Risk Factor For aGVHD Research Articles

Effect of CD8+ CD28- T Cells on Acute Graft-Versus-Host Disease after Haploidentical Hematopoietic Stem Cell Transplantation

To investigate the effect of CD8+ CD28- T cells on acute graft-versus-host disease(aGVHD) after haploidentical hematopoietic stem cell transplantation(haplo-HSCT). The relationship between absolute count of CD8+ CD28- T cells and aGVHD in 60 patients with malignant hematological diseases was retrospectively analyzed after haplo-HSCT, and the differences in the incidence rate of chronic graft-versus host disease(cGVHD), infection and prognosis between different CD8+ CD28- T absolute cells count groups were compared. aGVHD occurred in 40 of 60 patients after haplo-HSCT, with an incidence rate of 66.67%. The median occurrence time of aGVHD was 32.5(20-100) days. At 30 days after the transplantation, the absolute count of CD8+ CD28- T cells of aGVHD group was significantly lower than that of non-aGVHD group (P =0.03). Thus the absolute count of CD8+ CD28- T cells at 30 days after transplantation can be used to predict the occurrence of aGVHD to some extent. At 30 days after transplantation, the incidence rate of aGVHD in the low cell count group (CD8+ CD28- T cells absolute count < 0.06/μl) was significantly higher than that in the high cell count group (CD8+ CD28- T cells absolute count ≥0.06/μl,P =0.011). Multivariate Cox regression analysis further confirmed that the absolute count of CD8+ CD28-T cells at 30 days after transplantation was an independent risk factor for aGVHD, and the risk of aGVHD in the low cell count group was 2.222 times higher than that in the high cell count group (P =0.015). The incidence of cGVHD, fungal infection, EBV infection and CMV infection were not significantly different between the two groups with different CD8+ CD28- T cells absolute count. The overall survival, non-recurrent mortality and relapse rates were not significantly different between different CD8+ CD28- T cells absolute count groups. Patients with delayed CD8+ CD28- T cells reconstitution after haplo-HSCT are more likely to develop aGVHD, and the absolute count of CD8+ CD28- T cells can be used to predict the incidence of aGVHD to some extent. The absolute count of CD8+ CD28- T cells after haplo-HSCT was not associated with cGVHD, fungal infection, EBV infection, and CMV infection, and was also not significantly associated with the prognosis after transplantation.

Clonal Hematopoiesis-Associated Gene Mutations Affect Acute Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation in AML Patients.

BACKGROUND The relationship between clonal hematopoiesis (CH)-associated gene mutations and allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been extensively studied since next-generation sequencing (NGS) technology became widely available. However, research has mainly focused on the relationship between donor CH mutations and transplant prognosis, and research into the relationship between CH mutations in the recipient and acute graft-versus-host disease (aGVHD) is lacking. MATERIAL AND METHODS We analyzed NGS results and their correlation with aGVHD and prognosis in 196 AML patients undergoing allo-HSCT. RESULTS A total of 93 (47.4%) patients had CH mutations. The most frequently mutated genes were DNMT3A (28 of 196; 14.3%), TET2 (22 of 196; 11.2%), IDH1 (15 of 196; 7.7%), IDH2 (14 of 196; 7.1%), and ASXL1 (13 of 196; 6.6%). The incidence of aGVHD was higher in patients older than 45 years old with DTA mutations (DNMT3A, TET2 or ASXL1). DNMT3A mutation but not with TET2 or ASXL1 mutation was an independent risk factor for aGVHD in patients receiving allo-HSCT older than 45 years old. With a median follow-up of 42.7 months, CH mutations were not associated with overall survival and leukemia-free survival. CONCLUSIONS DNMT3A mutation, but not TET2 or ASXL1 mutation, was associated with higher incidence of aGVHD.

Impact of total marrow/lymphoid irradiation dose to the intestine on graft-versus-host disease in allogeneic hematopoietic stem cell transplantation for hematologic malignancies.

Graft-versus-host disease (GvHD) is a leading cause of non-relapse mortality in patients undergoing allogeneic hematopoietic stem cell transplantation. The Perugia Bone Marrow Transplantation Unit designed a new conditioning regimen with total marrow/lymphoid irradiation (TMLI) and adaptive immunotherapy. The present study investigated the impact of radiotherapy (RT) doses on the intestine on the incidence of acute GvHD (aGvHD) in transplant recipients, analyzing the main dosimetric parameters. Between August 2015 and April 2021, 50 patients with hematologic malignancies were enrolled. All patients underwent conditioning with TMLI. Dosimetric parameters (for the whole intestine and its segments) were assessed as risk factors for aGvHD. The RT dose that was received by each intestinal area with aGvHD was extrapolated from the treatment plan for each patient. Doses were compared with those of the whole intestine minus the affected area. Eighteen patients (36%) developed grade ≥2 aGvHD (G2 in 5, G3 in 11, and G4 in 2). Median time to onset was 41 days (range 23-69 days). The skin was involved in 11 patients, the intestine in 16, and the liver in 5. In all 50 TMLI patients, the mean dose to the whole intestine was 7.1 Gy (range 5.07-10.92 Gy). No patient developed chronic GvHD (cGvHD). No dosimetric variable emerged as a significant risk factor for aGvHD. No dosimetric parameter of the intestinal areas with aGvHD was associated with the disease. In our clinical setting and data sample, we have found no clear evidence that current TMLI dosages to the intestine were linked to the development of aGvHD. However, due to some study limitations, this investigation should be considered as a preliminary assessment. Findings need to be confirmed in a larger cohort and in preclinical models.

