Genome Wide Single Nucleotide Polymorphism Typing for Identification of Putative Minor Histocompatibility Antigens in Graft Versus Host Disease.

Abstract Previous studies have demonstrated that disparity across minor histocompatibility antigens (mHA) can cause graft versus host disease (GVHD) in patients who receive hematopoietic stem cell grafts from HLA-identical donors. mHA are peptide epitopes derived from normal cellular proteins presented by self MHC. Most autosomal mHA are generated as a result of non-synonymous coding single nucleotide polymorphisms (cSNPs), which lead to differences in the amino acid sequences of homologous proteins between donor and recipient cells. Although it is estimated that several hundred mHA exist in humans, only 16 have been definitively characterized to date. Using the Affymetrix 20K cSNP array we performed SNP typing on 97, HLA-A2+ hematopoietic stem cell transplant (HSCT) recipients and their sibling donors. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMC) obtained from patients and their donors. All patients were in remission at the time of sampling, all had undergone HSCT at the Dana-Farber Cancer Institute between 1998 and 2005 and all samples were drawn prior to transplantation. The transplants included myeloablative and non-myeloablative conditioning regimens, T cell depleted and non-T cell depleted grafts and sex matched and sex mis-matched donors. Using dChip software, we evaluated each of the 20,000 non-synonymous cSNPs on the array for mismatch between sibling pairs and for an association between mismatch in the GVHD direction and the development of acute or chronic GVHD. Mismatch in the GVHD direction was defined as a homozygous donor (AA or BB) and a heterozygote recipient (AB) or a homozygous donor (AA or BB) and a homozygously mismatched recipient (BB or AA). We ranked the cSNPs on the array in order of the strength of the association between mismatch in the GVHD direction and the development of either acute or chronic GVHD. There was no overlap between the 40 mismatched cSNPs most strongly associated with acute GVHD and the 40 most tightly associated with chronic GVHD. Mismatch at the SNP rs12407003 in the OMA1 gene was most highly associated with acute GVHD with mismatch in the GVHD direction occurring in 13 of 41 pairs with acute GVHD and 2 of 56 without (p=0.0003 by Fisher’s Exact Test). OMA1 encodes a mitochondrial membrane-bound metallopeptidase. 65 sibling pairs were assessable for chronic GVHD. Mismatch at the SNP rs2740349 in the GEMIN4 gene was most strongly associated with chronic GVHD with mismatch in the GVHD direction occurring in 10 of 26 pairs with chronic GVHD and 1 of 39 without (p=0.0002). GEMIN4 is part of a cytoplasmic multiprotein complex. This study demonstrates a novel, genome-wide method of identifying putative mHA using a cSNP array. It reveals that mismatch of non-synonymous cSNPs in the GVHD direction occurs at an appreciable frequency in sibling pairs consistent with the hypothesis that the number of mHA in humans is large. Interestingly, the pattern of mismatch differs between acute and chronic GVHD. The study also identifies individual non-synonymous cSNPs for which mismatch in the GVHD direction is highly associated with the development of GVHD. Further evaluation of these cSNPs in larger independent cohorts will be undertaken to validate this association and targeted immunologic analysis of peptides derived from these cSNPs will examine their role as putative mHA.

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Acute and chronic graft versus host disease after hematopoietic stem cell transplant

JBMTCT ◽

10.46765/2675-374x.2020v1n1p53-66 ◽

2020 ◽

Vol 1 (1) ◽

pp. 53-66

Author(s):

Vaneuza A. M. Funke ◽

Maria Claudia Rodrigues Moreira ◽

Afonso Celso Vigorito

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Transplant ◽

Primary Therapy ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

Graft versus host disease is one of the main complications of Hematopoietic stem cell, involving about 50% to 80% of the patients. Acute GVHD clinical manifestations and therapy is discussed, as well as new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both refractory chronic and acute GVHD is an important field of discussion once there is no superiority for the majority of the agents after primary therapy has failed. Hence, this review is meant to be a useful tool of consultation for clinicians who are dealing with this complex complication.

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Beyond HLA: Impact of Immunoreactive Mismatches of Minor Histocompatibility Antigens on Probability of Relapse and Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation from HLA-Matched Unrelated Donors.

