Unrelated Donor Allogeneic Hematopoietic Cell Research Articles

Efficacy of a Modified Post-Transplant Cyclophosphamide Regimen for Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients with Severe Aplastic Anemia: A Prospective Study

The aim of the present study was to examine the efficacy of the modified post-transplant cyclophosphamide (PTCy) regimen, which involved reducing the Cy dose to 40 mg on days +3 and +4 in patients with severe aplastic anemia (SAA) subjected to unrelated donor allogeneic hematopoietic stem cell transplantation (URD-HSCT). For this purpose, a prospective single-center trial was conducted and the clinical outcomes were collected from 30 patients with SAA treated with the modified PTCy regimen for URD-HSCT. The median time to neutrophil and platelet engraftment was 13 days (range, 11 to 16) and 12 days (range, 5 to 33), respectively. The cumulative incidence of neutrophil and platelet engraftment was 93.1% ± 0.3% and 96.6% ± 0.2%, respectively. The 2-year overall survival (OS) was 97% (95% confidence interval [CI]: 90%-100%] and 2-year graft-versus-host disease (GVHD) and rejection-free survival (GRFS) was 93% (95% CI: 85%-100%). The incidence rates of acute GVHD (aGVHD) and chronic GVHD (cGVHD) were 13.8 ± 0.4% and 10.3 ± 0.3%, respectively, and no patients developed grades III-IV aGVHD. However, only one patient developed a moderate extensive cGVHD. The incidence of reconstitution varies among different subsets of immune cells after URD-HSCT. Natural killer (NK) cells recover first, followed by CD8+ T and CD19+ B cells, and finally CD4+ T cells. In conclusion, the present study demonstrates that the modified PTCy regimen, with a reduced dose of 40 mg on days +3 and +4, may be an effective regimen for URD-HSCT in patients with SAA and reduce the occurrence of the GVHD.

Outcomes with low dose anti-thymocyte globulin based graft versus host disease prophylaxis after mismatched unrelated donor allogeneic hematopoietic cell transplantation.

Anti-thymocyte globulin (ATG) based graft versus host disease (GVHD) prophylaxis is widely used for mismatched unrelated donor allogeneic hematopoietic cell transplantation (HCT) although optimal dose remains unclear. Although recent literature suggested improved outcomes with PTCy-based regimens when compared to ATG-based regimens these studies used doses of ATG ≥5 mg/kg. Thus, we analyzed outcomes of HLA 9/10 MMUD allogeneic HCTs using lower-dose ATG-based regimens at our center. We retrospectively analyzed outcomes of HLA 9/10 MMUD allogeneic HCTs using lower dose ATG-based regimens for all adults undergoing allogeneic HCT at The Ottawa Hospital from 2015 to 2022. Data regarding demographics, conditioning regimen, dose of ATG, rates of GVHD, duration of remission, and survival, were collected and analyzed. Seventy-seven (n = 77) patients (males 62.3%; median age 50 years) underwent allogeneic HCT from MMUD. Majority(81%; n = 63) received 2.5 mg/kg of rabbit ATG and remaining 18.2% (n = 14) received 4.5 mg/kg. Grade II-IV acute GVHD occurred in 24.7% (n = 19) while any chronic GVHD occurred in 32.5% (n = 25) patients. After a median follow-up of 21 months, relapse occurred in 28.6% of patients. Two-year OS, GRFS, CIR, and NRM were 60.6%, 45.3%, 16.9%, and 18.2% respectively. Dose of ATG (2.5 mg/kg vs. 4.5 mg/kg) was not associated with outcomes in either univariate or multivariate analyses. When compared to published studies using ATG doses ≥5 mg/kg, GVHD prophylaxis using lower dose ATG may potentially lead to improved outcomes in patients undergoing MMUD allogeneic HCT. Further studies are needed to directly compare lower dose ATG to PTCy-based regimens to determine ideal GVHD prophylaxis for these patients.

High CD34-positive cell dose in matched unrelated donor allogeneic hematopoietic stem cell transplant is not associated with graft-versus-host disease or mortality.

