HLA-matched Sibling Donor Transplantation Research Articles

Risk Factors for Positive Posttransplantation Measurable Residual Disease in Patients with Acute Lymphoblastic Leukemia

Background: The level of 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-HSCT MRD. However, no work has been devoted to the risk factors for positive post-HSCT MRD in patients with ALL. This study evaluated the risk factors for post-HSCT MRD positivity in patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic HSCT (allo-HSCT). Methods: A total of 1683 ALL patients were enrolled. 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. Results: Both in total patients and in T-ALL or B-ALL, pediatric or adult, HLA-matched sibling donor transplantation or haploidentical HSCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity ( P < 0.001 for all). Disease status was also a risk factor for post-HSCT MRD positivity in all patients and in the B-ALL, pediatric, or haploidentical SCT subgroups ( 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 LFS and OS. Conclusion: 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 allogeneic HSCT.

Application prospect of low-dose porcine anti-thymocyte globulin in HLA-matched sibling donor transplantation

ABSTRACTObjectiveTo investigate the preventive effect of low-dose porcine anti-thymocyte globulin (P-ATG) on graft versus host disease (GVHD) in patients' donors over 40 years old or female donors undergoing HLA-matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT).MethodsThe clinical data of 30 patients received Low-dose Porcine antithymocyte globulin (P-ATG) as a part of the conditioning regimen (the P-ATG group), while the other 30 patients didn’t receive ATG (the Non-ATG group).ResultsThere was a significant difference in the incidence of aGVHD ([23.3 (10.1–39.7) %] vs [50.0 (30.8–66.5) %], P = 0.028), grade II–IV aGVHD ([16.7 (5.94–32.1) %] vs [40.0 (22.4–57.0) %], P = 0.049) and chronic GVHD (cGVHD) ([22.4 (6.03–45.1) %] vs [69.0 (43.4–84.8) %], P = 0.001) between two groups. But there was no significant difference in terms of moderate-severe cGVHD (P = 0.129), 1-year relapse rate (P = 0.742), non-relapse mortality (P = 0.237), or overall survival (P = 0.441).ConclusionThe application of low-dose P-ATG in patients/donors over 40 years old or female donors undergoing MSD-HSCT for hematological malignancy can significantly reduce the incidence of aGVHD, grade II–IV aGVHD and cGVHD, doesn’t increase the risk of relapse.

Cytomegalovirus infection is associated with rapid NK differentiation and reduced incidence of relapse in HLA matched sibling donor transplant patients.

The effect of cytomegalovirus (CMV) infection on leukemia relapse and the potential mechanism remains controversial. In this retrospective study, we evaluated the association among CMV infection, NK reconstitution and clinical outcomes in consecutive patients with hematologic malignancy who underwent HLA matched sibling donor transplantation (MST). In total, 228 patients were enrolled in the study between January 2010 and December 2011. The cumulative incidence of CMV infection on day 100 post-HSCT was 13.6 ± 4.9%. The probabilities of OS and DFS were 45.4% vs. 71.7% (P = 0.004) and 43.9% vs. 64.2% (P = 0.050) in the patients with CMV infection and without CMV infection, respectively. The cumulative incidence of treatment-related mortality (TRM) and relapse at 5 years was 48.6 ± 9.6% vs. 11.5 ± 2.9% (P < 0.001) and 6.2 ± 4.3% vs. 29.2 ± 3.9% (P = 0.024) in the patients with CMV infection and without CMV infection, respectively. In the multivariate analysis, CMV infection was associated with higher TRM, lower OS, and lower DFS. In addition, we found that CMV infection may promote the recovery of the absolute number of NK cells and promote the differentiation of NK cells post-MST. In conclusion, CMV infection may promote the recovery and differentiation of NK cells and was correlated with a lower relapse rate post-MST.

Distinct Immune Homeostasis Remodeling Patterns after HLA-Matched and Haploidentical Transplantation