Blood ◽

10.1182/blood.v108.11.3156.3156 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3156-3156

Author(s):

Miroslaw Markiewicz ◽

Urszula Siekiera ◽

Jerzy Wojnar ◽

Agata Wieczorkiewicz ◽

Iwona Wylezol ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Standard Operating Procedure ◽

Host Responses ◽

Histocompatibility Antigens ◽

Hematopoietic Stem ◽

Minor Histocompatibility Antigens ◽

Graft Versus Host ◽

Probability Of Survival ◽

Unrelated Donors

Abstract Factors contributing to relapses and GVHD following allogeneic Hematopoietic Stem Cell Transplantations (HSCT) from HLA-matched unrelated donors are not well established. We analyzed 35 patients (pts) transplanted from HLA 10/10 alleles (A, B, C, DRB1, DQB1) matched unrelated donors (URD) in the Dept. of Hematology and BMT, Katowice, Poland, with use of the same standard operating procedure from January 2004 until March 2006. Indication for HSCT was AML (13 pts), ALL (8), CML (7), MDS (2), PNH (3), CLL (1), myeloid sarcoma (1). Preparative regimen was Treosulfan+Fludarabine (23 pts), TBI+Cy (9) and Bu+Cy (3). Alleles encoding 11 minor Histocompatibility Antigens (mHA: HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, HwA-9, HwA-10, UGT2B17, HY) were analyzed for each donor-recipient pair with use of Dynal AllSet mHA typing kit and PCR-SSP method. Only immunogenic mHA mismatches were analyzed. Information on whether mHA mismatches might result in Host-versus-Graft or Graft-versus-Host responses was established with use of the minor Histocompatibility Knowledge Database of Leiden University Medical Center’s minor Histocompatibility Workshop. Patients transplanted from donors with mHA mismatched in HVG direction had significantly higher probability of relapse (64+/− 8% versus 10+/− 9%, p=0.003) when compared to pairs without mHA HVG immonogenicity. Patients transplanted from donors with mHA mismatched in GVH direction had higher probability of aGVHD (88+/− 8% versus 53+/− 11%, p=0.14) and cGVHD (41+/− 16% versus 37+/− 17%, p=0.65) when compared to pairs without GVH immunogenicity. GVHD was also observed more often on day +100 (33% versus 6%, p=0.06) when mHA mismatch in GVH direction was present. Observed influence of HVG and GVH immonogenicity on probability of relapse and GVHD did not lead to significantly different survival in observed groups of pts. These results indicate that mHA immunogenic mismatches in HVG and GVH direction may be responsible for relapse and GVHD, respectively, in HSCT recipients from HLA-matched unrelated donors. The study is being continued to confirm these primary observations and to establish the associations of specific mHA mismatches with HSCT outcomes. Impact of mHA mismatch on probability of relapse and GVHD Immunogenicity of mHA mismatches HVG no HVG p # of patients 18 17 Relapse at 1 year 64%+/−8 10%+/−9 0.003 Immunogenicity of mHA mismatches GVH no GVH p # of patients 16 19 aGVHD 88%+/− 8 53%+/−11 0.14 cGVHD at 1 year 41%+/−16 37%+/−17 0.65 Impact of mHA mismatch on probability of survival Immunogenicity of mHA mismatches HVG GVH only HVG only GVH no HVG no GVH p # of patients 9 9 7 10 Survival at 9 months 63%+/−17 57%+/−25 83%+/−15 69%+/−15 0.86

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The Effect of Costimulatory Moleculars on Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.4875.4875 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4875-4875

Author(s):

Zhenhua Qiao ◽

Fang Ye ◽

Lei Zu

Keyword(s):