CD34+ stem cells serve as the primary graft source for allogeneic transplants, with a minimum of 2-4 × 106 cells/kg needed for engraftment. There are conflicting data on outcomes at high stem cell doses, with studies limited by few patients receiving doses far above the minimum target. In this retrospective, single-center study of patients with hematologic malignancies who underwent matched unrelated donor transplants, we assessed outcomes for engraftment, survival, relapse, and graft-versus-host disease (GVHD) for the highest CD34+ dose quintile (>13 × 106 cells/kg, n = 36) compared to the remaining patients (n = 139). Similar analysis was performed correlating T cell dose and outcomes. There was no difference between the groups in neutrophil engraftment, with a trend toward faster platelet engraftment. There was no significant difference in mortality (adjusted risk ratio [aRR] = 1.02, 95% confidence interval [CI] = 0.85-1.22), relapse (aRR = 1.10, 95% CI = 0.85-1.42), or overall survival by Kaplan-Meier analysis (p = .44). High CD34+ dose was not associated with higher incidence of acute GVHD (aRR = 0.99 grades II-IV, aRR = 1.18 grades III-IV) or chronic GVHD (aRR = 0.87 overall, RR = 1.21 severe). There was limited correlation between CD34+ and T cell dose (R2 = .073), and there was no significant difference in survival, relapse, or GVHD in the highest T cell dose quintile (n = 33) compared to the remaining quintiles (n = 132). We found no difference in survival, relapse, or GVHD incidence or severity in patients receiving CD34+ doses above prior cutoffs reported in the literature. These data do not support the routine use of graft CD34+ dose reduction.

Haploidentical and matched unrelated donor allogeneic hematopoietic stem cell transplantation offer similar survival outcomes for acute leukemia.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has emerged as an effective approach for acute leukemia, primarily due to the inherent difficulty in finding human leukocyte antigen-matched unrelated donors (MUD). Nevertheless, it remains uncertain whether haplo-HSCT and MUD-HSCT can provide comparable outcomes in patients with acute leukemia. This study aimed to assess the overall survival (OS) and leukemia-free survival (LFS) outcomes between the MUD-HSCT and haplo-HSCT groups. This retrospective analysis encompassed adult patients with acute leukemia undergoing the initial allo-HSCT. Among these 85 patients, we stratified 33 patients into the MUD-HSCT group and 52 to the haplo-HSCT group. The primary outcomes were OS and LFS. The median OS was not reached in the haplo-HSCT group, while it reached 29.8 months in patients undergoing MUD-HSCT (p = .211). Likewise, the median LFS periods were 52.6 months in the haplo-HSCT group and 12.7 months in the MUD-HSCT group (p = .212). Importantly, neither the OS nor LFS showed substantial differences between the MUD-HSCT and haplo-HSCT groups. Furthermore, univariate analyses revealed that haplo-HSCT did not demonstrate a significantly higher risk of worse LFS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.25; p = .216) or OS (HR, 0.67; 95% CI, 0.36-1.26; p = .214) than MUD-HSCT. Notably, a high European Group for Blood and Marrow Transplantation risk score (HR, 1.44; 95% CI, 1.10-1.87; p = .007) and non-complete remission (HR, 2.48; 95% CI, 1.17-5.23; p = .017) were significantly correlated with worse OS. Haplo-HSCT may serve as an alternative to MUD-HSCT for the treatment of acute leukemia, offering similar survival outcomes.

Outcomes of Antithymocyte Globulin-Post-Transplantation Cyclophosphamide-Cyclosporine-Based versus Antithymocyte Globulin-Based Prophylaxis for 10/10 HLA-Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

In 2015, dual T cell depletion with antithymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) combined with cyclosporine A (CsA) replaced our prior institutional graft-versus-host disease (GVHD) prophylaxis regimen of 4.5 mg/kg ATG, CsA, and mycophenolate mofetil (MMF) (ATG-based) in 10/10 HLA-matched unrelated donor (MUD) peripheral blood allogeneic hematopoietic stem cell transplantation (allo-HCT). The initial ATG dose of 4.5 mg/kg [ATG(4.5)/PTCy] was reduced to 2 mg/kg [ATG(2)/PTCy] in 2018. This study compares the results obtained from 444 adults undergoing MUD allo-HCT at our institution who received ATG(4.5)/PTCy (n = 127) or ATG(2)/PTCy (n = 223) with those who received ATG-based prophylaxis without PTCy (n = 84). The rates of grade II-IV and grade III-IV acute GVHD (aGVHD) at day +100 and moderate/severe chronic GVHD (cGVHD) at 1 year were 35.7%, 21.6%, and 14.7%, respectively, in patients receiving ATG-based prophylaxis without PTCy; 16.5%, 4.9%, and 4.3% in patients receiving ATG(4.5)/PTCy; and 23.3% (P = .004), 8.0% (P < .001), and 14.1% (P =.006) in patients receiving ATG(2)/PTCy. One-year overall survival (OS), nonrelapse mortality (NRM), and GVHD-free relapse-free survival (GRFS) were 69.8%, 25.3%, and 52.0%, respectively, for patients receiving ATG-based prophylaxis without PTCy; 82.7%, 17.3%, and 59.8% for patients receiving ATG(4.5)/PTCy; and 78.3% (P = .446), 14.7% (P = 101), and 56.2% (P = .448) for patients receiving ATG(2)/PTCy. On univariate analyses, the use of ATG(2)/PTCy was associated with a lower risk of NRM (hazard ratio, .54; P = .023) compared with the use of ATG-based prophylaxis without PTCy. ATG(2)/PTCy prophylaxis effectively prevents GVHD and is associated with comparable relapse risk, OS, and GRFS as seen with ATG(4.5)/PTCy and ATG-based prophylaxis without PTCy.