The homeostatic immune system in a healthy state represents a dynamic balance between immunogenicity and immune tolerance. Allogenic hematopoietic stem cell transplantation (allo-HSCT) is not only a curative therapy for hematological malignancies, but also has been used to remodel the immune system to a homeostatic state, such as inducing allograft tolerance in solid organ transplantation and treating autoimmune diseases. Therefore, the homeostatic immune system after allo-HSCT represents donor-derived hematopoietic cells that reconstitute the immune system in recipients and establish tolerance to recipients. However, little is known about the responsible genes or relevant cell types that remodel immune homeostasis after allo-HSCT. Moreover, whether haploidentical stem cell transplantation (haplo-SCT) shares a similar pattern of immune homeostasis remodeling with HLA-matched sibling donor transplantation (MSDT) is also unclear. In this study, we used a comprehensive single-cell RNA-seq (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) approach coupled with bulk transcriptome (RNA-seq) and epigenome (ATAC-seq) analysis to dissect the landscape of the rebalanced homeostatic immune system in recipients after allo-HSCT (Fig. 1A). We identified 35 subpopulations in the 5 lineages based on the expression of cell type-associated genes, including the hematopoietic progenitor compartment with highly proliferative ability, T/NK lineage cells, B lineage cells, myeloid lineage cells and platelets (Fig. 1B). All cell subsets were present in both donors and recipients, which indicated that the immune system was successfully reconstituted in the recipients after allo-HSCT (Fig. 1B). Moreover, we found HSPC compartments adequately reconstitute in those recipients who have rebalanced to homeostasis after allo-HSCT. Although all immune cell subpopulations from donors were reconstituted in the paired recipients, there were different patterns of immune subpopulation distributions in recipients after allo-HSCT. In MSDT, donor-derived immune cell reconstitution in recipients as similar to that in their paired donors, while in haplo-SCT, there were low levels of CD4+ and CD8+ naïve T cells, Tcm cells, CD4+ Tem cells and CD4 Treg cells and high levels of CD4+ Teff cells, CD8+ Teff cells, CD8+ Tem cells and CD8+ Trp cells in recipients compared with their paired donors (Fig. 1C). We observed that memory-like CD8 T cells with immunoregulatory functions (CD8 regulatory precursors, CD8 Trp) were expanded in haplo-SCT recipients. CD8 Trp showed similar transcriptional profiling compared with CD4 Treg indicated that increased CD8 Trp subpopulations might act as regulatory cells and contribute to maintaining the tolerance of the donor-derived immune system in recipients of haplo-SCT. To investigate the dynamic changes in TCR clonotype after allo-HSCT, we integrated the analyzed single-cell transcriptomes and TCR sequences. We found that the dominant clonotype of CD8 Teff cells in MSDT recipients is the clonotype consistent with that in their paired donors, while the dominant clonotype of CD8 Teff cells in haplo-SCT recipients is the recipient's unique clonotype and educated by recipient thymic with high ZNF683 expression (Fig. 1D-E). Combined analysis of bulk CD8 T cell RNA-seq and ATAC-seq, we found that transcription factor ZNF683 was specifically activated in CD8+ T cells from haplo-SCT recipients compared with their paired donors (Fig. 1F). In vitro experiments indicated that a high expression level of ZNF683 in human primary T cells promoted inactivation of CD8+ T cells, maintained CD8+ T-cell replicative capacity and inhibited CD8+ T-cell apoptosis, which might suppress CD8 T cell senescence and corelated with CD8 T cell persistence. Moreover, ZNF683 could be downregulated when CD8+ T cells were activated, which suggests that ZNF683 might be a checkpoint of long-lived quiescent CD8+ T cells. In summary, our study provides a rich dataset of cellular states, gene programs, and T-cell repertoires in recipients whose donor-derived immune system rebalanced toward homeostasis after allo-HSCT. Understanding the molecular mechanisms underlying different patterns of immune homeostasis remodeling in different transplantation models will help us provide more precise medical care for patients who receive allo-HSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Haploidentical donor stem cell transplantation had a lower incidence of bronchiolitis obliterans syndrome compared with HLA-matched sibling donor transplantation in patients with hematologic malignancies: Benefit from ATG?

Haploidentical donor stem cell transplantation (HID-SCT) based on antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis had achieved a similar incidence of chronic graft-versus-host disease (cGVHD) with human leukocyte antigen (HLA)-matched sibling donor stem cell transplantation (MSD-SCT). However, bronchiolitis obliterans syndrome (BOS), which serves as pulmonary cGVHD, was rarely compared between HID and MSD transplantation. One thousand four hundred five patients with hematologic malignancies who underwent allogeneic SCT were enrolled in this retrospective study. Based on donor type, we divided the patients into three groups: HID, MSD, and match unrelated donor (MUD) groups. The cumulative incidences and risk factors of BOS were analyzed. The 5-year cumulative incidence of BOS was 7.2% in the whole population. HID transplantation had a lower 5-year cumulative incidence of BOS than MSD transplantation (4.1% vs. 10.0%, p < 0.001) and a similar incidence with MUD transplantation (4.1% vs. 6.2%, p = 0.224). The 5-year cumulative incidence of BOS was lower in the ATG group than that in the non-ATG group in both the whole and MSD populations (4.6% vs. 11.2%, p < 0.001, and 4.1% vs. 11.2%, p = 0.042, respectively). The 5-year incidence of BOS in mixed grafts [peripheral blood stem cell (PBSC) plus bone marrow] group was also lower than that in the PBSC group (4.2% vs. 9.1, p = 0.001). Multivariate analysis showed that HID, ATG, and mixed grafts were protective factors for BOS [odds ratio (OR) 0.3, 95% CI 0.2-0.6, p < 0.001; OR 0.3, 95% CI 0.2-0.7, p = 0.001; OR 0.3, 95% CI 0.1-0.8, p = 0.013], and acute graft-versus-host disease (aGVHD) and cGVHD were independent risk factors for BOS (OR 2.1, 95% 1.1-4.3, p = 0.035; OR 10.1, 95% CI 4.0-25.0, p < 0.001). HID transplantation had a lower incidence of BOS than MSD transplantation, which might be associated with ATG and mixed grafts.

