Incidence Of Severe Acute Graft-versus-host Disease Research Articles

Bronchial structural changes analyzed with three-dimensional computed tomography correlate with severe acute graft-versus-host disease after allogenic hematopoietic stem cell transplantation.

Severe acute graft-versus-host disease (GVHD) can occur during allogeneic hematopoietic stem cell transplantation (allo-HSCT), causing considerable morbidity and mortality. Although several biomarkers have been reported for predicting acute GVHD, they are often difficult to measure in routine clinical practice. Recently, three-dimensional computed tomography (3D-CT) has been used to quantify the detailed bronchial structure, which might correlate with acute GVHD. We retrospectively evaluated 55 patients who underwent their first allo-HSCT at our hospital between 2016 and 2020. Using 3D-CT analysis, the airway inner luminal area (Ai), wall area (WA), and wall thickness (WT) were measured at each third- to fifth-generation bronchus. Values were adjusted according to body surface area (BSA). Ratios of values at neutrophil engraftment to those of pre-conditioning were assessed. In the cohort, Ai/BSA narrowed, WA/BSA enlarged, and WT/BSA thickened during neutrophil engraftment compared with pre-conditioning. The cumulative incidence of grade II-IV acute GVHD after allo-HSCT was 24%. The ratio of WA/BSA at neutrophil engraftment to that of pre-conditioning in fourth-generation bronchi (WA4/BSA) was significantly lower in patients with grade II-IV acute GVHD compared with those with grade 0-I (0.99 vs. 1.08, P < 0.01). The ratio of WA4/BSA of < 0.955 was significantly associated with the incidence of grade II-IV acute GVHD (< 0.955; 60% vs. ≥ 0.955; 16%, P < 0.01). This is the first study to demonstrate that 3D-CT analyses could quantify changes in bronchial structure during neutrophil engraftment after allo-HSCT; these changes might correlate with the incidence of severe acute GVHD.

Haploidentical versus Cord Blood Transplantation in Pediatric AML. A Retrospective Outcome Analysis on Behalf of the Pediatric Subcommittee of GETH (Grupo Español de Trasplante Hematopoyético)

Haploidentical stem cell transplantation (Haplo-SCT) and cord blood transplantation (CBT) are both effective alternative treatments in patients suffering from acute myeloid leukemia (AML) and lacking a matched HLA donor. In the last years, many centers have abandoned CBT procedures mostly due to concern about poorer immune recovery compared with Haplo-SCT. We conducted a retrospective multicenter study comparing the outcomes using both alternative approaches in AML. A total of 122 transplants (86 Haplo-SCTs and 36 CBTs) from 12 Spanish centers were collected from 2007 to 2021. Median age at hematopoietic stem cell transplantation (HSCT) was 7 years (0.4-20). Thirty-nine patients (31.9%) showed positive minimal residual disease (MRD) at HSCT and a previous HSCT was performed in 37 patients (30.3%). The median infused cellularity was 14.4 × 106/kg CD34+ cells (6.0-22.07) for Haplo-SCT and 4.74 × 105/kg CD34+ cells (0.8-9.4) for CBT. Median time to neutrophil engraftment was 14 days (7-44) for Haplo-SCT and 17 days (8-29) for CBT (P = .03). The median time to platelet engraftment was 14 days (6-70) for Haplo-SCT and 43 days (10-151) for CBT (P < .001). Graft rejection was observed in 13 Haplo-SCTs (15%) and in 6 CBTs (16%). The cumulative incidence of acute graft versus host disease (GvHD) grades II-IV was 54% and 51% for Haplo-SCT and CBT, respectively (P = .50). The cumulative incidence of severe acute GvHD (grades III-IV) was 22% for Haplo-SCT and 25% for CBT (P = .90). There was a tendency to a higher risk of chronic GvHD in the Haplo-SCT group being the cumulative incidence of 30% for Haplo-SCT and 12% for CBT (P = .09). The cumulative incidence of relapse was 28% and 20% for Haplo-SCT and CBT, respectively (P = .60). We did not observe statistically significant differences in outcome measures between Haplo-SCT and CBT procedures: 5-year overall survival (OS) was 64% versus 57% (P = .50), 5-year disease-free survival (DFS) 58% versus 57% (P = .80), GvHD-free and relapse-free survival (GFRFS) 41% versus 54% (P = .30), and cumulative incidence of transplant-related mortality (TRM) 14% versus 15% (P = .80), respectively. In the multivariate analysis, MRD positivity and a disease status >CR1 at the time of HSCT were significantly associated with poorer outcomes (P < .05). In conclusion, our study supports that both haploidentical and cord blood transplantation show comparable outcomes in pediatric AML patients. We obtained comparable survival rates, although CBT showed a trend to lower rates of chronic GvHD and higher GFRFS, demonstrating that it should still be considered a valuable option, particularly for pediatric patients.

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.

Higher Proportions of Monocytic-Myeloid-Derived Suppressive Cells (mMDSC) before Allotransplant Predict Relapse in Acute Leukemia Patients