Favorable Outcomes with Low Dose Anti Thymocyte Globulin Based Graft Versus Host Disease Prophylaxis after Mismatched Unrelated Donor Allogenic Hematopoietic Cell Transplantation

DISCUSSION INTRODUCTION Anti thymocyte globulin (ATG) based Graft versus Host disease (GVHD) prophylaxis is widely used for unrelated donor allogeneic hematopoietic cell transplantation (HCT) although the optimal dose remains unclear. Recently, registry based and single centre retrospective analyses have suggested superior outcomes with the PTCy based GVHD prophylaxis regimens when compared to ATG based regimens in mismatched unrelated donor (MMUD) allogeneic HCT, however, these studies all used doses of ATG ≥ 5mg/kg. Outcomes following MMUD allogeneic HCT with lower dose ATG based GVHD prophylaxis regimens have not been extensively studied. Thus, we analysed outcomes of HLA 9/10 MMUD allogeneic HCTs using two low dose ATG based regimens as GVHD prophylaxis at our centre. All adult patients undergoing standard of care allogenic hematopoietic cell transplant at The Ottawa Hospital from January 1 st 2015- December 31, 2022 were included. Data regarding demographics, HLA mismatched allele, conditioning regimen, dose of ATG, time to engraftment, and rates of acute and chronic GVHD was collected. The primary outcome evaluated was overall survival (OS) and secondary outcomes were GVHD-free relapse-free survival (GRFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM). Survival outcomes were analyzed using Kaplan Meier analysis. Predictors of survival were identified using Cox-proportional hazards regression model. 77 patients (Males 62.3% (n=48); Median age - 50 years) underwent allogeneic HCT from MMUD. Most common indication for transplant was MDS/AML in 66.2% (n=51) followed by ALL in 11.3% (n=9) patients. Most frequently mismatched locus was HLA A in 37.7% (n= 29) followed by HLA B in 14.3% (n=11). Myeloablative conditioning regimen was received by 76.6% (n=59) while reduced intensity regimens were used in 23.4% (n=18) patients. Rabbit ATG was part of the GVHD prophylaxis regimen in all patients with majority (81%; n=63) receiving 2.5mg/kg and remaining 18.2% (n=14) receiving 4.5mg/kg of the drug. Grade II-IV acute GVHD occurred in 24.7% (n=19) while chronic GVHD occurred in 32.5% (n= 25) patients. After a median follow up of 21 months, relapse occurred in 28.6% (n=22) patients. Two year OS (Fig 1), and GRFS of the whole cohort were 60.6% and 45.3% respectively. 2-year incidence of non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) were 16.9% and 18.2% respectively. Dose of ATG (2.5 mg/kg vs 4.5 mg/kg) was not a predictor of outcomes in either univariate and multivariate analyses. Age more than 50 years, primary diagnosis of lymphoma, reduced intensity conditioning and mismatch in loci other than HLA C were significant predictors of poor OS after univariate analysis. Only primary diagnosis of lymphoma (Hazard Ratio (HR) - 7.76; p=0.045) and mismatch in loci other than HLA C (HR - 9.53; p=0.03) were significant predictors of poor OS after multivariate analysis. When compared to published single centre and registry-based studies using ATG doses ≥ 5 mg/kg, GVHD prophylaxis using ATG doses ≤4.5 mg/kg seems to provide improved outcomes in patients undergoing allogeneic HCT from mismatched unrelated donors (Table 1). Our findings suggest that further studies are needed directly comparing lower dose ATG based regimens to PTCy based regimens to determine the ideal GVHD prophylaxis regimen for patients undergoing allogeneic HCT from HLA mismatched unrelated donors.

