Unrelated HSCT Research Articles

Prognostic analysis of 8 patients with hepatic adenoma undergoing allogeneic hematopoietic stem cell transplantation

Objective: To evaluate the safety of patients with hepatic adenoma undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: A retrospective analysis of the clinical characteristics and prognosis of eight patients with hepatic adenoma who underwent allo-HSCT in the Hematology Department of Peking University People's Hospital from January 2010 to March 2024 was conducted. Results: Of the eight patients who underwent allo-HSCT with hepatic adenoma, one patient was considered MDS-h transfusion-dependent and seven had aplastic anemia. The median age of the patients was 23 years (13-48 years). The median time from the diagnosis of AA or MDS to transplantation was 14 years (6-24 years), whereas the median time from taking androgens to diagnosing hepatic adenoma was 9 years (5-13 years). Six cases underwent haplo-HSCT, one case underwent matched unrelated donor HSCT, and one case underwent matched related donor HSCT. All patients achieved neutrophil engraftment at a median time of 11.5 days (11-20 days) and PLT engraftment within 60 days at a median of 19 days (10-37 days) after haplo-HSCT. Moreover, seven patients developed CMV anemia after transplantation, three patients had hemorrhagic cystitis, and two patients developed acute GVHD. During and after transplantation, eight patients did not show severe liver function damage or rupture of hepatic adenoma. In relation to imaging size, four patients showed varying degrees of reduction in hepatic adenoma size after transplantation, whereas four patients did not show significant changes in hepatic adenoma size after transplantation. The median follow-up time was 540.5 (30-2 989) days. Of the eight patients, six survived and two died. Furthermore, no direct correlation was observed between death and hepatic adenoma. Conclusion: Patients with hepatic adenomas undergoing allo-HSCT are not contraindications for transplantation, which will not increase transplant-related mortality.

HLA-DPB1 and DPA1∼DPB1 linkage mismatch affects the survival of recipients receiving HLA-14/14 matched unrelated donor HSCT

HLA-DPB1 and DPA1∼DPB1 linkage mismatch affects the survival of recipients receiving HLA-14/14 matched unrelated donor HSCT

HLA-DPB1 and DPA1 ~ DPB1 linkage mismatch affects the survival of recipients receiving HLA-14/14 matched unrelated donor HSCT.

To analyse the effect of HLA-DPA1 and HLA-DPB1 allelic mismatches on the outcomes of unrelated donor haematopoietic stem cell transplantation (URD-HSCT), we collected 258 recipients with haematological disease who underwent HLA-10/10 matched URD-HSCT. HLA-A, -B, -C, -DRB1, -DQB1, -DRB3/4/5, -DQA1, -DPA1 and -DPB1 typing was performed for the donors and recipients using next-generation sequencing (NGS) technology. After excluding 8 cases with DQA1 or DRB3/4/5 mismatches, we included 250 cases with HLA-14/14 matching for further analysis. Our results showed that the proportion of matched DPA1 and DPB1 alleles was only 10.4% (26/250). The remaining 89.6% of donors and recipients demonstrated DPA1 or DPB1 mismatch. In the DPA1 matched and DPB1 mismatched group, accounting for 18.8% (47/250) of the cohort, DPB1*02:01/DPB1*03:01 allelic mismatches were associated with decreased 2-year OS and increased NRM. DPB1*02:02/DPB1*05:01 and DPB1*02:01/DPB1*05:01 mismatches showed no impact on outcomes. Moreover, the specific allelic mismatches observed were consistent with the DPB1 T-cell epitope (TCE) classification as permissive and non-permissive. We innovatively established an analysis method for DPA1 ~ DPB1 linkage mismatch for cases with both DPA1 and DPB1 mismatched, accounting for 70% (175/250) of the total. DPA1*02:02 ~ DPB1*05:01/DPA1*02:01 ~ DPB1*17:01 linkage mismatches were associated with lower 2-year OS, especially among AML/MDS recipients. DPA1*02:02 ~ DPB1*05:01/DPA1*01:03 ~ DPB1*02:01 linkage mismatches showed no impact on outcomes. In conclusion, applying the DPA1 ~ DPB1 linkage mismatch analysis approach can identify different types of mismatches affecting transplant outcomes and provide valuable insight for selecting optimal donors for AML/MDS and ALL recipients.

Excellent Outcome Following Haplo-Identical and Unrelated Donor HSCT for Young Patients with Sever Aplastic Anemia Using Reduced Dose TBI and Post-Transplant Cyclophosphamide for Gvhd Prophylaxis

Excellent Outcome Following Haplo-Identical and Unrelated Donor HSCT for Young Patients with Sever Aplastic Anemia Using Reduced Dose TBI and Post-Transplant Cyclophosphamide for Gvhd Prophylaxis

Effective Prevention of Steroid-Requiring Chronic Graft-Vs.-Host Disease with B Cell Depletion: A Randomized, Placebo-Controlled Trial

