Matched Unrelated Donor Hematopoietic Stem Cell Transplantation Research Articles

Retrospective study to compare the outcomes of matched related donor vs matched unrelated donor in patient with acute myeloid leukaemia

BackgroundIndia's need for bone marrow donation and transplantation is increasing in the context of the rising incidence of haematological neoplasms like acute myeloid leukaemia (AML). The use of matched related donors (MRD) for hematopoietic stem cell transplantation (HSCT) is a feasible option, but the lack of HLA-matched donors in India remains a significant obstacle to successful treatment. MethodologyThis retrospective study was conducted at the Department of Hemato-Oncology & Bone Marrow Transplant, Rajiv Gandhi Cancer Institute in New Delhi, India over a period of 6 months. The study enrolled 77 AML MRD and 19 AML MUD patients based on the inclusion and exclusion criteria. ResultThe one-year survival rate was higher in MRD than in MUD, but there was no significant difference in mortality in multivariate analysis. The study also found that chronic graft-versus-host disease (GVHD) and relapse were associated with worse survival outcomes in both MRD and MUD HSCT. ConclusionThis study supports the use of matched unrelated donor (MUD) transplant for HSCT in AML patients when a matched sibling donor is not available.

Post-Transplant Cyclophosphamide versus Anti-Thymocyte Globulin in Patients with Hematological Malignancies Treated with Allogeneic Hematopoietic Stem Cell Transplantation from Haploidentical and Matched Unrelated Donors: A Real-Life Experience.

Background: Post-transplant cyclophosphamide (PTCY) is widely used as graft versus host disease (GvHD) prophylaxis in allogeneic hematopoietic stem cell transplant (HSCT) recipients, with reported clinical benefits in patients who underwent transplant from a matched unrelated donor (MUD). However, real-life data on clinical efficacy and safety of PTCY in haploidentical and MUD transplantations are still poor. Methods: In our real-life retrospective observational study, we included a total of 40 consecutive adult patients who underwent haploidentical or MUD HSCT for various hematological malignancies and who received PTCY (n = 24) or ATG (n = 16) as GvHD prophylaxis at Hematology Units from hospitals of Salerno and Avellino, Italy, and clinical outcomes were compared. Results: We showed protective effects of PTCY against disease relapse with the relapse rate after transplantation of 16% versus 50% in the ATG arm (p = 0.02). All-cause mortality was lower (36% vs. 75%; p = 0.02) and the 2-year overall survival was slightly superior in patients administered PTCY (61% vs. 42%; p = 0.26). Conclusions: We support the use of PTCY, even in a real-life setting; however, the optimization of this protocol should be further investigated to better balance relapse prevention and GvHD prophylaxis.

Alemtuzumab, Dual Graft-versus-Host Disease Prophylaxis, and Lower CD3+ T Cell Doses Equalize Rates of Acute and Chronic Graft-versus-Host Disease in Pediatric Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation with Matched Unrelated Donor Peripheral Blood Stem Cells or Bone Marrow Grafts

Data comparing hematopoietic stem cell transplantation (HSCT) using bone marrow (BM) or peripheral blood stem cell (PBSC) grafts in children after alemtuzumab-based conditioning are lacking. We investigated whether in vivo T cell depletion using alemtuzumab could reduce the risk of severe acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) after HSCT with matched unrelated donor (MUD) BM or PBSCs. This retrospective multicenter study included 397 children (BM group, n = 202; PBSC group, n = 195) who underwent first MUD HSCT at 9 pediatric centers in the United Kingdom between 2015 and 2019. The median age at transplantation was 7.0 years (range, .1 to 19.3 years), and the median duration of follow-up was 3.1 years (range, .3 to 7.5 years). The 3-year overall survival was 81% for the entire cohort (BM group, 80%; PBSC group, 81%). The incidence of grade II-IV aGVHD was significantly higher in the PBSC group (31%) compared to the BM group (31% versus 19%; P = .003), with no difference in the incidence of grade III-IV aGVHD (BM, 7%; PBSC, 12%; P = .17). CD3+ T cell dose >5 × 108/kg and the use of PBSCs were independent predictors of grade II-IV aGVHD. When considering CD3+ T cell dose and GVHD prophylaxis, PBSC transplantation with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) and a CD3+ T cell dose ≤5 × 108/kg had a comparable grade II-IV aGVHD to BM transplantation plus a CNI (20% versus 18%; P = .52). PBSC transplantation was associated with a lower incidence of cGVHD compared to BM transplantation (6% versus 11%; P = .03). Within the limits of this study, we identified a potential strategy to reduce the risk of severe GVHD in pediatric PBSC recipients that includes a combination of in vivo T cell depletion using alemtuzumab and dual GVHD prophylaxis (with a CNI and MMF) and limiting the CD3+ T cell dose to ≤5 × 108/kg.

A phase 2 trial of CD24Fc for prevention of graft-versus-host disease

AbstractPatients who undergo human leukocyte antigen–matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor–based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD–free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD–free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622.