PB2188: APPLICATION PROSPECT OF LOW DOSE PORCINE ANTITHYMOCYTE GLOBULIN IN HLA MATCHED SIBLING DONOR TRANSPLANTATION

Background: To investigate the preventive effect of low-dose porcine antithymocyte globulin (P-ATG) on graft versus host disease (GVHD) in HLA matched sibling donor transplantation. Aims: To investigate the preventive effect of low-dose porcine antithymocyte globulin (P-ATG) on graft versus host disease (GVHD) in HLA matched sibling donor transplantation. Methods: The clinical data of 60 patients with hematological malignancies who received MSD-HSCT from July 2020 to October 2021 were analyzed retrospectively. These patients / donors were older than 40 years old or the donors were female. Of these, 30 patients received Low-dose porcine ATG as a part of conditioning regimen (P-ATG group), while the other 30 patients didn’t receive ATG (No-ATG group). In addition to the fact that the ages of the patients and donor were older in P-ATG group, all patients’ other baseline characteristics and donor condition of the two groups were similar. Results: All patients engrafted in two groups. There were significant differences in the incidence of aGVHD ([23.3 (10.1-39.7)%] vs [50.0 (30.8-66.5)%], P = 0.0276), grade III-IV aGVHD ([16.7 (5.94-32.1)%] vs [40.0 (22.4-57.0)%], P = 0.0491) and cGVHD ([22.4 (6.03-45.1)%] vs [69.0 (43.4-84.8)%], P = 0.0009) between the P-ATG and No-ATG groups. But there was no significant difference in terms of 1-year OS ([79.9 (60.5-90.4)%] vs [84.0 (61.2-94.0)%], P = 0.4411) or RR ([13.6 (2.73-33.2)%] vs [15.2 (4.40-32.1)%], P = 0.7416). And there was also no significant difference with regard to the incidence of severe bacterial infection (P = 0.612), invasive fungal disease (P = 1.000) or CMV infection (P = 0.2976). 80% (4 / 5) of patients in P-ATG group died of secondary infection after grade III-IV aGVHD, and 16.7% (2 / 12) in No-ATG group. Summary/Conclusion: The application of low-dose P-ATG in the conditioning regimen of MSD-HSCT can significantly reduce the incidence of aGVHD, grade III-IV aGVHD and cGVHD, doesn’t increase the risk of recurrence after transplantation in patients / donors older than 40 years old or female donors. However, the patients in P-ATG group were older and had high mortality caused by secondary infection after grade III-IV aGVHD. Therefore, there was no significant difference in OS between the two groups.

RETRACTED: The impact of second-donor lymphocyte infusion on secondary graft failure after allogeneic hematopoietic stem cell transplantation through activation of Foxp3 and regulatory T cells

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Editor of Cytotherapy has retracted this article. The article duplicates significant parts of a paper that had already appeared in Transplantation and Cellular Therapy, Volume 28, Issue 3, 2022, Pages 152.e1-152.e7, https://doi.org/10.1016/j.jtct.2021.12.017 In accordance with Committee on Publication Ethics (COPE) and Elsevier's policies, the authors have been contacted. After considering the author's response, the decision has been made to retract the paper. Redundant publications overweigh the relative importance of published findings and distort the academic record of the authors. One of the conditions of submission of a paper for publication is therefore that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.

Pre-Transplant Minimal Residual Disease Determined By Multiparameter Flow Cytometry Is Better Than RQ-PCR to Predict the Outcomes of Ph+ALL Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

▪Acute lymphoblastic leukemia with the Philadelphia (Ph) chromosome (Ph+ALL) occurs in about 25-30% adult patient ALL. Though the appearance of tyrosine kinase inhibitors (TKIs) greatly improved the outcomes of this kind of leukemia, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still a radical approach for this kind of leukemia. Several previous studies had demonstrated that minimal residual disease prior to transplantation (pre-MRD) could predict the transplant outcomes, especially leukemia relapse. For Ph+ALL, multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RQ-PCR) were used to monitor MRD. In this study, we compared the impact of pre-MRD determined by MFC and BCR/ABL expression on the outcomes of Ph+ALL who underwent allo-HSCT. Total 155 patients who received HLA-matched sibling donor transplantation (MSDT, n=49) and unmanipulated haploidentical HSCT (haplo-HSCT, n=106) were enrolled. Pre-MRD was determined using MFC (pre-MFC) and RQ-PCR-based BCR/ABL expression (pre-BCR/ABL). The results showed that patients received MSDT and haplo-HSCT could have the comparable clinical outcomes. When pre-MRD was evaluated by RQ-PCR, the patients with or without BCR/ABL expression in both MSDT and haplo-HSCT groups didn't show any significant difference in cumulative incidence of relapse (CIR), transplantation related mortality (TRM), leukemia-free survival (LFS) and overall survival (OS). In addition, we also divided patients into 5 groups based on pre-BCR/ABL level: group 1, BCR/ABL=0; group 2, 0<BCR/ABL<0.1%; group 3, 0.1%<BCR/ABL<1%; group 4, 1%<BCR/ABL<10%; group 5, BCR/ABL>10%. Through kaplan-meier analysis, it showed that only patients of group 5 would show the extremely higher CIR (75.0%) while there was no significant difference among the other four groups (group 1 vs. 2 vs. 3 vs. 4, 14.5% vs. 10.2% vs. 20.6% vs. 10.0%, P>0.05). However, when pre-MRD was determined by MFC, patients with negative pre-MFC had a lower 2-year CIR and a slight higher 2-year leukemia-free survival (LFS) than those with positive pre-MFC in whole crowd (CIR: 7.5% vs. 40.0%, P<0.001; LFS: 74.4% vs. 61.2%,P=0.119). For those pre-BCR/ABL positive patients, they were further stratified by pre-MFC in both MSDT and haplo-HSCT groups. Patients with pre-MFC prior to MSDT showed a higher 2-year CIR and lower 2-year LFS compared to those with negative MRD (CIR: 44.4% vs. 6.6%, P=0.002; LFS: 44.4% vs. 85.7%, P=0.019). In patients undergoing haplo-HSCT, the 2-year CIR in pre-MFC positive group was higher than that of pre-MFC negative group (32.4% vs. 5.9%, P=0.014), while the 2-year LFS was comparable between above two groups (62.9% vs. 73.8%, P=0.513). Multivariate analysis indicated that prolonged neutrophil engraftment (HR, 1.243; 95% CI, 1.073-1.440, P=0.004) and positive pre-MFC (HR, 5.492; 95% CI, 1.574-19.161; P=0.008) was associated with a higher CIR. The results indicated that, pre-transplant MRD determined by MFC was better than RQ-PCR-based BCR/ABL expression in predicting outcomes of Ph+ALL patients receiving allo-HSCT. DisclosuresNo relevant conflicts of interest to declare.

