Donor Allogeneic Hematopoietic Cell Transplantation Research Articles

Post-transplantation cyclophosphamide and cyclosporine A versus methotrexate and cyclosporine A for graft-versus-host disease prophylaxis after allogeneic peripheral stem cell transplantation in adult acute myeloid leukemia patients

BackgroundDifferent prophylactic protocols are available for preventing graft-versus-host disease (GVHD) after matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to compare the effectiveness of post-transplantation cyclophosphamide plus cyclosporine A (PT-CY/CSA) versus methotrexate plus CSA (MTX/CSA) as GVHD prophylaxis protocols in adult acute myeloid leukemia (AML) patients who received peripheral blood stem cells (PBSC) from fully matched donors. MethodsThe 1-year outcomes of 89 patients treated with PT-CY/CSA and 90 patients treated with MTX/CSA who had MSD allo-HCT for AML using unmanipulated mobilized PBSC were examined and compared. ResultsThe cumulative incidence of acute GVHD at 100 days was considerably lower in the PT-CY/CSA group (4% vs 19.3%, p = 0.002), however there were no statistically significant difference in the cumulative incidence of chronic GVHD at 1-year (19.6% vs 37.4%, p = 0.053). Significant delays in neutrophil and platelet engraftments were reported in the PT-CY/CSA group (17 vs 12 days) and (13 vs 12 days), respectively (p < 0.001). The cumulative incidences of relapse (19.1% vs 13.7%, p = 0.470), overall survival (79.1% vs 77.3%, p = 0.986), non-relapse mortality (16.5% vs 16.8%, p = 0.837), and the GVHD and relapse-free survival (GRFS) (53.7% vs 46.6%, p = 0.478) did not differ statistically at 1-year. ConclusionPT-CY/CSA demonstrated a significant decrease in the rate of acute GVHD. However, it was associated with engraftment delay.

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.

Hematopoietic stem cell transplantation for B-thalassemia major with alemtuzumab

While matched related donor (MRD) allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for transfusion-dependent beta-thalassemia (TDT), the use of alternative sources has increased, resulting in the exploration of novel transplant-conditioning regimens to reduce the contribution of graft-versus-host disease (GVHD) and graft failure (GF) to transplant-related morbidity and mortality. Alemtuzumab is a CD52 monoclonal antibody that has been successfully incorporated into myeloablative conditioning regimens for other hematologic conditions, yet there have been limited studies regarding the use of alemtuzumab in HSCT for TDT. The purpose of this study was to evaluate engraftment, incidence of GVHD, and transplant related morbidity and mortality in patients with TDT who received alemtuzumab in addition to standard busulfan-based conditioning. The primary endpoint was severe GVHD-free, event-free survival (GEFS). Our cohort included 24 patients with a median age of 6.8 years (range 1.5-14.9). Eleven patients received a 10/10 MRD HSCT, eleven 10/10 unrelated donor (UD), and two mismatched UD. All patients achieved primary engraftment. For all patients, 5-year GEFS was 77.4% and 5-year overall survival (OS) was 91%. The 5-year cumulative incidence of GF (attributed to poor graft function) without loss of donor chimerism was 13.8% (95% CI: 4.5, 35.3). We report low rates of significant acute GVHD grade II–IV (12.5%) and chronic GVHD (4.4%). Younger age and MRD were associated with significantly improved GEFS, OS and EFS. Our results show that the use of alemtuzumab promotes stable engraftment, may reduce rates of severe GVHD, and results in acceptable GEFS, OS, and EFS.

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.

