = 0.866 and 0.161, respectively). In either the retrospective (n = 65) or the prospective study (n = 76), pre-MRDpos subjects receiving Haplo-SCT experienced a lower incidence of relapse than those who underwent MSDT (P < 0.001 and p = 0.017, respectively). Of the patients with pre-MRDpos in either the total (n = 141) or the subgroup excluding cases which received donor lymphocyte infusion (DLI; n = 105), those who underwent MSDT had a higher incidence of relapse than those receiving haplo-SCT (P < 0.01 for all). Multivariate analysis showed that, for pre-MRDpos cases, haplo-SCT was associated with a low incidence of relapse and with better LFS and OS in either retrospective group, prospective group, combination groups, or subgroup not including cases which received DLI.ConclusionsThe results indicated that, for pre-MRD-positive AML patients, haplo-SCT was associated with lower incidence of relapse and better survival, suggesting a stronger anti-leukemia effect.

High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia.

Use of high-dose cyclophosphamide without hematopoietic stem cell transplant to treat severe aplastic anemia (SAA) has been controversial due to concern for increased infectious toxicity as compared with antithymocyte globulin and cyclosporine A. As children often tolerate dose-intensive therapy better than adults, we sought to perform a detailed retrospective analysis of both treatment response and toxicity in 28 patients younger than 22 years of age treated with 29 courses of high-dose cyclophosphamide as the sole form of immunosuppression. Children and adolescents with SAA who lacked an human leukocyte antigen-matched sibling donor were treated with cyclophosphamide 50 mg/kg/d for 4 consecutive days then received daily granulocyte colony stimulating factor until neutrophil recovery, transfusion support, and antimicrobial prophylaxis. Overall survival was 85%, with hematologic response of 79% and complete response of 66%. Cumulative incidences of bacterial infection (86%) and fungal infection (62%) were high but deaths due to infection were rare, as were clonal evolution (1/28), clinically relevant paroxysmal nocturnal (1/28), and relapse (2/28). Response rates and survival following high-dose cyclophosphamide in pediatric patients with SAA exceed those seen in adults and compare favorably to antithymocyte globulin/cyclosporine A with manageable infectious toxicity.

Efficacy of allogeneic hematopoietic stem cell transplantation in treatment of children with severe aplastic anemia-II

Objective To explore the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for children with severe aplastic anaemia (SAA) Ⅱ. Methods The clinical data of 19 children with SAA-Ⅱ receiving allo-HSCT from January 2003 to May 2015 were retrospectively analyzed, including 11 male and 8 female, with median age of 9(2-14) years old.There were 9 patients received human leukocyte antigen-matched sibling donor (MSD) allo-HSCT, and 10 patients received unrelated donor (URD) allo-HSCT.Conditioning regimen was Cyclophosphamide+ Antithymocyte globulin±Fludarabine±Busulfan±total body irradition; graft-versus-host disease (GVHD) preventing regimen was cyclosporine A/Tacrolimus + Methotrexate±Mycophenolate mofetil.The median reinfusion quantity of CD34+ was 8.82×106/kg in 15 cases received bone marrow transplantation or peripheral blood stem cell transplantation, and 6.32×105/kg in 4 cases received cord blood transplantation. Results Hemato-poiesis reconstitution was achieved in 18 children (94.74%). The median time of neutrophils and platelets were 13 d (10-22 d) and 14 d (10-49 d) in the evaluable patients, respectively.The cumulative incidence of acute GVHD, chronic GVHD and graft rejection were 22.22%(4/18 cases), 11.11%(2/18 cases) and 11.11%(2/18 cases), respectively.In all the recipients, the infection of bacteria and fungus, cytomegalovirus and EB virus were 84.21%(16/19 cases), 72.22%(13/18 cases)and 44.44%(8/18 cases), respectively.The cumulative incidence of the liver, the kidney and the heart failure was 5.26%(1/19 cases), 21.05%(4/19 cases) and 21.05%(4/19 cases), respectively.Median follow-up time was 17 months (6-153 months). Fifteen patients survive, and estimated 5 years over survival (OS) was (77.8±9.3)%; transplant-related mortality was 21.05%.There was no difference in OS between URD allo-HSC and MSD allo-HSCT(χ2=1.198, P=0.656). Conclusions Allo-HSCT is an effective therapy for children with SAA-Ⅱ, especially for those receiving MSD allo-HSCT.URD allo-HSCT is feasible for SAA-Ⅱchildren without HLA-matched sibiling donors. Key words: Aplastic anemia, severe; Child; Hematopoietic stem cell transplantation, allogeneic; Unrelated donor