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

Group A ◽

Group B

Abstract Objective: To explore the effect of costimulatory molecular and CD25 expressed on peripheral CD4+ T lymphocytes on graft-versus-host disease(GVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Methods: 1. The 21 patients who suffered of hematology diseases or malignant solid tumors and were underwent allo-HSCT and 10 normal individuals were enrolled in the study.2. For the sake of difference conditioning regimens we divided the 21 patients into two groups: patients undergoing non-myeloablative stem cell transplantation(NST) belonged to group A, others undergoing traditional myeloablative stem cell transplantation belonged to group B; we divided them into five groups for with GVHD or without GVHD and types of GVHD: group 1(group A with acute GVHD), group 2(group A with chronic GVHD), group 3(group B with acute GVHD), group 4(group B without GVHD), group 5(group A without GVHD).3. The levels of CD28, CD80, CD152 and CD25 expressions on peripheral CD4+ T lymphocytes were detected by three colors flow cytometry (FCM)in different time(before allo-HSCT,7days,14days,21days,30days after allo-HSCT, the time of GVHD and the time after GVHD treated).4.STR-PCR for detecting micro-satellites chimeras forming. Results: 1. All 21 patients achieved engraftment. By STR-PCR assay,12 cases formed complete chimeras(CC) and 9 cases formed mixed chimeras(MC). In group A,3 cases developed acute GVHD and 4 cases developed chronic GVHD; in group B,4 cases developed aGVHD. The incidence of GVHD and infection rates between group A and B has no difference(X2=3.711, P=0.144).2. Among these 21 cases,5 cases died:2 cases died of multiple organs function failure due to primary disease relapse,1 case died of bleeding in brain and 2 cases died of liver function failure for the sake of complicated with acute GVHD; others survive with disease free till present.3. The results of multivariate logistic regression models and Kaplan-Meier survival curves analyses showed: age, sex, infection, HLA-type, blood type, conditioning regiment and the times of absolute neutrophil counts and platelets recovering to normal, had no association with the incidence of GVHD;A multivariate COX survival function model analysis showed CD4CD152 and CD4CD25 are independent prognostic factors for GVHD(X2=13.128, P<0.0001).4. Patients with GVHD demonstrated higher CD4+CD28+ and CD4+CD80+ T cell levels than those without GVHD(P<0.01);patients with aGVHD demonstrated higher than those with cGVHD(P<0.05) and without GVHD(P<0.05); Patients with GVHD demonstrated lower CD4+CD152+ and CD4+CD25+ T cell levels than those without GVHD(P<0.01); the same result occurs between aGVHD and cGVHD and without GVHD. After effective treatment, unnormal CD4+CD28+, CD4+CD80+, CD4+CD152+ and CD4+CD25+ T cell levels recovered to the levels before transplantation. Conclusions: The incidences of GVHD between NST and traditional myeloablative stem cell transplantation had no difference. B7-CD28/CD152 costimulatory pathway plays a critical role in developing of GVHD. Peripheral CD4+CD28+, CD4+CD80+, CD4+CD152+ and CD4+CD25+ T cell levels were relative to recipient GVHD, especially CD4+CD152+ and CD4+CD25+ T cell levels. Down-grade CD4+CD28+ and CD4+CD80+ T cell levels and up-grade CD4+CD152+ and CD4+CD25+T cell levels could reduce the incidence of GVHD.

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Graft-Versus-Host Disease Following Myeloablative Busulfan Plus Fludarabine and Busulfan Plus Cyclophosphamide For Allogeneic Hematopoietic Stem Cell Transplantation In Acute Myeloid Leukemia In First Complete Remission

Blood ◽

10.1182/blood.v122.21.3290.3290 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3290-3290

Author(s):

Qifa Liu ◽

Hui Liu ◽

Daihong Liu ◽

Yongrong Lai ◽

Jing Sun ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

Tnf Α ◽

Before And After ◽

First Complete Remission

Abstract Background Results from single institutions had shown that compared with busulfan plus cyclophosphamide (BuCy) conditioning, limiting tissue damage by myeloablative busulfan plus fludarabine (BuFlu) conditioning might decrease cytokines release, leading a lower incidence of the graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In our prospective, multicenter and parallel-group study, further comparison was made of the incidences and severities of GVHD following BuCy and BuFlu myeloablative conditioning regimens in patients undergoing allo-HSCT for AML in first complete remission (CR1), and analyzed plasma cytokines before and after the conditioning. Methods A total of 148 patients with AML-CR1 undergoing allo-HSCT were enrolled into BuCy (busulfan1.6mg/kg, iv q12 hours, -7 ∼ -4d; cyclophosphamide 60 mg/kg.d, -3 ∼ -2d) or BuFlu (busulfan 1.6 mg/kg, iv q12 hours, -5 ∼ -2d; fludarabine 30 mg/m2.d, -6 ∼ -2d) group between January 2007 and January 2013. For patients enrolled between January 2012 and January 2013, plasma concentrations of IL-6, IL-1β, TNF-α, CXCL-10 and IL-17A before and after conditioning were measured by Enzyme-linked immunosorbent assay (ELISA) and compared between the two groups. Regimen-related toxicity (RRT), incidences and severities of acute and chronic GVHD, and overall survival were compared between the two groups. Results Of the 148 patients enrolled in the study, the data of 142 cases were used to determine the endpoints in the intent-to-treat population (72 in BuFlu group and 76 in BuCy group). The levels of TNF-α and IL-6 were significantly higher after the conditioning (5.60±4.40 vs 8.94±5.50 and 2.19±1.24 vs 6.06±12.16 pg/ml, P <0.001 and P =0.045 ), however, there were no significant differences on these cytokines between the two groups. The levels of CXCL-10 in BuCy group was significantly higher than that in BuFlu group (P =0.012). The incidence of I-II° and III-IV° acute GVHD were 42.1% and 6.8%, and 36.1% and 5.7%, respectively, in BuCy and BuFlu group (P=0.363 and P=0.770, respectively). Chronic GVHD occurred in 29 of 69 (41.7%) and 30 of 72 (41.7%) patients, respectively, in BuCy and BuFlu group (P= 1.000). And the incidence of extensive chronic GVHD were 14.3% and 16.7%, respectively, in BuCy and BuFlu group (P= 0.670). The median follow up duration was 824 (range, 3–2345) days. The 5 year overall survival were 79.2 ± 4.4% and 78.6 ± 76.1% (P= 0.555), respectively in BuCy and BuFlu group Conclusion In this report, the incidences and severities of acute GVHD as well as chronic GVHD were similar between BuFlu and BuCy regimen in AML-CR1 patients undergoing allo-HSCT. Disclosures: Liu: National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding; It was supported by 863 Program (No. 2011AA020105), National Public Health Grand Research Foundation (Grant No. 201202017): Research Funding.