Introduction: The pathophysiology of chronic graft-vs.-host disease (cGVHD) is complex, with many cell types playing critical roles. B cells are involved in cGVHD pathobiology, and strategies that eliminate or inhibit B cells (rituximab, ibrutinib) can be therapeutic in advanced disease. We previously demonstrated effective prevention of cGVHD in a phase II trial of B cell depletion with rituximab. Obinutuzumab (Obin, Genentech) is a 2 nd generation monoclonal anti-CD20 antibody with enhanced B cell depletion activity over rituximab. Here we present the results of a randomized trial of Obin for the prevention of cGVHD. Methods: We performed a randomized double-blind, placebo-controlled trial of B cell depletion using 4 doses of Obin to determine if steroid-requiring cGVHD (SR-cGVHD) could be prevented 12 months from HSCT (NCT# 02867384). Eligible subjects previously underwent myeloablative or reduced intensity 7-8/8 HLA-matched, related or unrelated HSCT using peripheral blood stem cells (PBSC) and tacrolimus-based primary GVHD prophylaxis without T cell depletion. Subjects without evidence of cGVHD, active Gr II-IV acute GVHD, or malignancy were enrolled between 60-90 days following HSCT. Eligibility included adequate hematopoiesis (ANC > 1000/mL, plt > 50 000/mL) and stable donor chimerism (> 80%). All subjects provided informed consent. Obin (1000 mg iv) or placebo was administered at 3, 6, 9 and 12 months after HSCT (+/- 10 days) with acetaminophen and diphenhydramine prior to each study drug dose. The primary endpoint was the cumulative incidence (CI) of SR-cGVHD, which was felt to be a more objective measurement of cGVHD severity than NIH cGVHD stage alone. Results: 181 subjects were enrolled (92 Obin, 89 placebo). 167 subjects who have been followed for >1 year from HSCT (84 Obin, 83 placebo) are included in this analysis. Baseline clinical characteristics, including age, recipient/donor gender, donor type/match, primary malignancy/DRI, conditioning intensity and HCT-CI, and prior Gr II-IV GVHD were balanced. The median number of study drug doses was equivalent (median 2.5 vs. 2 for Obin and placebo groups). For the entire cohort, the median follow-up time among survivors was 24 months (range 4, 74). The primary endpoint, the CI of SR-cGVHD at 12 months from HSCT, was significantly reduced with Obin - 11% (95% CI 5.8-20) in comparison with placebo - 38% (95% CI 28-49) (p=0.008, Fig 1). The corresponding rates of NIH Moderate-Severe cGVHD at 12 months were 20% vs. 35% (p=0.069). The rate of SR-cGVHD by 2 years remained lower in the Obin group (28% vs. 44%). In multivariable modeling, only study arm (Obin vs. placebo) was associated with SR-cGVHD (p=0.01). Obin was safe and well tolerated with only 5 Gr 3-4 infusion reactions (placebo - 0). There was more Gr 3-4 neutropenia (32.1% vs. 4.8%) but only 1 case of neutropenic fever in the Obin group. Neutropenia responded to G-CSF, administered at investigator discretion. There were 9 non-relapse related deaths in the Obin arm (COVID 3, infection 2, pulmonary 2, acute GVHD 1, unknown 1) compared with 3 in the placebo arm (unknown 2, pulmonary 1) (p=NS). There was no difference in the CI of relapse at 2 years (20% vs. 28%, p=NS). The SR-cGVHD-free, relapse-free survival in the Obin group was superior (CRFS, 43% vs. 30%, p=0.009, Fig 2) without a change in overall survival 82% vs. 86%, p=NS). CD19 + B cell depletion was complete in the Obin arm through 1 year (median cell count 0) while B cell recovery was normal in the placebo arm (p<0.0001 at 3, 6, 9, 12 months) and remained lower at 24 and 36 months (36 month median 55.5 vs. 484.4 cells/mL, p=0.02). Similar findings were noted for CD19 +CD27 + memory B cells and CD19 +CD27 - naïve B cells. No differences in T cells were noted, but NK cells were reduced in the Obin arm at late time points. H-Y antibody studies in F to M donor/recipient pairs are underway. Conclusions: In subjects undergoing well-matched PBSC HSCT using tacrolimus-based GVHD prophylaxis, a strategy of B cell depletion with 4 doses of Obin significantly reduces the requirement for corticosteroids for treatment of cGVHD and significantly increases CRFS. Obin is well tolerated and is associated only with transient neutropenia. Further studies may determine whether prolonged B cell depletion may be of greater utility, however this double-blind, placebo-controlled randomized trial supports practice changing cGVHD prophylaxis in tacrolimus-based HSCT.

The Area Under Tacrolimus Concentrations on Day 14-28 Is the Independent Predictor of the Development of Chronic Gvhd in Patients without Severe Acute Gvhd after Unrelated Allogeneic HSCT