Favorable Outcomes after Single Cord Blood Transplantation for Patients with High-Risk Hematologic Diseases: A Single-Institute Retrospective Analysis

The donor selection algorithm for cord blood (CB) with regards to matched related and unrelated donors has not been fully investigated. To assess the potential of CB transplantation (CBT) in patients with hematologic malignancies, especially for high-risk patients, we performed a single-institute retrospective analysis and compared the clinical outcomes of CBT with those of HLA-matched sibling and unrelated donor transplantation. We included 394 patients aged 16 years and older with hematologic diseases who received their first allogeneic hematopoietic cell transplantation between 1990 and 2018 at Kyoto University Hospital. These included 394 recipients of single unrelated cord blood units (UCB, n=108), HLA-matched sibling donors (MSDs, n=143), or HLA-matched unrelated donors (MUDs, n=143). There was no significant difference in relapse-free survival (RFS) between UCB, MSD, and MUD recipients (P=.975). However, we found a significant interaction between transplant year and CBT outcomes (P=.010), with significantly better outcomes observed in the more recent years. Furthermore, we found that CBT showed better RFS than matched donor transplantation (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.30 to 0.84). This impact was more prominent in high-risk patients (HR, 0.35; 95% CI, 0.16 to 0.77), with lower relapse rates (HR, 0.25; 95% CI, 0.11 to 0.54), and comparable non-relapse mortality (NRM) compared to matched donor transplantation. Extensive chronic graft-versus-host disease was less frequently observed in CBT (HR, 0.58; 95% CI, 0.26 to 1.28). CBT associated with favorable outcomes, particularly in high-risk patients, with good RFS and low relapse rates without an increase in NRM in the single-institute study. Although the findings should be externally validated, CBT might serve as a reasonable donor choice, particularly in high-risk patients.

Antithymocyte Globulin for Matched Sibling Donor Transplantation in Patients With Hematologic Malignancies: A Multicenter, Open-Label, Randomized Controlled Study.

The role of antithymocyte globulin (ATG) in preventing acute graft-versus-host disease (aGVHD) after HLA-matched sibling donor transplantation (MSDT) is still controversial. We performed a prospective, multicenter, open-label, randomized controlled trial (RCT) across 23 transplantation centers in China. Patients ages 40-60 years with standard-risk hematologic malignancies with an HLA-matched sibling donor were randomly assigned to an ATG group (4.5 mg/kg thymoglobulin plus cyclosporine [CsA], methotrexate [MTX], and mycophenolate mofetil [MMF]) and a control group (CsA, MTX, and MMF). The primary end point of this study was grade 2-4 aGVHD on day 100. From November 2013 to April 2018, 263 patients were enrolled. The cumulative incidence rate of grade 2-4 aGVHD was significantly reduced in the ATG group (13.7%; 95% CI, 13.5% to 13.9%) compared with the control group (27.0%; 95% CI, 26.7% to 27.3%; P = .007). The ATG group had significantly lower incidences of 2-year overall chronic GVHD (27.9% [95% CI, 27.6% to 28.2%] v 52.5% [95% CI, 52.1% to 52.9%]; P < .001) and 2-year extensive chronic GVHD (8.5% [95% CI, 8.4% to 8.6%] v 23.2% [95% CI, 22.9% to 23.5%]; P = .029) than the control group. There were no differences between the ATG and control groups with regard to cytomegalovirus reactivation, Epstein-Barr virus reactivation, 3-year nonrelapse mortality (NRM), 3-year cumulative incidence of relapse (CIR), 3-year overall survival, or 3-year leukemia-free survival. Three-year GVHD relapse-free survival was significantly improved in the ATG group (38.7%; 95% CI, 29.9% to 47.5%) compared with the control group (24.5%; 95% CI, 16.9% to 32.1%; P = .003). Our study is the first prospective RCT in our knowledge to demonstrate that ATG can effectively decrease the incidence of aGVHD after MSDT in the CsA era without affecting the CIR or NRM.

Comparison of HLA-matched sibling and unrelated donor transplantation in adult patients with acquired severe aplastic anemia.

The recent improvements in the outcomes of severe aplastic anemia (SAA) patients who received allogeneic stem cell transplantation (SCT) from unrelated donors (URD) suggest the possibility of its alternative first-line treatment. To address this issue, results of adult SAA patients receiving allogeneic SCT were compared between the following three donor-type groups: 8/8-matched sibling (MSD; n = 153), 8/8 well-matched unrelated (WM-URD; n = 72), and 6-7/8 partially matched unrelated (PM-URD; n = 33). Proportion of patients who experienced immunosuppressive treatment failures was significantly higher in the URD groups than in the MSD group (P< 0.01). The incidences of graft failure and transplant-related mortality, and graft-vs.-host disease-free, failure-free survival rates of the MSD, WM-URD, and PM-URD groups were 14.6, 0, and 0% (P< 0.01); 6.1, 10.3, and 21.7% (P= 0.03); and 76.7, 55.5, and 51.5% (P< 0.01), respectively. The overall survival (OS) rate of the MSD group (93.9%) was higher than that of the PM-URD (78.3%; P < 0.01) group, but not to that of the WM-URD (86.2%; P= 0.18) group. Our study showed comparable OS between the MSD group and WM-URD group, which suggest that the URD-SCT can be used as a first-line treatment for adult SAA patients with WM-URD.