Association of Pre-Transplant Angiopoietin-2 Index with the Risk of Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation

Objective:Angiogenic factors (AFs) released under endothelial stress are reflective of tissue healing, while some may also contribute to tissue damage/inflammation. We investigated whether alterations in the pre-transplant levels of AFs were associated with the risk of acute graft-versus-host disease (aGvHD).Materials and Methods:The pre-conditioning plasma levels of angiopoietin-2 (Ang2), endoglin, and follistatin were measured for 37 patients together with inflammatory markers. The index values defined were evaluated to better identify the alterations.Results:The patients had higher pre-conditioning levels of Ang2, endoglin, and follistatin compared to controls. The patients with aGvHD had higher Ang2 index and lower albumin index scores in comparison to those without aGvHD. Multivariate analysis revealed that the pre-transplant Ang2 index was an independent risk factor for aGvHD development.Conclusion:Pre-transplant evaluation of plasma Ang2 levels along with inflammatory status even before conditioning is associated with endothelial vulnerability. The pre-transplant Ang2 index could be a promising candidate to estimate the risk of aGvHD.

Identifying Risk Factors for Acute and Chronic Graft-Versus-Host Disease in T-Replete HLA-Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Introduction: Acute(aGVHD) and chronic graft-versus-host disease (cGVHD) cause significant morbidity and mortality in patients post hematopoietic cell transplantation (HCT). The use of T-replete HLA-haploidentical transplantation (HIDT) with post-transplant cyclophosphamide has become a common donor source for patients lacking a suitably matched donor. In spite of the increase in HIDT, there is paucity of data describing aGVHD and cGVHD outcomes and potential risk factors for developing graft-versus-host disease after HIDT.Methods: The outcomes and the characteristics of 203 patients undergoing first allogeneic transplantation using HIDT with post-transplant cyclophosphamide between 2005 and 2016 were retrospectively assessed to identify the incidence and risk factors for aGVHD and cGVHD. Variables included in the analysis included patient related (age, sex, race, karnofsky, HCT-CI), disease related (diagnosis, disease type, disease risk index DRI, CIBMTR risk status) and transplant related (graft source as marrow vs peripheral blood, donor age, donor/recipient relationship, donor/recipient gender match, donor/recipient CMV match, conditioning intensity, high dose TBI in conditioning intensity, CD34 cell dose, CD3 cell dose and year of transplant). Univariate analysis with Gray's test and log-rank was carried for cumulative incidence and survival respectively. The proportional hazard cox model was used with backward elimination to select significant covariates. Multivariate analyses for developing GVHD, overall survival (OS), disease free survival (DFS), and relapse were conducted.Results: The median age was 51 years (range 19, 75) with a median follow up for survivors of 37 months. Seventy patients (34%) received bone marrow as graft source and 43% had Myeloablative conditioning. All patients received GVHD prophylaxis consisting of post-transplant cyclophosphamide on Days +3 and +4, MMF till day +35 and tacrolimus till day +180. The cumulative incidence for aGVHD grade II-IV and grade III-IV were 45% and 12% respectively. The common organs involved in aGVHD were skin (76% of cases, 39% stage 3 /4), gut (58% of cases, stage 3 /4 11%) and liver (7% of cases, stage 3 /4 of 1%). Subsequent aGVHD flare developed in 6 patients (5 with gut GVHD and 1 skin GVHD). The cumulative incidences of all grade cGVHD and moderate-severe cGVHD were 32% and 24% respectively (table 1). Conditioning intensity was the only risk factor associated with developing grade 2-4 aGVHD (p=0.04). Patients that received myeloablative regimens as compared to those who received a reduced intensity or non-myeloablative regimen had statistically higher rates of grade 2-4 aGVHD (hazard ratio [HR] of 1.52 (95% CI, 1.01-2.29, p=0.04). Risk factors for cGVHD showed that race and hematopoietic cell transplantation-comorbidity index (HCT-CI) had a statistically significant bearing on the likelihood of developing all-grade cGVHD (p=0.004 and 0.01 respectively). Graft source (marrow vs Peripheral blood) was a significant risk factor for developing moderate-severe cGVHD (p=0.03). Multivariate analysis on OS, DFS and relapse showed that Patients aged 55 or older (HR of 1.91, 95% CI 1.22-2.99, p =.005) and High/very high DRI risk (HR 2.06, CI 1.05-4.00, p=0.03) had worse overall survival rates. Older age, not developing chronic GVHD and receiving a transplant between 2005 and 2010 were all associated with a worse DFS (P<0.01 for all). High/very high DRI, male gender and not developing cGVHD were all significant factors for a higher relapse rate.Conclusions: This single center analysis of GVHD incidence and risk factors after HIDT using post-transplant cyclophosphamide showed that conditioning intensity, graft source and HCT-CI to be factors affecting incidence of GVHD. Higher disease risk and older patient age were associated with worse overall survival. [Display omitted] DisclosuresSolh:Amgen: Speakers Bureau; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau.