331 - Outcomes of Posttransplant Cyclophosphamide with Mycophenolate and Tacrolimus As Prophylaxis for Graft Versus Host Disease in Matched-Related and Matched-Unrelated Donor Hematopoietic Stem-Cell Transplantation: A Single Center Experience

331 - Outcomes of Posttransplant Cyclophosphamide with Mycophenolate and Tacrolimus As Prophylaxis for Graft Versus Host Disease in Matched-Related and Matched-Unrelated Donor Hematopoietic Stem-Cell Transplantation: A Single Center Experience

Impact of FLT3 Inhibitor-Based Therapies on Outcomes of Acute Myeloid Leukemia (AML) Patients Receiving Allogenic Stem Cell Transplantation: A Retrospective Study

Background The FMS-like tyrosine kinase 3 (FLT3) mutation affects approximately 30% of patients with acute myeloid leukemia (AML) and is associated with increased relapse and mortality. FLT3 inhibitors are known to improve survival when used in the induction, consolidation and relapsed/refractory phases of AML. However, due to their novelty, little is known about the impact of FLT3 inhibitors on graft-versus-host disease (GVHD), relapse and survival after hematopoietic stem cell transplantation (HSCT). Methods We retrospectively analyzed adult patients treated at the University of Southern California Norris Comprehensive Cancer Center between May 2017 and July 2022. All patients had an AML diagnosis with either a FLT3-ITD or FLT3-TKD mutation, received a FLT3 inhibitor at one or more time points during their treatment course, and underwent HSCT. Our primary endpoint was graft-versus-host disease-free, relapse-free survival (GRFS). Secondary endpoints included 2-year overall survival (OS), 2-year relapse-free survival (RFS), and FLT3 inhibitor discontinuation due to adverse side effects. Acute GVHD was defined per the 2018 MAGIC criteria and chronic GVHD was defined per the 2014 NIH criteria. Results Of the 40 patients included in this study, 30 (75%) had the FLT3-ITD mutation, and 10 (25%) had the FLT3-TKD mutation. Age at time of HSCT ranged from 30-69 years old (median= 47). Males and females were evenly represented, and most patients were Hispanic (55%). The majority of patients (67.5%) were in first complete remission (CR1) at the time of HSCT. ELN 2022 genetic risk stratification was mainly intermediate (77.5%) and adverse (15%). All patients received peripheral blood stem cells, and most (70%) underwent myeloablative conditioning regimens. All patients received a FLT3 inhibitor before HSCT, during the induction/consolidation phase or relapsed/refractory phase before achieving CR. Of the 29 patients who used maintenance therapy after HSCT, 18 (62%) received gilteritinib while 11 (38%) received midostaurin. Using Cox survival analysis, univariate predictors of adverse events in GRFS were matched unrelated donor (MUD) when compared to haploidentical-HSCT (HR = 4.77, p=0.023), pre-transplant ATG (HR =3.99, p=0.049), and lack of maintenance FLT3 inhibitors (HR = 3.03, p = 0.034). On bivariate analysis, MUD HSCT continued to be predictive when controlling for time from induction to HSCT (Table 1, Model 2) and age at HSCT (Table 1, Model 3). Patients who received a FLT3 inhibitor for post-HSCT maintenance therapy had significantly improved OS (p = 0.033) and RFS (p=0.016) on Kaplan-Meier survival analysis, with an OS of 96.2% and RFS of 89.7% at 24 months, and an OS of 90.1% and RFS of 82.8% at 36 months. Eight patients discontinued FLT3 inhibitors at maintenance due to side effects, having a shorter length of FLT3 inhibitor use, 116 days vs. 230 days (p = 0.005). Discussion Our results found multiple factors were associated with worsened GRFS, including MUD transplant, pre-transplant ATG and lack of maintenance FLT3 inhibitors. Post-HSCT maintenance, primarily with gilteritinib, resulted in improved OS and RFS in our patients, similar to the findings of prior studies with other FLT3 inhibitors. Amongst our patients receiving FLT3 inhibitors for maintenance, OS at 24 months was 96.2% compared to prior reports of 90.5% with sorafenib and 85% with midostaurin. RFS in our FLT3 inhibitor maintenance group was 89.7% at 24 months, compared to prior reports of 85% with sorafenib and midostaurin. OS and RFS for our FLT3 inhibitor maintenance group remained high at 36 months. Additional studies, such as the ongoing phase III clinical trial BMT CTN Protocol 1506, can be used to confirm our findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Cytomegalovirus Infection with Post-Transplantation Cyclophosphamide in Haploidentical and HLA-Matched Unrelated Donor Transplantation