Choice of conditioning regimens for bone marrow transplantation in severe aplastic anemia

AbstractAllogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

Related and Unrelated Donor Transplantation for β Thalassemia Major: Results of an International Survey

▪We studied 1110 children, adolescents and young adults with β thalassemia major transplanted with grafts from HLA-matched relative (n=677; 61%), HLA-mismatched relative (n=78; 7%), HLA-matched unrelated (n=252; 23%) and HLA-mismatched unrelated (n=103; 9%) donors in 2000 - 2016. The median age at transplantation was 6 years (range <1 - 25). Eight-five percent received ≥20 transfusions and 88% were reported as “inadequately” chelated. Most patients (73%) had hepatomegaly (2 cm or greater below the right costal margin) and 50% reported serum ferritin ≥2500 ng/mL. The Pesaro risk class could be assigned for only 526 (47%) of transplantations: Class I (39%), Class II (8%) and Class III (54%). Liver biopsies are not routinely performed in China. All patients received a myeloablative transplant conditioning regimen; 34% received busulfan (Bu; IV 8.4 - 13.2 mg/kg) + cyclophosphamide (Cy; 100-120 mg/kg) + thiotepa (TT; 5 mg/kg) + fludarabine (FLU; 200 mg/m2), 23%, Bu (IV 11-16 mg/kg) + Cy (100-120 mg/kg) + FLU (200 mg/m2), 22%, Bu (PO or IV 16 mg/kg) + Cy (200 mg/kg), 15%, treosulfan (42 mg/m2) + TT (8 mg/kg) + FLU (120 mg/m2) and the remaining 5%, Bu (PO or IV 12 or 16 mg/kg) or melphalan (140 mg/m2) + FLU (150 - 180 mg/m2) ± TT (8-10 mg/kg). Bu dosing was based on pharmacokinetic studies. In vivo T-cell depletion (anti-thymocyte globulin), graft-versus-host disease (GVHD) prophylaxis and graft type were confounded with transplant conditioning regimen. Ninety percent of transplants were in 2006-2016. The median follow-up was 48 months (range 3 - 193). The day-28 incidence of neutrophil recovery in patients aged ≤6 years, 7-15 years and 16-25 years were 92%, 93%, and 82%, respectively, p=0.28. The corresponding day-100 incidence of platelet recovery were 93%, 90%, and 70%, respectively, p<0.001. The 5-year incidence of graft failure was higher for patients aged 16-25 years at 23% compared to 8% and 10% for patients aged ≤6 and 7-15 years (p=0.01). Risk factors associated with overall mortality and treatment failure (graft failure or death from any cause) are shown in Table 1. Overall survival and disease-free survival (alive with sustained engraftment) were highest in children aged ≤6 years and received grafts from an HLA-matched sibling or HLA-matched unrelated donor. The 5-year probabilities of overall survival for patients aged ≤6 years, 7-15 years and 16-25 years were 91%, 83% and 55%, respectively, p<0.001. The corresponding probabilities for disease-free survival were 87%, 79% and 55%, p<0.001 (Figure 1). In the subset of patients for whom Pesaro risk class could be assigned, mortality and treatment failure were higher for Class II and Class III compared to Class I (Table 1). We tested for an effect of transplant center on survival and found none. Risks for acute grade II-IV GVHD were higher after HLA-mismatched related (hazard ratio [HR] 3.04, p<0.001), HLA-matched unrelated (HR 3.35, p<0.001) and HLA-mismatched unrelated (HR 2.21, p=0.003) compared to HLA-matched sibling transplants. Similarly, chronic GVHD risks were also higher after HLA-mismatched related (HR 2.64, p=0.002), HLA-matched unrelated (HR 2.13, p=0.018) and HLA-mismatched unrelated (HR 4.25, p<0.001) compared to HLA-matched sibling transplants. Nevertheless, mortality and treatment failure risks did not differ after HLA-matched sibling and HLA-matched unrelated donor transplants. In conclusion, transplantation for β thalassemia major should be offered early (aged 6 years or younger) from an HLA-matched sibling or an HLA-matched unrelated donor. Mismatched related donor transplants were associated with higher treatment failure and overall mortality. These data suggest cautious use of the following conditioning regimens: Bu + Cy, treosulfan + TT + FLU and Bu or melphalan ± TT ± FLU although identifying an optimal conditioning regimen(s) are best studied in the setting of carefully controlled clinical trials. [Display omitted] DisclosuresDvorak:Jazz Pharmaceuticals: Consultancy; Chimerix, Inc.: Membership on an entity's Board of Directors or advisory committees. Shenoy:Novartis, Vertex, Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

Classifying AML Patients with Inv(16) into High-Risk and Low-Risk Relapsed Patients Based on Peritransplantation Minimal Residual Disease Determined By CBFβ/MYH11 Gene Expression