Risk Factors for Occurrence and Outcome of Acute Graft Versus Host Disease in Allogeneic Hematopoietic Stem Cell Transplant: Analysis of 7 Year Health Care Utilization Project Data

Introduction: Acute Graft versus Host Disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplant (allo-HSCT). Despite advances in prevention and treatment methods, it remains significant cause of morbidity and mortality in this group of patients. Most of the studies assessing risk factors and outcome have yielded inconsistent results. In the current study, we have utilized the national database, which provided us with larger sample size to adequately assess the risk factors for occurrence and mortality of aGVHD in allo HSCT patients.Methods: aGVHD risk factors for occurrence and mortality were identified in 46652 patients from year 2008 to 2014 utilizing national inpatient sample (NIS) of health care utilization project (HCUP) data. Occurrence was defined as established diagnosis of aGVHD (identified with ICD-9 code of 279.51) and mortality as death prior to hospital discharge. Predictors were defined as baseline patient characteristics that influence incidence and outcome of aGVHD. We performed regression analysis using these baseline patient characteristics as covariates and calculated odd ratio (OR) with 95% confidence interval (CI) in both univariate and multivariate model to assess the risk for occurrence and outcome of aGVHD. In addition we also assessed the burden of the disease on our healthcare system by identifying the difference in length of stay and hospital charges in patients with and without aGVHD.Results: On multivariate analysis significant risk factors for occurrence of aGVHD were age 0-49 years (OR = 1.70, CI = 1.14-2.53), white race (OR = 1.57, CI = 1.20-2.07), allogeneic cord stem cell transplant (OR = 1.48, CI = 1.07-2.05), conditioning regimen with use of total body irradiation (OR = 1.40, CI = 1.15-1.71), infections including bacterial sepsis (OR = 1.99, CI = 1.67-2.36), viral infections OR = 1.88, CI = 1.53-2.31), fungal infections (OR = 1.54, CI = 1.22-1.98) and c diff colitis (OR = 1.52, CI = 1.21-1.90). Similarly on multivariate analysis significant risk factors for mortality of aGVHD were age >65 years (OR = 3.44, CI = 1.28-9.22), infections including bacterial sepsis (OR = 6.30, CI = 3.83-10.35), viral infections (OR = 1.85, CI = 1.09-3.16), fungal infections (OR = 2.14, CI = 1.25-3.66), presence of comorbidities assessed by charlson comorbidity scale (OR 2.28, CI = 1.34-3.88). These results were replicated on univariate analysis as well with the exception of race (white) for aGVHD occurrence and age (>65 years) for aGVHD mortality, which were only significant on multivariate analysis.The median length of stay (in days) was significantly higher in patients of allo HSCT with aGVHD, 42 (CI= 39-44) as compared to without aGVHD, 26 (CI = 26-27). Similarly the median total charges for hospital stay (in US dollars) were also significantly higher in patients of allo HSCT with aGVHD, 512025 (CI = 462567-561482) as compared to without aGVHD with a median of 298447 (CI = 275865-321029).Conclusion: Our study confirmed several previously established risk factors for aGVHD. In addition we identified certain new factors, which increases risk for occurrence and mortality of aGVHD. Additionally we identified that aGVHD substantially increases the burden on our healthcare system as measured by increase in both length of stay and cost. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Recombinant Thrombombomodulin for the Prophylaxis of Vaso-Occlusive Complications in Allogenic Hematopoietic Stem Cell Transplantation : A Systematic Review and Meta-Analysis

Background: Hepatic veno-occlusive disease (VOD) also termed as sinusoidal obstruction syndrome (SOS) is a lethal complication seen after haematopoietic stem cell transplantation (HSCT). There are a limited number of options for prevention of this fatal complication. Recombinant thrombomodulin (rTM), an endothelial anticoagulant co-factor, has been shown to help prevent veno-occlusive complications after stem cell transplantation. Various trials have shown safety and efficacy of recombinant thrombomodulin in preventing SOS. Methods: A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following keywords, "thrombomodulin" AND "stem cell transplantation" from the inception of literature till June 2020. Out of 239 articles, we screened and included nine trials (N=850) in the systematic review and meta-analysis. We extracted the data for VOD episodes, graft vs host disease (GVHD) episodes and survival after stem cell transplantation. We excluded case reports, preclinical trials, review articles, meta-analysis, and trials not providing any information about the above-mentioned. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: Total number of patients tested was 356 in thrombomodulin group and 494 in control group. The age range was 16 to 74 years. Thrombomodulin group had 254 males and control group had 190 (Table 1.). For VOD, risk ratio (RR) was 0.53 (I2= 0%, 95% CI=0.32-0.89) in favor of rTM vs heparin or no therapy for prevention of VOD after stem cell transplantation (Fig 1.). rTM was effective in prevention of transplant-associated thrombotic microangiopathy (TA-TMA) after HSCT. RR was 0.48 (I2= 62%, 95% CI=0.20-1.17) with significant lower incidence of TMA in rTM group (Fig 2.). In a trial, seven of nine patients recovered from TA-TMA in the rTM group, but none recovered in the control group who received various therapies including fresh frozen plasma, therapeutic plasma exchange(TPE) or others (p=0.003) (Fujiwara et al). The risk of GVHD was also significantly lower in rTM group and RR was 0.48 (I2= 64%, 95% CI=0.32-0.72) which again favours rTM vs heparin or no therapy (Fig 3.). Ishii et al showed that stepwise multivariate logistic regression analyses revealed that anti-coagulation therapy without rTM was an independent risk factor for aGVHD (p=0.000, odds ratio=3.006) and VOD (p=0.015, odds ratio=2.65). Yakushijin et al compared rTM with Defibrotide and found similar complete remission (CR) rate and the overall survival (OS) at day 100 in both the groups. Therefore, rhTM could be one of the potential novel candidate for SOS treatment. Use of rTM improved the survival rate of patients with disseminated intravascular coagulation (DIC), diagnosed according to the criteria established by the Ministry of Health, Labor and Welfare of Japan, at day 100 (83% vs. 50%, P = 0.026) and significantly prolonged the OS of these patients (P = 0.044). The Kaplan-Meier curves clearly showed the improved non-relapse-related mortality of patients who received rTM after HSCT (Ikezoe et al). Mean DIC scores improved significantly with the use of rhTM (p = 0.003; DIC withdrawal rate 91.7%). FDP and CRP levels were also significantly decreased (p = 0.042 and p = 0.001). The recovery rate from DIC at 28 days was significantly better in rTM than in antithrombin or heparin group (p = 0.011) (Inoue et al). The mean peak plasminogen activator inhibitor type one (PAI- 1) level was significantly lower in the rTM group vs heparin and ursodiol group (P = 0.04), and the mean peak activated protein C (APC) level was significantly higher in the rTM group (P = 0.01) (Yamamoto et al). No serious grade 3 or 4 adverse events were reported by trials. Conclusion: This systematic review and meta-analysis shows that prophylactic rTM (380 units/kg) has a beneficial role in the prevention of post- HSCT SOS complication in patients that are at high risk of developing the condition. It appears to help improve treatment-related mortality and overcome the poor survival rates. Additional randomized clinical trials are needed to establish efficacy and safety of rTM to prevent VOD and to confirm these results. Disclosures Anwer: Celgene: Research Funding; Millennium Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AbbVie Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau.