Post-transplantation cyclophosphamide (PTCy) is effective for graft-versus-host disease (GVHD) prevention but is associated with an increased risk of cytomegalovirus (CMV) infection. The effect of PTCy on CMV infection in matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) is unclear, and whether there is any difference in CMV risk with 1 or 2 doses of PTCy is not well established. This study aimed to compare the incidence of CMV infection and the association between T cell recovery in patients who received PTCy-based GVHD prophylaxis and those who received non-PTCy-based GVHD prophylaxis. We conducted a retrospective study to compare the risk of CMV infection in 3 cohorts: cohort A (n=94), matched related donor (MRD)/MUD HSCT with calcineurin inhibitor-based GVHD prophylaxis; cohort B (n=103), MRD/MUD HSCT with 1 dose of PTCy, tacrolimus, and mycophenolate mofetil (MMF); and cohort C (n=28), haploidentical donor HSCT with 2 doses of PTCy, tacrolimus, and MMF. The day +100 cumulative incidence of CMV infection was 29% for cohort A, 39% for cohort B, and 61% for cohort C (P=.009), with no difference among the cohorts in the duration of viremia (P=.46). CD3+ and CD4+ T cell counts were significantly higher in cohort A at day +30 but not at days +60 and +90. Nonrelapse mortality (NRM) trended higher and relapse was significantly lower with PTCy. There was no difference in survival among the 3 cohorts. There is an increased risk of early CMV infection in patients receiving PTCy irrespective of donor type and number of PTCy doses compared with those not receiving PTCy. Strategies focusing on CMV prevention in PTCy recipients to mitigate the risk of NRM may lead to improved long-term outcomes.

Post-Transplantation Cyclophosphamide-Based Haploidentical versus Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

The use of haploidentical related donors (HRDs) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). However, there have been no studies comparing HRD HSCT with post-transplantation cyclophosphamide (PTCy) and matched unrelated donor (MUD) HSCT with antithymocyte globulin using similar busulfan-based myeloablative conditioning regimens in pediatric acute leukemia. Here we compared the outcomes in children and adolescents with high-risk acute leukemia who underwent HRD HSCT with PTCy (n=35) or MUD HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median duration of follow-up was 3.7 years in the HRD group and 4.6 years in the MUD group. No engraftment failure was observed in either group. There were no significant between-group differences in the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) (34.3% versus 48.9%; P=.142), grade III-IV acute GVHD (2.9% versus 8.9%; P=.272), moderate to severe chronic GVHD (11.4% versus 18.3%; P=.417), relapse (25.6% versus 28.0%; P=.832), and nonrelapse mortality (0% versus 2.2%; P=.420). The 3-year severe chronic GVHD-free/relapse-free survival (GRFS), leukemia-free survival (LFS), and overall survival (OS) rates in the HRD and MUD groups were 62.9% (95% confidence interval [CI], 45.8% to 80.0%) versus 49.8% (95% CI, 34.9% to 64.7%; P=.318), 74.4% (95% CI, 58.7% to 90.1%) versus 67.5% (95% CI, 53.4% to 81.6%; P=.585), and 88.6% (95% CI, 78.0% to 99.2%) versus 83.7% (95% CI, 72.5% to 94.9%; P=.968), respectively. In a subgroup analysis of patients with acute lymphoblastic leukemia (HRD, n=17; MUD, n=26), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 49.4% (95% CI, 24.3% to 74.5%) versus 39.5% (95% CI, 19.7% to 59.3%; P=.601), 61.8% (95% CI, 37.5% to 86.1%) versus 63.6% (95% CI, 44.4% to 82.8%; P=.872), and 82.4% (95% CI, 64.4%, 100%) versus 84.2% (95% CI, 70.1% to 98.3%; P=.445), respectively. In patients with acute myelogenous leukemia (AML) (HRD, n=16; MUD, n=16), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 80.8% (95% CI, 61.2% to 100%) versus 61.9% (95% CI, 37.8% to 86.0%; P=.326), 87.1% (95% CI, 70.2% to 100%) versus 73.9% (95% CI, 51.8% to 96.0%; P=.478), and 93.8% (95% CI, 81.8% to 100%) versus 85.6% (95% CI, 67.0% to 100%; P=.628), respectively. Although the difference was not statistically significant and the number of patients was small, the promising outcomes of HRD HSCT in AML patients were encouraging. Our results demonstrate that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen has outcomes similar to those of MUD HSCT with antithymocyte globulin. HRD HSCT with PTCy could be a feasible option for pediatric high-risk acute leukemia patients who lack an HLA-matched related or unrelated donor.

Turn around time in matched unrelated donor search workup national versus international registries: Retrospective study

Background: Timeline is a key factor for hematopoietic stem cell transplant (HSCT) recipient. HSCT by matched unrelated donor (MUD) is a standard definitive therapeutic approach for many hematological disorders which are not amenable to chemotherapy and other conventional treatment. Aims and Objectives: The aim of the present study was to compare the turnaround time (TAT) involved in completion of MUD HSCT workup from an Indian registry (Genebandhu) with international registries. Materials and Methods: On receipt of pre-transplant matching request through a transplant physician, patient's human leukocyte antigen (HLA) type was entered in both Genebandhu and World Marrow Donor Association search tool for initiating a “search.” The software gave the descending order of the best possible matches by performing computational analysis. The search result was considered a “match” when potential 10/10 HLA match was found. The average TAT was calculated in the middle of search request and HLA confirmatory typing (CT) and infectious disease marker (IDM). Further, TAT was also determined between the infusion of harvested stem cell product and CT and IDM. At last, the total time engaged in completion of each MUD HSCT workup was determined and compared in national versus international registries. Results: The average TAT involved in between search request and CT and IDM was 71 days in case of global registry and 67 days in case of Genebandhu. Similarly, the average TAT involved between infusion of harvested cell product and CT and IDM testing in case of donor identified in global stem cell registry was 65 days whereas 45 days in case of Genebandhu. At last, the average time associated with the finishing of a MUD workup was 136 days in case of global registry, whereas 112 days in the case of Genebandhu at P ≤ 0.05 with a 95% confidence interval. Conclusion: To conclude, the average TAT obtained through this study clearly demonstrates the advantages in terms of donor availability for MUD HSCT through the national registry.