A subtype of patients with core binding factor acute myeloid leukemia (AML) is characterized by the presence of the presence of inv(16)(p13q22) and rarely by a translocation t(16;16)(p13;q22). The final genetic product is the fusion of the CBFβ gene at 16q22 to the smooth muscle myosin heavy chain (MYH11) at 16p13, which is termed as CBFβ/MYH11 fusion gene. Although this type of AML is considered a favorable cytogenetic subgroup both in NCCN guideline or ELN classification, in particular with the application of high-dose cytarabine-based consolidation chemotherapy regimens, disease relapse remains one of the most important causes leading to death, occurring in around 35% of patients. Thus, for this cohort of patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is needed to as salvage treatment to improve the overall survival.It has been reported that when patients achieved hematological remission, the MRD prior to transplantation (pre-MRD) has been demonstrated to be a useful parameter to predict leukemia relapse after allo-HSCT. Evaluating minimal residual disease (MRD) by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) can quantify the expression level of fusion transcript at different time points along with the treatment. More recently, CBFβ/MYH11 fusion gene has been confirmed to be a good MRD marker and further screening out the patients in high-risk of relapse either during the treatment or after transplantation. However, due to the limit number of patients, there has been no studies about predictive value of CBFβ/MYH11expression after allo-HSCT.Therefore, in this study, we attempted to investigate the impact of pre-MRD determined by RQ-PCR-based CBFβ/MYH11 gene expression on transplant outcomes of AML patients with inv(16)(p13q22) or t(16;16)(p13;q22). Besides, our previous studies has demonstrated that in compared to HLA-identical transplantation, haplo-identical allo-HSCT had superior graft-versus-leukemia (GVL) effect in AML patients with standard-risk. Thus, here we also wanted to know whether the level of CBFβ/MYH11 pretransplant could further divide this form of AML into high-risk and low-risk relapse patients before allo-HSCT.Ninety AML patients with inv(16) in complete remission (CR) were monitored CBFβ/MYH11 transcript before and after allo-HSCT as MRD. A total of 23 patients received HLA-matched sibling donor transplantation (MSDT) and 67 patients received unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) were analyzed in this study. Patients were divided into four groups based on the value of CBFβ/MYH11 prior to transplantation (pre-MRD): with negative (group 1)/positive (group 2) pre-MRD before MSDT; with negative (group 3)/positive (group 4) pre-MRD before haplo-HSCT. The results showed that patients in group 2 had the highest cumulative incidence of relapse (2-year CIR, 40.7%), the lowest leukemia-free survival (2-year LFS, 50.8%) and the overall survival (2-year OS, 62.5%) among all four groups. The other three groups of patients had comparable CIR, TRM and OS (P>0.05). The patients were also classified into the other three groups according to CBFβ/MYH11 value of +1 month after transplantation: group 5: pre- and post-transplant MRD were both negative; group 6: the value of post-transplant MRD was lower than 0.2%; group 7: the value of post-transplant MRD was higher than 0.2%. Group 7 had the highest CIR compared to group 5 and 6 (P=0.217 & P=0.001, respectively) and the lowest LFS (P=0.072 & P=0.002, respectively), though the TRM and OS of these three groups were comparable (P>0.05). These results indicated that AML patients with inv(16) were able to be separated into high-risk and low-risk relapse groups based on peritransplant MRD determined by RQ-PCR-based CBFβ/MYH11. Haplo-HSCT might overcome the negative impact of pre-MRD on patient outcomes compared to MSDT. DisclosuresNo relevant conflicts of interest to declare.

Antithymocyte globulin improves the survival of patients with myelodysplastic syndrome undergoing HLA-matched unrelated donor and haplo-identical donor transplants

Significant advances have been achieved in the outcomes of patients with myelodysplastic syndromes (MDS) after both HLA-matched sibling donor transplants (MSDT) and non-MSDT, the latter including HLA-matched unrelated donor (MUDT) and haplo-identical donor transplants (HIDT). In this retrospective study, we analyzed the data of 85 consecutive patients with MDS who received allogeneic HSCT between Dec 2007 and Apr 2014 in our center. These patients comprised 38 (44.7%) who received MSDT, 29 (34.1%) MUDT, and 18 (21.2%) HIDT. The median overall survival (OS) was 60.2 months, the probabilities of OS being 63%, 57%, and 48%, at the first, second, and fifth year, respectively. Median OS post-transplant (OSPT) was 57.2 months, the probabilities of OSPT being 58%, 55%, and 48% at the first, second, and fifth year, respectively. The survival of patients receiving non-MSDT was superior to that of MSDT, median OSPT being 84.0 months and 23.6 months, respectively (P = 0.042); the findings for OS were similar (P = 0.028). We also found that using ATG in conditioning regimens significantly improved survival after non-MSDT, with better OS and OSPT (P = 0.016 and P = 0.025). These data suggest that using ATG in conditioning regimens may improve the survival of MDS patients after non-MSDT.

Autoimmune hematological diseases following haploidentical donor hematopoietic stem cell Transplant compared with matched sibling and unrelated donor.

Autoimmune hematological diseases (AHDs) occur more frequently than other autoimmune complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are often refractory to treatment. This study was to analyze the incidence and risk factors of AHDs as well as their response to treatment. Four hundred and forty-five adult malignant hematopoietic disorders underwent allo-HSCT were enrolled in this retrospective study, including 124 haploidentical donor (HRD), 140 unrelated donor (MUD) and 181 HLA-matched sibling donor (MSD) transplants. Twelve patients developed AHDs, including 6 autoimmune hemolytic anemia and 6 Evans syndrome. Evans syndrome all occurred in HRD transplants. The 3-year cumulative incidence of AHDs was 4.0 ± 1.3%, and HRD had higher incidence than MUD (8.7 ± 3.0% vs 1.8 ± 1.2%, P = 0.012) and MSD (8.7 ± 3.0% vs 3.5 ± 2.6%, P = 0.004 ). The steroids combined with Cyclosporine A were acted as the first line treatment, and the response rate was 73%. No patients experienced recurrence at a median follow up of 313 days after stopping treatment. HRD transplants (vs MUD: HR, 5.87; CI, 1.24 to 27.73; p = 0.026 and vs MSD: HR, 7.70; CI, 1.63 to 36.44; P = 0.010) and concurrent chronic graft versus host disease (HR, 3.76; CI, 1.18 to 11.92; P = 0.025) were risk factors for AHDs.