Human Mesenchymal Stem Cell Therapy for Acute Graft Versus Host Disease

Acute graft versus host disease (GVHD) is the most critical complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The understanding of major histocompatibility complex (MHC) and the development of acute GVHD prophylaxis have contributed to decreasing the incidence of severe acute GVHD. However, these progresses expand the chance of receiving allo-HSCT from human leukocyte antigen (HLA) mismatched donor. In addition, the expanding of indication for allo-HSCT to elderly patients or patients with organ dysfunction by the pervasiveness of reduced-intensity conditioning is associated with increased risk of acute GVHD. Unexpectedly, severe refractory acute GVHD can occur even in allo-HSCT from HLA matched sibling donor. The first line therapy for severe acute GVHD is corticosteroid, but the second line therapy has not been established and the prognosis of steroid-resistant acute GVHD remains poor. Recently, the efficacy of human bone marrow mesenchymal stem cell (MSC) therapy for steroid-resistant acute GVHD has been consistently reported. MSCs are approved as a cell therapy drug for steroid-resistant acute GVHD in some countries. We here review the history and the future of MSC therapy for acute GVHD.

Update of hematopoietic cell transplantation for sickle cell disease.

Hematopoietic cell transplantation (HCT) is a curative therapy for sickle cell disease (SCD) that is utilized very rarely because of limited allogeneic donor availability, limited healthcare resources needed to expand the treatment to regions in the world where most affected individuals reside, and by a view among SCD experts that HCT lacks the evidential rigor with short and long-term toxicity profiles that together might support its broader application. In this update, recent advances focused on donor selection, reduced toxicity preparation for HCT, and treatment of young adults will be presented. The current status of conventional bone marrow transplantation with a human leukocyte antigen-identical sibling donor is summarized. HCT for SCD is curative in almost all children who have a human leukocyte antigen-matched sibling donor. The future of this therapy will hinge on expanding the number of individuals who might be treated.

Outcomes of Human Leukocyte Antigen–Matched Sibling Donor Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia: Myeloablative Versus Reduced-Intensity Conditioning Regimens

Allogeneic hematopoietic cell transplantation (HCT) can cure some chronic lymphocytic leukemia (CLL) subjects. This study compared outcomes of myeloablative (MA) and reduced-intensity conditioning (RIC) transplants from HLA-matched sibling donors (MSD) for CLL. From 1995 to 2007, information regarding 297 CLL subjects was reported to the Center of International Blood and Marrow Transplant Research; of these, 163 underwent MA and 134 underwent RIC MSD HCT. The MA subjects underwent transplantation less often after 2000 and less commonly received antithymocyte globulin (4% versus 13%, P = .004) or prior antibody therapy (14% versus 53%; P < .001). RIC was associated with a greater likelihood of platelet recovery and less grade 2 to 4 acute graft-versus-host disease compared with MA conditioning. One- and 5-year treatment-related mortality (TRM) were 24% (95% confidence intervals [CI], 16% to 33%) versus 37% (95% CI, 30% to 45%; P = .023), and 40% (95% CI, 29% to 51%) versus 54% (95% CI, 46% to 62%; P = .036), respectively, and the relapse/progression rates at 1 and 5 years were 21% (95% CI, 14% to 29%) versus 10% (95% CI, 6% to 15%; P = .020), and 35% (95% CI, 26% to 46%) versus 17% (95% CI, 12% to 24%; P = .003), respectively. MA conditioning was associated with better progression-free (PFS) (relative risk, .60; 95% CI, .37 to .97; P = .038) and 3-year survival in transplantations before 2001, but for subsequent years, RIC was associated with better PFS and survival (relative risk, 1.49 [95% CI, .92 to 2.42]; P = .10; and relative risk, 1.86 [95% CI, 1.11 to 3.13]; P = .019). Pretransplantation disease status was the most important predictor of relapse (P = .003) and PFS (P = .0007) for both forms of transplantation conditioning. MA and RIC MSD transplantations are effective for CLL. Future strategies to decrease TRM and reduce relapses are warranted.