The Blood Levels of the Amino Acid Kynurenine and Indoloxigenase are Predictive of Acute Graft Versus Host Disease (aGVHD)

The main barrier to the success of hematopoietic stem cell transplantation (HSCT) is acute graft versus host disease (aGVHD). The risk factors for aGVHD are mainly clinical and can be improved if additional biological factors are incorporated, such as the metabolomic profile.

Inflammatory Cytokine Profile in Individuals with Inherited Chromosomally Integrated Human Herpesvirus 6.

Acute graft-versus-host-disease (aGVHD) is a major complication following hematopoietic cell transplantations (HCTs). We have shown that HCT recipients in whom either the donor or patient had inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) have a higher incidence of developing more severe aGVHD. Previous studies established that increased proinflammatory cytokines are associated with increased risk for aGVHD and nonrelapse mortality post-HCT. We hypothesized that HCT recipients with donor or recipient iciHHV-6 (iciHHV-6pos HCT cases) will have higher cytokine levels compared with HCT recipients without iciHHV-6 (iciHHV-6neg HCT controls). We identified 64 iciHHV-6pos HCT cases with plasma from days 7, 14, and/or 21 post-HCT and before aGVHD onset in patients who developed aGVHD. We identified 64 iciHHV-6neg HCT controls matched for aGVHD risk factors. We also identified 28 donors with iciHHV-6 and 56 matched donors without iciHHV-6. We measured plasma cytokine concentrations for IL-6, suppression of tumorigenicity 2, T cell immunoglobulin and mucin-domain containing 3, TNFα, soluble TNF receptor 1 (TNFRp55), and C-reactive protein (CRP). We used Mann-Whitney tests and repeated-measures models to compare cytokine levels. iciHHV-6pos HCT cases had higher CRP levels on day 7 and day 21 and higher TNFRp55 levels on day 14 and day 21 compared with iciHHV-6neg HCT controls. These findings were recapitulated in a repeated-measures model. The differences were most evident among patients who subsequently developed aGVHD grades 2 to 4. Additionally, iciHHV-6pos HCT cases had earlier-onset aGVHD (median, 20 versus 27 days post-HCT; P = .02). There were no differences in cytokine levels among healthy donors with or without iciHHV-6. This study demonstrates that HCT recipients with iciHHV-6 have higher proinflammatory cytokines that may be associated with increased risk for aGVHD.

Investigation of MHC gamma block C4A and C4B polymorphisms in unrelated hematopoietic stem cell transplantation.

BackgroundImmunological life-threatening complications frequently occur in post-hematopoietic stem cell transplantation (HSCT), despite matching recipient and donor (R/D) pairs for classical human leukocyte antigens (HLA). Studies have shown that R/D non-HLA disparities within the major histocompatibility complex (MHC) are associated with adverse effects post-HSCT.MethodsWe investigated the impact of mismatches of single-nucleotide polymorphisms (SNPs) in C4A/C4B genes, for showing the highest diversity in the MHC gamma block, on 238 patients who underwent HLA 10/10 unrelated donor (URD) HSCT. The endpoints were acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD) and mortality. One hundred and twenty-nine R/D pairs had 23 C4-SNPs typed by PCR-SSP (Gamma-Type™v.1.0), and 109 R/D pairs had these 23 SNPs identified by next-generation sequencing (NGS) using the Illumina platform.ResultsThe percentage of patients who received HSC from HLA 10/10 donors with 1–7 mismatches was 42.9%. The R/D pairs were considered C4 mismatched when bearing at least one disparity. These mismatches were not found to be risk factors for aGVHD, cGVHD or mortality after unrelated HSCT when SNPs were analyzed together (matched or mm ≥ 1), independently or according to the percentage of incompatibilities (full match for 23 SNPs; 1–3 mm and >3 mm). An exception was the association between 1–3 mismatches at the composite of SNPs C13193/T14952/T19588 with the development of aGVHD (P = 0.012) and with grades III-IV of this disease (P = 0.004).ConclusionOur data are not consistent with the hypothesis that disparities in C4A/C4B SNPs increase the risks of post-HSCT adverse effects for the endpoints investigated in this study.

Premature cyclosporine cessation and TBI-containing conditioning regimen increase the risk of acute GvHD in children undergoing unrelated donor hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGvHD) is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Identifying its risk factors would enable the proper prophylaxis and management, which may significantly improve the general outcome of children treated with HSCT. The aim of this single-center, retrospective cohort study was to assess the potential risk factors for grades II-IV of aGvHD in children after the 1st allo-HSCT from an unrelated donor (UD), performed as a result of an underlying malignant disease. From among patients who received HSCT in our center in the years 2004-2015, 237 were included in the study cohort. All the patients received standard aGvHD prophylaxis consisting of cyclosporine (CsA) and a short course of methotrexate (MTX). Various clinical and epidemiological features, the transplant proceedings, graft composition, conditioning regimens, as well as the duration and coherence of aGvHD prophylaxis were analyzed as potential risk factors for aGvHD. The incidence of II-IV aGvHD in the study cohort was 58.6%. The median time of the diagnosis of aGvHD was 18 days post-HSCT. In the multivariate analysis, risk factors significantly associated with grades II-IV of aGvHD were: myeloablative conditioning regimen containing total body irradiation (TBI-MAC) (RR (relative risk): 1.69; p = 0.03), premature termination of CsA administration due to its toxicity (RR: 1.99; p = 0.0003) and HSCT performed before the year 2009 (RR: 1.97; p = 0.0001). Donor and recipient age, donor-recipient sex mismatch, stem cell source, risk of disease, and amount of infused CD34+ cells seem to be insignificant as risk factors for aGvHD. The overall survival (OS) of patients with aGvHD was noticeably worse that in those who were aGvHD-free: 60.8% vs 74.1% (p = 0.08). The conditioning regimen and the proper aGvHD prophylaxis, including continuous CsA administration, have a major impact on aGvHD occurrence. According to our results, the termination of CsA therapy should be carefully considered, and avoided if possible.

The impact of pretransplant malnutrition on allogeneic hematopoietic stem cell transplantation outcomes

Malnutrition is a common finding in allogeneic hematopoietic stem cell transplantation (alloHSCT) patients, and there is some evidence that malnutrition might negatively affect the transplant outcomes. We performed a retrospective study with 148 patients aged 18-75 years, who underwent alloHSCT between 2011 and 2017. Patients were classified according to the body mass index (BMI) and the Subjective Global Assessment (SGA). The SGA was assessed on the day of hospitalization for the transplant, and classifies patients into three groups: A (well-nourished), B (moderately malnourished) and C (severely malnourished). The SGA classified 49 (33%) patients as well-nourished, 54 (37%) as moderately malnourished, and 45 (30%) as severely malnourished. SGA-C was also associated with severe acute graft versus host disease (aGVHD) with a cumulative incidence (CI) of 31% vs. a CI of 14% for combined well-nourished or moderately malnourished group (SGA-A or -B, P=0.017). In multivariate analysis, SGA-C compared to SGA-A or -B, remained as an independent risk factor for aGVHD (hazard ratio - HR 1.68, 95% confidence interval - 95% CI 1.02-2.74), and nonrelapse mortality (NRM - HR 3.63, 95% CI 1.76-7.46), worse progression free survival (HR 2.12, 95% CI 1.25-3.60), and worse overall survival (HR 3.27, 95% CI 1.90-5.64). Malnutrition increases the risk of aGVHD and NRM and has a negative impact on survival.

History of Infection Prior to Hematopoietic Stem Cell Transplant in the Recipient as a Risk Factor to Develop Acute Graft versus Host Disease

Background: Acute graft-versus-host disease (aGVHD) is the most frequent and severe complication after allogeneic hematopoietic stem cell transplantation (HSCT). Objective: To determine if a history of prior infection in the allogeneic HSTC recipient is a risk factor to develop aGVHD. Methods: A retrospective cohort study based on data collected from the Department of Hematopoietic Stem Cell Transplantation at the Instituto Nacional de Pediatría (INP) from January 1998 to December 2016 was performed to identify if prior infection was a predictive risk factor for aGVHD. Results: 27 patients developed aGVHD (36.4%). Median time to aGVHD presentation was 82 days (9 to 273 days). Most patients developed grade III aGVHD. Following the multivariate analysis peripheral blood > bone marrow (OR 12.3; p 8.3 × 106/kg (OR 7.1; p = 0.05), peripheral blood (OR: 11.4; p Conclusions: Either bacterial infection or CMV infection in the recipient was significant risk factor within the aGVHD recipients; it is important to consider these factors for patients that are going to receive an allogeneic HSCT.

The Influence of Genetic Variations in the CD86 Gene on the Outcome after Allogeneic Hematopoietic Stem Cell Transplantation.

CD86 molecule is the ligand for both costimulatory (CD28) and coinhibitory (CTLA-4) molecules, and it regulates immune response after allogeneic hematopoietic stem cell transplantation (alloHSCT). Therefore, we postulate that CD86 gene variations might influence the outcome after alloHSCT. Altogether, 295 adult patients (pts) undergoing related (105 pts) and unrelated (190 pts) donor-matched HSCT were genotyped for the following CD86 gene polymorphisms: rs1129055, rs9831894, and rs2715267. Moreover, the donors' rs1129055 polymorphism was determined. None of the investigated SNPs alone were associated with aGvHD and rate of relapse. However, we showed that rs2715267 SNP influenced overall survival (OS) after alloHSCT. The 24-month OS for the rs271526GG recipients was worse than that for the recipients possessing T allelle (TT or GT genotypes) (p = 0.009). Moreover, analysis of gene-gene interaction between CD86 and CTLA-4 showed that having both the A allele for CD86 rs1129055 and the CTLA-4 CT60GG genotype in recipients increased the risk of aGvHD about 3.5 times. Interestingly, the donors' rs1129055GG genotype and the recipients' CT60GG genotype also increased the risk of aGvHD about 2.7-fold. We postulate that recipients' CD86 gene polymorphisms influence the overall survival after alloHSCT and, together with CTLA-4 polymorphisms, might be considered a risk factor for aGvHD.

The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation

ABSTRACTThe intestinal microbiota plays a key role in the pathogenesis of acute graft-versus-host disease (aGVHD). High-dose conditioning regimens given prior to allogeneic hematopoietic stem cell transplantation (aHSCT) modulate the composition of gut microbiota and damage the gut epithelial barrier, resulting in increased systemic inflammation. We assessed whether gut decontamination with antibiotics (ATB) prior to aHSCT influenced the frequency of aGVHD and mortality in 500 patients from two Canadian centers between 2005 and 2012. The rate of grade II–IV aGVHD was higher in the ATB arm compared with the arm without ATB (42% vs 28%; p < 0.001). This difference was mainly driven by a 2-fold higher rate of grade II–IV gastrointestinal aGVHD (GI-GVHD) in the ATB arm compared with the arm without ATB (20.7% vs 10.8%; p = 0.003). Multivariate analyses adjusted for known aGVHD risk factors revealed that more patients in the ATB group developed clinically significant GI-GVHD and liver aGVHD; adjusted odds ratio (aOR) = 1.83; p = 0.023 and aOR = 3.56; p = 0.047, respectively. Importantly, median overall survival (OS) was significantly lower in the group receiving ATB and the OS at 10 y remained decreased in the ATB group; adjusted hazard ratio (aHR) = 1.61 (p < 0.001).Without undermining the role of ATB prophylaxis to prevent infection in aHSCT, we have shown that the use of ATB that targets intestinal bacteria is associated with a more severe aGVHD that involves the GI organs and impacts OS. Prospective studies that evaluate the contribution of bacterial decontamination to aGVHD are warranted.

Early Post-Transplantation Tacrolimus Levels Correlate with Acute Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation from Related and Unrelated Donors

Introduction: Acute graft-versus-host disease (aGVHD) is a leading cause of transplant related mortality following allogeneic hematopoietic stem cell transplantation (HCT). The most widely used aGVHD prophylaxis regimen is a combination of a calcineurin inhibitor and a short course of methotrexate. Results of studies on the optimal blood levels of the calcineurin inhibitor tacrolimus to prevent aGVHD are mixed, with some showing no correlation and others indicating that trough levels between 7-15 ng/mL required to adequately prevent aGVHD. Currently, the established target trough level for this agent is 10 to 20 ng/mL. We retrospectively evaluated the relationship between tacrolimus blood concentration and the incidence of grade II-IV aGVHD in a large cohort of adult patients following allogeneic HCT from either an HLA-matched related or matched unrelated donors.Methods: We evaluated all related/unrelated allografts between January 2004 and December 2012 at the Cardinal Bernardin Cancer Center at Loyola University. Inclusion criteria included age 18 years or older, first allogeneic HCT for a hematological malignancy, and use of tacrolimus and short term methotrexate for aGVHD prophylaxis. Donors included human leukocyte antigen (HLA) identical sibling (Allo-Sib) or unrelated donors (MUD) either fully matched or 1 antigen mismatched (10%). Both myeloablative and non-myeloablative conditioning regimens were included. Disease risk was defined by the ASBMT classification and Co-Morbidity Index by Sorror et al (HCT-CI). Infusional tacrolimus was initiated on day -2 of HCT at dose of 0.03 mg/kg/d and AM trough blood concentrations measured every other day during the entire hospital stay with the goal of maintaining a level of 10-15 ng/ml and then twice weekly after discharge. Dose adjustments or withholds were based primary on serum creatinine and trough levels per a set protocol that withholds for levels greater than 20 ng/ml or creatinine greater than 2.0 mg/dl. Acute GVHD was graded based on the International Bone Marrow Transplant Registry System. Univariate and multivariate analyses exploring all risk factors for aGVHD were performed.Results: A total of 428 patients met the inclusion criteria. Median age was 48.5 years with a male predominance (60.6%). HCT-CI was evenly distributed with 121 (28.2%) low risk, 151 (35.3%) intermediate risk, and 156 (36.4%) high risk. Per ASBMT disease risk classification, more patients had high disease risk (n=211, 49.3%); 64 (15%) with intermediate risk, and 153 (35.7%) with low risk. Acute GVHD II-IV developed in 186 (43%) patients in this largely myeloablative patient population (89%), with donor source split nearly evenly between MUD (45%) and Allo-sib (55%). An extensive univariate analysis for the factors associated with the development of aGVHD was developed (Table 1). The strongest predictor of aGVHD was a level of tacrolimus < 5 ng/ml in weeks 3 and 4 after transplant: of those with no aGVHD only 16.9% had a level < 5 ng/ml during these weeks vs 27.4% with aGVHD (p = .009). Other tacrolimus trough cut points, i.e. 10 ng/ml, 2.5 ng/ml and the mean (13.4 ng/ml in each group) were not associated with a higher rate of aGVHD. In the univariate analysis, AML and allo-sib grafts were noted to be associated with lower risk of aGVHD. In multivariate analysis (Table 2), tacrolimus levels less than 5 ng/ml in weeks 3 or 4 was found to be the most statistically significant factor in predicting aGVHD incidence (Odds ratio 82 95% CI 1.13-2.94; p = .01); other significant factors include HCT-CI (p = .02) and graft source (p = .04).Conclusion: In one of the largest retrospective studies examining the correlation of early tacrolimus blood concentrations and acute GHVD incidence, we show that trough tacrolimus levels less than 5 ng/ml in weeks 3-4 following Allo-Sib or MUD HCT is a strong predictor for an increased risk of aGVHD. We affirm that higher HCT-CI and donor source are risk factors for aGVHD after allografts. This not only helps define more accurately the lower limits of acceptable tacrolimus levels, but appears to emphasize the importance for close monitoring and dose adjustment of these levels at a time when patients are typically discharged to the outpatient setting. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Number of Leukoreduced RBC and Platelet Transfusions Does Not Increase the Incidence of aGVHD in Allogeneic Peripheral Blood Stem Cell Transplant Recipients

▪ INTROThe pathophysiology of acute graft versus host disease(aGVHD) after stem cell transplant has been described as a three-phase process. The first involves damage to host tissue by inflammation. In the second, both recipient and donor antigen-presenting cells and inflammatory cytokines trigger activation of donor T cells which expand into effector T cells. In the third phase, activated donor T cells mediate cytotoxicity against host cells by multiple mechanisms. Known risk factors for aGVHD include: stem cell source, graft type, unrelated donor, HLA mismatched donor, older age of donor, multiparous female donor, older age of recipient, GVHD prophylaxis and certain conditioning regimens. The transfusion (Tx) of red blood cells (RBC) and platelets (PLT) expose the recipient to additional white blood cells and cytokines, even in leukoreduced products. Potentially, ABO-non identical (ABO-NI) RBC and PLT Tx could further increase the release of cytokines. This study investigated whether more Tx, or more ABO-NI RBC or PLT Tx, were associated with an increased risk of aGVHD. METHODSAll ABO-identical allogeneic peripheral blood stem cell transplants at our center since 2012 were included. Primary outcome was development of Grade I-IV aGVHD (skin, liver or gastrointestinal tract). Any patient who received more than 1 transplant or did not have aGVHD status documented in the transplant database was excluded. Adjustment was performed for recipient age and gender. The following parameters were evaluated for an association with aGVHD: combined number of RBC and PLT Tx, number of RBC Tx, number of PLT Tx, number of ABO-NI RBC Tx, and number of ABO-NI PLT Tx. Only Tx within 1 year after transplant and prior to development of aGVHD or relapse (if applicable) were included. Statistical analysis (logistic regression and chi-square) was performed using STATA 14.1. RESULTSEighty-four patients were included. Forty-one percent were MUD and 59% were MRD. Thirty-six patients developed aGVHD (43.4%). Twenty-seven percent of platelet Tx were ABO-NI (99.9% major ABO incompatible). ABO-NI (all minor ABO incompatible) accounted for 2.5% of RBC Tx. Patients who developed aGVHD received an average of 4 RBC (0 ABO-NI) and 6 PLT (3.7 ABO-NI) per patient. Patients who did not develop aGVHD received an average of 4.6 RBC (0.4 ABO-NI) and 5.6 PLT (2.7 ABO-NI) per patient. There was no association seen between the number of RBC+PLT (p=0.88), RBC (p=0.57), PLT (p=0.65) and development of aGVHD. Receiving any ABO-NI RBC or PLT did not put a patient at increased risk of aGHVD and total number of transfusions received (RBC p=0.19; PLT p=0.13). CONCLUSIONAn increased number of RBC or PLT transfusions, or receiving ABO non-identical RBC or PLT transfusions, did not increase the risk of aGVHD after allogeneic peripheral blood stem cell transplant. Additional studies are needed to evaluate whether patients receiving ABO minor incompatible platelets have an increased risk of aGVHD. DisclosuresPhillips:Kyowa Kirin: Research Funding; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

Pretransplant Levels of CRP and Interleukin-6 Family Cytokines; Effects on Outcome after Allogeneic Stem Cell Transplantation.

Several pretransplant factors, including CRP (C-reactive protein) levels, reflect the risk of complications after allogeneic stem cell transplantation. IL-6 induces CRP increase, and we therefore investigated the effects of pretransplant IL-6, soluble IL-6 receptors, IL-6 family cytokines and CRP serum levels on outcome for 100 consecutive allotransplant recipients. All patients had related donors, none had active infections and 99 patients were in complete remission before conditioning. The incidence of acute graft versus host disease (aGVHD) requiring treatment was 40%, survival at Day +100 82%, and overall survival 48%. Despite a significant correlation between pretransplant CRP and IL-6 levels, only CRP levels significantly influenced transplant-related mortality (TRM). However, CRP did not influence overall survival (OS). Pretransplant IL-31 influenced late TRM. Finally, there was a significant association between pretransplant IL-6 and early postconditioning weight gain (i.e., fluid retention), and this fluid retention was a risk factor for aGVHD, TRM and OS. To conclude, pretransplant CRP, IL-31 and early posttransplant fluid retention were independent risk factors for TRM and survival after allotransplantation.

Recombinant Thrombomodulin for the Treatment of Transplantation-Associated Coagulopathy after Allogeneic Hematopoietic Stem Cell Transplantation: A Multi-Center Study in Japan

Background:Thrombotic microangiopathy (TMA) and veno-occlusive disease (VOD) as well as acute GVHD (aGVHD) are closely relevant to inflammation and coagulation involving endothelium in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is named as transplantation associated coagulopathy (TAC) to overcome challenges and achieve better survival. Recombinant thrombomodulin (rTM) is a new drug for treating disseminated intravascular coagulation (DIC) approved by the Japanese Ministry of Health, Labour and Welfare in 2008. Membranous TM has many aspects to inhibit inflammation via activated Protein C (APC), lectin-like domain, and activated thrombin-activatable fibrinolysis inhibitor as well as to inhibit coagulation by binding factor IXa and Xa through APC. We investigated the effects of rTM on levels of the biomarkers and examined whether we could prevent TAC using rTM among registered patients in the SIGHT study group. We reported that significant improvements in elevation of TNF-α, E-selectin, VCAM-1, HMGB-1, PAI-1 and PDMP were exhibited following alloHSCT with rTM-treatment. Here we studied which biomarker were predictive for TAC and contributed to reduce the probability of these complications.Methods:SIGHT study group was composed of 70 hospitals and research centers in Japan. Patients eligible for alloHSCT treatment for hematopoietic disorders who secured attending physicians clearance were permitted in the study. Blood samples were collected from the patients before and after transplantation through day 28. Levels of cytokines (IL-6, TNF-α, HMGB1, MCP-1, RANTES) and soluble molecules (VCAM-1, E-selectin, PAI-1, PDMP) were measured by ELISA. rTM was administered as a prophylactic therapy for TAC in day 4-14 after alloHSCT. The dose of rTM, 380 u/kg, was employed as same dose as the treatment for DIC. Control group received 100 u/kg heparin, or no anti-coagulation therapy as prophylaxis at the same schedule as the rTM group. Patients were not randomized to these three arms but allowed to select one by their physician's decision. Complications following transplantation were reported by attending physicians.Results:The subjects were 293 patients who underwent alloHSCT in SIGHT study group between June 2010 and February 2014. 194 patients out of them, in whom complications following alloHSCT were reported, were analyzed to measure level of above biomarkers. No G3/4 adverse events of bleedings or severe organ damages were reported. Regarding complications following alloHSCT, the rate of developing aGVHD and VOD was significantly lower in rTM group than without it (36.5% vs. 62.2%, p=0.000; 12.5% vs. 24.5%, p=0.032, respectively), while TMA did not differ (8.4% vs. 10.2%, p=0.961). Stepwise multivariate logistic regression analyses revealed that anti-coagulation therapy without rTM was an independent risk factor for aGVHD (p=0.000, odds ratio=3.006) and VOD (p=0.015, odds ratio=2.65). We explored candidates for predictive biomarkers for TAC following alloHSCT. Only HMGB-1 levels were useful markers associated with risk of VOD among them (p=0.001, odds ratio=1.433). Also, the levels of HMGB-1 since the day of transplantation were significantly associated with risk of VOD after analyzing the whole dynamics of HMGB-1 level. E-selectin, PAI-1, VCAM-1, PDMP, and HMGB-1 were found to be closely relevant to one another by the principal component analysis (principal component loading=0.797, 0.876, 0.675, 0.780, and 0.691, respectively).Conclusion:The present findings suggested that rTM had the possibility to play a therapeutic role for aGVHD and VOD. HMGB-1 worked as an inflammatory cytokine, which exhibited peak level on the day of transplantation influenced by toxicity of conditioning regimen. VOD develop in relatively early days up to 20 days after alloHSCT, the elevation of HMGB-1 levels since day 0 after transplantation could be an early predictive biomarker for it. Once condition regimens are initiated, HMGB-1 is released from the injured cells including endothelial cells. HMGB-1 induces to release inflammatory cytokines and express adhesion molecules as well as tissue factor on endothelium (Yang H. Proc Natl Acad Sci USA. 2010;107:11942). These reactions facilitate pro-coagulant state resulting in VOD. We concluded that HMGB-1 was a major factor for VOD and rTM was effective to treat VOD attributable to suppression on HMGB-1. DisclosuresIshida:Bristol-Myers Squibb: Honoraria.

KIR2DS4 and Its Variant KIR1D Are Associated with Acute Graft-versus-Host Disease, Cytomegalovirus, and Overall Survival after Sibling-Related HLA-Matched Transplantation in Patients with Donors with KIR Gene Haplotype A.

Outcomes for hematopoietic stem cell transplantation (HSCT) in various donor and recipient killer immunoglobulin-like receptor (KIR) genotypes have been studied extensively. The associations between KIR2DS4 and its variant KIR1D with outcomes of HSCT from a sibling-related HLA-matched donor with KIR haplotype A have not been explored, however. To study this, we genotyped donor-recipient pairs and divided 165 recipients of HSCT from a KIR gene haplotype A donor into 3 groups: 2DS4+/2DS4+ (2 intact KIR2DS4 alleles), 2DS4+/1D+ (heterozygous), and 1D+/1D+ (homozygous for the deletion variant KIR1D). No difference in the recovery of neutrophils and platelets among the 3 groups was observed. The cumulative incidence of grade III-IV acute graft-versus-host disease (aGVHD) within day+100 was 28.94% in the 2DS4+/2DS4+ group, 14.11% in the 2DS4+/1D+ group, and 44.44% in the 1D+/1D+ group (P= .0159). Multivariate analysis identified 1D+/1D+ as an independent risk factor for aGVHD (hazard ratio [HR], 4.221; 95% confidence interval [CI], 1.470 to 12.124; P= .007). In contrast, the cumulative incidences of chronic GVHD, 3-year cumulative relapse, and treatment-related mortality did not differ significantly among the 3 groups. The rate of cytomegalovirus (CMV) reactivation was 46.96% in the 2DS4+/2DS4+ group, 20.16% in the 2DS4+/1D+ group, and 53.25% in the 1D+/1D+ group (P= .0017). Multivariate analysis identified 2DS4+/1D+ as an independent protective factor for CMV reactivation (HR, 0.268; 95% CI, 0.125 to 0.574; P= .001). Although overall survival (OS) did not differ among the groups in the first year, the 2DS4(+)/2DS4(+) group had significantly better OS than the other groups after 1 year (P= .0361). In patients with advanced-stage disease, the 3-year probability of disease-free survival was 51.06% in the 2DS4+/2DS4+ group, 34.01% in the 2DS4+/1D+ group, and 0% in the 1D+/1D+ group (P= .0314). Collectively, our data suggest that the KIR 2DS4/1D allelic variance is associated with the outcome of sibling-related HLA-matched HSCT, and that donor subclassification of KIR 2DS4/1D alleles should be considered in this setting.