Introduction: In unrelated allogeneic hematopoietic stem cell transplantation (UR-SCT), chronic graft-versus-host disease (GVHD) is a critical complication that affects not only patients' quality of life but also post-transplant outcome. Acute GVHD is a major risk factor for the subsequent development of chronic GVHD. The combination of tacrolimus and short-term methotrexate (TAC+sMTX) has been widely used as a GVHD prophylaxis for UR-SCT in Japan. Previous reports have shown that tacrolimus blood concentrations early after transplantation are associated with the development of acute GVHD, but not with that of chronic GVHD. On the other hand, among UR-SCT recipients who did not develop severe acute GVHD, the relationship between tacrolimus blood concentrations and the development of chronic GVHD remains unclear. Methods: To examine the association between tacrolimus blood concentrations and post-transplant outcomes, the area under the tacrolimus concentration on day 0-14 (AUTC 0-14) and day 14-28 (AUTC 14-28) was calculated simply as the sum of the area of the trapezoid for the corresponding period ( Figure). Tacrolimus was initiated by continuous intravenous administration from day -1 in all patients, and no patients were switched to oral administration prior to day 28. Short-term methotrexate was administered at 10 mg/m 2 on day 1 and 7 mg/m 2 on day 3, day 6, and day 11. Among all 151 adult patients with hematopoietic malignancies who underwent first UR-SCT with GVHD prophylaxis of TAC+sMTX between 2010 and 2022 at the Jikei University Hospital, the following were excluded from the analysis: developing grade III-to-IV acute GVHD, using prednisolone or methyl-prednisolone ≥0.5 mg/kg within day 100, engraftment failure, death before day 100, and relapse before day 100. Results: A total of 68 patients were included in the analysis. Median age was 50.5 (range, 16-68) years. Twenty-seven (40%) patients had acute myeloid leukemia, and 18 (27%) had acute lymphoblastic leukemia. Fifty-five (81%) were in complete remission/chronic phase/early stage. The donor source consisted of 42 (62%) bone marrow transplantation (BMT), 20 (29%) cord blood transplantation (CBT), and 6 (9%) peripheral blood stem cell transplantation (PBSCT). BMT recipients transplanted from 22 (52%) HLA 8/8 matched donor, 19 (45%) HLA 7/8 matched donor, and one (3%) HLA 6/8 matched donor. CBT recipients transplanted from 15 (75%) HLA 4/6 matched donor and 5 (25%) HLA 5/6 matched donor. PBSCT recipients transplanted from 5 (83%) HLA 8/8 matched donor and one (17%) HLA 7/8 matched donor. Fifteen (22%) patients were administered additional low-dose anti-thymocyte globulin (ATG) as GVHD prophylaxis. Fifteen male patients transplanted from female donors (22%). Thirty-nine (57%) patients received myeloablative conditioning regimen. The median time from UR-SCT to neutrophil engraftment was 19 days (range, 11-34). Regarding acute GVHD, 46 patients (68%) developed none, 13 patients (19%) developed grade I, and 9 patients (13%) developed grade II. The median observation period for all 68 patients was 48.2 months (4.0 years). The 4-year cumulative incidence (CI) of chronic GVHD was 51%, of which 24% were moderate-to-severe. The CI of moderate-to-severe chronic GVHD was not associated with age, disease status, donor source, HLA incompatibility, ATG use, female to male, intensity of conditioning regimen, and grade I-to-II acute GVHD development. AUTC 14-28 <200 was the only risk factor (AUTC 14-28<200: 32% vs AUTC 14-28≥200: 11%; p=0.047). Multivariate analysis also showed that AUTC 14-28 <200 was the independent factor for development of moderate-to-severe chronic GVHD ( p=0.04). In all 68 patients, 4-year CI of relapse was 20%, 4-year CI of non-relapse mortality was 10%, 4-year GVHD-free, relapse-free, survival (GRFS) was 50%, and 4-year Overall survival was 80%, all of which did not differ between AUTC 14-28 <200 and AUTC 14-28 ≥200 groups. Conclusion: In UR-SCT, our data showed that AUTC 14-28 <200 may be an independent risk factor for developing moderate-to-severe chronic GVHD, even in patients who did not develop severe acute GVHD.

Impact of Donor and Patient CMV Serology in Children Receiving First Geno-Identical or Unrelated HSCT for Malignant Hematological Disease: An EBMT Retrospective Registry Study

Impact of Donor and Patient CMV Serology in Children Receiving First Geno-Identical or Unrelated HSCT for Malignant Hematological Disease: An EBMT Retrospective Registry Study

Optimized therapeutic strategy for patients with refractory or relapsed acute myeloid leukemia: long-term clinical outcomes and health-related quality of life assessment.

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 by multiple measurable residual disease (MRD) and graft-versus-host disease (GvHD)-guided DLIs. 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. 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 GvHD was 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. Our study indicated that total therapy is not only associated with decreased CIR, comparable TRM, and better long-term LFS, but also with satisfactory HR-QoL for refractory or relapsed AML, compared with those of standard of care therapy reported previously. Therefore, total therapy may be an optimized therapeutic strategy for refractory or relapsed AML.

Allogeneic Hematopoietic Stem Cell Transplantation (allo HSCT) in Patients with IPSS Low or Intermediate-1 Myelodysplastic Syndrome (MDS): A Prospective Multicenter Phase II Study Based on Donor Availability By the GFM & SFGM-TC “MDS-ALLO-Risk”

Allogeneic Hematopoietic Stem Cell Transplantation (allo HSCT) in Patients with IPSS Low or Intermediate-1 Myelodysplastic Syndrome (MDS): A Prospective Multicenter Phase II Study Based on Donor Availability By the GFM & SFGM-TC “MDS-ALLO-Risk”

Outcomes with Mismatched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation Following Reduced Intensity Conditioning: A Systematic Review and Meta-Analysis