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.

A Calcineurin Inhibitor Free Graft Versus Host Disease Prophylaxis for Patients Undergoing Matched Related and Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplant

Post-transplantation cyclophosphamide (PTCy) and calcineurin inhibitor (CNI)-based graft versus host disease (GVHD) prophylaxis has been associated with lower rates of acute and chronic GVHD compared with the traditional prophylaxis of CNI and methotrexate (MTX) in matched related donor (MRD) and matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo-HCT). The combination of PTCy with sirolimus (PTCy-Siro) as CNI-free GVHD prophylaxis has shown promising results, with cumulative rates of grade II-IV acute and chronic GVHD in the range of 15% to 27% and 20% to 27%, respectively, in patients undergoing MRD, MUD, and haploidentical allo-HCT. We report a single-center, nonrandomized comparison of patients undergoing matched donor allo-HCT receiving PTCy-Siro with those receiving the standard GVHD prophylaxis of tacrolimus and methotrexate (Tac-MTX). One hundred and sixteen consecutive patients who had undergone an MRD or MUD allo-HCT between January 2018 and January 2021 and received either PTCy-Siro (n = 29) or Tac-MTX (n = 87) as GVHD prophylaxis regimens were eligible for inclusion. Patients receiving PTCy-Siro had a significantly shorter median time to immunosuppression withdrawal than patients receiving Tac-MTX (138 days [range, 37 to 312 days] versus 232 days [range, 66 to 1120 days]; P < .001). There was no significant difference between the 2 arms in the incidence of grade II-IV acute GVHD, grade III-IV acute GVHD, steroid-refractory acute GVHD, or clinical infections. At a median follow-up of 1.1 years (range, 0 to 1.8 years), patients receiving PTCy-Siro were significantly less likely to have chronic GVHD, with 2-year freedom from GVHD of 75% (95% confidence interval [CI], 58% to 98%) versus 20% (95% CI, 10% to 40%) for those receiving Tac-MTX (P = .005).

307 - Recipient Immune Parameters Are Associated with Outcomes after Unrelated Donor (URD) Allogeneic Hematopoietic Cell Transplant (alloHCT)

307 - Recipient Immune Parameters Are Associated with Outcomes after Unrelated Donor (URD) Allogeneic Hematopoietic Cell Transplant (alloHCT)

Low dose post-transplant cyclophosphamide as GVHD prophylaxis for matched unrelated donor allogeneic hematopoietic stem cell transplants in children

Low dose post-transplant cyclophosphamide as GVHD prophylaxis for matched unrelated donor allogeneic hematopoietic stem cell transplants in children