Introduction: Myeloid-derived suppressive cells (MDSC) are an heterogeneous group of immature myeloid cells with strong immunosuppressive activities which made them of particular interest in the context of allogeneic stem cell transplant (Allo-SCT). In mice models, MDSC modulate the function of alloreactive T cells and prevent graft versus host disease (GVHD) without impairing graft versus leukemia (GVL) effect. Data are limited in humans, but higher proportions of MDSC in the graft seem to protect against both acute and chronic GVHD. However, the influence of circulating MDSC is not fully explored especially regarding their impact on post-transplant GVL effect and survivals. Here we focused on the role of peripheral levels of monocytic-MDSC (mMDSC) in a cohort of adults with acute (both myeloid or lymphoid) leukemia (AML or ALL) having received Allo-SCT. Methods: This prospective monocentric study aimed at documenting the impact of the percentage of mMDSC before and after allo-SCT in terms of incidence of acute and chronic GVHD, overall (OS) and leukemia-free (LFS) survivals, (grade 3/4 acute or extensive chronic) GVHD-free relapse-free survival (GRFS), relapse and non-relapse mortality (NRM) in a cohort of ALL or AML patients (pts). Inclusion was performed after informed consent at diagnosis as part of a more global study (Abstract ASH 2021 # 3465), pts who were ultimately transplanted being included in this sub-group analysis. mMDSC were defined by the minimal CD14+/CD11b+/CD33+/HLA-DR-/low immunophenotypic pattern, at variance from granulocytic MDSC that lack CD14 and express bright CD15. Cells were assessed in a lysis-no-wash flow cytometry technique using peripheral blood collected on EDTA before conditioning then at day+60 post-transplant. Data acquisition was performed on a Navios® flow cytometer (Beckman Coulter, Miami, FL). mMDSC were expressed as a percentage (%) of total nucleated cells defined as CD45+. The study was registered at the French Commission Nationale de l'Informatique et des Libertés as CNIL 2016-038 and approved by the Ethic Review Board of Nantes University Hospital. Results: Among 73 AML and 14 ALL pts included at diagnosis, 47 and 9, respectively, were ultimately allografted between February 2018 and October 2021. Pts characteristics are provided in Table 1A. The median follow-up for alive pts from Day 0 was 24 months (range: 8-48). Considering the whole cohort, 2-year OS, LFS and GRFS were 61.9+6%, 55.9+7% and 32.4+6%, respectively, while 2-year NRM and Relapse incidence were 11+4% and 29.6+6%. In pre-graft, 46 pts were evaluated at a median of 20 days from Day 0 (range: 6-83). The median % of mMDSC was 0.45% (range: 0-11.85) with no differences between AML and ALL (p=0.32). The best cut-off assessed by ROC analyses was 0.47%. According to this value, the incidence of cytologic relapse at 2 years was significantly higher in pts with >0.47% of mMDSC (14.5+8% vs 44.4+11%, p=0.02, Figure 1) while no impact on survivals, NRM or GVHD was observed. Of note, the incidence of relapse was similar between AML and ALL (29% vs 37.5%, p=0.95). In multivariate analysis (Table 1B), higher pre-graft mMDSC % remained associated with higher risk of relapse (HR: 3.71; 95%CI: 1.05-13.09, p=0.04). At day+60, 42 pts were evaluated. The mMDSC median level was 0.52% (range: 0-5.03) with no differences between AML and ALL (p=0.32). No best cut-off was determined. Survivals were similar between pts with ≤ or >0.52% of mMDSC at this time. It was also the case for incidences of relapse, NRM and chronic GVHD. However, the incidence of severe acute GVHD (grade 3/4) was significantly and paradoxically higher in the group of pts with >0.52% mMDSC (33% vs 5%, p=0.04) suggesting a possible amplification of immunosuppressive mMDSC as a reaction to GVHD since the median time of GVHD grade 2-4 occurrence was 30 days (range: 20-123) post-transplant. Of note, the kinetics (increases or decreases of mMDSC %) between pre-graft and D60 had no influence on outcomes. Conclusion: This prospective study demonstrates a negative impact of higher proportions of mMDSC before allotransplant in leukemic pts. This higher proportion is predicting relapse, suggesting a protective role and tolerance of tumoral cells by mMDSC themselves. This paves the way to therapeutic intervention to decrease the incidence of relapse in such pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1351: CHARACTERIZING ALLOGENEIC STEM CELL TRANSPLANTATION SAFETY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES AFTER PEMBROLIZUMAB THERAPY

Background: Although allogeneic stem cell transplantation (allo-SCT) and programmed cell death 1 (PD-1) blockade have separately shown efficacy in some lymphoid malignancies, the safety of allo-SCT after anti–PD-1 therapy in these patients remains a high clinical interest. Aims: We present data from an analysis from 4 KEYNOTE phase 1-3 studies to describe predetermined complications in patients who received allo-SCT following pembrolizumab therapy. Methods: The analysis included patients from the KEYNOTE-013 (NCT01953692, n=20), KEYNOTE-087 (NCT02453594, n=31), KEYNOTE-170 (NCT02576990, n=5), and KEYNOTE-204 (NCT02684292, n=14) trials who have a known allo-SCT transplantation date received within 2 years of the last dose of study pembrolizumab. Descriptive statistics were used for predefined post–allo-SCT complications of interest. The cumulative incidence of acute grade 2-4 graft-versus-host disease (GVHD), acute grade 3-4 GVHD, and chronic GVHD was estimated. The corresponding competing risk events were death without acute grade 2-4 GVHD, death without acute grade 3-4 GVHD, and death without chronic GVHD, respectively. The cumulative incidence of post–allo-SCT transplant-related mortality (TRM) was estimated with relapse as a competing risk. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Seventy patients were included in the analysis. Median age was 30 y (range, 18-65), 57 (81.4%) had classical Hodgkin lymphoma (cHL), and the rest had non-Hodgkin lymphoma. 69 of 70 (98.6%) patients received pembrolizumab monotherapy; 1 patient received pembrolizumab + lenalidomide. Median duration on study treatment was 5.3 months (range, 0.7-29.6) and median time from last pembrolizumab dose to first allo-SCT was 4.6 months (range, 1-20). Before transplantation, 49 patients (70.0%) had intervening anticancer regimen; 34 (48.6%) had active disease, 31 patients (44.3%) were in remission at time of transplant, and 5 patients (7.1%) had unknown disease status. Overall, 55 patients (78.6%) developed GVHD (acute, 38; chronic, 17). The estimated 6-month post–allo-SCT cumulative incidence was 0.41 (95% CI, 0.30-0.53) for grade II-IV acute GVHD and 0.20 (95% CI, 0.12-0.30) for grade III-IV acute GVHD; 1 year post–allo-SCT was 0.21 (95% CI, 0.12-0.31) for chronic GVHD. Other predetermined complications, including critical illness, immune-mediated adverse events, pulmonary complications, and veno-occlusive liver disease, occurred in 32 patients (45.7%). After a median follow-up (defined as the time from allo-SCT to data cutoff) of 40.1 months (range, 5.1-71.2), the post–allo-SCT median PFS was not reached (NR) (95% CI, 14.5-NR) and the 30-month post–allo-SCT PFS rate was 56.8% (95% CI, 42.9-68.5) (Figure A); median OS was NR (95% CI, NR-NR) and the OS rate at 12 months was 82.2% (Figure B). The estimated post–allo-SCT cumulative incidence for TRM at 6 months was 0.09 (95% CI, 0.03-0.17) and for relapse at 26 months was 0.27 (95% CI, 0.16-0.38). PFS and OS outcomes were comparable in the subgroup of patients with cHL. Image:Summary/Conclusion: The incidence of GVHD in this population is comparable to historical data (40%-80% and 30%-70%, respectively). The incidence of severe acute GVHD may be higher than a typical modern allo-SCT series, although TRM was low. The observed PFS and OS outcomes compare favorably to historical benchmarks (2-year PFS ranging from 45%-48%; 1-year OS >80%). Altogether, this analysis lends confidence that allo-SCT is feasible for patients with lymphoid malignancies after PD-1 blockade.