Background:Allogeneic hematopoietic cell transplantation (HSCT) is often the optimal and only potentially curative therapy in several high-risk hematologic malignancies. Although human leukocyte antigen (HLA)-matched donors remain the preferred choice for HSCT recipients, haploidentical and umbilical cord blood HSCT has increased access to transplantation. Despite these advances, many patients lack an appropriate donor, in particular the ethnic minorities. The use of mismatched unrelated donors (MMUD) has increased over the years but concerns regarding increased risk of graft versus host disease (GVHD) and non-relapse mortality (NRM) limits the utility of MMUD HSCT. The intensity of the conditioning regimen has a significant impact on survival in case of mismatched donors. We conducted a systematic review and meta-analysis aimed to investigate the outcomes with MMUD HSCT using reduced intensity conditioning (RIC).Methods:Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was performed on three databases (PubMed, Cochrane Library, and ClinicalTrials.gov) from date of inception through February 2021 using the MeSH and entry terms for “hematopoietic stem cell transplantation”, OR “hematologic neoplasms”, AND unrelated donors“ AND ”treatment outcome“. A total of 2477 records were identified and primary and secondary screening was done. After excluding review, duplicate, and non-relevant articles, we included 6 (4 retrospective, 2 prospective) studies reporting outcomes following RIC MMUD HSCT. The Joanna Briggs Institute (JBI) critical appraisal checklist for studies reporting prevalence data and randomized control trial was used for quality assessment, and all studies were reported as good. Proportions along with a 95% confidence interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2). The variance between the studies was calculated using Der Simonian Laird Estimator.Results:We identified 895 participants in the 6 studies, who had MMUD HSCT with RIC. (Table 1) Median age was 57.5 (18-76) years and 56% (n= 415) were males as reported by four studies (n=740). In five studies with available data (n=855), source of the primary graft was peripheral blood (PB) and bone marrow (BM) in 72% (n=614) and 28% (n=241) of the HSCT recipients respectively. After a median follow-up of 48 (3-125) months, we estimated a pooled overall survival (OS) of 62% (95% CI 0.52-0.72, I 2=84%, n=895) at one year and 43.5% (95% CI 0.33-0.54, I 2 =84% n=855) at three years. The pooled incidence of acute GVHD (grade II-IV), acute GVHD (grade III-IV), and chronic GVHD were 37% (95% CI 0.26-0.49, I 2=81%, n=610), 16% (95% CI 0.07-0.29, I 2=87%, n=542), and 28% (95% CI 0.13-0.47, I 2=95%, n=848) respectively. Progression free survival (PFS) and relapse rates (RR) were 46% (95% CI 0.30-0.62, I 2=92%, n=814) and 31% (95% CI 0.24-0.39, I 2=65%, n=814) respectively. The pooled incidence of non-relapse mortality (NRM) was 23% (95% CI 0.09-0.40, I 2=91%, n=707). Kasamon et al. and Shaw et al. reported 1-year OS of 75-79% with MMUD HSCT using fludarabine, cyclophosphamide and 2 Gy total body irradiation RIC, bone marrow graft and post-transplant cyclophosphamide, sirolimus and mycophenolate for GVHD prophylaxis.Conclusion:Mismatched unrelated donor HSCT has shown favorable outcomes with reduced intensity conditioning using a post-transplant cyclophosphamide-based regimen, comparable to the historical outcomes with mismatched related donor (haploidentical) HSCT. MMUD HSCT with RIC can be considered in patients lacking an HLA-matched donor. This strategy will expand access to HSCT in patients with ethnic minorities who often lack a matched donor. [Display omitted] DisclosuresMcGuirk: EcoR1 Capital: Consultancy; Allovir: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding.

Downregulation of MHC Class II in Relapsed AML Cells after Allogeneic Transplantation

The evolutionary model of Acute Myeloid Leukemia (AML) progression suggests that malignant clones survive initial therapy and acquire new genetic and epigenetic changes, ultimately resulting in therapy-resistant disease. Allogeneic hematopoietic stem cell transplant (HCT) is a potent therapy that provides benefit in part through an immune-mediated Graft-vs-Leukemia (GVL) effect, although relapse after HCT remains a major clinical problem. Recent studies have demonstrated the gain and loss of specific AML-associated mutations at the time of relapse, consistent with a model of clonal evolution; however, a comprehensive screen of genetic changes in AML relapsed after HCT has not yet been reported. We hypothesized that the distinctive, immune-mediated GVL effect imposed by HCT may result in distinct patterns of tumor evolution in relapse after this therapy.To test this, we performed enhanced exome sequencing of matched diagnosis and relapse tumors to identify somatic mutations in 15 patients who relapsed after matched related or unrelated donor HSCT. For comparison, we analyzed 20 cases of AML relapsed after chemotherapy alone. In the majority of samples, new somatic variants were identified, and copy number analysis demonstrated gain and loss of genomic regions, as has been previously reported. However, compared to cases relapsed after chemotherapy alone, there were no gene mutations or copy number changes that were specific to relapse after HCT. Specifically, we found no changes in genes involved in antigen presentation, cytokine production, or immune checkpoints, and an unbiased pathway analysis revealed no enrichment for mutations in immune response pathways. Overall, the spectrum of mutations found at relapse after HCT did not differ from that observed in relapse after chemotherapy only.Since no canonical genetic changes were observed in relapsing AML after HCT, we speculated that clonal evolution of AML after HCT may instead occur through selection of randomly occurring epigenetic changes in AML cells that allow them to escape immune surveillance. To test this hypothesis, we performed RNA sequencing on purified AML blasts (CD45 positive, side scatter low) from presentation and relapsed AML sample pairs from both post-HSCT and post-chemo relapses. Interestingly, in the post chemotherapy relapse cases, only 8 genes were identified with expression changes that met pre-specified cutoffs for significance (FDR<0.5). In contrast, in the post relapse cohort, 34 genes were found to be significantly upregulated, and 187 genes were significantly downregulated, compared to the same sample at presentation. Gene pathway analysis revealed significant dysregulation of immune response genes (the most dysregulated pathway, p<10-35) as well as pathways encompassing cell adhesion/motility and the innate immune response.Four classical MHC Class II genes were among the 187 genes that were downregulated after post-HCT relapse: HLA-DPA1 (mean fold change -11.9 in 6/7 cases), HLA-DPB1 (mean fold change -6.5 in 6/7 cases), HLA-DQB1 (mean fold change -9.7 in 6/7 cases), and HLA-DRB1 (mean fold change -11.9 in 6/7 cases) (Figure 1). In these same 6 cases, there was a strong (but not significant) trend towards downregulation in the remaining MHC Class II genes: HLA-DQA1, HLA-DRB3, and HLA-DRA, as well as CIITA, a transcriptional activator believed to act as the “master regulator” of MHC Class II genes (Figure 1). Several other genes involved in MHC Class II antigen processing and presentation were significantly downregulated post-HCT (FDR<.05), including HLA-DMA, HLA-DMB, and CD74 . In contrast, there was no significant downregulation of MHC Class I genes observed after allo-relapse, raising the possibility that loss of MHC Class II presentation may play a particularly important role in immune evasion after HCT. To validate these findings, we performed flow cytometry for Class II and Class I genes on banked post-HCT relapse samples, and this confirmed significant downregulation of MHC Class II (but not Class I) expression on post-HCT relapse samples (Figure 2). Taken together, these results suggest that loss of MHC Class II-mediated antigen presentation may be an important mechanism of immune escape after HCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML)— Transplant Outcomes Post HMA Therapy in a Large International Patient Cohort