Ptcy-ATG-CSA Vs. ATG-MMF-CSA for Gvhd Prevention for 10/10 HLA Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Post-transplant cyclophosphamide (PTCY) combined with other immunosupressant agents has been a milestone in haploidentical-HCT (haplo-HCT). Secondary to its efficaty, it use is being expanded to allo-HCT performed from matched donors with notable success. However, despite that using PTCY out of the haplo-HCT setting is becoming prevalent, a standard drug combination has not been yet established. The use of PTCY at a dose of 50mg/kg and administered on day 3 and 4, combined with 4.5mg/kg of anty-thymocyte globuline (ATG) and cyclosporine (CsA) (PTCY-ATG(4.5)-CsA) become our Institutional GVHD prophylaxis for 10/10 HLA-matched unrelated donor (MUD) peripheral blood (PB) allo-HCT in 2015. The use of this prophylaxis induced an effective GVHD prevention. However, infectious diseases were the most prevalent complication derived from the use of this approach (Salas et al. BMT, 2019). Based on these results, the ATG dose was lowered to 2mg/kg (PTCY-ATG(2)-CsA) in 2018. The use of this refined combination resulting on a comparable effectivenes on GVHD prevention and less infectious complications (Salas et al. Eur. J. Hematology 2021). The present análisis aims to compare the results provided by using PTCY-ATG(2)-CsA with those obtained using PTCY-ATG(4.5)-CsA and the previous Institutional GVHD prophylaxis used for 10/10 MUD PB allo-HCT which was composed by 4.5mg/kg of ATG combined with mycophenolate mofetil (MMF) and CsA (ATG-MMF-CsA). METHODS Between 2011 and 2021, 444 patients underwent first PB allo-HCT from 10/10 MUD at our Institution and were included in the study. The study cohort was dividied into 2 groups: 84 adults that received ATG-based prophyaxis, 127 that received PTCY-ATG(4.5)-CsA and 233 received PTCY-ATG(2)-CsA. All patients received PB stem cell grafts from 10/10 MUD. RESULTS Baseline charateristics are summarized in Table 1. As reported, the proportion of patients older tan 60 years was higher in patients receiving PTCY-ATG(2)-CSA than in the other 2 groups. Moreover, the proportions of patients with an HCT-CI score >3 and a high/very-high disease risk index were lower in this group of patients. As shown in Figure 1, the cumulative incidence functions (CIF) of grade II-IV acute GVHD, grade III-IV acute GVHD at day 100, and moderate/severe chronic GVHD at 1 year were: 23.3%, 8.0% and 14.1% in patients receiving PTCY-ATG(2)-CsA, 16.5%, 4.9%, and 5.4% in patients receiving PTCYATG(4.5)-CSA, and 35.7%, 21.6%, and 14.7% in those receiving ATG-based prophylaxis. Lastly, as reported in Figure 1, the estimated 1-year OS, RFS, GRFS, NRM and CIR were 78.3%, 69.2%, 56.2%, 14.7% and 16.1% for patients receiving PTCY-ATG(2)-CsA, 72.4%, 66.1%, 53.5%, 17.3%, and 16.5% for patients receiving PTCY-ATG(4.5)-CsA, and 68.6% (P=0.443), 66.3% (P=0.573), 43.0% (P=0.448), 25.3% (P=0.100), and 8.4% (P=0.243) for patients receiving ATG-based prophylaxis. CONCLUSION The use of ATG-PTCY-CsA provides an effective prevention of acute and chronic GVHD, aceptable relapse rates, and results on a high overall survival. Compared with using ATG-MMF-CSA, the use of this prophylaxis decreased rates of acute GVHD. Moreover using PTCY-ATG(4.5)-CsA decreased the proportion of moderate/severe cGVHD to only 8%. Lastly, a trend to higher 1-year OS was documented in patients receiving PTCY-ATG(2)-CsA than in the rest ( 78.3% vs. 72.6% and 68.6%). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intensified conditioning regimens improved disease-free survival and engraftment after unrelated single-unit cord blood transplantation but not after matched sibling or matched unrelated donor allogeneic hematopoietic cell transplantation.

The impact of conditioning intensity on different donor groups has been unclear in allogeneic transplantation. The objective of this study was to clarify the effect of conditioning intensity on disease-free survival (DFS), relapse, non-relapse mortality (NRM), neutrophil engraftment, and graft-versus-host disease for each donor type. We retrospectively evaluated the effect of conditioning intensity on transplant outcomes for patients with acute leukemia or myelodysplastic syndrome aged between 16 and 60years in Japan using the transplant conditioning intensity (TCI) scoring system. A total of 8526 patients who received first allogeneic transplantation from 6/6 antigen-matched sibling donor (MSD, n=2768), 8/8 allele-matched unrelated donor (MUD, n=2357), and unrelated single-cord blood (UCB, n=3401) were eligible for the analyses. Compared to conditioning with TCI score 4.0, which was corresponds to conventional myeloablative conditioning, including cyclophosphamide with total body irradiation 12Gy or busulfan 12.8mg, and was considered as the reference group in the multivariate analyses, intensified conditioning with TCI score ≥4.5 improved DFS (hazard ratio [HR],0.81, P<0.001) and relapse rate (HR, 0.70, P<0.001) but only after UCB transplants and not MSD and MUD transplants. In contrast, NRM was higher after intensified conditioning with TCI score ≥4.5 for MSD (HR, 1.39, P=0.008) and MUD (HR, 1.47, P=0.002) transplants but not UCB transplants (HR, 1.12, P=0.240). Neutrophil engraftment was also significantly higher after intensified conditioning with TCI score ≥4.5 but only for UCB transplants (HR, 1.24, P<0.001), whereas it was significantly lower after reduced-intensity conditioning with TCI score ≤3.5 for MSD transplants only (HR, 0.82, P<0.001). These data demonstrated that an intensified conditioning regimen improved survival and engraftment rate only after a UCB transplants. Therefore, TCI scoring system could enable the optimization of conditioning intensity according to donor type, particularly in terms of survival and engraftment.