Antithymocyte Globulin Potentially Could Overcome an Adverse Effect of Acute Graft-versus-Host Disease in Matched-Related Peripheral Blood Stem Cell Transplantation

Previous Japanese studies have shown that bone marrow transplantation (BMT) is associated with better survival compared with peripheral blood stem cell transplantation (PBSCT) from a matched related donor (MRD). PBSCT recipients have shown higher incidences of severe graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) compared with BMT recipients. In recent years, the efficacy and safety of antithymocyte globulin (ATG) for PBSCT recipients has been evaluated worldwide. In the present study, we aimed to compare BMT and PBSCT recipients to identify current improvements and unmet needs among MRD PBSCT recipients. In addition, we evaluated the impact of ATG administration on the outcomes of PBSCT recipients. We retrospectively analyzed patients age ≥16 years with acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia who underwent their first BMT or PBSCT from an MRD between 2009 and 2018 in Japan. A total of 3599 transplantations were performed (BMT, n=1218; PBSCT without ATG [PBSCT-ATG(-)], n=2288; PBSCT with ATG [PBSCT-ATG(+)], n=93). The PBSCT-ATG(-) group had a higher NRM (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.08 to 1.57; P=.005) and lower overall survival (OS) (HR, 1.16; 95% CI, 1.04 to 1.30; P=.011) compared with the BMT group. Furthermore, the PBSCT-ATG(-) group had higher incidences of grade III-IV, stage 2-4 gut, high-risk, and steroid-refractory acute GVHD compared with the BMT group. Acute GVHD had a negative impact on NRM and OS. The PBSCT-ATG(-) group also was associated with an elevated risk of chronic GVHD (HR, 1.89; 95% CI, 1.24 to 2.57; P < .001) and extensive chronic GVHD (HR, 1.44; 95% CI, 1.23 to 1.68; P < .001). The incidences of acute GVHD, chronic GVHD, and NRM and chronic GVHD-free relapse-free survival rates were comparable between the PBSCT-ATG(+) and BMT groups. The OS of patients with acute GVHD was similar in the 3 donor groups. Patients treated with reduced-intensity conditioning in the PBSCT-ATG(+) group had a higher relapse rate and lower OS rate compared with those in the BMT group. In this Japanese cohort, standard calcineurin inhibitor-based GVHD prophylaxis was not sufficient for recipients of MRD PBSCT because of the high incidence of severe acute GVHD. Prophylactic ATG was found to be a promising strategy against GVHD.

Characterizing Safety in Patients with Hematologic Malignancies Receiving Allogeneic Stem Cell Transplant (Allo-SCT) Following Pembrolizumab Therapy

Characterizing Safety in Patients with Hematologic Malignancies Receiving Allogeneic Stem Cell Transplant (Allo-SCT) Following Pembrolizumab Therapy

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by HMOX1) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the Hmox1 allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT)n repeat polymorphism (L/L) in the HMOX1 promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT)n repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human HMOX1 (GT)n microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD.

Does Mixed Chimerism After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients With Fanconi Anemia Impact on Outcome?

Fanconi anemia (FA) cells are characterized by genomic instability, which places FA patients at risk for malignancies such as leukemia and oropharyngeal/urogenital cancers. The risk of development of leukemia is theoretically eliminated after hematopoietic cell transplantation (HCT). Mixed chimerism (MC) in FA patients might have a unique implication because the persistent existence of FA cells might give rise to a malignant clone. We have studied a large population of FA patients who underwent allogeneic HCT at our institution and report here the outcome according to chimerism status. Patients with FA who had evidence of progressive bone marrow failure and were blood products-transfusion dependent (packed red blood cells, platelets, or both) were included in the study. Those who had myelodysplasia (MDS) or an abnormal clone or evidence of leukemia were excluded. All but 3 patients had normal renal and cardiac function at the time of transplantation. In total, 160 patients with FA underwent allogeneic HCT at our center from January 1995 to December 2017; mean age at HCT was 8.4. Chimerism data at last follow-up visit were available on 97 patients who are the subjects of this analysis (no day +100 chimerism data on one of them). On day +100, 46 patients (47.9%) had full chimerism (FC) and 50 (52.1%) had MC, whereas at last follow-up 50 (51.5%) exhibited FC and the remaining 47 (48.5%) had MC. Cumulative incidence of all grades acute graft-versus-host disease (GVHD) was 13.4% and that of grade III to IV GVHD was 4.1%. Chronic GVHD was seen in eight (8.0%) patients. Incidence of severe acute GVHD (grade ≥ III) and that of chronic GVHD were not significantly associated with FC or MC measured at day +100 (P values=.347 and .254, respectively), nor at the last follow-up. Graft failure occurred in 2 patients; both from the MC at day +100 group. No graft failures occurred in the FC at day +100 group (P value=1.00). At a median follow-up of 83.8 months (95% confidence interval, 51.0-116.6; range, 19.3-181.1 months) the cumulative probability of overall survival (OS) at 5 years was 95.7% ± 2.1%. Mean follow-up time in our cohort was 90.7 months. Five-year overall survival was not significantly associated with FC or MC evaluated at day +100 (95.7% ± 3.0% versus 95.6% ± 3.1%, P value=.908) nor at the last follow-up (96.0% ± 2.8% versus 95.4% ± 3.2%, P value = .925). No patient in either group developed MDS/leukemia during the follow-up period. We conclude that mixed chimerism in patients with FA appears to have no adverse effect on outcome in our follow-up period. A longer follow-up period is needed, however, to confirm the validity of this statement.

Can Planned CD34+ Stem Cell Boost Prevent Poor Graft Function after Peripheral Blood Haploidentical Hematopoietic Transplantation?