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Evaluation of Graft Versus Host Disease and Relapse Free Survival As Novel Endpoint in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Joint Naples-Paris Study

Blood ◽

10.1182/blood.v128.22.2285.2285 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2285-2285

Author(s):

Simona Pagliuca ◽

Antonio M Risitano ◽

Sylvie Chevret ◽

Flore Sicre de Fontbrune ◽

Alienor Xhaard ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Graft Versus Host

Abstract The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Classical endpoints such as overall survival (OS), desease free survival (DFS) and non relapse-mortality (NRM) had become more and more unsuitable for transplant research because of their inability to a dynamic mesure of transplant-associated comorbidity. For this reason several composite endpoints taking into account also GVHD-associated comorbidity were proposed in the last years. GVHD free/relapse free survival (GRFS), proposed by Holtan et al (Blood 2015), includes grades 3-4 acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse , or death for any cause considered as events. This endpoint seems to completely characterize the survival without mortality or ongoing morbidity. With the intent to analyse the outcomes of our transplanted cohort, we retrospectively analysed GRFS of 959 consecutive patients receiving HSCT at Federico II University in Naples (n=119) and Saint-Louis Hospital (n=840) in Paris between 2007 and 2014, identifying prognostic factors associated with a better outcome and estimating the incidences of all components of this endpoint: rates of acute and chronic GVHD, disease relapse and death. Patient, disease and transplant characteristics are listed in table 1. Median duration of follow-up after HSCT was 22.1 months (IQR: 5.6-51 months). Cumulative incidence at day 100 of grade II-IV acute GVHD and grade III-IV were 42% and 16%, respectively. Cumulative incidence of chronic GVHD requiring systemic treatment at 1 and 5 years was 23% and 33%, respectively, diagnosed according to NIH criteria [14% of patients had score 1 (mild), 58% score 2 (moderate) and 27% score 3 (severe)cGVHD]. Cumulative incidence of relapse (considering all malignant and non-malignant diseases) was 26.7% (N=219) at 5 years. Overall survival for the whole population was 57% (95%CI, 53.3-60.8) at 5 years and Disease free survival (DFS) and non-relapse mortality (NRM) were respectively 50% (95%CI, 46.6-53.8) and 23% at 5 years. GRFS was 25% (95%CI, 21.8-28.5) at 5 years. Factors identified as influencing GRFS based on univariate analyses were age higher than 45 years (HR=1.64, 95%CI, 1.40-1.92), bone marrow (BM) as stem cell source (HR=0.40, 95%CI, 0.32-0.50); reduced intensity conditioning (RIC) (HR=0.63, 95%CI, 0.53-0.74); disease type [non-malignant disorders: HR=0.24, 95%CI, 0.17-0.33; myelodysplastic and myeloproliferative syndromes (MPN/CML/MDS): HR=1.34, 95%CI, 1.10-1.63; whereas other diagnosis did not influence GRFS] and than unrelated donor (matched: HR=1.71, 95%CI, 1.41-2.07;mismatch:HR=1.81, 95%CI, 1.48-2.23). Based on a multivariable Cox model, only diagnoses (non-malignancies, HR=0.27, 95%CI, 0.19-0.38 and MPN/CML/MDS, HR= 1.35, 95%CI, 1.11-1.65), and HLA unrelated graft (matched, HR=1.42, 95%CI, 1.17-1.73 and mismatched, HR=1.55, 95%CI, 1.26-1.92) remained associated with the outcome (Figure 1 and 2). GRFS could represent the ideal endpoint following HSCT. It differs significantly based upon type of disease and donor type, essentially. This composite indicator yields more information regarding complications of HSCT than the simpler measurement of OS or DFS. Its use willbetter compare these clinically important outcomes that accompany disparate HSCT techniques. All examined prognostic factors could enhance our ability to optimally judge the risk and the probability of true recovery after allogeneic HSCT. Our data support the use of this composite endpoint to describe HSCT outcome, and also pave the way for the investigation of novel endpoints, which may also track the dynamic changes of post-transplant events in the long-term. These retrospective data represent the background to investigate the impact of novel strategies of HSCT aiming to improve the outcome of HSCT, as detectable, by using more sensitive endpoints, tracking clinical events associated with detrimental long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Novartis: Research Funding; Alnylam: Research Funding; Rapharma: Research Funding. Peffault de Latour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