A Tale of Two Rashes in a Bone Marrow Transplant Patient

A 68-year-old female patient with myelofibrosis was admitted for scheduled matched unrelated donor allogeneic hematopoietic stem cell transplant for the treatment of myelofibrosis. Her past medical history was also significant for Grover disease, also known as transient acantholytic dermatosis, characterized by chronic pruritic skin eruptions. On admission, the patient had no complaints with stable vital signs and benign physical examination. Laboratory values were notable for anemia with hemoglobin of 8.33g/dL, white blood cell count of 7.22 k/uL, and platelet count of 297 k/uL.

Letermovir vs. high-dose valacyclovir for cytomegalovirus prophylaxis following haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation receiving post-transplant cyclophosphamide

Patients undergoing haploidentical or mismatched unrelated donor (haplo/MMUD) allogeneic hematopoietic cell transplantation (alloHCT) receiving post-transplant cyclophosphamide (PTCy) are at high risk of cytomegalovirus (CMV) infection. Experience with letermovir (LET) in this population is limited. This single center retrospective cohort study compared CMV and transplant outcomes between LET and a historical control with high-dose valacyclovir (HDV) prophylaxis in adults undergoing haplo/MMUD alloHCT. Thirty-eight CMV seropositive patients were included, 19 in each arm. LET reduced the incidence of CMV infection (5% vs. 53%, RR 0.01, 95% CI 0.014–0.71, p = .001) and need for CMV treatment by day +100 (5% vs. 37%, RR 0.14, 95% CI 0.18–0.99, p = .017) compared to HDV. Median CMV event-free-survival was improved with LET (not reached vs. 80 days, HR 0.114, 95% CI 0.07–0.61, p = .004). These data support the efficacy of LET in alternative donor transplants.

Randomized Trial of Tacrolimus and Methotrexate Versus Tacrolimus, Reduced Dose Methotrexate, and Mycophenolate Mofetil for Prevention of Graft-Versus-Host Disease after Myeloablative Related and Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Background: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). The combination of tacrolimus (Tac) and methotrexate (MTX) is a standard regimen for GVHD prophylaxis; however, it is associated with several toxicities and patients are often not able to complete the full MTX regimen. The combination of Tac, reduced dose (“mini”)-MTX, and mycophenolate mofetil (MMF) has been investigated with a well-tolerated toxicity profile and low incidence of GVHD, although comparison with standard dose MTX has not been done. We performed a randomized non-inferiority trial comparing Tac/MTX (Full-MTX) to Tac/mini-MTX/MMF (Mini-MTX) for prevention of GVHD after myeloablative related and unrelated donor HCT.Methods: Patients <70 years in age receiving first myeloablative allogeneic HCT using 8/8 HLA-matched related or unrelated donor were eligible; all diagnoses and both bone marrow and peripheral blood stem cell grafts were allowed. Full-MTX patients received MTX dose of 15 mg/m 2 day +1, and 10 mg/m 2 days +3, +6, and +11. Mini-MTX patients received doses of 5 mg/m 2 on days +1, +3, and +6 plus MMF 1000 mg BID. MTX and MMF doses were adjusted for body weight in pediatric recipients. Primary endpoints were incidence of acute GVHD, mucositis, and hematopoietic engraftment. Secondary endpoints included incidence of chronic GVHD, organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). Based on our local incidence rates, 45 patients/arm were needed to detect a hazard ratio of at most 1.7 for acute GVHD (no difference between two arms) using a one-sided non-inferiority log-rank test with 5% significance and 80% power.Results: We enrolled 101 patients; 5 were excluded due to change in eligibility or withdrawal of consent prior to HCT. Analysis is based on 96 patients who were randomized to receive Full-MTX (N=49) or Mini-MTX (N=47). Patient characteristics are described in the Table, and were generally balanced between the two groups . All patients in the Mini-MTX arm received their 3 planned doses of MTX; in the Full-MTX arm, 71% received all 4 doses, 26% received 3 doses, and 1 patient received 2 doses of MTX. There was no significant difference in cumulative incidence of grade 2-4 acute GVHD by day 100 between arms (28% Mini-MTX vs 27% Full-MTX, P=0.41) (Figure 1); however, there was a trend toward higher grade 3-4 acute GVHD in Mini-MTX arm (13% vs 4%, P=0.07). Mini-MTX recipients had lower incidence of severe WHO grade 3-4 mucositis (57% vs 82%, P=0.010), shorter duration of mucositis (median 11 vs 18 days, P<0.001), and had faster engraftment of both neutrophils (median 15 vs 17 days, P<0.001) and platelets (median 23 vs 27 days, P=0.023), with resultant shorter hospital stay (median 27 vs 31 days, P<0.001). There were no significant differences between the two arms in any grade of chronic GVHD (36% vs 25%, P=0.09) or moderate-severe chronic GVHD at 1 year (23% vs 20%, P=0.14). There were also no differences in bacterial (P=0.18), viral (P=0.52) or fungal (P=0.74) infections. There were no significant differences in hepatotoxicity, but lower proportion of patients receiving Mini-MTX experienced nephrotoxicity (creatinine ≥3X upper limit of normal: 2% vs 26%, P<0.001). Mini-MTX recipients also had less respiratory failure in the first 6 months (6% versus 22%, P=0.026). There was no difference in relapse between arms (2-year incidence 22% vs 21%, P=0.89), although Mini-MTX was associated with lower NRM (11% vs 25% at 2 years) (Figure 2), and non-significant but higher OS (70% vs 52% at 2 years; P=0.06).Conclusions: Compared to Full-MTX, a Mini-MTX regimen that incorporates MMF was associated with no difference in acute or chronic GVHD incidence and a more favorable toxicity profile, with faster engraftment, less mucositis, less organ toxicity, and lower NRM. The combination of Tac/mini-MTX/MMF is an acceptable alternative to Tac/MTX after myeloablative related and unrelated donor HCT. [Display omitted] DisclosuresHamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Gerds: Imago: Research Funding; AbbVie: Consultancy; Constellation: Consultancy; Brystol Myers Squibb: Consultancy; Sierra Oncology: Consultancy; Incyte: Research Funding; PharmaEssentia: Consultancy; Novartis: Consultancy; Constellation: Research Funding; Krtos: Research Funding; CTI Biopharma: Research Funding; Accutate: Research Funding. Hill: Gentenech: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding. Copelan: Amgen: Consultancy. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.