<h3>Introduction</h3> Traditional outcome measurements for hematopoietic recovery after Haploidentical HCT (haplo-HCT) with post-transplant cyclophosphamide (PTCy) may not capture a subset of patients who meet engraftment milestones, and have full donor chimerism, but subsequently suffer poor graft function (PGF) resulting in prolonged cytopenias and requiring transfusion support. This is termed secondary PGF, occurs in 5-26% of patients, and is associated with significant morbidity and mortality. CD34+ selected donor cell infusions have been employed in this setting without causing graft versus host disease (GVHD). <h3>Objectives</h3> We hypothesized that planned CD34+ stem cell boost (SCB) after PTCy could be used to prevent PGF after haplo-HCT. <h3>Methods</h3> Full donor chimerism was defined as ≥ 95% donor chimerism from bone marrow on day +30. Poor graft function was defined as transfusion dependence with ≥ two cytopenic lines (ANC < 1500 cells/mm3, platelets < 30 000/mm3 and Hgb < 8.5 g/dL) in the presence of full donor chimerism and in the absence of severe GVHD, CMV infection, and relapse. Patients underwent haplo-HCT per institutional protocol. Part of the donor product underwent CD34+ selection and cells were cryopreserved. On day 5-6, CD34+ selected donor product was infused. <h3>Results</h3> Between February 1, 2018 and August 30, 2018, nine patients underwent planned SCB after haplo-HCT. All patients received GVHD prophylaxis with PtCY, tacrolimus, and mycophenolate per institutional guidelines. The comparison cohort consisted of all patients who have undergone haplo-HCT at our institution between July 7^th, 2009 and October 8^th, 2018. All nine SCB patients had neutrophil engraftment (NE) with a median time of 16 days (13 – 25) compared with 17 days (12 – 78) in the comparison cohort (p = 0.40). Six of eight evaluable SCB patients had platelet engraftment (PE) with a median time of 22.5 days (12 – 55) compared with 26 days (9 – 134) in the comparison cohort (p = 0.675). One patient was censored due to death prior to PE on day +19. None of the 8 surviving patients developed secondary PGF. Two patients in the planned SCB group developed grade III acute GVHD involving the GI tract. The remaining seven had no GVHD. <h3>Conclusion</h3> These patients were selected on the basis of being high risk for graft failure or poor graft function. Two patients had active disease at the time of transplant and five of the nine patients were undergoing their second HCT. Time to NE and PE in the SCB group were 1 and 3.5 days faster than in the comparison group. This equivalency is notable given that the SCB patients were specifically selected for being high risk or graft failure. None of the SCB patients had secondary graft failure, compared with published rates between 5.6% and 26%. This approach appears to be safe with acceptable incidence of severe acute GVHD.

No Engraftment Advantage after Single or Double Umbilical Cord Blood Transplant (CBT) with the Addition of a Non-HLA Matched Off-the-Shelf Expanded Cord Blood Unit Compared to Conventional CBT: Results of a Randomized Trial

Background: Based on pilot study data demonstrating safety and excellent survival [Blood 2014 124:46] in acute leukemia patients undergoing myeloablative cord blood transplant (CBT) plus infusion of an off-the-shelf non-HLA matched expanded CB unit (OTS) for bridging hematopoiesis, a randomized trial was conducted to determine whether myeloablative CBT with or without an OTS would confer more rapid neutrophil (ANC) engraftment and therefore a survival advantage. Methods: We conducted a multi-center, randomized controlled phase II trial (RCT) with a primary endpoint of ANC engraftment defined as the first of 2 consecutive days in which neutrophil count ≥ 500 cells/μL. Secondary endpoints included platelet engraftment, overall survival (OS), disease free-survival (DFS), acute/chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), and relapse. 160 patients were enrolled between February 2013 and June 2018. Patients were randomized to receive either a conventional single or double CBT (SOC group) (n=78) or SOC + OTS (OTS group) (n=82). Unmanipulated CB units had to be at least 4/6 HLA-matched to the patient (intermediate resolution for HLA-A, -B and allele-level for HLA-DRB1) with no HLA matching required for the OTS. Patient disease (AML=68, ALL=77, MDS=7, CML/other=8), disease risk, gender, age, race, ethnicity, CMV serology, performance score and HLA-match were balanced between the two study groups. Patients received conditioning with either FLU 75mg/m2, TBI 13.2 Gy, CY120 mg/kg or with FLU 150mg/m2, TBI 4Gy, CY 50 mg/kg and Thiotepa 10 mg/kg. Cyclosporin and MMF were used for GVHD prophylaxis in all patients (Table 1). Results: The median follow-up of surviving patients was 15 months. Approximately 30% of patients enrolled were &amp;lt;18 years and most patients received the high dose TBI (13.2Gy) regimen (85% in OTS group and 91% in SOC group). The median pre-cryopreserved total nucleated cell dose was 5.4 × 107/kg for both groups while the median pre-cryopreserved CD34 cell dose was 0.30 and 0.28 × 106/kg for the OTS and SOC group, respectively. Patients in the OTS group received an additional median CD34+ cell dose of 10.5x106/kg. Median time to ANC engraftment was similar between the 2 groups, at 20 days (range 7-46) in the OTS group and 19 days (13-51) in the SOC group. Five patients experienced graft failure, 2 in the OTS group and 3 in the SOC group. Similarly, no difference was seen for median time to platelet engraftment [38 days (35-43) vs. 40 days (30-42) for the OTS and the SOC group]. Peripheral blood chimerisms performed weekly (day 7-28) revealed that the initial circulating myelomonocytes present in the peripheral blood of OTS patients at day 7 were nearly all generated from the OTS product. Contribution to engraftment of the OTS graft was transient, and generally undetectable after day 21. All outcomes were similar between the two groups. OS and DFS at 2 years were 70% and 60% vs 61% and 55% for the OTS and the SOC groups, respectively. Cumulative incidence of relapse and NRM at 2 years were 18% and 21% in the OTS group and 21% and 22% in the SOC group. Grade III-IV aGVHD was 16% and 14% for the and the SOC group, respectively. The OTS product was well tolerated, and serious adverse events rates similar between the 2 groups. Patients continue to be followed through 2 years to assess cGVHD, and graft-relapse-free-survival. Conclusion: In this multi-center RCT, no significant difference was observed in the primary or secondary endpoints. Importantly, while the median time to ANC recovery in the OTS group was unchanged (20 days) from our pilot study, the observed time to neutrophil recovery in the SOC group was 7 days quicker than expected based on previously observed outcomes following myeloablative CBT (median 26 days). During the 5 years that this study was open to accrual, the criteria for CB donor selection have improved, now regularly utilizing CD34+ cell content and high-resolution HLA-typing where available, as has the quality of the CB inventory. This RCT highlights that delayed engraftment should no longer be a barrier in the consideration of SOC CBT for patients with hematological malignancies. As expected, and observed consistently following CBT, both groups demonstrated low incidence of severe acute GVHD and relapse at 2 years. Interventions in CBT should focus on improving immune reconstitution and reducing the risk of NRM but must be easily adopted into SOC in order to be adopted clinically. Disclosures Milano: ExCellThera: Research Funding; Amgen: Research Funding. Rezvani:Kaleido: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; Nohla Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; AbbVie: Other: Principal investigator ; U.S. Department of Justice: Other: Expert medical witness; Johnson &amp; Johnson: Employment, Other: Brother is employed. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees.