Clinical Analysis of Matched Sibling Donor Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Young Patients with Multiple Myeloma

To investigate the efficacy and safety of matched sibling donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of young patients with multiple myeloma (MM). The clinical data of 8 young patients (median age：46 years) with MM who underwent allo-HSCT from HLA-indentical sibling donors in the First Affiliated Hospital of Chongqing Medical University from June 2013 to September 2021 were collected, and their survival and prognosis were retrospectively analyzed. All the patients were successfully transplanted, and 7 patients could be evaluated the efficacy after transplantation. The median follow-up time was 35.2 (2.5-84.70) months. The complete response (CR) rate was 2/8 before transplantation and 6/7 after transplantation. Acute GVHD developed in 2 cases and extensive chronic GVHD developed in 1 case. Within 100 days, 1 case died of non-recurrent events, and 1-year and 2-year disease-free survival were 6 and 5 cases, respectively. At the end of follow-up, all the 5 patients who survived for more than 2 years survived, and the longest disease-free survival time has reached 84 months. With the development of new drugs, HLA-matched sibling donor allo-HSCT may be a curable treatment for young patients with MM.

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)

300 - Outcomes of HLA-Matched Related Donor (MRD) and Haploidentical Donor (Haplo) Allogeneic Hematopoietic Cell Transplant Recipients By Immune Profiles of Recipients and Donors

300 - Outcomes of HLA-Matched Related Donor (MRD) and Haploidentical Donor (Haplo) Allogeneic Hematopoietic Cell Transplant Recipients By Immune Profiles of Recipients and Donors

Efficacy of Activated Autologous Hematopoietic Stem Cell Transplantation in the Treatment of Acute Myeloid Leukemia

To compare the efficacy of activated autologous bone marrow and peripheral blood hematopoietic stem cell transplantation (Auto-HSCT) and matched sibling donor allogeneic hematopoietic stem cell transplantation (MSD-HSCT) for the first complete remission of adult acute myeloid leukemia (AML-CR1). For 86 adult patients with first complete remission of AML who underwent auto-HSCT (41 cases) and MSD-HSCT (45 cases) in our hospital from June 2012 to June 2020, the patients were treated with modified MAC ［Malflane 160 mg/(m2·d), -3 days, Ara-C 2 g/(m2·2), -3 days 21∶00, -2 days 9∶00, CTX 60 mg/(kg·d),-3 d, -2 d］, the stem cells were activated by IL-2 (1 000 U/ mL), IFN-α (100 U/ mL) and IFN-γ (100 U/ml). The overall survival (OS), leukemia free survival (LFS), cumulative incidence of recurrence (CIR) and non-recurrence mortality (NRM) of patients with different types of transplantation were compared. The 3-year OS rates of Auto-HSCT group and MSD-HSCT group were 75% and 69.5%, and the 3-year LFS rates were 70.6% and 82.4%, respectively. There was no statisticaly significant difference in the 3-year OS rates of low risk, medium risk and high risk patients in the Auto-HSCT and MSD-HSCT group (90.2% vs 87.5%, 68.4% vs 68.8%, 28.6% vs 53.3%), the LFS rates of low risk, medium risk and high risk patients in the auto-HSCT and MSD-HSCT group were 90.2% and 87.5%(P=0.838), 71.8% and 91.7%(P=0.184), 0 and 67.5%(P=0.027), respectively. The NRM of Auto-HSCT and MSD-HSCT group were 4.9% and 20% (P=0.036), and CIR were 24.4% and 13.3% (P=0.188). Univariate analysis showed that the survival time of patients was significantly correlated with the number of CR courses and disease risk stratification (P=0.005, P=0.000). Cox multivariate analysis showed that disease risk stratification was an independent risk factor affecting OS (P=0.001). For adult patients with primary AML-CR1, Auto-HSCT is safe and effective. In the absence of sibling donor, Auto-HSCT can be regarded as an effective post-remission treatment for patients with intermediate risk AML-CR1.