Antithymocyte Globulin Improves the Survival of Patients with Myelodysplastic Syndrome Undergoing HLA-Matched Unrelated Donor and Haplo-Identical Donor Transplants

Background: Significant advances have been achieved in the outcomes of patients with myelodysplastic syndromes (MDS) after both HLA-matched sibling donor transplants (MSDT) and non-MSDT in the past few years, the latter including HLA-matched unrelated donor (MUDT) and haplo-identical donor transplants (HIDT).Methods: We retrospectively analyzed the data of 85 consecutive patients with MDS who received allogeneic HSCT between Dec 2007 and Apr 2014 in our center. These patients comprised 38 (44.7%) who received MSDT, 29 (34.1%) MUDT, and 18 (21.2%) HIDT.Results: The median follow-up was 30.0 months. Over all, the median overall survival (OS) was 60.2 months and the probabilities of OS at the first, second and fifth year were 63%, 57% and 48%, respectively. Median OS post transplant (OSPT) was 57.2 months and the probabilities of OSPT at the first, second and fifth year were 58%, 55% and 48%, respectively. Relapses occurred in 16 patients (18.8%), and the cumulative incidence of relapse at the first, second and third year were 14%, 23% and 27%, respectively. The survival of patients receiving non-MSDT was superior to that of MSDT, median OSPT being 84.0 months and 23.6 months, respectively (P=0.042);And the similar result was observed when we analyzed the OS of patients who underwent non-MSDT or MSDT (median OS: 120 months vs. 27.0 months; P=0.028). We also found that using antithymocyte globulin (ATG) in conditioning regimens significantly improved survival after non-MSDT, with better OS and OSPT (P=0.016 and P=0.025). Furthermore, we compared OS or OSPT of patients who received non-MSDT with ATG (n=38) and MSDT without ATG (n=37). Our results showed that using ATG in conditioning regimen significantly improved survival of non-MSDT, with better OSPT (median OS: 84.0 months vs. 23.0 months; P=0.026) and OS (median OS: 120 months vs. 25.1 months; P=0.016).Conclusions: These data suggest that, non-MSDT could be a valid alternative when MSDT is not available, and ATG may improve the survival of MDS patients after non-MSDT. DisclosuresNo relevant conflicts of interest to declare.

Autoimmune Hematological Diseases Following Haploidentical Donor Hematopoietic Stem Cell Transplant Compared with Matched Sibling and Unrelated Donor

Objective:Autoimmune hematological diseases (AHDs) occur more frequently than other autoimmune complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are often refractory to treatment. The aim of this study was to analyze the incidence and risk factors of AHDs as well as its response to treatment in a series of patients undergoing allo-HSCT at our single institution.Method:Forty hundred and forty-five adult malignant hematopoietic disorders underwent allo-HSCT were enrolled in this retrospective study, including 181 cases underwent HLA-matched sibling donor (MSD) transplants, 140 unrelated donor (MUD) transplants and 124 haploidentical donor transplants (HRD).Result:Twelve patients developed AHDs, including 6 autoimmune hemolytic anemia (AIHA)and 6 Evans' syndrome.The median time of AHDs onset was 196 days (range, 60-756). Evans' syndrome all ocuured in HRD. The 3-year cumulative incidence of AHDs was 2.7%,and HRD had higher incidence than MSD (6.5% vs 1.1%,P=0.017) and MUD(6.5%vs1.4%,P=0.049). Eight of them received complete response (CR) and 3 no response (NR) after 11 patients received the corticosteroids combined with CSA as the initial treatment for 4 weeks. One obtained CR and 2 PR after 3 NR cases treated by rituximab. Eleven cases all not were AHDs recurrence at a median followup of 313 days (range, 153 to 1051 days after CR. HRD transplantation(vs MSD: hazard ratio [HR], 7.70; 95% confidence interval [CI], 1.63 to 36.44; P=.01 and vs MUD: hazard ratio [HR], 5.87; 95% confidence interval [CI], 1.24 to 27.73; P=.026) and concurrent chronic GVHD (hazard ratio [HR], 3.76; 95% confidence interval [CI], 1.18 to 11.92; P=.025)were risk factors for AHDs.Conclusion:The patients undergoing HRD transplantation had higher risk of AHDs and manifested as Evan's syndrome was very common compared with MSD and MUD. Corticosteroids combined with CSA as the first line treatment of AHDs results in good response and low recurrence rate. DisclosuresLin:National Natural Science Foundation of China 81400141: Research Funding; National Natural Science Foundation of China 81270647: Research Funding; Science and technology planning project of Guangdong Province 2014B020226004: Research Funding; The project of health collaborative innovation of Guangzhou City 201400000003-4: Research Funding.