Cost Utility of Lifelong Immunoglobulin Replacement Therapy vs Hematopoietic Stem Cell Transplant to Treat Agammaglobulinemia

Lifelong immunoglobulin replacement therapy (IRT) is standard-of-care treatment for congenital agammaglobulinemia but accrues high annual costs ($30 000-$90 000 per year) and decrements to quality of life over patients' life spans. Hematopoietic stem cell transplant (HSCT) offers an alternative 1-time therapy, but has high morbidity and mortality. To evaluate the cost utility of IRT vs matched sibling donor (MSD) and matched unrelated donor (MUD) HSCT to treat patients with agammaglobulinemia in the US. This economic evaluation used Markov analysis to model the base-case scenario of a patient aged 12 months with congenital agammaglobulinemia receiving lifelong IRT vs MSD or MUD HSCT. Costs, probabilities, and quality-of-life measures were derived from the literature. Microsimulations estimated premature deaths for each strategy in a virtual cohort. One-way sensitivity and probabilistic sensitivity analyses evaluated uncertainty around parameter estimates performed from a societal perspective over a 100-year time horizon. The threshold for cost-effective care was set at $100 000 per quality-adjusted life-year (QALY). This study was conducted from 2020 across a 100-year time horizon. Immunoglobulin replacement therapy vs MSD or MUD HSCT for treatment of congenital agammaglobulinemia. The primary outcomes were incremental cost-effectiveness ratio (ICER) expressed in 2020 US dollars per QALY gained and premature deaths associated with each strategy. In this economic evaluation of patients with congenital agammaglobulinemia, lifelong IRT cost more than HSCT ($1 512 946 compared with $563 776 [MSD] and $637 036 [MUD]) and generated similar QALYs (20.61 vs 17.25 [MSD] and 17.18 [MUD]). Choosing IRT over MSD or MUD HSCT yielded ICERs of $282 166 per QALY gained over MSD and $255 633 per QALY gained over MUD HSCT, exceeding the US willingness-to-pay threshold of $100 000/QALY. However, IRT prevented at least 2488 premature deaths per 10 000 microsimulations compared with HSCT. When annual IRT price was reduced from $60 145 to below $29 469, IRT became the cost-effective strategy. Findings remained robust in sensitivity and probabilistic sensitivity analyses. In the US, IRT is more expensive than HSCT for agammaglobulinemia treatment. The findings of this study suggest that IRT prevents more premature deaths but does not substantially increase quality of life relative to HSCT. Reducing US IRT cost by 51% to a value similar to IRT prices in countries implementing value-based pricing may render it the more cost-effective strategy.

Posttransplant Cyclophosphamide-Based Haploidentical Vs Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

Haploidentical related donor (HRD) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis is an attractive option when performing a HRD HSCT because of its promising outcomes and easy application. However, there have been no studies comparing HRD HSCT with PTCy and MUD HSCT with antithymocyte globulin, using similar busulfan-based myeloablative conditioning regimen in pediatric acute leukemia. Herein, we compared the outcomes in children and adolescents with acute leukemia after HRD HSCT with PTCy (n=35) and matched unrelated donor (MUD) HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median follow-up times of the HRD and MUD groups were 3.7 and 4.6 years. No engraftment failure was observed. The cumulative incidence of GVHD grades II-IV (34.3% versus 48.9%, p=0.142), grades III-IV (2.9% vs. 8.9%, p=0.272), extensive chronic GVHD (11.4% vs. 18.3%, p=0.417), relapse (25.6% vs. 28.0%, p=0.832), and non-relapse mortality (0% vs. 2.2%, p=0.420) were not significantly different. The 3-year severe chronic GVHD-free/relapse-free, leukemia-free and overall survival rates in the HRD and MUD groups were 62.9±8.7% versus 49.8±7.6% (p=0.318), 74.4±8.0% versus 67.5±7.2% (p=0.585), and 88.6±5.4% versus 83.7±5.7% (p=0.968), respectively. In subgroup analyses of patients with acute lymphoblastic leukemia and acute myeloid leukemia, there were no significant differences in outcomes between the groups. Our results demonstrated that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning shows outcomes similar to those of MUD HSCT. HRD HSCT with PTCy could be considered for pediatric acute leukemia patients who lack an HLA-matched donor. DisclosuresKang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding.