Hypomethylating Agents (HMAs) in Patients with Relapsed and Refractory Acute Myeloid Leukemia (RR-AML)— Transplant Outcomes Post HMA Therapy in a Large International Patient Cohort

260 - Retrospective Single Institution Comparative Study of Outcomes after Post-Transplant Cyclophosphamide for Haploidentical, Matched Unrelated, Mismatched Unrelated and Matched Sibling PB HSCT

260 - Retrospective Single Institution Comparative Study of Outcomes after Post-Transplant Cyclophosphamide for Haploidentical, Matched Unrelated, Mismatched Unrelated and Matched Sibling PB HSCT

Human leukocyte antigen disparities reduce relapse after hematopoietic stem cell transplantation in children with juvenile myelomonocytic leukemia: A single-center retrospective study from China.

HSCT is the only proven curative therapy for JMML. Matching donor and recipient HLA alleles is considered optimal to reduce the risk of GVHD after HSCT but is not always possible. Only a limited number of studies have compared the influence of HLA disparities on HSCT outcomes for patients with JMML. We conducted a retrospective study among 47 children with JMML who received related or unrelated unmanipulated HSCT (March 2010-October 2018). Among our participants, 27 (57.4%) donor-recipient pairs had 0-1 HLA disparities (Group 1: HLA-matched or ≤1 allele/antigen mismatch donor) and 20 (42.6%) had ≥2 HLA disparities (Group 2: 2-3 mismatched/haploidentical donors). The median follow-up period was 26.0months (range: 1-105months), and the 5-year probabilities of DFS and RI for the whole cohort were 54.6±7.7% and 34.8±15.0%, respectively. Compared to Group 1, Group 2 patients had a significantly lower RI (5.3±10.5% vs 55.5±20.9%, P˂.001), though similar rates of grade II-IV acute GVHD (60.0±22.4% vs 33.3±18.2%, P=.08), grade III-IV acute GVHD (25.0±19.5% vs 7.4±10.1%, P=.08), chronic GVHD (30.0±20.9% vs 34.9±18.8%, P=.85), NRM (20.0±18.0% vs 3.9±7.7%, P=.07), and DFS (74.4±9.9% vs 41.3±10.0%, P=.08). Disease relapse remains the major cause of treatment failure in JMML patients, especially in patients receiving HLA-matched and limited HLA-mismatched HSCT. Our findings suggest that donor-recipient HLA disparities may improve the outcome of HSCT in children with JMML.

Cytokine release syndrome after allogeneic stem cell transplantation with posttransplant cyclophosphamide.

Cytokine release syndrome (CRS) is a systemic inflammatory response with aberrant immune activation and immune hyperstimulation, that leads to increased cytokine levels and inflammation. CRS has been described after antibody and cellular-based therapies. The use of posttransplant cyclophosphamide (PTCy) as graft-vs-host disease (GVHD) prophylaxis in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has led to the extension of allogeneic HSCT to patients without HLA-identical donors. Furthermore, PTCy has also been introduced in matched and unrelated donor HSCT. However, description of incidence and clinical impact of CRS on outcomes in these patients is scarce. We retrospectively analyzed 107 consecutive haplo-HSCT and 39 HLA-identical HSCT with PTCy from 2010 to 2017 in our institution. We used published CRS criteria to identify 76% and 14% of patients who developed CRS after haplo-HSCT and HLA-identical HSCT, respectively. Most patients presented CRS grades 1 and 2. Only one patient from the whole series presented grade 3 CRS and required tocilizumab therapy. The use of peripheral blood stem cells (PBSC), as well as total nucleated cells infused were associated with an increased risk of CRS. Patients who presented CRS developed grade II-IV acute GVHD more frequently than those who did not (60% vs 28.6% respectively, P = .012). The development of CRS was not significantly associated with nonrelapse mortality or overall survival. CRS is a frequent complication after PBSC haploidentical T-repleted HSCT, but significantly less frequent after HLA-identical HSCT. Most cases are mild. Prompt identification allows adequate management of severe forms.

Fludarabine, Campath, and Low-Dose Cyclophosphamide (FCClow) with or without TBI Conditioning Results in Excellent Transplant Outcomes in Children with Severe Aplastic Anemia.