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

Successful Desensitization of Severe Alloimmune Platelet Refractoriness and Provision of Permissive Platelet Transfusions with a Novel IgG-Targeted Enzyme Therapeutic

AK and JCS contributed equallyBACKGROUND Alloimmune platelet refractoriness (APR), inadequate response to platelet transfusion secondary to alloantibodies targeting Human Leukocyte Antigens (HLA), affects ~25% of acute myeloid leukemia (AML) patients. For profoundly sensitized thrombocytopenic patients, HLA- or crossmatch-compatible platelet units may be unavailable, increasing the risk of thrombocytopenic hemorrhage. Imlifidase cleaves systemic IgG precluding complement fixation/phagocytosis and has been used to desensitize renal allograft recipients.1 Here we show that desensitization with imlifidase can significantly improve compatible platelet availability in APR and post-hematopoietic stem cell transplant platelet nadir. PATIENT CASE A 43-year-old woman with AML treated with cytarabine and daunorubicin was referred for matched-unrelated donor allogeneic hematopoietic progenitor cell transplantation. Her induction, at an outside institution, was complicated by bilateral retinal and mucosal hemorrhage secondary to APR and profound thrombocytopenia (platelet count to 0/µL). On presentation, her panel reactive antibody (PRA) showed exquisite sensitization (99.9%, i.e. ~99.9% of all donor platelet units predicted incompatible), precluding identification of HLA-compatible platelet units to support the patient through her anticipated platelet nadir. Desensitization included rituximab 375 mg/m2 (transplant D-13 and -6), therapeutic plasma exchange (TPE, D-2 and -1) and FDA-emergency-use-authorized imlifidase 0.25 mg/kg IV (D-1 and D+1). Following imlifidase administration, the number of unacceptable antigens and PRA decreased significantly (Figure) allowing sufficient compatible platelets to be identified and procured. During admission, the patient received 7 total platelet transfusions and experienced no hemorrhage (Table). She was discharged stable, post-platelet engraftment on D+19. STUDY DESIGN With IRB approval, the number of predicted clinically significant alloantibodies (antibodies with ≥ 3000 mean fluorescence intensity, MFI) and PRA (LABScreen single antigen and PRA Class I, One Lambda/ThermoFisher, West Hills, California) were compared at baseline, after rituximab/TPE, and after imlifidase administration. Corrected count increment (CCI) to platelet transfusions administered following imlifidase desensitization was calculated. CCI > 5000 was judged a permissive transfusion. Categorical variables were compared with Chi-squared followed by Fisher's Exact. P < .05 was significant. RESULTS AND CONCLUSION Compared to the baseline, unacceptable antigens (antigens targeted by antibodies at clinically significant levels) decreased significantly after rituximab/TPE (N=53/55 to 44/55 antigens, P = .015) and imlifidase (N = 44/55 to 16/55, P < .0001). PRA did not decrease significantly with rituximab/TPE (99.9 to 99.5%, P = .22) but did following imlifidase (99.5 to 87.2%, P < .0001). Of 7 transfusions given post imlifidase, the median CCI was 6000 (interquartile range: 500-7500), N=5/7 were judged permissive. In summary, the imlifidase-mediated decrease in PRA significantly aided the identification of numerous compatible platelet units for this patient and prevented further thrombocytopenic hemorrhage. Our limited data suggest a potentially novel application of imlifidase for desensitization of highly platelet allo-refractory patients requiring multiple platelet transfusions over a short period. We will perform western blot analysis of antibodies from in vivo samples collected over the treatment course to compare antibody fragmentation over time, as partially cleaved immunoglobulin detected by our microbead-based assays may not be pathologic.2 Additionally, as the patient's initial antibody levels exceeded the range of linearity of the bead-based assay, serial dilution studies of patient serum over the treatment course will more precisely semi-quantitate the true peak antibody levels. REFERENCES 1. Jordan SC, Legendre C, Desai NM, et al. Imlifidase desensitization in crossmatch-positive, highly sensitized kidney transplant recipients: results of an international phase 2 trial (Highdes). Transplantation. 2021;105(8):1808-1817. 2. Bockermann R, Järnum S, Runström A, et al. Imlifidase-generated single-cleaved IgG: implications for transplantation. Transplantation. 2022;106(7):1485-1496. 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.