CD34+ Stem Cell Selection and CD3+ T Cell Add-Back from Matched Unrelated Adult Donors in Children with Primary Immunodeficiencies and Hematological Diseases

Less than 25% of children who require hematopoietic stem cell transplantation (HSCT) for primary immunodeficiencies (PIDs) or genetic hematological diseases have an HLA-identical sibling. For them, a matched unrelated donor (MUD), although baring a greater risk of graft failure, delayed engraftment and immune reconstitution, and severe graft-versus-host disease (GvHD), represents a valid alternative. The stem cell source is also important, as unprocessed peripheral blood stem cells (PBSCs) contain 5 to 10 times more T cells than bone marrow (BM)-derived grafts, a major risk especially for small children with PID. A CD34+ positive selection can mitigate HLA compatibility issues, but the resulting CD3+ T cell depletion hampers engraftment and facilitates infections. To mitigate those problems, we decided to add back a certain number of T cells (30×106 cells/kg body weight [BW]) to the positive CD34+ selection derived from MUD BM or PBSCs and report the results in terms of time to engraftment and immune reconstitution, GvHD incidence, infections, and survival. Our aim was to show not only the feasibility and clinical efficacy of this addback but also that PBSC-derived CD34+ selected grafts with calibrated T cell addback would be equivalent to BM-derived grafts. We analyzed retrospectively our single-center cohort of 76 children (median age, 1.9 years) affected by PID (61) and hematological diseases (15) who received a total of 79 MUD HSCTs with CD34+ selection and addback of 30×106 CD3+ cells/kg BW between 2001 and 2019. We used descriptive and analytic statistics (chi-square, Student's t-test, Mann-Whitney U test, as appropriate) and constructed Kaplan-Meier curves using the log-rank test to compare patients grafted with BM or PBSC-derived inocula. The two groups showed no statistically significant differences in terms of age, sex, HLA-mismatch, or amount of CD3+ cells/kg BW added back to the CD34+ selection. However, the latter being higher in the PBSC group (P=.0001). Overall engraftment rate was 96% (73/76) and occurred faster in the PBSC group than in BM recipients: polymorphonuclear cells, 16 versus 21 days (P=.006); platelets, 15 versus 22 days (P=.001). GvHD incidence was low. No acute GvHD was diagnosed in 24 children, whereas grades I, II, III, and IV occurred in 19, 28, five, and three children, respectively (P not significant). Chronic GvHD was seen in only two children. The CD4+ count at six months after HSCT was higher in PBSC recipients as compared to those receiving BM (184 versus 88 CD4+ cells; P=.003). Overall survival for the whole cohort was 80% at 10 years, with no significant difference between the two stem cell sources (P not significant). Viral infections occurred among five of the PBSC grafted children and 14 in the BM group (P not significant), and no patient suffered from post-transplant lymphoproliferative disorder (PTLD). The results we present show that an addback of 30×106 donor CD3+ cells/kg recipient BW to a MUD BM or PBSC-derived CD34+ selection gives promising results in infants and young children undergoing HSCT for PID or hematological diseases. Furthermore, with this manipulation the inherent limits of PBSC-derived grafts can be overcome, allowing both swift engraftment and immune reconstitution without an increase in GvHD, infections, or PTLD.

Pretransplant myeloid and immune suppression, reduced toxicity conditioning with posttransplant cyclophosphamide: Initial outcomes of novel approach for matched unrelated donor hematopoietic stem cell transplant for hemoglobinopathies.

Hematopoietic stem cell transplant (HSCT) is currently the only curative option for thalassemia major (TM) and sickle cell disease (SCD). We report our experience of using pretransplant immune suppression (PTIS), augmented Johns Hopkins conditioning, and posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GvHD) prophylaxis for matched unrelated donor (MUD) transplant in TM/SCD. At a median follow-up of 307.5days (range 251-395), all patients (three TM, one SCD) are alive and disease free. MUD HSCT with PTIS, augmented Johns Hopkins conditioning, and PTCy as GvHD prophylaxis is a promising way of treating patients with hemoglobinopathies with low regimen-related toxicity (RRT), no risk of graft failure (GF) and minimal GvHD rates.

Matched unrelated donor hematopoietic stem cell transplantation: Roles and responsibilities of workup coordinator - An observational study

Background: With only 25% chances of finding a human leukocyte antigen matched stem cell donor within the family, in case of minimal residual disease, the dependence on matched unrelated donor (MUD) is inevitable. With increasing awareness about the MUD stem cell registries, the numbers of registrations for voluntary stem cell donations are also increasing each day. A workup coordinator is a strong and the most crucial link in the MUD hematopoietic stem cell transplantation (HSCT) workup. The coordination between the stem cell registry and transplant center TC in need of a MUD HSCT workup is handled by a workup coordinator. Aims and Objectives: The aim here is to highlight key roles and responsibilities of workup coordinators, without whom it can be impossible to complete a MUD HSCT. Materials and Methods: We accessed the roles and responsibilities of workup coordinators via the MUSD HSCT workup assisted by Genebandhu from May 2012 to August 2020. The methodology mainly involved was electronic communication between stem cell registry/transplant center (TC)/donor center/collection center/patient/donor. All these activities of coordinators were closely observed to understand their roles, requirements, and responsibilities in detail. Results: The workup coordinator has been successfully involved in 33 MUD HSCT workups since its inception. Out of these, 18 were from international stem cell registries and 15 with TC s from India. Discussion: Workup coordinator acts like a catalyst during a MUD HSCT. Appropriate and timely exchange of information between the registry and the TC is managed by a coordinator. Conclusion: This study showed the crucial role, requirements, and responsibilities of the coordinators and their importance in MUD HSCT workups.