Excellent Outcomes of Combined Haploidentical and Cord-Blood (Haplo-Cord) Transplantation and HLA-Matched Sibling (Matched-Sib) Donor Transplantation for High-Risk Patients with Severe Aplastic Anemia (SAA) Refractory to Immunosuppressive Therapy

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for SAA unresponsive to immunosuppressive therapy (IST). For SAA patients (pts) with a HLA-identical sibling donor, the use of peripheral-blood (PB) grafts have been reported to have increased risk of graft-versus-host disease (GVHD) compared with using the bone marrow (BM) as the stem cell source. For pts lacking an HLA-identical donor, transplantation using unrelated cord blood (UCB) or haplo-identical donors has historically been associated with high graft failure rates and poor survival. Here we report and compare the clinical outcomes for two novel transplantation strategies under investigation at our center aimed at improving engraftment and survival and reducing GVHD in high-risk SAA pts refractory to IST: combined haploidentical and cord-blood (haplo-cord) transplants vs. HLA-matched sibling (matched-sib) donor PB HSCT with partial T-cell depletion.Methods: Forty-seven pts with SAA or SAA evolved to MDS that was unresponsive to IST underwent HSCT at a single center between 2008 and 2016, and received either a haplo-cord transplant (n= 28; pt eligibility included lack a HLA-matched donor but availability of a haploidentical relative, a ≥4/6 HLA matched UCB unit and severe neutropenia with an ANC<500 cells/µL) or an HLA matched-sib transplant (n=19). Both cohorts were treated with cyclophosphamide, ATG, and fludarabine, with the haplo-cord cohort also receiving 200 cGy of total body irradiation. For the haplo-cord cohort, pts received a CD34-selected G-CSF mobilized haplo-donor allograft combined with a ≥ 4/6 HLA-matched UCB unit (minimum TNC dose ≥1.5x107 cells/kg). For the matched-sib cohort, pts received G-CSF-mobilized PBSC-allograft containing high numbers of CD34+ selected cells combined with BM transplant equivalent-dose of non-mobilized CD3+T-cells/kg from a ≥9/10 HLA-matched sibling donor. GVHD prophylaxis included tacrolimus and MMF (haplo-cord) or CSA and MTX (matched-sib). Results: The median age at transplant was 20 years (range 5-49) in haplo-cord and 22 years (6-67) in matched-sib. Pts were heavily transfused and allo-immunized: pre-transplant serum ferritin was markedly elevated at a median 3368 µg/l (range 980-21465) and 1978 µg/l (161-13928) for haplo-cord and matched-sib cohorts, respectively. For the haplo-cord cohort, 18 pts received a 4/6 and 10 pts received a ≥5/6 HLA-matched UCB unit; UCB units contained a median of 3.6x107 TNCs/kg and 1.5x105 CD34+ cells/kg; haplo-grafts contained a median of 3.2x106 CD34+ cells/kg and 1.0x103 CD3+ T-cells/kg. For the matched-sib cohort, PBSC allografts from 10/10 (n=18) or 9/10 (n=1) HLA-matched donors contained a median of 8x106CD34+ cells/kg and 2x107 non-mobilized CD3 T-cells/kg. At a median follow-up of 40 months in haplo-cord and 32 months in matched-sib, most post-transplant clinical outcomes were comparable between two cohorts. In both cohorts, all pts (100%) had donor engraftment with neutrophil recovery occurring at a median of 10 days (range 6-28) in haplo-cord and 14 days (10-23) in matched-sib (Figure); median times to platelet recovery were 28 and 18 days. No patients in the matched-sib and only one pt (4%) in haplo-cord group developed late graft failure. The 200-day survival were 100% and 95%, and overall survival at 5 years were 91% and 87% in haplo-cord and matched-sib cohorts, respectively (Figure, P=0.7). The cumulative incidences of grade II-IV and III-IV acute GVHD were 37% and 4% in haplo-cord, compared to 21% and 11% in matched-sib. The cumulative incidence of chronic GVHD was higher in haplo-cord than matched-sib (45% vs.12%), however, only 8% and 0% extensive chronic GVHD occurred in two cohorts, respectively. Conclusion: Both transplant regimens being studied our center for SAA pts with high-risk ATG-refractory disease resulted in rapid neutrophil recovery, durable donor engraftment and excellent long-term survival. Despite pts being heavily transfused, iron overloaded and HLA allo-immunized, adverse outcomes of graft failure, severe acute grade III-IV GVHD and extensive chronic GVHD rarely occurred with either transplant approach. Remarkably, most transplant outcomes including survival were similar between haplo-cord and matched-sib cohorts, establishing haplo-cord transplantation to be a viable and promising transplant strategy for SAA pts who lack an HLA identical sibling. [Display omitted] DisclosuresYoung:GSK/Novartis: Research Funding.

HLA-Mismatched Stem Cell Microtransplantation Compared to Matched-Sibling Donor Transplantation for Acute Myeloid Leukemia in First Complete Remission

HLA-mismatched stem cell microtransplantation is a new transplantation which has been reported in recent years. We treated 41 patients with intermediate- or high-risk acute myelogenous leukemia (AML) in first complete remission (CR1) undergoing HLA-mismatched stem cell microtransplantation and compared with 56 patients undergoing HLA-matched sibling donor (MSD) transplantation at the same period in our center from July 2012 to August 2015. The estimated leukemia-free survival (LFS) at 2-year was 65.6% ± 9.5% in the MSD group and 27.6% ± 14.0% in the microtransplantation group (P = 0.011). The estimated overall survival (OS) at 2-year was 73.6% ± 8.6% in the MSD group and 46.2% ± 15.6% in the microtransplantation group (P = 0.056). The cumulative incidences of relapse were 22.5% and 58.7% among MSD and microtransplantation groups (P = 0.011). The cumulative incidence of nonrelapse mortality was 7.8% in MSD group, and no nonrelapse mortality in microtransplantation group (P = 0.265). Hematopoietic recovery time was shorter in the microtransplantation group than MSD group (P < 0.05). The infection rate of MSD group was higher than in the microtransplantation group (91.1% vs 75.6%, P = 0.037). The preliminary results suggest that LFS of microtransplantation is inferior to MSD transplantation and a trend toward the OS of microtransplantation was lower than MSD transplantation for intermediate- or high-risk AML in CR1. DisclosuresNo relevant conflicts of interest to declare.