Various reduced-intensity conditioning regimens are in use for allogeneic hematopoietic cell transplant (HSCT) in patients with idiopathic severe aplastic anemia (SAA). We describe the use of fludarabine, Campath, and low-dose cyclophosphamide (FCClow) conditioning in 15 children undergoing related or unrelated donor transplants. Total body irradiation (TBI) of 2 Gy was added for unrelated donor HSCT. At a median follow-up of 2.3 years, the failure-free survival was 100%, with low rates of infection and toxicity. There was no occurrence of grade III to IV acute graft-versus-host disease (GVHD). All patients had full donor myeloid chimerism post-HSCT, even with mixed chimerism in the T cell lineage. The absence of chronic GVHD and long-term stable mixed donor T cell chimerism confirms immune tolerance following FCClow (± TBI) conditioned transplantation in children with SAA.

The impact of donor full-length KIR2DS4 in the development of acute and chronic GVHD after unrelated allogeneic HSCT.

Killer Ig-like receptor 2DS4 (KIR2DS4) is the most prevalent activating killer Ig-like receptor gene. It is divergent and encodes either full-length or deleted allele variants. The studies of donor killer KIR2DS4 in unrelated allogeneic hematopoietic stem cell transplantations were limited. KIR and HLA genotyping were determined in 75 pairs of Chinese pediatric hematologic malignancy patients. Among the 75 donor-recipient pairs, 77.3% (58/75) of the donors were positive for full-length KIR2DS4 and 22.7% (17/75) were negative. Patients who had donors positive for full-length KIR2DS4 had higher cumulative incidence of aGVHD than patients whose donor negative for full-length KIR2DS4 (86.2% versus 76.5%, P=.038). Multivariate analysis showed full-length KIR2DS4 was the significant factor for I-IV aGVHD (HR=2.166, 95% CI: 1.01-4.26, P=.025). Subgroup analysis showed that AML and CML patients who received donors negative for full-length KIR2DS4 have a higher cumulative incidences of cGVHD (75% vs 62%, P=.008). There were no significant effects of full-length KIR2DS4 on overall survival (P=.13), relapse-free survival (P=.14), CMV reactivation (P=.52), and relapse (HR=0.38, 95% CI: 0.09-1.6, P=.1875). Our findings indicated a significant correlation of donor full-length KIR2DS4 on aGVHD and cGVHD. These results suggested that combining KIR and HLA genotyping may help make a better sense of transplants in these patients.

T-Cell Reconstitution after Unrelated Donor HSCT Using Immunotherapy with CD25/71 Allodepleted Donor T Cells: Results of the Randomised Icat Study

Karl S Peggs and Sarah J Albon contributed equally to the work and are joint first author Introduction Alemtuzumab reduces the incidence of GVHD after unrelated donor stem cell transplant (MUD SCT) but delays immune reconstitution resulting in high morbidity/mortality from viral infections. Previous studies have suggested that adoptive transfer of allodepleted donor T cells (ADTs) improves immunity after SCT but this has never been tested in a randomised study. We developed a methodology for selective immunomagnetic depletion of alloreactive T-cells upregulating CD25 and CD71 after activation with host dendritic cells (DC) and showed that ADTs retain anti-viral responses with minimal host alloreactivity (Samarasinghe et al Blood 2010). We have now tested whether ADTs can safely be used to improve immune reconstitution after MUD SCT for haematological malignancies in a randomised Phase II multi-centre clinical study; ICAT (NCT01827579). Methods Patients undergoing Alemtuzumab-based peripheral blood SCT from a 9/10 or 10/10 MUD for haematological malignancy were randomised 2:1 to receive either the ATIMP (ADTs) or standard of care. Two weeks prior to SCT, patients randomised to ATIMP underwent a leucapheresis from which DCs were generated. Irradiated patient-derived DCs were then co-cultured with peripheral blood mononuclear cells (PBMC) from an unstimulated leucapheresis/500ml blood draw from the donor to activate alloreactive T cells. Four days later, the co-culture was depleted of CD25+ and CD71+ fractions by immunomagnetic depletion on the CliniMACs, sampled for residual alloreactivity and sterility, and cryopreserved. Patients randomised to the ATIMP were scheduled to receive 3 escalating doses of ADTs (0.1x106/Kg at day 30, 0.3x106/Kg at day 60 and 1x106/Kg at day 90 post-SCT) until either there was &gt;grade 1 aGVHD or they had normal circulating T cells (&gt;700/µL). The primary end-point of the study was circulating CD3+ T cell count at 4 months post-SCT with one-sided 15% significance level. Acute/chronic GVHD were graded using the Seattle/NIH criteria respectively. Results Twenty one patients were treated, 13 on the ATIMP arm and 8 on the control arm. The median age was 53 years and 67% (14) were male. 12 were AML/Myelodysplasia, 5 NHL, 3 CLL/CML and 1 HL. The median follow-up time is 14 months. Five of 13 ATIMP patients received 1 dose of ADTs, 4/13 2 doses and 4/13 all 3 doses. The incidence of acute and chronic GVHD was comparable between the arms. Overall, 7/13 ATIMP patients developed significant (&gt;Grade 2) acute GVHD compared to 4/8 of the control arm (p&gt;0.99). 3/13 patients in the ATIMP arm and 2/8 patients in the control arm developed severe aGVHD (all Grade 3). Three of 13 ATIMP cohort patients developed chronic GVHD (1 mild, 1 moderate, 1 severe), compared to 3/8 (all mild) in the control cohort. At 4 months, the circulating CD3+ T cell count mean was 730/µL (range 10-4080) in the ATIMP group and 212.5/µL (range 10-500) in the control group (1-sided p=0.11). However, the data was not normally distributed (Wilcoxon 1-sided p=0.18). Three ATIMP patients had high CD3+ T cell count at 4 months (&gt;1000/µL). At 6 months, the mean circulating CD3+ T cell count was 833.6/µL (range 20-2690) and 327.5/µL (range 10-860). At month 4, the mean PHA stimulation index in the ATIMP arm was 16.8 (range 0.67- 73.1) vs 3.8 (range 1.1-8.2) in the control group. At 4 and 6 months post-SCT, spectratyping analysis showed no evidence of a difference in Vβ diversity between the 2 arms in both CD4+ and CD8+ cells. The 1-year survival rate in the ATIMP cohort is 92% vs 88% in the control, and 1-year disease free survival rate 67% in the ATIMP cohort vs 70% in the control. Conclusions These data suggest that adoptive transfer of ADTs improves T cell reconstitution in some patients after MUD SCT and that the GVHD rates were similar between ATIMP and control groups. Figure 1: Kinetics of T cell recovery after transplant in ATIMP (blue) and Control (red) patients. Mean +/- SEM shown. Figure 1 Disclosures Peggs: Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees. Ghorashian:UCLB: Patents &amp; Royalties: UCLB; Celgene: Honoraria; novartis: Honoraria. Amrolia:UCLB: Patents &amp; Royalties.