Abatacept Is Effective for Gvhd Prophylaxis after Unrelated Donor Stem Cell Transplantation (URD SCT) for Severe Sickle Cell Disease (SCD)

Background In 2016, results from the first URD SCT for SCD (the SCURT Trial) revealed a 2-year overall survival (OS) and event-free survival (EFS) of 79% (95% CI 59-90) and 69% (95% CI, 48-82) respectively following reduced intensity conditioning (RIC).1 Though the RIC approach provided successful engraftment in the majority, the transplant approach was not considered safe for widespread adoption due to high rates of graft-versus-host disease (GVHD) especially in children &amp;gt;13 years, a predominant cause of mortality. Strategies to minimize GVHD were essential if URD SCT was to be considered with curative intent in SCD. Aim/Method Multicenter trial (NCT03128996) with the primary objective of determining EFS in non-malignant disorders at one-year was amended as follows. The phase I SCD cohort included conditioning with hydroxyurea, proximal alemtuzumab, fludarabine, and melphalan in patients with 8/8 HLA-matched URD (-A, -B, - C and -DRB1).1 Thiotepa (8 mg/kg) was added in 7/8 HLA-mismatched SCT. GVHD prophylaxis included a calcineurin inhibitor and methotrexate as previously described. Abatacept (10 mg/kg) was administered on days -1, +5, +14, +28, +60, +100, +180, +270 and +365 based on efficacy described against acute GVHD with early dosing after SCT for malignant disorders.2,3 The latter 3 doses were omitted in cord transplant recipients. Result Thirteen children (7-21 years) underwent SCT (8/8 URD marrow- 7; 7/8 URD marrow or cord-6) primarily for stroke (N=6), ≥3 severe vaso-occlusive pain crises (N=4) or ≥2 acute chest syndrome episodes per year (N=3). The conditioning regimen was well tolerated. One patient had primary graft rejection after CMV infection (7%) and had autologous recovery. All other patients engrafted; neutrophils at median of 18 days (10-24), platelets at median of 28 days (16-39) and are surviving free of SCD with median follow-up of 12 months (range 4-59). Myeloid lineage donor chimerism was &amp;gt;95% and lymphoid was 39%- 100% at day+100. Two-year OS and EFS was 100% and 92.3% (95% CI, 6.57-35.7), respectively. The day+100 incidence of grade II-IV and III-IV acute GVHD incidence was 23% and 15% respectively. One-year incidence of chronic GVHD was 38%. However, only one patient (7%) developed extensive cGVHD. One patient (7%) developed posterior reversible encephalopathy syndrome and recovered. Viral replication in blood was detected in 7 of 13 patients (7 CMV, 1 EBV reactivation). No patient developed EBV PTLD or required EBV-related intervention. Conclusion In comparison to previous experience1 with RIC and URD SCT, our early observations are (1) a lower incidence of PRES (7 vs 34%) (2) low incidence of severe acute GVHD (15% vs 17% grade III -IV) despite mismatched donors, (3) low incidence of extensive chronic GVHD (7% vs 38%) and (4) no mortality despite patient age (10/13 were &amp;gt;13 years old). We attribute this gain to avoiding steroid use, and the benefit of including abatacept into the treatment regimen. The engraftment, safety, and immune reconstitution profile continue to be monitored in this ongoing trial now accruing in a Phase II cohort. As we and others work toward expanding donor options for SCD transplants, we submit that all alternate donor transplants for severe SCD are experimental and should be performed on clinical trials that track success and pitfalls. Reference: 1. Shenoy S et al. A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. Blood. 2016 Nov 24; 128(21): 2561-2567. 2. Koura et al. In vivo T cell costimulation blockade with abataceptfor acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant. 2013 Nov; 19(11): 1638-49. 3. Watkins BK et al. T cell co-stimulation blockade with CTLA-4 Ig (Abatacept) for acute GVHD prevention in HLA-matched and mismatched unrelated donor transplantation: Results of a Phase 2 trial. Abstract 65. ASTCT Meetings, Houston 2019. Figure Disclosures Shah: Jazz pharmaceuticals: Speakers Bureau. OffLabel Disclosure: Abatacept, FDA approved for rheumatoid arthritis is a fusion protein that inhibits T-cell activation by binding to CD80/CD86 on antigen-presenting cells (APCs).It is used for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation in this study

Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation.

The use of anti-thymocyte globulin (ATG) has represented the standard of care in graft-versus-host disease (GVHD) prophylaxis in patients undergoing a mismatched unrelated donor (MMUD) transplant. The safety and feasibility of posttransplant cyclophosphamide (PTCY) in this setting have been reported recently, but no study has compared the outcomes of PTCY vs ATG in 9/10 MMUD transplants. Using the registry data of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we performed a matched-pair analysis comparing those 2 strategies in a 9/10 MMUD setting. Ninety-three patients receiving PTCY were matched with 179 patients receiving ATG. A significantly lower incidence of severe acute GVHD was observed with PTCY compared with ATG. Recipients of the former also showed higher leukemia-free survival and GVHD/relapse-free survival (GRFS). When performing a subgroup analysis including patients receiving peripheral blood stem cells, being in complete remission, or receiving the same associated immunosuppressive agents, superiority of PTCY over ATG was confirmed. Similar to the haploidentical setting, use of PTCY is an effective anti-GVHD prophylaxis in the 9/10 MMUD transplant. Use of PTCY may also provide better outcomes in long-term disease control. These results need confirmation in large prospective randomized trials.

Post-Transplant Cyclophosphamide Versus Antithymocyte Globulin in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation from One Antigen HLA-Mismatched Donors: A Retrospective Analysis from the Acute Leukemia Working Party of the EBMT

Introduction. Several alternative donor sources are currently available for patients who lack an HLA-matched related or unrelated donor, including haploidentical, cord blood and one antigen HLA-mismatched donors (9/10 mMUD). Use of post-transplant (allo-HSCT) cyclophosphamide (PTCY) as graft-versus-host disease (GVHD) prophylaxis allowed outcome improvements in the haploidentical setting. Its use has also been reported as a safe and feasible option in 9/10 mMUD transplants. However, to date, the main strategy used as GVHD prophylaxis in 9/10 mMUD allo-HSCT is in vivo T-cell depletion with antithymocite globulin (ATG). Data comparing these two different anti GVHD prophylaxis strategies in 9/10 mMUD allo-HSCT are limited.Methods. We compared PTCY versus ATG as GVHD prophylaxis in patients undergoing 9/10 mMUD allo-HSCT for which high-resolution HLA-allele typing was available in the ALWP/EBMT data registry. Included were adult patients (age>18 years) undergoing their first allo-HSCT for acute myeloid leukemia (AML) during the period 2007-2017. All disease status were allowed. Propensity score matching was performed to reduce and eliminate confounding effects. Each patient receiving PTCY was matched with two patients receiving ATG using the nearest neighbor or exact matching. Variables included in the propensity score model were: disease status at time of allo-HSCT, conditioning regimen, age, secondary AML, female donor to male recipient, source of stem cells, patient and donor CMV serology status.Results. Globally, 93 patients receiving PTCY were identified and matched with 179 patients receiving ATG. Secondary AML was reported in 20% and 18% of patients in ATG and PTCY groups, respectively. Most patients were in first complete remission at time of allo-HSCT (55% and 56% in PTCY and ATG group, respectively), while nearly 29% of patients in both groups underwent allo-HSCT with active disease. Ciclosporine (csA) and mycophenolate mofetil (MMF) were the systemic immunosuppressive agents more frequently associated to either PTCY (42%) or ATG (49%). Other well represented associated immunosuppressive agents were tacrolimus and MMF in ATG group (20%), followed by 14% of patients receiving csA alone with ATG. In PTCY group, 39% of patients received csA and methotrexate as associated immunosuppressive agents. Conditioning regimen was myeloablative in 50% of patients in both groups. Peripheral blood was the preferred stem cell source (91% in both groups). Among the variables not included in the propensity score model, some differences were observed between the two groups. Median follow-up was longer in the ATG group (27.4 versus 14.2 months, p<0.01). Gender was more frequently male in PTCY group (60% versus 45%, p<0.02). Median year of allo-HSCT was 2014 and 2015 in ATG and PTCY groups, respectively (p<0.01). Similar engraftment rates were observed for both groups (95% and 96% in PTCY and ATG groups, respectively). At 2 years, leukemia-free survival (LFS) was higher in patients receiving PTCY (55% vs 35%, p<0.05), severe (grade III-IV) acute GVHD was lower (9% vs 19%, p<0.04) and GRFS higher (37% vs 21%, p<0.02) as compared to patients receiving ATG, while no differences were observed in relapse incidence (RI)( 29% vs 37%, p=0.31), overall survival (OS, 56% vs 38%, p=0.06) and in non-relapse mortality (NRM) (16% vs 29%, p=0.06). Main causes of death were similarly distributed in both groups, with infectious complications being more frequently represented (25% and 22% in the PTCY and ATG groups, respectively). Grade II-IV acute GVHD (30% vs 32%, p=0.39) and chronic GVHD (39% vs 36%, p=0.35) were also similar in the two groups.Conclusions. In patients undergoing 9/10 mMUD allo-HSCT, use of PTCY as GVHD prophylaxis is a safe and feasible option, representing a possible valid and superior alternative to ATG. Use of PTCY, indeed, may ensure a lower incidence of severe acute GVHD and higher LFS and GRFS as compared to ATG. These registry based results may serve the basis for a prospective randomized trial comparing PTCY to ATG as anti GVHD prophylaxis in 9/10 mMUD allo-HSCT. DisclosuresHilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Mohty:MaaT Pharma: Consultancy, Honoraria.

Clinical evaluation of haploidentical hematopoietic combined with human umbilical cord-derived mesenchymal stem cells in severe aplastic anemia

BackgroundThis study not only evaluated the clinical effects of treatment using haploidentical hematopoietic stem cells (haplo-HSCs) combined with human umbilical cord mesenchymal stem cells (UC-MSCs) in patients with severe aplastic anemia (SAA), but also investigated the factors related to graft versus host disease (GVHD).MethodsCotransplantation of haplo-HSCs and UC-MSCs was performed in 24 SAA patients. The conditioning regimens consisted of rabbit anti-human T-lymphocyte immunoglobulin (ATG), cyclophosphamide, and fludarabine with or without busulfan. GVHD was prevented using cyclosporine A, ATG, anti-CD25 monoclonal antibody, and mycophenolate material.ResultsThe incidence of acute GVHD was 50%. The incidence of severe acute GVHD was not related to gender, age, donor-recipient relations, and patient/donor pair, while patient/donor pair (r = 0.541, P = 0.022) was significantly correlated with incidence of chronic GVHD. Upon follow-up for a median of 13 months, 5 of the 24 patients (20.8%) were dead. The survival rates at 3 and 6 months in all patients were 87.5% (21/24) and 83.3% (20/24), respectively.ConclusionCotransplantation of haplo-HSCs combined with UC-MSCs was an effective and safe approach for the treatment of patients with SAA. The appropriate conditioning regimen and early treatment for infection also played a critical role in the success of HSCT.

Human Mesenchymal Stem Cell Therapy for Acute Graft Versus Host Disease

Acute graft versus host disease (GVHD) is the most critical complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The understanding of major histocompatibility complex (MHC) and the development of acute GVHD prophylaxis have contributed to decreasing the incidence of severe acute GVHD. However, these progresses expand the chance of receiving allo-HSCT from human leukocyte antigen (HLA) mismatched donor. In addition, the expanding of indication for allo-HSCT to elderly patients or patients with organ dysfunction by the pervasiveness of reduced-intensity conditioning is associated with increased risk of acute GVHD. Unexpectedly, severe refractory acute GVHD can occur even in allo-HSCT from HLA matched sibling donor. The first line therapy for severe acute GVHD is corticosteroid, but the second line therapy has not been established and the prognosis of steroid-resistant acute GVHD remains poor. Recently, the efficacy of human bone marrow mesenchymal stem cell (MSC) therapy for steroid-resistant acute GVHD has been consistently reported. MSCs are approved as a cell therapy drug for steroid-resistant acute GVHD in some countries. We here review the history and the future of MSC therapy for acute GVHD.

Similar Incidence of Severe Acute Gvhd and Less Extensive Chronic Gvhd in PBSCT from Unmanipulated Haploidentical Donor Compared with That from Matched Sibling Donor for Patients with Hematologic Malignancies

▪Unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HCT) resulted in encouraging outcomes for treatment of hematologic malignancies and become an alternative option in case of lacking HLA matched sibling donor (MSD). Transplantation with G-CSF mobilized peripheral blood stem cell (PBSCT) has been a stable transplant setting with MSD. Unmanipulated haploidentical donor (haplo-PBSCT) has been applied in patients with hematologic malignancies. However, the characteristics of graft-versus-host disease (GVHD) in unmanipulated haplo-PBSCT are not clear. Here, we report the results of a cohort study on the clinical features of acute and chronic GVHD in haplo-PBSCT compared with PBSCT from MSD in patients with hematologic malignancies.PATIENTS AND METHODSBetween July, 2007 and June, 2014, 94 patients with hematologic malignancies received haplo-PBSCT and 100 patients received PBSCT from MSD consecutively at our unit (Table 1). The PBSCs were collected on day 5 and 6 after 4 days of rhG-CSF (5 mg.kg¨C1 °¤day¨C1), then were infused on the day of collection. The conditioning regimen consisted of Bu (9.6 mg.kg-1, iv, days -10~-8), Carmustine, (250 mg.m-2, day -5), cytarabine (8 g.m-2, days -7~-6), CY (120mg kg-1, days -4~-3). Antithymoglobulin (ATG, rabbit; 10 mg.kg-1, days -5~-2) was used for haplo-PBSCT. All recipients received cyclosporine A, mycophenolate mofetil, and short-term methotrexate for GVHD prophylaxis. The endpoint of the last follow-up for all surviving patients was July 15, 2015.RESULTSAmong the patients with acute GVHD, there was no difference of the rate of the involved organs between these two groups (skin: 67.4% vs 68.0%, p=1.000; liver: 15.2% vs 20.0%, p=0.742; gut: 33.3% vs 32%, p=1.000). Haplo-PBSCT was associated with higher incidence of acute GVHD grade 2-4 (HR: 3.04, 95% CI: 1.55-5.98, P =0.001) and lower incidence of extensive chronic GVHD (HR: 0.49, 95% CI: 0.24-0.99, P =0.047) compared with MSD PBSCT. There was no difference of the incidence of acute GVHD grade 3-4 between these two groups (haplo-PBSCT, 9.6% vs MSD PBSCT 8.9%, P =1.000). According to NIH criteria, the incidence of severe chronic GVHD was lower in haploidentical group (13.6%) compared with MSD group (40.5%, p=0.041). There was no difference of those for mild and moderate chronic GVHD (mild: 27.3% vs 13.5%, p=0.189; moderate: 59.1% vs 45.9%, p=0.422).CONCLUSIONIn this cohort study, haplo-PBSCT was associated with similar incidence of severe acute GVHD, lower extensive chronic GVHD and lower severe chronic GVHD compared with MSD-PBSCT. It suggested the potential advantage of ATG in improvement of long-term quality of life of the transplant recipients.Table 1Characteristics of patients and donorsHaploidentical donor, n = 94Matched sibling donor, n = 100P valueGender, n (%)Receipt, male73 (77.7)64 (64.0)0.041Donor, male63 (67.0)60 (60.0)0.371AgePatient, y, median27380.055Donor, y, median38390.364Hematologic malignances, n (%)Acute leukemia72 (76.6)61 (61.0)MDS3 (3.2)21 (21.0)0.000CML5 (5.3)10 (10.0)Lymphoma14 (14.9)8 (8.0)Status of disease, n (%)0.000CR142 (44.7)76 (76)CR214 (14.9)5 (5)NR/beyond CR238 (40.4)19 (19)Time to transplant (d)3612990.946Conditioning Regimen, n (%)0.354BuCy60 (63.8)66 (66.0)TBIcy28 (29.8)23 (23.0)FB6 (6.4)11 (11.0)CD34+ in graft (106/kg)5.864.770.057≥4.6051 (54.3)41 (41.0)0.084 DisclosuresNo relevant conflicts of interest to declare.

Partial T-Cell Depletion By Low-Dose Anti-Thymocyte Globulin to Reduce Severe Acute and Chronic Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

Background: T cells from a stem cell source are inevitably contaminated, and over 5.0×104/kg T cells are thought to induce graft-versus-host disease (GVHD) in HLA-mismatched or haplo-identical stem cell transplantations (SCTs) [4]. To suppress GVHD reactions, a procedure for T-cell depletion (TCD) was developed over the past several decades, especially for HLA-mismatched and haplo-identical SCTs, which are at high risk for GVHD. To reduce the incidence of GVHD, a potentially effective agent is anti-thymocyte globulin (ATG), which is generally administered at a dose of ≥ 5-10 mg/kg. Based on data regarding the use of ATG for the treatment of aplastic anemia, we hypothesized that ATG might accommodate engraftment and inhibit GVHD. We attempted to use a lower dose of ATG to decrease non-relapse mortality (NRM) in Japanese patients undergoing an HLA-matched SCT.Patients and method: We treated patients with hematological diseases who underwent an allogeneic SCT after March 2010 without or with 2.5 mg/kg ATG. The inclusion criteria for underlying disease included both hematological malignancies and bone marrow failures. All consecutive patients transplanted from an allogeneic related or unrelated donor were included. Cord blood transplantations were omitted from this analysis. The patients who underwent an SCT before February 2010 (n=20) were examined as the control group without ATG treatment. ATG was administered 1 day prior to the transplantation day at 2.5 mg/kg with 500 mg/body methylpredonisolone as a preconditioning procedure. GVHD prophylaxis, tacrolimus 0.03 mg/kg and short-term MTX (10-7-7 mg/m2) was adapted for both the ATG group and the control group.Results: Thirty-nine (21 male, 18 female) recipients were recruited (median age 49 yrs, range 19-64 yrs). Their underlying diseases were acute myeloid leukemia (n=14), acute lymphoblastic leukemia (n=10), myelodysplastic syndrome (n=5), lymphoma (n=7), and myeloma, aplastic anemia, and other malignancy (n=1 each). Preparation regimens were myeloablative for 17 patients (14 cyclophosphamide [CY]/total body irradiation [TBI], two busulfan [BU]/CY, and another) and non-myeloablative for the other 22 patients (14 fludarabine/melphalan [Flu/Mel] and eight Flu/BU). All but one patient achieved engraftment, and one secondary graft failure was observed. The overall incidences of acute and chronic GVHD were 63.2% and 15.8% for the ATG-treated patients (40.0% and 25.0% for the control cohort), respectively. Acute GVHD (grades II to IV and III to IV) in the recipients who received ATG occurred in 21.1% and 0.0% (control cohort, 10.0% and 5.0%), respectively. The estimated probability of overall survival (OS) 2.5 yrs after transplantation was 77.8% for the ATG group (controls, 57.1%). The relapse rate 2.5 yrs after transplantation was 21.1% and 20.0% in the ATG and control groups, respectively. The NRM rate was decreased after ATG treatment: 25.0% vs. 10.5% (not significant). The causes of mortality with or without ATG were recurrent diseases (n=1 and 2), infection (n=1 and 0), and adverse events caused by transplant-related complication (n=1 and 5), respectively. No deaths due to acute or chronic GVHD occurred.Discussion: Low-dose ATG could suppress the incidence of severe acute GVHD and chronic GVHD without increasing the NRM, although our study design did not have enough power to make a conclusion about the efficacy of low-dose ATG. However, partial T-cell depletion may be effective for HLA-matched SCT recipients. Our results show that ATG at 2.5 mg/kg can be used safely for the Japanese transplant population of HLA-matched donors. Low-dose ATG is a potential treatment to partially disempower T cells from a stem cell source, which are inevitably contaminated. Recent developments in the prophylaxis for GVHD, such as selective cytotoxic T-cell depletion by using a post-transplant CY regimen, are promising strategies to fully suppress T cells as the GVHD enhancer. Previous studies revealed the clinical efficacy of GVHD prophylaxis but did not clarify the significance of its survival benefit. Likewise, our present findings indicated a lack of survival benefit by ATG treatment in this small study. However, the low-dose ATG contributed to a reduction of severe GVHD. Although early mortality after transplantation is decreasing, late-onset comorbidity including chronic GVHD remains a significant problem. DisclosuresNo relevant conflicts of interest to declare.

Graft-versus-host disease (GVHD) prophylaxis by using methotrexate decreases pre-engraftment syndrome and severe acute GVHD, and accelerates engraftment after cord blood transplantation.

GVHD and graft failure are serious problems in CBT. PES after CBT also occurs frequently and is associated with transplantation-related complications such as acute GVHD. We reviewed medical records for 70 consecutive child CBT recipients between December 1997 and April 2015. Forty-nine patients received prophylaxis against GVHD with CsA or Tac in combination with mPSL from day +7 (mPSL group), and 21 patients received CsA or Tac with MTX on day +1 and day +3 (MTX group). Neutrophil engraftment was detected in 59 patients (84.3%). Neutrophil engraftment rate in the MTX group was significantly higher than that in the mPSL group (21/21 (100%) and 38/49 (77.6%), respectively, p = 0.027). PES developed in 35 patients, and the incidence of PES in the mPSL group was significantly higher than that in the MTX group (p = 0.036). The incidence of severe acute GVHD (grade III or IV) in the MTX group was significantly lower than that in the mPSL group (p = 0.049). Although this study was a small-scale study, the results showed that increase in the rate of engraftment and decrease in the incidence of early immune reactions such as PES and severe acute GVHD could be achieved by early commencement of immunosuppression using MTX.

Clinical Characteristics, Risk Factors and Outcomes of CMV Disease after Allogeneic Stem Cell Transplantation

▪Introduction:Cytomegalovirus disease (CMV-D) is a major complication following allogeneic hematopoietic stem cell transplant (HSCT). CMV monitoring and preemptive therapy has been effective in decreasing CMV disease rates but this disease remains a challenge for many patients, especially with the increasing trend of using alternative donors, T-cell depletion (TCD) and more immunosuppressive regimen. In this study, we attempted to evaluate clinical characteristics; risk factors for progression from CMV viremia (CMV-V) to disease and the impact on transplant outcomes.Methods:A total of 548 patients were evaluated after receiving HSCT between 2005 and 2012 at Princess Margaret Cancer Centre for occurrence of CMV infection (viremia or disease). CMV-V was diagnosed in peripheral blood samples obtained on two occasions either by PCR (³ 200 IU/ml) or antigenemia testing (³2 positive cells/100000). CMV disease (CMV-D) was defined by pathological evidence of virus in the involved organ. A total of 246 were included in the analysis. Patients were stratified into two groups, CMV-V only group versus CMV-D with or without preceding viremia.The CMV-D group median age was 50 years (range 17-71) and 17 (34%) were female. Matched related donors were used for twenty-two patients (54%). Twenty-four patients (59%) were transplanted for a myeloid and 15 (37%) for a lymphoid malignancy. Twenty patients (49%) were CMV sero-positive recipient and negative donor (R+D-) while 20 (49%) were recipient and donor CMV sero-positive (R+D+) and 1 (2%) was CMV sero-negative recipient and sero-positive donor (R-D+). Graft versus host disease (GVHD) prophylaxis included CSA/MMF (n=19, 46%) and CSA/MTX (n=22, 54%). Conditioning regimen with myeloablative preparative regimens were administered to 29 patients (71%), 12 patients (29%) were treated with reduced intensity regimen (RIC). Thirty-seven patients (90%) received peripheral blood stem cells as a stem cell source. In vivo TCD with alemtuzumab was used in 15 (37%).Results: With a median follow-up of 40 months among survivors (range 12-88), CMV-D occurred in 17% (n=41). The median time of onset of CMV-D was 11 months (range 1-88). CMV-D was preceded by viremia in 89% (n=36) versus 11% (n=5) without previous viremia. >3 CMV-V events occurred prior to disease in 39% (n=14) versus 1-2 events in 61%(n=22) of patients. CMV-D affected the lung in 76% (n=31), colon in 15% (n=6), retina in 2% (n=1), liver in 2% (n=1) and 5% of the patients had multi-organ involvements (n=2). Multiple CMV-D (> 2) occurred in 17% (n=7) of the patients. The involved organs differ only in 25% (n=2) of the patients.The transplant outcomes showed higher incidence of acute and chronic GVHD in CMV-D group (Table 1) and NRM (p=0.03; Fig 1B) in CMV-D group but no confirmed differences in OS or relapse. [Display omitted] A multivariate analysis for the risk of progression from viremia to disease demonstrated chronic GVHD (p< 0.03, HR 2.09) together with the use of total body irradiation (TBI) of 1200 cGY (P=0.01, HR 2.77) as an independent risk factors. Neither CMV sero-status nor the numbers of previous CMV-V events were confirmed as independent factors. For survival analyses, CMV-D was not confirmed as independent risk factor for NRM, OS or relapse.A correlation between the time of diagnosis with CMV-D and NRM using the ROC analysis showed day 120 as significant cutoff with AUC=0.722 (sensitivity=0.522, specificity=0.800). The NRM & OS in early CMV-D (i.e. within 120 days from HSCT) was 80% and 7% versus 42% (P=0.004) and 54% (P=0,003) in late CMV-D group (>120 days; Fig 1A), respectively. There were no differences in relapse rate between both groups.The cumulative incidence of grades 1-4 acute GVHD, grades 2-4, grades 3-4 at day 120 and overall chronic GVHD at 2 years in early CMV-D was 93%, 87%, 73% and 27% versus 85%, 58%, 7% and 92% in late CMV-D group, suggesting very higher incidence of severe acute GVHD in early CMV-D versus higher incidence of chronic GVHD in late CMV-D.Conclusion:1) Chronic GVHD and TBI 1200cGY are independent risk factors for progression from CMV-V to disease. 2) CMV-D may occur without proceeding viremia 3) Early CMV-D within the first 120 days from allogeneic HSCT is associated with very higher mortality rate which probably affected in part by the occurrence of severe acute GVHD. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.