Comparison of mycophenolate mofetil and calcineurin inhibitor versus calcineurin inhibitor-based graft-versus-host-disease prophylaxis for matched unrelated donor transplant in acute myeloid leukemia. A study from the ALWP of the EBMT.

The association of Cyclosporine A (CsA) and mycophenolate mofetil (MMF) has increased in the setting of reduced intensity conditioning (RIC). Nevertheless, the use of CsA or CsA+MMF has not been reported in a large and uniform cohort. We analyzed 497 patients with acute myeloid leukemia in complete remission (CR) who underwent matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT). All patients received a fludarabine busulfan RIC regimen and anti-thymocyte globulin (ATG) with either CsA alone or in combination with MMF. The cumulative incidence (CI) of grade II-IV acute GvHD was 27% (95% CI 21-33%) for CsA and 33% (95% CI 27-38%) for CsA+MMF (p = 0.25). The 2-year CI of chronic GvHD was 38% (95% CI 31-45%) and 33% (95% CI 28-39%) for the CsA and the CsA+MMF group, respectively (p = 0.26). On multivariate analysis, no statistically significant differences with respect to relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), acute and chronic GvHD were found between the two groups, also when conducting a subgroup analysis in peripheral blood stem cells (PBSC) recipients. Our results support the importance of randomized trial to identify patients who could benefit from the addition of MMF in MUD HSCT.

Outcomes of Allogeneic Stem Cell Transplantation with Individualized Dosing of Antithymocyte Globulin

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. However, relapse disease and graft-versus-host disease (GVHD) remain to be the main obstacle for a successful HCT. Thus, adequate immune suppression to minimize the risk of high-grade GVHD while not over suppression of donor immunity to allow graft versus tumor effect is crucial. Matched unrelated donor transplant has a higher rate of GVHD as compared to matched sibling donor transplant due to minor histocompatibility mismatch. Rabbit antithymocyte globulin (ATG), a polyclonal antibody produced by immunizing rabbits with human thymocytes, has been utilized as prophylaxis against GVHD. ATG dosing by weight has been the standard. Recent pharmacokinetic (PK) studies revealed that ATG levels and clearance vary significantly among patients receiving weight-based dosing of ATG. Recipient lymphocyte count before receiving ATG has been described as a modulator of both ATG PK and clinical outcomes after ATG-conditioned HCT. The Parachute-Study utilizing an individualized ATG dosing approach has shown more rapid immune reconstitution without affecting the incidence of acute GVHD and graft failure. In this study, we are comparing the outcomes of individualized dosing of ATG versus weight-based dosing. Method: This is a single institutional study carried out at the Bone Marrow Transplant Program at the University of Oklahoma Health Science Center. It was started as a case-control cohort study in July 2018 when individualized dosing of ATG was initiated, and continues as a historically controlled non-randomized prospective clinical study investigating individualized versus weight-based dosing of ATG. Subjects over 18 years of age who are undergoing matched unrelated donor (MUD) stem cell transplant, with myeloablative or reduced-intensity conditioning, peripheral blood or bone marrow stem cell source, for myeloid or lymphoid malignancies were included in the study. We excluded subjects with HLA mismatch or sibling donors. Individualized dosing was based on the previously validated PK model with cumulative doses varying between 2 to 10 mg/kg, based on weight, recipient lymphocyte counts before the first dose of ATG, and stem cell source, starting day -9; while the standard weight-based dosing of ATG is 4 mg/kg divided into 3 days pre-transplant. The study endpoints are to evaluate the difference between treatment groups on (1) GVHD and its severity; (2) relapse-free survival (RFS) and (3) overall survival (OS). Univariate logistic regression analysis was used to evaluate the probabilities of GVHD in both treatment arms. Multivariable analysis was done to adjust for all covariates between study arms using adjusted logistic. OS and RFS were computed using the Kaplan-Meier curves. Results: The study included 38 subjects undergoing MUD HCT for myeloid or lymphoid malignancies. Subjects included are in 2 cohorts, 19 subjects in the intervention arm using individualized targeted ATG (tATG group), and 19 subjects in the matched control arm using weight-based dosing ATG (ATG group). In a univariate unadjusted logistic regression analysis, the risk of developing GVHD is numerically higher in the ATG group than in the tATG group (OR=1.339, p=0.70). However, the proportion of acute GVHD is significantly higher in the tATG group than the ATG group (73.68% vs 31.58%, p=0.022). Also, the proportion of higher grade acute GVHD is significantly higher in the tATG group than the ATG group (31.58% vs 0%, p=0.020). RFS is longer in the tATG group than the ATG group, tending statistical significance (p=0.063). However, there is no difference in OS between study arms (p=0.645). [Figures 1 and 2] In a multivariable-adjusted logistic regression, adjusting for age at HCT, diagnosis, disease status at HCT, prior lines of therapy, and stem cell source, no confounder was found to be significantly associated with GVHD. Conclusion: Individualized targeted dosing of ATG (tATG), based on weight, recipient lymphocyte counts and stem cell source, increases the risk of acute GVHD when compared to standard fixed-dosing method, however, it improves RFS, implying possibly better immune reconstitution providing improved graft versus leukemia effect. Disclosures No relevant conflicts of interest to declare.