From Ex-Vivo T-Cell Depletion to Post-Transplant Cyclophosphamide: Improved GvHD-Free & Relapse-Free Survival but Comparable Chronic GvHD Incidence in Haploidentical Transplantation. A 15 Years EBMT Registry Analysis on Behalf of the TCWP-EBMT

Background: Haploidentical stem cell transplantation (Haplo HSCT) has emerged in the past three decades as an alternative curative option when an HLA match donor is not available. Over time, the use of Haplo has increased dramatically, reaching superimposable results when compared to unrelated and related HSCT strategies, confirming its validity. The widespread use of Haplo mainly relies upon technical advances, control of alloreactivity through graft-versus-host disease (GvHD) prophylaxis combined with a rapid and almost universal probability to find an Haplo donor for any candidate patient. The aim of our study was to provide a picture of acute (aGvHD) and chronic GvHD (cGvHD) incidence in Haplo HSCT across different platform in the past 15 years, where Haplo moved from ex-vivo T-cell depleted (TCD) platform to in-vivo TCD platform to the post-transplantation cyclophosphamide (PTCy). Methods: We compared the outcomes of adult patients receiving a 1st Haplo HSCT for any hematological malignancy according to GvHD prophylaxis - ex-vivo + in-vivo TCD (n=160), in-vivo only TCD (n=507) or PTCy (n=2593) - and reported to the EBMT registry in 2004-2016. Patients with missing data on disease status at last follow-up and GvHD information were excluded. Primary endpoint was GvHD-free &amp; Relapse-free survival (GRFS) with events defined by death or relapse or grade ≥3 aGvHD or extensive (ext) cGvHD. Secondary endpoints were progression-free survival (PFS), overall survival (OS), aGvHD and cGvHD, incidence of relapse (IR) and non-relapse-mortality (NRM). Due to sample size in the first cohort of ex-vivo TCD, multivariate analysis compared only in-vivo TCD vs PTCy cohorts. Table 1 illustrates patients' characteristics. Results: Univariate analysis for 3-year outcomes are reported on table 2. PTCy provides better GRFS, OS, PFS, NRM versus ex-vivo or in-vivo. IR was not significantly different. Likewise, the 3-year CI of cGvHD and ext cGvHD were similar between PTCy, in vivo TCD and ex-vivo TCD (cGvHD 27% [25-29%], 25% [21-29%], 18% [12-25%], p 0.03; ext cGvHD 11% [10-12%], 10% [8-13%], 8% [4-13%], p 0.45). On the contrary the 100-day CI of grade ≥2 aGvHD were lower in the ex-vivo TCD vs PTCy and in-vivo TCD (19% [14-26%], 28% [26-30%], 32% [28-36%], p 0.002) while grade ≥3 aGvHD were lower in the PTCy group vs ex-vivo and in-vivo TCD (9% [8-10%], 11% [7-17%], 14% [11-18%], p &amp;lt;0.001). After adjustment for diagnosis, patient age, disease status, Karnofsky PS, donor/patient gender and CMV, cell source, conditioning intensity, previous auto and year of transplant, the multivariable model comparing in-vivo TCD and PTCy showed better outcome for PTCy. Compared to in-vivo TCD, the hazards for GRFS was 0.76 for PTCy (p 0.004), the HR for PFS was 0.71 (p 0.001) and the HR for OS was 0.7 (p 0.0008), the HR for NRM was 0.63 (p 0.001). Moreover, compared to in-vivo TCD, PTCy yielded similar hazards for grade≥2 aGvHD (HR: 1.02, p 0.89), grade≥3 aGvHD (HR 0.79, p 0.27), cGvHD (HR 1.17, p 0.37), ext cGvHD (HR 1.18, p 0.52) and relapse (HR 0.8, p 0.1). Variables associated with GRFS were active disease, Karnofsky PS ≥90%, diagnosis, donor/patient gender and CMV. An ancillary analysis evaluating the stem cell source effect in the PTCy cohort only, demonstrates comparable outcome endpoints (OS, PFS, NRM, IR) at 2-year between bone marrow (BM) and peripheral blood (PB) PTCy. In univariate analysis GRFS and the 2-year CI of cGvHD were not different between BM and PB (GRFS 47% [45-50%], 46% [44-49%], p 0.085; 2-year CI of cGvHD 25% [23-28%], 27% [25-30%], p 0.2) while ext cGvHD, 100-day CI of grade ≥2 aGvHD and grade ≥3 aGvHD were lower in BM PTCy vs PB PTCy (ext cGvHD 8% [7-10%], 12% [10-14%], p &amp;lt;0.001; grade ≥2 aGvHD 20% [18-22%], 36% [33-38%], p &amp;lt;0.001; grade ≥3 aGvHD 6% [5-7%], 12% [10-14%], p &amp;lt;0.001). Compared to BM PTCy, the HR for cGvHD was 1.55 for PB PTCy (p 0.001), the HR for ext cGvHD was 2.04 (p 0.0003), the HR for grade ≥2 aGvHD was 1,94 (p &amp;lt;0.0001), the HR for grade ≥3 aGvHD was 2.01 (p 0.0001). Conclusions: In the present EBMT registry study on more than 3000 patients transplanted from an Haplo donor, we report improved outcome (better GRFS - in spite of comparable chronic GvHD - OS and PFS, lower NRM) and widespread use in different diagnosis setting other than acute leukemia in PTCy platform. PTCy strategy provides a concrete progress into the field: even if cGvHD still represent a major issue, exploitation of BM PTCy seems to protect against most severe GvHD manifestation. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Basak:Celgene: Honoraria; Teva: Honoraria.