Racial and Socioeconomic Disparities in Long-Term Outcomes in ≥ 1 Year Allogeneic Hematopoietic Cell Transplantation Survivors: A CIBMTR Analysis

Introduction: It has been shown that racial/ethnic minorities have worse survival after matched unrelated donor allogeneic hematopoietic cell transplantation(allo-HCT) compared to Whites. Whether the racial disparity in allo-HCT outcomes persists in long-term survivors, and possibly may even be exacerbated in this population that frequently transitions back from the transplant center to their local healthcare providers, is unknown. In the current study we sought to compare long-term outcomes among one-year survivors, by race/ethnicity and socioeconomic status (SES), after allo-HCT reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).Methods: The CIBMTR database was used to identify 5,473 patients with Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myeloid Leukemia (CML), or Myelodysplastic Syndrome (MDS) who received HCT between 2007-2017, who were alive and in remission for at least 1 year after allo-HCT. Study was restricted to patients transplanted in the United States. Cox regression model was used to determine association of ethnicity/race and SES with overall survival (OS), relapse, and treatment related mortality (TRM). Standardized mortality ratio (SMR) was calculated to compare mortality rates of the study patients to their general population peers matched on race/ethnicity, age and sex.Results: Patients were reported to be Non-Hispanic White (W) (n=4385), Non-Hispanic Black (B) (n=338), Hispanic (H) (n=516), and Asian (A) (n=234). Median follow up after 1 year allo-HCT (months): 69 W, 50 B, 59 H and 57 A (Table 1). Patient neighborhood poverty level was estimated from residential ZIP code at the time of allo-HCT. A ZIP code with ≥20% of persons below the federal poverty level was considered high poverty area. In multivariable analysis, we observed no significant differences in OS, relapse or TRM based on race or poverty level when adjusted for patient-, disease- and transplant-related covariates (Table 2).Conclusions: Our study highlights that among those who survived at least 1-year in remission after allo-HCT, previously reported disparities in post HCT outcomes based on racial/ethnic factors, are not evident in contemporary practice. This might suggest that previously recognized disparity in outcomes could be due to factors that mostly affect patients in their first year post HCT. Future studies are needed to identify these early adverse factors and implement strategies to mitigate them. [Display omitted] DisclosuresBlue: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; WebMD: Consultancy. Wood: Pfizer: Research Funding; Teladoc: Consultancy; Koneksa Health: Consultancy, Current equity holder in publicly-traded company. Majhail: Incyte Corporation: Consultancy; Anthem, Inc: Consultancy. Saber: Govt. COI: Other.