“Real World” Australian Experience of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Adults with Severe Aplastic Anaemia.

Acquired Severe Aplastic Anaemia (SAA) is a rare bone marrow failure syndrome, for which allogeneic haematopoietic stem cell transplant (HSCT) is a proven curative therapy. Despite excellent outcomes for matched sibling SAA recipients in terms of engraftment and survival, HSCT remains highly challenging in older matched-unrelated-donor (MUD) recipients, due to increased non-relapse mortality (NRM) from causes such as graft versus host disease (GVHD), organ failure and infection. We sought to evaluate our local HSCT outcomes for SAA, determine factors that predict for inferior outcomes, and benchmark local outcomes against international cohorts. To define outcomes for sibling and MUD HSCT in adults ≥17 years of age with SAA at a single Australian institution between 2002 and 2018 and compare these outcomes to internationally published cohorts. The primary outcome was 1-year overall survival (OS). Secondary outcomes included the incidences of engraftment, response, secondary graft failure, GVHD, and moderate to severe organ dysfunction. All 21 patients comprising 10 sibling and 11 MUD HSCTs, with a median age of 30 (range 17-64), received bone marrow grafts. At a median follow up of 3.5 years, 17 (81%) of 21 patients remained alive and in remission from SAA. 1-year OS, non-relapse mortality (NRM), and GVHD incidence were 85%, 15%, and 48% respectively. Two patients died prior to engraftment at Day+27 and Day+33. When comparing sibling and MUD HSCT recipients, incidences of survival, engraftment and post-HSCT complications were similar; however, MUD HSCT survivors experienced a higher incidence of chronic GVHD (67% vs. 11%; p=0.04). Age >40 years, AKI by Day+28, infection by Day+100 and deviation from intended GVHD prophylaxis predicted for worse OS. Our outcomes following HSCT for SAA are comparable to international cohorts with age >40 years, early onset infection, AKI and deviation from intended GVHD prophylaxis protocol negatively impacting OS. Further research is warranted to optimise MUD HSCT conditioning and GVHD prophylaxis protocols for SAA, particularly in older patients.

A Phase II Clinical Trial of Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prevention Following Myeloablative Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation

<h3>Background</h3> The optimal regimen for graft versus host disease (GVHD) prophylaxis in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. Post-transplant cyclophosphamide (PT-Cy) mitigates GVHD after T-cell replete HLA haploidentical (Haplo) bone marrow transplant. We investigated the benefit of PT-Cy in preventing GVHD following myeloablative peripheral blood stem cell (PBSC) MUD HSCT. <h3>Methods</h3> We conducted a phase II clinical trial of PT-Cy for GVHD prophylaxis following MUD HSCT. GVHD prophylaxis consisted of 1 dose of PT-Cy 50mg/kg on day +3, mycophenolate mofetil starting day +5 to +35 and tacrolimus starting on day +5 with taper starting at day +100. The primary endpoint of the study was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), disease free survival (DFS), non-relapse mortlity (NRM) and time to engraftment. <h3>Results</h3> There were 39 patients enrolled in the study. The mean age of the study population was 47.36 years (SD 13.41). There were 23 females (59%) and majority of the patients were white (85%). Thirty six donors were 8/8 HLA MUD and 3 were 7/8 matched unrelated. The stem cells were collected from peripheral blood in all cases. Indications for HSCT included AML/MDS (62%), ALL (15%), myelofibrosis (10%), NHL/HL (10%) and CML (3%). The most commonly used conditioning regimen was Busulfan and Fludarabine (74%). All 6 patients with ALL received TBI (12 Gy) based conditioning. There was 1 death within the first 30 days before engraftment. The remaining 38 patients (97%) successfully engrafted. The median time to ANC engraftment was 12 days (range 9-14 days). The incidence of day 100 acute GVHD maximum grade was 36% for grade I/II and 5% for grade III/IV. The incidence of limited and extensive chronic GVHD was 10% and 36% respectively. There were 8 (21%) confirmed relapses within the first year after HSCT. Twenty four patients were alive at the 1-year mark after transplant and 17 of these were in complete remission. The 1-year and 2-year OS rates were 61.5% and 51.2% respectively. The median OS for the entire cohort was 21.2 months with a median follow up of 50 months (Figure 1). The day 100, 1-year and overall NRM rates were 10%, 28% and 33% respectively with infectious complications being the most common cause of death. <h3>Conclusion</h3> The use of one dose of PT-Cy in combination with MMF and tacrolimus is effective in preventing acute severe GVHD in myeloablative PBSC MUD HSCT recipients. We observe modest control over chronic GVHD with this regimen which may be explained by giving one dose of PT-Cy only. We report favorable survival outcomes along with acceptable levels of NRM for the entire cohort. The use of PT-Cy in combination with other immunosuppressant agents for GVHD prevention appears to be a promising strategy in MUD and may play a vital role in mismatched unrelated donor transplants as well.

A Phase II Clinical Trial of Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prevention Following Myeloablative Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation

Background: The use of post-transplant cyclophosphamide (PT-Cy) in combination with other immunosuppressive agents for graft versus host disease (GVHD) prophylaxis in matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. PT-Cy mitigates GVHD after T-cell replete HLA haploidentical (Haplo) bone marrow transplant. Extrapolating from the success of PT-Cy in haplo transplants, we investigated the benefit of PT-Cy (at a lower dose than that used in haplo HSCT) in preventing GVHD following myeloablative peripheral blood stem cell (PBSC) MUD HSCT. Methods: We conducted a phase II clinical trial between September 2013 and June 2018 of PT-Cy for GVHD prophylaxis following myeloablative MUD HSCT. GVHD prophylaxis consisted of 1 dose of PT-Cy 50mg/kg on day +3, mycophenolate mofetil starting day +5 till day +35 and tacrolimus starting on day +5 with taper starting at day +100. The primary endpoint of the study was to determine the incidence of grade II-IV acute GVHD. Secondary endpoints included overall survival (OS), disease free survival (DFS), non-relapse mortlity (NRM) and time to engraftment. Approval for the study was obtained from the Institutional Review Board. Results: There were 39 patients enrolled in the study (Table 1). The mean age of the study population was 47.36 years (SD 13.41). There were 23 females (59%) and majority of the patients were white (85%). Thirty six donors were 8/8 HLA MUD and 3 were 7/8 matched unrelated. The stem cells were collected from peripheral blood in all cases. Indications for HSCT included AML/MDS (62%), ALL (15%), myelofibrosis (10%), NHL/HL (10%) and CML (3%). Based on disease risk index (DRI) assessment, 6 (15%) patients were DRI high, 32 (82%) were intermediate and 1 (3%) was low. The most commonly used myeloablative conditioning regimen was Busulfan and Fludarabine (74%). All 6 patients with ALL received TBI (12 Gy) based conditioning. Three patients with NHL received Fludarabine and Melphalan. There was 1 death within the first 30 days before engraftment. The remaining 38 patients (97%) successfully engrafted. The median time to ANC engraftment was 12 days (range 9-14 days). The incidence of day 100 acute GVHD maximum grade was 36% for grade I/II and 5% for grade III/IV (Table 2). The overall incidence of limited and extensive chronic GVHD was 10% and 36% respectively. There were 8 (21%) confirmed relapses within the first year after HSCT. Twenty four patients were alive at the 1-year mark after transplant and 17 of them were in complete remission. The 1-year and 2-year OS rates were 61.5% and 51.2% respectively. The median OS for the entire cohort was 21.2 months with a median follow up of 50 months (Figure 1). The day 100, 1-year and overall NRM rates were 10%, 28% and 33% respectively with infectious complications being the most common cause of death. Conclusion: We report a low incidence of acute severe GVHD with the combination of one dose of PT-Cy in combination with MMF and tacrolimus following myeloablative PBSC MUD HSCT. The single dose of PT-Cy may explain the modest control over chronic GVHD with this regimen. We also report favorable survival outcomes along with acceptable levels of NRM for the entire cohort. The use of PT-Cy in combination with other immunosuppressant agents for GVHD prevention appears to be a promising strategy in MUD HSCT and may play a vital role in mismatched unrelated donor transplants as well. Disclosures Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; GSK: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy. Saad:Actinium Pharma Inc: Consultancy; Amgen: Other: Research Support; Kadmon: Other: Research Support; OrcaBio: Other: Research Support.

HLA-10/10 matched unrelated donor versus sibling donor hematopoietic stem cell transplantation for adult acute myeloid leukemia

目的观察人类白细胞抗原（HLA）匹配的无关供者造血干细胞移植（MUD-HSCT）治疗成人急性髓系白血病（AML）的疗效。方法回顾性分析2008年1月至2017年4月接受MUD-HSCT的成人AML病例资料，并以同期同胞全相合供者移植（MSD-HSCT）病例为对照，分析两组患者总生存（OS）率、无病生存（DFS）率、复发率、非复发死亡率（NRM）、植活率及急慢性移植物抗宿主病（aGVHD、cGVHD）发生率的差异。结果共247例连续性病例入组，MUD组46例，MSD组201例。除1例MSD组患者早期死亡外，两组患者均获粒细胞植活，但MUD组中位植活时间长于MSD组（15 d对14 d，P=0.017），血小板累积植活率差异无统计学意义（93.5%对98.0%，P=0.128）。两组患者aGVHD、cGVHD累积发生率差异无统计学意义（50.0%对46.3%，P=0.421；37.8%对43.0%，P=0.581）。与MSD组相比，MUD组患者3年累积NRM显著升高（22.0%对10.4%，P=0.049），但累积复发率差异无统计学意义（20.5%对28.3%，P=0.189）。两组患者3年OS率和DFS率差异均无统计学意义（61.6%对63.3%，P=0.867；57.5%对61.6%，P=0.760）。经多因素分析发现，患者年龄≥45岁、移植前第2次完全缓解（CR2）及以上或未缓解状态、有髓外浸润病史及Ⅲ~Ⅳ度aGVHD是影响生存的独立危险因素。结论与MSD-HSCT相比，MUD-HSCT治疗成人AML的NRM较高，粒细胞植活中位时间较长，但GVHD发生率、复发率、OS率及DFS率并无显著差异，是缺乏MSD的成人AML患者的理想替代移植方案。