Allogeneic Hematopoietic Stem Cell Transplantation in Patients of 65 Years or Older: A Monocenter Analysis on 252 Patients

Advanced hematologic malignancies in older patients are unmet medical needs due to increased incidence in the aging population and the lack of effective treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potential curative option for most of hematologic malignancies. However, two main limitations limited this development for a long period of time. High rates of fatal non-relapse morbidities have been progressively addressed using reduced toxicity conditioning approaches and pushing up the age limit of patients considered for transplant. The search for a donor has been also a high limitation in older population, due to the lower incidence of matched sibling donors in this population. The development of allo-HSCT from a familial haplo mismatch donor (Haplo donor) after a reduced intensity (RIC) or non-myeloablative conditioning (NMAC) has allowed for the recent development of allo-HSCT in older population. Here we analyzed a cohort of 252 consecutive patients aged of 65 years or older treated in a single institution. Patients were selected on the following parameters: age of 65 or older on the day of transplant, first allogeneic transplant, no unrelated cord blood HSCT, hematologic malignancies, transplant between 01/01/2004 and 31/12/2018. During this period of time, the search for a one-mismatch haplotype donor (Haplo) has been introduced, the upper limit age for transplant progressively increased, more advanced diseases were considered and patients have gradually benefit from improvement in transplant care. Patient characteristics: Median age: 67,9 (65-77) years; Male patients: 61 %; CMV Positive (70%); Acute leukemia (AL): 43%; Myelodysplastic/myeloproliferative syndromes (MDS/MPS): 35%; Chronic Leukemia: 5%; Lymphoma: 11%; Plasma cell disorders (PCD): 6%. Complete remission (CR) or Chronic phase: 155 (62%) (of whom 81 CR1 AL) Donor characteristics: median age: 62,45 (19-77); Male patients: 63 %; Matched sibling donor (MSD) (24%): 60: Unrelated donor: 75 (29%); Haplo Donor: 118 (47%). Transplant characteristics: % patients per period of time: year range: 2004-2010: 12% (Median age: 67; % Haplo D: 0; No CR/CP: 23%); 2011-2015: 40% (Median age: 68; % Haplo D: 35%; No CR/CP: 39%); 2016-2018: 48% (Median age: 69; % Haplo D: 69%; No CR/CP: 42%); PBSC: 97%; Non Myeloablative/ Reduced toxicity conditioning: 35%/65%; All patients received Post-Transplant (PostT) CSA; PT Cyclophosphamide: 49%; Pre-Transplant ATG: 47%. Median follow-up: 17 (3-112) months; ANC recovery in 96%: 19 (10-44) days; untransfused platelet recovery above 20 in 75%: 17 (7-56) days. In evaluable patients for aGVHD: No: 58%; Grade 1: 13%; Grade 2: 14%; Grade 3: 10%; Grade 4: 4%; 85% patients were evaluable for cGVHD: No: 68%; limited: 17%; extensive:16%; 64 patients (25%) patients died from non-relapse mortality at a median of 122 days (13-3934): 2004-2010: 10/30 (33%); 2011-2015: 36/101 (25%); 2016-2018: 28/121 (23%); 53 patients relapsed/progressed at a median of 252 (30-2764) days. Three year overall and disease-free survivals are respectively of 56% (95% CI: 6.35-7.04) and 47% (95% CI: 7.17-7.55) without any difference according to age or donor type but with an impact of disease status (EFS: CR/CP 51% (95% CI: 8.7-9.5) vs others 38% ((95% CI: 11.9-12.0)) Overall these data show that allo HSCT is a valid option in older patients with high-risk malignancies. They show also that over a long period of time patient typology (more advanced diseases, older patients) and transplant practice (lower number of MSD) show a regular evolution making transplant realization more challenging. This field needs specific approach taking into account comorbidities, performance status and geriatric evaluation, to adapt treatment to every given patient. In this perspective we performed from 2015 in patients older than 65 years systematic and combined evaluation of comorbidities score, performance status and geriatric assessment (instrumental activity of daily living (AIDL); vulnerability assessment). Disclosures Chabannon: Sanofi SA: Other: research support, speaker's fees, hospitalities; Gilead: Other: speaker's fees, hospitalities; Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Terumo BCT: Other: speaker's fees; Miltenyi Biotech: Other: research support; Fresenius Kabi: Other: research support; EBMT: Other: Working Party Chair, Board member. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria.