Unrelated Donor Peripheral Blood Stem Research Articles

Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis following mismatched unrelated donor peripheral blood stem cell (PBSC) transplantation.

6503 Background: Our prior prospective multi-center clinical trial (15-MMUD; NCT02793544) estimated 79% overall survival (OS) at one year in adult patients with hematological malignancies undergoing reduced intensity conditioning (RIC), receiving bone marrow (BM) grafts from HLA-mismatched unrelated donors (MMUD), and post-transplant cyclophosphamide (PTCy)-based graft- versus-host disease (GVHD) prophylaxis (Shaw et al, J Clin Oncol 2021). We sought to determine whether OS in adults receiving mobilized PBSC from MMUD would be comparable. Methods: We conducted a prospective, multi-center Phase II study (ACCESS; NCT04904588) to assess the impact of PTCy-based GVHD prophylaxis on OS following MMUD transplantation in adults and children with advanced hematological malignancies. The study included three strata: two for adults based on conditioning regimen intensity [myeloablative (MAC) or RIC] using PBSC, and one pediatric cohort using MAC and BM. Eligible donors were matched at 4-7/8 HLA-loci (HLA -A, -B, -C, and -DRB1) and < 35 years. The primary endpoint was OS at one year following transplantation. We report the results of a planned interim analysis of the first 70 adult patients enrolled on the RIC PBSC stratum. Results: Thirteen sites enrolled 70 patients with the following demographics: median age of 65 years (range 24-77); 50% male; diagnoses: AML (53%), MDS (26%), ALL (7%), other heme malignancies (14%); and patient race/ethnicity: non-Hispanic white (48%). Donor characteristics included: median age 25y (range 18-35); male (44%); and HLA match level: 7/8: 67%; 6/8: 27%; 5/8: 6%. Conditioning regimens included fludarabine (flu) and melphalan (63%), flu/busulfan (20%), other (17%). OS at one year post HCT was 79% (95% confidence interval (CI): 68-87%). Secondary endpoints are provided in the table. Conclusions: Encouraging OS was observed at one year following MMUD PBSC in patients receiving RIC and PTCy. Notably, half of enrolled patients were people of color. OS was similar to our prior study using BM grafts. Rates of GVHD and other complications appear comparable to those in HLA-matched donor recipients, suggesting MMUD HCT could expand access to a potentially life-saving therapy. Accrual to both adult strata of ACCESS is complete, with over 200 patients in follow-up. Accrual to the pediatric stratum continues. Clinical trial information: NCT04904588 . [Table: see text]

A prospective study of posttransplant cyclophosphamide for unrelated donor peripheral blood stem cell transplant with special attention to graft content and the impact of a higher γδ T cell dose.

Posttransplant cyclophosphamide (PtCy) has been shown to decrease post-hematopoietic stem cell transplant acute and chronic graft-versus-host disease (GVHD). In this study, PtCy was used in 44 patients along with mycophenolate and tacrolimus with HLA matched (29) and mismatched (15) unrelated donors to determine the impact of graft content on outcome; thus, all patients had flow cytometric analysis of their graft content including the number of B cells, NK cells, and various T cell subsets. Higher γδ T cell dose was associated with the development of acute GVHD (p = .0038). For PtCy, further studies of the cell product along with further graft manipulation, such as selective γδ T cell depletion, could potentially improve outcomes.

Haploidentical donor peripheral blood stem cell transplantation using third-party cord blood compared with matched unrelated donor transplantation for patients with hematologic malignancies

Objectives: To assess the efficacy of cord blood-assisted haploid peripheral blood stem cell transplantation (haplo-cord-PBSCT) versus unrelated donor peripheral blood stem cell transplantation (UD-PBSCT) in the treatment of malignant hematological diseases. Methods: A retrospective analysis was performed on one hundred and four patients with malignant hematological diseases who underwent haplo-cord-PBSCT and fifty-two patients who underwent UD-PBSCT at Xiangya Hospital of Central South University between January 2016 and December 2021. Results: ①The median implantation time for neutrophils in the haplo-cord-PBSCT and UD-PBSCT groups was 13 (9-22) days and 13 (10-24) days, respectively (P=0.834), whereas the median implantation time for platelets was 15 (7-103) days and 14 (8-38) days, respectively (P=0.816). The cumulative implantation rate of neutrophils at 30 days after transplantation in the haplo-cord-PBSCT group and the UD-PBSCT group was 100% (P=0.314), and the cumulative platelet implantation rate at 100 days after transplantation was 95.2% (95% CI 88.3% - 98.1% ) and 100% (P=0.927), respectively. 30 days after transplantation, both groups of patients achieved complete donor chimerism, and no umbilical cord blood stem cells were implanted. ②The cumulative incidence rates of grade Ⅱ-Ⅳ acute GVHD within 100 days after transplantation in the haplo-cord-PBSCT group and the UD-PBSCT group were 29.1% (95% CI 20.1% -38.1% ) and 28.8% (95% CI 17.2% -41.6% (P=0.965), respectively. The cumulative incidence rates of grade Ⅲ/Ⅳ acute GVHD were 7.8% (95% CI 3.6% -14.0% ) and 9.6% (95% CI 3.5% -19.5% ) (P=0.725). The cumulative incidence rates of 2-year chronic GVHD in the haplo-cord-PBSCT group and the UD-PBSCT group were 45.3% (95% CI 36.1% -56.1% ) and 35.1% (95% CI 21.6% -44.1% ), respectively (P=0.237). The cumulative incidence rates of severe chronic GVHD at 2 years after transplantation were 13.6% (95% CI 7.6% -21.3% ) and 12.9% (95% CI 5.1% -24.3% ), respectively (P=0.840). ③The 2-year CIR after transplantation in the haplo-cord-PBSCT group and UD-PBSCT group were 12.8% (95% CI 7.0% -20.5% ) and 10.0% (95% CI 3.6% -20.2% ), respectively (P=0.341), and the NRM were 14.7% (95% CI 8.4% -22.6% ) and 16.2% (95% CI 7.4% -28.0% ), respectively (P=0.681). ④The 2-year OS rates in the haplo-cord-PBSCT and UD-PBSCT groups after transplantation were 82.2% (95% CI 74.8% -90.3% ) and 75.5% (95% CI 64.2% -88.7% ), respectively (P=0.276). The 2-year DFS rates were 69.9% (95% CI 61.2% -79.8% ) and 73.8% (95% CI 62.4% -87.3% ), respectively (P=0.551). The 2-year rates of GVHD-free/recurrence-free survival (GRFS) were 55.3% (95% CI 44.8% -64.8% ) and 64.7% (95% CI 52.8% -79.3% ), respectively (P=0.284) . Conclusion: The findings of this study indicate that haplo-cord-PBSCT and UD-PBSCT have comparable efficacy and safety in the treatment of malignant hematological diseases and can be used as an alternative treatment options.

A Standardized Cell Dose to Optimize Unrelated Donor Peripheral Blood Stem Cell (PBSC) Collections: A Prospective Study between the Sarah Cannon Transplant and Cellular Therapy Network (SCTCTN) and the National Marrow Donor Program (NMDP)

A Standardized Cell Dose to Optimize Unrelated Donor Peripheral Blood Stem Cell (PBSC) Collections: A Prospective Study between the Sarah Cannon Transplant and Cellular Therapy Network (SCTCTN) and the National Marrow Donor Program (NMDP)

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.

UM171 Expanded Cord Blood Transplantation Outcomes Compare Favorably to All Different Stem Cell Sources: An EBMT Registry Case-Control Analysis

Background: Cord blood (CB) transplantation (CBT) has several advantages compared with other graft sources, such as permissive human leucocyte antigen (HLA) mismatches, and low risk of chronic graft-versus-host disease (GVHD) and relapse. However, CBT has fallen into disfavor because of its high risk of non-relapse mortality (NRM) and prolonged hospitalization due to its low cell dose. Furthermore, the need for the rare large cord bloods (CBs) leads to selection of poorly HLA-matched CBs, known to further increase NRM. UM171 is a small molecule that expands hematopoietic stem cells. A phase I-II study of a single UM171-expanded, myeloablative and reduced intensity CBT for patients with high-risk hematologic malignancies who lacked a donor, demonstrated prompt neutrophil engraftment, the ability to use smaller, better HLA-matched CBs, and a low NRM of 5% (Cohen S et al. Lancet Haematol 2020). The aim of the current analysis was to compare outcomes after a UM171 CBT to real-world cohorts of 6 other stem cell sources identified in the European Society for Blood and Marrow Transplantation (EBMT) registry. Methods: This is a retrospective study comparing 22 adults who received a single UM171-expanded CBT in the phase I-II study between 2016-2018, to 6 cohorts of patients allografted from different stem cell sources and reported to the EBMT registry. Control patients were eligible if they had received a myeloablative or reduced intensity allogeneic transplant for a hematologic malignancy in Europe during 2010-2021, were between the ages of 18-65 years, and had a Karnofsky performance status (KPS) score ≥70. The different donor control cohorts were: 1) CB, single or double units, with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) for GVHD prophylaxis, 2) 10/10 HLA-matched unrelated donor (MUD) peripheral blood stem cells (PBSC) with a CNI and MMF or methotrexate (MTX), 3) 10/10 MUD bone marrow (BM) with a CNI and MMF or MTX, 4) 9/10 HLA-MUD BM or PBSC (9/10 UD), 5) T cell replete haploidentical donor (haplo) BM or PBSC, and 6) matched sibling donor (MSD) BM or PBSC. Exclusion criteria included in vitro manipulated grafts and CBT recipients who received anti-thymocyte globulin or alemtuzumab. Patients were directly matched for disease and status at transplant and propensity score matching was used for prior allograft, age, KPS, and conditioning regimen. Endpoints included engraftment, GVHD, NRM, relapse, progression-free survival (PFS), overall survival (OS), and GVHD-free relapse-free survival (GRFS). The EBMT attempted to identify 3 controls for each patient. If no control was identified for a UM171 patient, the latter was excluded from the analysis. Results: Between 17 and 21 UM171 CB patients were compared to 36 to 62 controls depending on the donor group as 1-3 controls could not be identified for each patient (Table 1). Median follow-up for the UM171 group was 36 months and generally longer for the controls. Neutrophil engraftment with UM171 CB was similar to all donor groups except slower for CB and MUD BM. Platelet engraftment was consistently slower for UM171 CB except when compared to conventional CB. The incidence of severe acute GVHD was similar across all donor groups. As there was no severe chronic GVHD in the UM171 group, the latter was associated with less extensive/severe chronic GVHD compared to MUD (PBSC and BM) and MSD. There was a trend towards lower NRM for UM171 CB compared to haplo and 9/10 UD but it did not reach statistical significance. PFS, OS and GRFS were all better with UM171 CB compared to haplo. Finally, GRFS was improved with UM171 CB when compared to MUD PBSC (Figue 1), 9/10 UD, and MSD. Conclusions: This registry matched case-control analysis demonstrated real-word evidence suggesting UM171-expanded CBT recipients have improved outcomes compared to other donor types. More specifically and due to the absence of severe chronic GVHD with UM171 CB, GRFS was better with UM171 CB when compared to other graft sources except for CB and MUD BM. Also, OS and PFS were superior with UM171 CB compared to haplo donors. Limitations of this study included the small number of UM171 patients, the inability to identify controls for each case, and certain missing data for the controls. UM171 expansion of CB appeared to achieve the desired outcome of maintaining benefits of CB while removing its disadvantages. Thus, prospective randomized studies are warranted to confirm these results.

Hematopoietic Stem Cell Transplantation for Fanconi Anemia: Outcome and Prognostic Factors for Survival and Subsequent Neoplasms

Introduction Fanconi anemia (FA) is an inherited disorder of impaired DNA repair, associated with progressive bone marrow failure (BMF), leukemia, and cancer predisposition. Hematopoietic cell transplantation (HCT) may be curative for FA associated BMF, and changes in HCT practice over the past decades may have impacted outcomes in FA patients. Methods We used CIBMTR database to perform a retrospective cohort study of children and adults undergoing first allogeneic HCT for FA BMF (patients with MDS/AML excluded) from 2000-2018. We hypothesized that contemporary HCT approaches, including decreases in radiation and increase in use of serotherapy and ex-vivo graft manipulation, would associate with improved outcomes in FA patients receiving HCT. The primary endpoints were overall survival (OS) and early subsequent malignant neoplasm (SMN; by 5 yr post-HCT). Secondary endpoints included event free survival (EFS; death, SMN or graft failure), treatment related mortality (TRM), graft failure, and acute (grade II-IV) and cGVHD. Univariate and multivariate Cox regression models were created to evaluate the impact of conditioning, donor and graft source, treatment era, and patient characteristics on outcomes, adjusting for other significant covariates. Due to confounding factors, we were not able to create a single multivariate model that included radiation, ex-vivo graft manipulation, and donor and graft source; therefore, we performed subgroup univariate analysis for patients receiving unrelated donor bone marrow (BM) or peripheral blood stem cell (PBSC) HCT. Results We analyzed 652 HCTs from 2000-07 (n=353) and 2008-18 (n=293). 223 (35%) patients had a matched related donor (MRD) with any graft type, 244 (38%) had an unrelated donor BM or PBSC grafts, 123 (19%) had an unrelated cord blood graft, and 44 (7%) had a related haploidentical donor with any graft type. Between the two treatment eras, 5-yr OS has dramatically improved (78.8% 2008-18 v 62.5% 2000-07, p<0.01; figure 1) driven by lower 5-yr TRM (15.2% v 25.5%, p=0.004) and lower rates of primary (7.9% v 12.9% at 42 days, p=0.038) and secondary (4.1% v 8.9% at 1 year, p=0.014) graft failure. No statistically significant change was observed for aGVHD, cGVHD, or early SMN. Assessing the entire cohort, use of total body irradiation (TBI) >300cGy was associated with lower OS (HR=1.75, 95% CI 1.24-2.47) and increased TRM (HR=3.36, 95% CI 1.54-7.34; figure 2) on multivariable analysis. For patients that received unrelated BM or PBSC HCT, use of TBI was associated with inferior OS survival (HR=1.93, 95% CI 1.18-3.17), EFS (HR=1.78, 95% CI 1.13-2.80), and TRM (HR=2.31, 95% CI 1.20-4.46) on univariate analysis. Among all patients, CD34 selection or T-cell depletion ( ex vivo depletion) were not associated with better OS (95% HR=1.014, 95% CI 0.84-1.56), EFS (HR=1.163, 95% CI 0.86-1.58), or TRM (HR=0.79, 95% CI 0.52-1.19) but was associated with less aGVHD (HR=0.35 95% CI 0.22-0.57) and lower but not-statistically significant cGVHD (HR=0.54, 95% CI 0.29-1.01) on multivariable analysis. Within the unrelated donor setting, univariate analysis showed reduced aGVHD (HR=0.39 95% CI 0.23-0.68) and cGVHD (HR=0.47 95% CI 0.28-0.79) but did not have a significant effect on OS, EFS, or TRM. Early SMN occurred in 3.2% of participants by 5-years post-HCT and was associated with cGVHD occurrence (HR=2.14, 95% CI 1.06-4.33) and older age (>18 v <9 years, HR=6.35, 95% CI 2.66-15.14), but not ex-vivo depletion or use of ATG or alemtuzumab. Early SMN risk was not impacted by the use of TBI (HR=1.60, 95% CI 0.77-3.34), but secondary analysis demonstrated a trend towards a relationship with doses >300 cGy (HR=2.24, 95% CI 0.99-5.08). Conclusions Outcomes for patients with FA BMF have improved significantly in more recent HCT eras, driven by reductions in TRM and graft failure risk. Although radiation doses >300cGy were associated with greater toxicity, doses of 100-300cGy were not associated with inferior outcomes in our cohort. Use of CD34 selection or T-cell depletion may reduce the risk of GVHD in transplant FA patients, but does not appear to impact 5-yr OS. Risk for early SMN development in FA patients receiving HCT associates with older age and cGVHD.

Liquid Storage of Peripheral Blood Stem Cell Products: Effects of Time and Temperature on Product Quality

Unrelated donor peripheral blood stem cell (PBSC) products often require transport to distant locations, which may take up to 72 hours. Temperature is an important variable that can be controlled during PBSC storage or transport; therefore, we studied the impact of temperature on prolonged storage of clinical-grade, mobilized PBSC products. PBSC products were collected by apheresis from 3 granulocyte colony-stimulating factor-mobilized donors, split into 2 PVC blood bags of equal volume, and stored at room temperature (RT) (18°C to 25 ºC) or 4 °C (2°C to 8 ºC) for 96 hours. Samples were obtained at 24-hour intervals for pH, cell counts, flow cytometry phenotyping and viability (7AAD), and hematopoietic colony-forming units (CFU). Starting PBSC products contained 52, 65, and 38×109 total nucleated cells (TNCs), with cell concentrations of 125, 263, and 94.6×106 TNCs/mL, respectively. Product pH dropped during storage, with significantly lower values for RT stored products than for 4 ºC stored products, and was greatest in the product with the highest TNC count. The percent recovery of viable CD34+ progenitor cells, CD3+ T cells, CD4+ T helper cells, CD8+ cytotoxic T cells, CD19+ B cells, CD15+ granulocytes, CD14+ monocytes, and CD16+/56+ natural killer (NK) cells all decreased over 96 hours but decreased more dramatically in the RT group. Cell recovery differences were statistically significant at most time points for all cell populations except CD15+ granulocytes. For CD34+ cells stored at 4 °C, mean recovery from prestorage values were 97 ± 3% at 24 hours, 87 ± 4% at 48 hours, 88 ± 10% at 72 hours, and 78 ± 1% at 96 hours, compared to RT product values of 45 ± 11%, 19 ± 19%, 2 ± 2%, and 0 ± 0%, respectively. CFUs were well preserved through 96 hours at 4 ºC but not at RT. During PBSC storage, pH and content of viable CD34+ cells, T cells, B cells, monocytes, NK cells, and CFU all declined. However, at 4 ºC, viable cell recoveries are relatively well preserved, even at 72 hours, whereas RT storage resulted in rapid product deterioration. PBSC products requiring prolonged liquid storage or transport before cryopreservation or infusion should be maintained at 4 ºC.

189 - Performance of the Endothelial Stress Activation Index and Hematopoietic Cell Transplantation Comorbidity Index for Prediction of Early Survival in Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation

189 - Performance of the Endothelial Stress Activation Index and Hematopoietic Cell Transplantation Comorbidity Index for Prediction of Early Survival in Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation

Allogeneic Stem Cell Cryopreservation Is Associated with Equivalent Survival and Relapse Rates with Lower Rate of Severe Chronic Gvhd

The ongoing COVID-19 pandemic continues to raise challenges for safe administration of allogeneic hematopoietic stem cell transplantation (allo-HSCT). From March to August 2020, unrelated donor (URD) peripheral blood stem cell (PBSC) products were shipped to central national hubs and cryopreserved either at the site of collection or infusion, a shift from the traditional practice of infusing fresh stem cells. The National Marrow Donor Program (NMDP) instituted this mandate due to uncertainty around international transportation of stem cells as well as a fail-safe to prevent interruptions to a planned transplant if a donor contracted COVID-19 after the recipient started conditioning chemotherapy. We previously published our single institution experience demonstrating equivalent short-term clinical outcomes (overall survival [OS], progression free survival [PFS], relapse, and non-relapse mortality [NRM]) between adult recipients of fresh vs cryopreserved allogeneic stem cells (median follow up time 16 months [fresh] vs 8 months [cryopreserved]) (PMID: 34581754). We also demonstrated lower T-cell chimerism at day 30 and 100 after receipt of cryopreserved grafts. There is a paucity of data evaluating longer term outcomes of patients receiving cryopreserved stem cells compared to fresh. Currently there is variability among donation and transplant centers around the practice of cryopreservation prior to allo-HSCT. With ongoing surges of COVID-19 and evolution of new variants, the risk of donors or recipients contracting COVID-19 leading to delays or disruptions in planned allo-HSCT remains high. In January 2022 with the rise of the Omicron variant of COVID-19, the NMDP reinstated the cryopreservation recommendation. Anecdotal reports indicate multiple recent instances of a planned URD testing positive for COVID-19 after conditioning chemotherapy had started but before stem cell harvest, raising the potential for severe deleterious outcomes in the intended transplant recipient. Given the unremitting COVID-19 surges three years into the pandemic and continued uncertainty around longer-term survival and relapse rates of allo-HSCT using cryopreserved stem cells, we reanalyzed our prior cohort and added 116 additional patients (40 cryopreserved, 76 fresh) with at least 1-year follow up for a total of 141 and 279 patients receiving cryopreserved versus fresh (respectively) URD PBSCs between January 1, 2019, and July 31, 2021. The cohorts had similar baseline characteristics including donor/recipient age/sex, disease, and conditioning regimen/intensity. Patients receiving cryopreserved cells were more likely to receive post-transplant cyclophosphamide as part of the graft versus host disease (GVHD) prophylaxis regimen (24% vs 15%, p=0.015). Median follow-up time among survivors in this cohort was 22 months (range, 4-41 months). Two-year OS was not different in patients receiving fresh versus cryopreserved stem cells (63% vs 63%, p=0.73) (Figure 1A). Two-year PFS was also similar (57% for fresh, 52% for cryopreserved, p=0.27) (Figure 1A). Relapse (36% vs 30%, p=0.17) and NRM (12% vs 13%, p=0.79) at two years were comparable between patients receiving fresh versus cryopreserved stem cells (Figure 1B). In total, 8 patients died of COVID-19 in this cohort (4 fresh, 3 cryopreserved). Cumulative incidence of moderate/severe chronic GVHD (cGVHD) was higher in patients receiving fresh stem cells versus cryopreserved (24% vs 9%, p=0.0003). Whereas cryopreservation was associated with lower T-cell chimerism early after transplant, by 1-year post-transplant, T-cell chimerism was not different (2% vs 5% of fresh vs cryopreserved patients with T-cell chimerism <75% at 1 year, p=0.14). However, Day 30 T-cell chimerism <75% was associated with a reduction in OS and PFS regardless of cryopreservation of stem cells (data not shown). As the COVID-19 pandemic continues with frequent surges in case numbers and rapid viral evolution, the risk for interruptions in life-saving allo-HSCT therapies remains high. Our data show that allo-HSCT with cryopreserved URD PBSCs results in similar OS, PFS, relapse rates, and NRM at 2 years post-transplantation. We found that cryopreservation is associated with lower 1-year cumulative incidence of moderate/severe cGVHD without compromise in OS. While this is an intriguing finding, larger multicenter analyses are needed to confirm these observations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Outcomes of UM171-Expanded Cord Blood Transplantation Compared with Other Graft Sources: Real World Evidence

Background: Cord blood (CB) transplantation (CBT) has several advantages compared with other graft sources. CBT has low rates of chronic graft-versus-host disease (GVHD) and allows for several human leukocyte antigen (HLA) mismatches, thus expanding donor availability. However, CBT has fallen into disfavor because of its low cell dose and associated prolonged cytopenias, which result in prolonged hospitalization and higher risk of non-relapse mortality (NRM). Furthermore, the need for large CBs leads to selection of poorly HLA matched CBs, further increasing NRM. UM171 is a small molecule that expands hematopoietic stem cells. From 2016 to 2018, 22 patients with high-risk malignancies who lacked a donor were transplanted on a phase I-II clinical trial with a single UM171-expanded CB (Cohen S et al. Lancet Haematol 2019) after a myeloablative conditioning. The goal was to accelerate engraftment while selecting smaller, better HLA matched CBs to decrease NRM while preserving the benefits of CBT. Results demonstrated that indeed UM171-expanded CB has the potential to overcome slow neutrophil engraftment and diminish NRM. The aim of the current analysis was to examine outcomes after conventional single/double ≥ 4/6 HLA-matched CB and 8/8-matched unrelated donor (MUD) peripheral blood stem cell (PBSC) transplantation with UM171-expanded CBT. Methods: Data on UM171-expanded adult CBT recipients were drawn from the phase I-II trial. Data for adult recipients of myeloablative CB and PBSC transplants for hematologic malignancies (acute myeloid and lymphoblastic leukemia, chronic myeloid leukemia, non-Hodgkin and Hodgkin lymphoma) in the United States and Canada during 2014-2019 with a Karnofsky performance status (KPS) score ≥70 were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. CB recipients who received anti-thymocyte globulin or alemtuzumab in the conditioning were excluded from the CIBMTR population. Patients were directly matched for the number of prior allogeneic transplants (alloHCT), refined disease risk index (for 1st alloHCT), disease status (for 2nd alloHCT), and acute myeloid leukemia cytogenetic risk. Patients were matched by propensity score for age, comorbidity index and KPS. CIBMTR attempted to identify 4 controls per UM171 patient. Clinical outcomes included engraftment, NRM, progression-free survival (PFS), overall survival (OS), relapse, GVHD-free, relapse-free survival (GRFS), acute GVHD grade III-IV, and chronic GVHD. PFS, OS, and GRFS were estimated by Kaplan-Meir method; other outcomes were calculated using cumulative incidence estimates; marginal Cox regression models were used for analyzing NRM and GRFS. Results: Overall, 137 CIBMTR (67 CB, 70 PBSC) and 22 UM171-expanded CBT patients participated. Univariate analysis and marginal Cox regression analysis results are shown in Tables 1 and 2, respectively. Median time to neutrophil engraftment was 18 days (range 10-30) for UM171-expanded CB recipients compared to 21 days (range 8-53) for CIBMTR CB recipients (p<0.01) (data not shown). Univariate analysis revealed less 1- and 2-year NRM, improved 2-year PFS, improved 1-year OS, and 1- and 2-year GRFS for UM171-expanded CBT compared to CIBMTR CB controls. The UM171 cases had less 1- and 2-year NRM, improved 2-year PFS, and improved 1- and 2-year GRFS compared to CIBMTR PBSC controls. Furthermore, UM171-expanded CB patients experienced less acute GVHD III-IV and chronic GVHD compared to PBSC recipients. In marginal Cox regression analysis, UM171-expanded CBT recipients were 87% and 63% less likely than CIBMTR CB controls to experience NRM and GRFS events, respectively, and 73% less likely to experience GRFS events than CIBMTR PBSC recipients. Conclusions: This real-word evidence suggests that UM171-expanded CB recipients have select improved outcomes compared to conventional CB and MUD PBSC recipients. While this study was limited by the small number of UM171 CB trial participants and inability to identify the planned number of controls for each case, UM171 expansion of CB appeared to achieve the desired outcome of maintaining CB's benefits while removing its disadvantages. Thus, prospective randomized studies of UM171-expanded CBT compared to MUD PBSC alloHCT are warranted to confirm these results. Study Support: This study was funded by ExCellThera. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Should anti-thymocyte globulin be added in post-transplant cyclophosphamide based matched unrelated donor peripheral blood stem cell transplantation for acute myeloid leukemia? A study on behalf of the Acute Leukemia Working Party of the EBMT.

In this registry-based study which includes acute myeloid leukemia patients who underwent a matched unrelated donor allogeneic peripheral-blood stem cell transplantation in complete remission and received post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GvHD) prophylaxis, we compared 421 recipients without anti-thymocyte globulin (ATG) with 151 patients with ATG. The only significant differences between PTCY and PTCY + ATG cohorts were the median year of transplant and the follow-up period (2017 vs 2015 and 19.6 vs 31.1 months, respectively, p < 0.0001). Overall, 2-year survival was 69.9% vs 67.1% in PTCY and PTCY + ATG, respectively, with deaths related to relapse (39% vs 43.5%), infection (21.9% vs 23.9%) or GvHD (17.1% vs 17.4%) not differing between groups. On univariate comparison, a significantly lower rate of extensive chronic GvHD was found when ATG was added (9.9% vs 21%, p = 0.029), a finding which was not confirmed in the multivariate analysis. The Cox-model showed no difference between PTCY + ATG and PTCY alone with respect to acute and chronic GvHD of all grades, non-relapse mortality, relapse, leukemia-free survival, overall survival, and GvHD-free-relapse-free survival between study cohorts. Our results highlight that the addition of ATG in PTCY does not provide any extra benefit in terms of further GvHD reduction, better GRFS or better survival.

Low-dose post-transplant cyclophosphamide with low-dose antithymocyte globulin for prevention of graft-versus-host disease in first complete remission undergoing 10/10 HLA-matched unrelated donor peripheral blood stem cell transplants: a multicentre, randomized controlled trial

The most widely used regimens of graft-versus-host disease (GVHD) prophylaxis in HLA-matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT) are based on anti-thymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). To improve the efficiency of GVHD prophylaxis, a novel regimen, composed of low-dose PTCy (20 mg/kg on day +3 and +4) and low-dose ATG (6 mg/kg), was evaluted in patients with hematological malignancies ungoing 10/10 HLA MUD-PBSCT in first remission (CR1). In our prospective, multicenter study, 104 patients were randomly assigned one-to-one to low-dose PTCy-ATG (n = 53) or standard-dose ATG (10 mg/kg, n = 51). Both the cumulative incidences (CIs) of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at 2 years in low-dose PTCy-ATG cohort were significantly reduced (24.5% vs. 47.1%; P = 0.017; 14.1% vs. 33.3%; P = 0.013). The CI of non-relapse-mortality (NRM) was much lower (13.2% vs. 34.5%; P = 0.049) and GVHD-free, relapse-free survival (GRFS) was significantly improved at 2 years in low-dose PTCy-ATG arm (67.3% vs 42.3%; P = 0.032). The low-dose PTCy-ATG based GVHD prophylaxis is a promising strategy for patients in CR1 after 10/10 HLA MUD-PBSCT.

High Failure-Free Survival after Unrelated Donor Peripheral Blood Stem Cell Transplantation in Pediatric Severe Aplastic Anemia

The use of alternative donor peripheral blood stem cell transplantation (PBSCT) has increased in recent years. In this study, we analyzed the effect of stem cell source and HLA disparity on outcomes in pediatric patients with severe aplastic anemia (SAA). A total of 134 patients who underwent HSCT with nonmyeloablative conditioning between 2006 and 2020 were enrolled and classified into 3 groups: HLA-matched bone marrow transplantation (M-BMT; n = 24), HLA-matched PBSCT (M-PBSCT; n = 66), and HLA-mismatched PBSCT (MM-PBSCT; n = 44). Significantly higher stem cell doses were obtained for PBSCT than for BMT. A total of 13 patients experienced secondary graft failure (GF), with a cumulative incidence (CI) of 10.0%. HLA-mismatched PBSCT and a very severe degree of disease significantly decreased the incidence of secondary GF. The CI of grade II-IV acute graft-versus-host disease (GVHD) was significantly higher in PBSCT than in BMT, but the CI of grade III-IV acute GVHD and CI of chronic GVHD requiring systemic treatment did not increase in PBSCT. The estimated 5-year overall survival (OS), failure-free survival (FFS), and GVHD-free failure-free survival (GFFS) of the total cohort were 93.0%, 89.5%, and 77.5%, respectively. The most favorable FFS was observed in the MM-PBSCT group (97.6%; P = .03), whereas OS and GFFS were similar across the 3 groups. In multivariate analysis, HLA mismatch and short time from diagnosis to transplantation were associated with superior FFS. Unrelated donor PBSCT with low-intensity SAA conditioning showed favorable outcomes in terms of low rate of secondary GF, higher FFS, and manageable GVHD regardless of HLA compatibility. Our findings suggest the feasibility of PBSCT from unrelated donors, resulting in the possible expansion of the donor pool in transplantation for pediatric SAA. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Impact of cryopreservation and transit times of allogeneic grafts on hematopoietic and immune reconstitution

AbstractWe sought to evaluate the impact of cryopreservation of unrelated donor (URD) peripheral blood stem cell (PBSC) grafts on engraftment, chimerism, and immune reconstitution in the context of the COVID-19 pandemic. We reviewed stem cell product characteristics and clinical outcomes in 101 patients receiving cryopreserved PBSCs from URDs between January 1, 2019 and 31 December, 2020, compared with 203 patients receiving fresh URD PBSCs. We observed no differences in 6-month overall survival, progression-free survival, or nonrelapse mortality. Patients receiving cryopreserved PBSCs had delayed platelet engraftment and impaired reconstitution of white blood cells and T-cell subsets at day 30. Thirty-four percent of patients receiving cryopreserved grafts had CD3 chimerism <50% at day 30 after transplantation, compared with 14% of patients receiving fresh PBSCs (P = .0002). At day 100, this difference persisted (CD3+ chimerism <50%: 17% of cryopreserved cohort vs 6% of fresh cohort; P = .016). Greater product age at infusion was associated with increased graft failure, independent of cryopreservation. Receipt of grafts >48 hours old at time of cryopreservation or infusion significantly increased the risk of graft failure (subdistribution hazard ratio = 4.57; 95% confidence interval, 1.71-12.3; P = .0025). Our data indicate that cryopreservation is associated with similar overall short-term clinical outcomes compared with fresh PBSC. However, patients must be monitored closely for increased risk of other potentially adverse outcomes, including graft failure and poor immune recovery, particularly for grafts with older overall age at infusion. Longer-term follow-up is needed to determine impact on relapse and survival.

Unrelated Donor Peripheral Blood Stem Cell Transplantation for Thalassaemia: A Single Institution Experience of 53 Patients

AbstractBackground: Thalassemia major (TM) is a fatal genetic disease currently only curable with allogeneic stem cell transplantation, which is limited by the lack of suitable donors. For patients lacking matched related donors, unrelated donor peripheral blood stem cell transplantation (UD-PBSCT) is increasingly being utilized. Despite this success in leukemia patients, UD-PBSCT is not widely practiced in thalassemia patients because of higher graft-versus-host disease (GVHD) risk and increased transplant-related mortality (TRM).Methods: The purpose of the study is to assess the safety and efficacy of UD-PBSCT for patients with thalassemia major. The trial was designed as a prospective, open-label, single-center clinical protocol, where 53 TM patients were enrolled between March 2013 and April 2017 and transplanted with peripheral blood stem cell (PBSC), from an HLA-matched unrelated donor. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and was registered at the Chinese Bone Marrow Transplant Registry (CBMTR). The primary end point was 2-year thalassemia free survival (TFS). Secondary end points included 2-year overall survival (OS), the cumulative incidence of GVHD, transplant related mortality (TRM), graft rejection (GF). The conditioning regimen were: 1) busulphan (BU) 1mg/kg given intravenously (IV) four times per day for 4 days (day -9 to day -6); 2) fludarabine (FLU) (50mg/m2/day) given IV for 3 days (day -12 to day -11); 3) cyclophosphamide (CTX) (50 mg/kg/day) given IV for 4 days (day -5 to day -4); 4) anti-thymocytes globulin (ATG, Genzyme ) (2.5 mg/kg/day) given IV for 4 days (days -4 and day -1). All patients were placed on 30 mg/kg hydroxyurea orally once daily for 2-3 months before transplantation. GVHD prophylaxis consisted of a combination of cyclosporin A, methotrexate and mycophenolate mofetil regimen.Results: Data cut off for survival follow-up was June 30, 2017. The median follow-up time was 22 months (range, 4 months -58 months). The median age of patients was 5 years (range, 2-13 years). The median numbers of MNCs and CD34 cells infused per graft were 17.6 ×108/kg (range, 10.0 to 34.6)and 9.2×106/kg (range, 3.5 to 32.9), respectively. A total of 52 (98.1%) patients achieved sustained myeloid engraftment. The median time of absolute neutrophil count engraftment was 11(range 9-15) days. The median time of platelet engraftment was 13(range, 9 to 35) days. The rate of Graft rejection was 1.9%. The cumulative incidence of acute (a)GVHD and grade II-IV aGVHD were 41.5% (95% confidence interval [CI], 29.1 to 56.2) and 32.0% (95% CI, 21.1 to 48.6) , respectively . The chronic (c)GVHD and extensive cGVHD were 6.2% (95% confidence interval [CI], 2.1 to 16.6) and 2.2% (95% CI, 0.3 to 15.1), respectively. The cumulative incidence of TRM at 2 years was 8.0% (95% CI, 3.1 to 20.4). The OS and TFS at 2 years were 92.0% (95% CI, 87.8 to 100) and 90.1% (95% CI, 85.0 to 99.6), respectively. (Figure 1)Conclusion: Our results demonstrate that MUD-PBSCT in TM yields excellent engraftment rate and TFS when the protocol consisted of busulphan, cyclophosphamide, fludarabine and antithymocyte globulin was used, and suggest that patients without an available HLA-compatible sibling but who have well-matched unrelated donors should also be considered for MUD-PBSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Day 90 Post-Allogeneic Hematopoietic Cell Transplantation T Cell Receptor Diversity Level Correlates with Risk of Relapse in Patients with Multiple Myeloma

BACKGROUNDRobust immune reconstitution following allogeneic hematopoietic cell transplantation (HCT) has been associated with better outcomes in meeting the challenges of infections and malignancy relapse. One major component of reconstitution is the depth of diversity of the T cell receptor (TCR) repertoire but it is not clear what time frame is relevant and how much diversity is critical. HYPOTHESISWe hypothesized that at 90 days and/or 180 days, repertoires with more restricted diversity would predict for the increased risk of relapse and infections in the first year post-transplant. We herein present the results related to the risk of relapse. METHODSPatients with multiple myeloma were conditioned with reduced intensity conditioning (77%) and non-myeloablative (23%) with FM (13.6%), FluCyTBI (18.2%), FluMelVel (63.6%) and FluCy (4.6%). At day 0, they received a matched related (72.7%) or unrelated donor (27.3%) peripheral blood (86-89%) or bone marrow (11-14%) stem cell transplant. Peripheral blood samples were collected from the patients at day 90 and 180 (+/- 30 days) post-transplantation. Peripheral blood mononuclear cells isolated on ficoll-hypaque gradients were cryopreserved and sent to Adaptive Biotechnologies for immunosequencing. The level of TCR diversity was assessed at day 90 for 22 patients (13 male, 9 female) who underwent HCT. This cohort had a follow-up time for PFS of median=18.5 months (IQR, 10 to 33 months), ranging from 6.0 months to 52 months. Acute GVHD was evident in 59% of the patients and the same percentage exhibited chronic GVHD. Additional samples were available for immunosequencing for 18 patients (10 male, 8 female) from day 180 post HCT. The median PFS for this dataset was 23.5 months (IQR, 10 to 33 months), ranging from 6 to 50 months; 61% of these patients developed acute GVHD and 56% exhibited chronic GVHD. RESULTSDay 90 post TCR diversity (median=412,245.6; IQR, 81,615.7 to 666,525.8) was significantly associated with relapse/progression of disease when either the 25th percentile cutoff value (TCR diversity ≤ 81,615.7) (hazard ratio=5.60, 95% CI 1.10 - 28.49, and logrank test P=0.0198) or the 50th percentile cutoff value (TCR diversity ≤ 412,245.6) (hazard ratio=10.29, 95% CI 1.25 - 84.80 and logrank test P=0.0079) were reported. In contrast, this approach did not find a significant association between Day 180 post TCR diversity (median=175,453.9; IQR, 94,715.3 to 501,422.4) and risk of subsequent relapse/progression of disease for either the 25th or 50th percentile cutoff values. CONCLUSIONMeasuring the extent of TCR diversity at 90 days post-allogeneic HCT in multiple myeloma patients correlates with the risk of eventual relapse. This potential diagnostic tool could serve as the basis for early interventions to boost the level of donor T cells and to expand the repertoire, perhaps by delayed donor infusions, in order to prevent malignant relapse. [Display omitted] DisclosuresMcKiernan:Novartis: Speakers Bureau. Emerson:Adaptive Biotechnologies: Employment, Other: Equity ownership. Vignali:Adaptive Biotechnologies: Employment. Rubinstein:Adaptive Biotechnologies: Employment. Robins:Adaptive Biotechnologies: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Siegel:Merck: Consultancy; Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau.

Low-dose antithymocyte globulin plus low-dose posttransplant cyclophosphamide combined with cyclosporine and mycophenolate mofetil for prevention of graft-versus-host disease after HLA-matched unrelated donor peripheral blood stem cell transplantation

The standard regimens for graft-versus-host disease (GvHD) prophylaxis in matched unrelated donor (MUD) transplantation were based on antithymocyte globulin (ATG) in combination with calcineurin inhibitors (CNIs). To improve the efficiency of GvHD prophylaxis in MUD peripheral blood stem cell transplantation (MUD-PBSCT), 51 patients with hematological malignancies received a novel regimen for GvHD prophylaxis, which is composed of low dose of ATG (5 mg/kg) plus low-dose posttransplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy) combined with cyclosporine A (CsA) and mycophenolate mofetil (MMF). The cumulative incidences (CIs) of grades I–IV and II–IV acute GvHD (aGvHD) were 14.5% (95% CI, 9.4–19.6%) and 6.2% (95% CI, 2.8–9.6%) within 100 days after transplantation, respectively. The CI of mild-to-moderate chronic GvHD (cGvHD) within 1 year was 11.5% (95% CI, 6.6–16.4%). The 1-year probabilities of GvHD and relapse-free survival, relapse-free survival, and over survival were 70.6% (95% CI, 64.2–77.0%), 76.5% (95% CI, 70.6–82.4%), and 82.0% (95% CI, 76.5–87.5%), respectively. The CIs of CMV and EBV reactivation by day 180 were 10.4% (95% CI, 1.5–19.4%) and 8.3% (95% CI, 0.2–16.4%), respectively. The results suggested that low-dose ATG/PTCy combined with CsA/MMF as GvHD prophylaxis in MUD-PBSCT had promising activity.

Pacritinib Combined with Sirolimus and Low-Dose Tacrolimus for GVHD Prevention after Allogeneic Hematopoietic Cell Transplantation: Preclinical and Phase I Trial Results.

In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation. The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells. In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4+ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias. We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.

Absolute lymphocyte count on the first day of thymoglobulin predicts relapse-free survival in matched unrelated peripheral blood stem cell transplantation

Anti-thymocyte globulin (ATG) targets in-vivo T lymphocytes. Variations in the recipient absolute lymphocyte count (ALC) might result in a variable exposure of ATG. We hypothesized that recipient ALC on the first day of ATG might predict transplant outcomes. We evaluated 217 patients undergoing 8/8 HLA-matched unrelated donor (MUD) peripheral blood stem cell transplant (PBSCT) between January 2005 and December 2017, and receiving rabbit ATG (Thymoglobulin, total dose 4.5 mg/kg) on days −3, −2 and −1. With a median follow up of 3.68 years for survival (OS), one-year OS, relapse rate, non-relapse mortality (NRM), and relapse-free survival (RFS) were 64.7%, 15.9%, 25.8%, and 58.4%, respectively. Multivariable analysis revealed that ALC > 100 k/mm3 was associated with superior RFS (HR 0.64, p = .03). Our study indicates that ALC on the first day of thymoglobulin affects relapse-free survival in MUD PBSCT when weight-based thymoglobulin is used.