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

BackgroundAllogeneic hematopoietic stem cell transplantation (HCT) is the optimal and potentially curative therapy in various high-risk hematologic malignancies. Although a human leukocyte antigen (HLA)-matched sibling or unrelated donor is a clinically preferred stem cell source, the use of haploidentical family donors and umbilical cord blood HCT now offers the option of HCT in patients lacking a matched donor. However, many patients lack an appropriate donor, in particular the ethnic minorities. Mismatched unrelated donors (MMUD) have historically been utilized as alternative donor source for these patients due to ease of donor availability but is associated with increased risk of graft versus host disease (GVHD) and non-relapse mortality (NRM). In this systematic review and meta-analysis, we aimed to assess the outcomes with MMUD HCT.Methods:Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was performed on three databases (PubMed, Cochrane Library, and ClinicalTrials.gov) from date of inception through February 2021 using the MeSH and entry terms for “hematopoietic stem cell transplantation”, OR “hematologic neoplasms”, AND unrelated donors“ AND ”treatment outcome“. A total of 2477 records were identified and primary and secondary screening was done. After excluding review, duplicate, and non-relevant articles, we included 13 studies (11 retrospective, 2 prospective) reporting outcomes following MMUD HCT. The Joanna Briggs Institute (JBI) critical appraisal checklist for studies reporting prevalence data and randomized control trial was used for quality assessment, and all studies were reported as good. Proportions along with a 95% confidence interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2). The variance between the studies was calculated using Der Simonian-Laird Estimator.Results:We identified 2588 patients from 13 included studies who had MMUD HCT. (Table 1) Median age was 51.7 (18-76) years and 52% (n=1347) were males. Source of primary graft was bone marrow (BM) in 19% (n=478/2508) and peripheral blood (PB) in 81% (n=2030/2508) HCT recipients. Median time to transplant was 10.45 (1.5-139.6) months and median follow up was 41.5 (0.4-136.5) months. Reduced intensity conditioning (RIC) conditioning was used for 73% (n=1884) of the patients while 27.2% (n= 704) patients received myeloablative conditioning (MAC). We estimated a pooled overall survival (OS) of 59% (95% CI 0.52-0.66, I 2 = 92%, n=2563) at one year and 44% (0.36-0.53, I 2=92%, n=1972) at three years. The pooled incidence of acute GVHD (grade II-IV), acute GVHD (grade III-IV), and chronic GVHD were 39% (95% CI 0.33-0.44, I 2=84%, n=2282), 19% (95% CI 0.15-0.23, I 2=65%, n=1417), and 38% (95% CI 0.32-0.47, I 2=93%, n=2477) respectively. Progression free survival (PFS) was 39.5% (95% CI 0.31-0.48, I 2=94% n=2505). The pooled incidence of relapse rate (RR) and NRM were 31% (95% CI 0.25-0.38, I 2=90%, n=2482) and 27% (95% CI 0.21-0.34, I 2 =90% n=2448) respectively.Conclusion:Mismatched unrelated donor HCT has shown favorable outcomes with acceptable toxicity profile. MMUD HCT represents a promising option for patients lacking an HLA-matched donor and has expanded access to HCT in patients with ethnic minorities who often lack a matched donor. [Display omitted] DisclosuresAbhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Juno Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding.

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

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

Post-Transplant Cyclophosphamide Is Associated with Improved Clinical Outcomes in HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation

Post-Transplant Cyclophosphamide Is Associated with Improved Clinical Outcomes in HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation

Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation.

BackgroundIdentification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT.MethodsWe performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000–2011.FindingsUsing meta-analyses of both cohorts, genome-wide significant associations (p < 5 × 10−8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24–1.56, p = 3.3 × 10−8) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21–1.48, p = 2.0 × 10−8); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41–2.05, p = 3.15 × 10−8), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49–2.31, p = 2.84 × 10−8), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31–1.73, p = 6.9 × 10−9) and CT49 (rs32250, HR = 1.44, 95% CI1.26–1.64, p = 2.6 × 10−8); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74–3.12, p = 1.26 × 10−8) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92–3.58, p = 4.6 × 10−9). Results publicly available at https://fuma.ctglab.nl/browse.InterpretationThese data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies.FundingThis project was funded by grants from the National Institutes of Health, USA