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Does Donor Epstein-Barr Virus (EBV) Seropositivity Affect Recipient's Risk of Graft Versus Host Disease (GVHD) in Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT)?

Blood ◽

10.1182/blood.v128.22.5766.5766 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5766-5766

Author(s):

Erden Atilla ◽

Esmanur Kaplan ◽

Pinar Ataca Atilla ◽

Selami Kocak Toprak ◽

Pervin Topcuoglu ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Graft Versus Host Disease ◽

Peripheral Blood ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

Abstract Introduction: EBV seropositivity in general population is 80%. Reactivation of latent infection in pre-transplant seropositive patients causes post-transplant lenfoproliferative disease (PTLD) following Allo-HSCT. The effect of donor EBV positivity on recipient's risk of graft versus host disease is not clear. Our aim is to present EBV seroprevalence and PTLD incidence as well as demonstrating the relation of EBV seropositivity with GVHD. Patients and Methods: A total of 364 allogeneic stem cell transplant recipients and donors were evaluated retrospectively from 2006 to 2015. During Allo-HSCT preparation procedures all recipients and donors were serologically tested. EBV specific IgG (VCA-IgG, EBNAIgG, EA-IgG) and IgM (VCA-IgM) antibodies were determined by Chemiluminescence by ARCHITECT lab analyzers using commercially available kits (Abbott, USA). All patients were followed for reactivation. Results: EBV IgG positivity was detected in 338 of recipients (92.8%) and 283 of donors (77.7%). There was no statistically difference detected between related or unrelated transplants. The mean age was 37 (range 16-67). 217 recipients were male (60%). 295 (81%) patients were transplanted for malign hematological diseases. The majority of patients were grafted from full-matched related donors (258, 71%). The most common source of stem cell was peripheral blood in 299 patients (82%) followed by bone-marrow in 56 patients (15%), bone-marrow plus peripheral blood in 9 patients (3%). 273 (75%) patients received myeloablative conditioning regimen. All patients received prophylactic acyclovir (in related transplants 400mg 3 times daily, in un-related transplants 800mg 3 times daily) starting from conditioning and up to three months posttranplant period. One pretransplant seropositive 26 year-old aplastic anemia patient had PTLD with EBV IgM positivity within 3 months posttransplant. He received 4 cycles of rituximab and prednisolone and achieved complete response. Three patients had EBV IgM positivity in posttransplant 4, 9 and 24th months with symptoms of infectious mononucleosis. The seropositivity resolved without treatment. Acute GVHD developed in 223 patients (61%) whereas chronic GVHD was detected in 285 (78%) of patients. The incidence of acute GVHD was similar when donor was EBV seropositive compared to seronegative (78% vs 22%, p=0.72). Chronic GVHD incidence was similar between donor EBV seropositive group compared to seronegative group (80% vs 20%, P=0.199). Conclusion: EBV seropositivity is common detected in 92.8% of our allo-HSCT recipient cohort. Donor EBV status did not have an effect on developing acute or chronic GVHD. Disclosures No relevant conflicts of interest to declare.

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Genome-wide surveillance of mismatched alleles for graft-versus-host disease in stem cell transplantation

Blood ◽

10.1182/blood-2015-03-630707 ◽

2015 ◽

Vol 126 (25) ◽

pp. 2752-2763 ◽

Cited By ~ 20

Author(s):

Aiko Sato-Otsubo ◽

Yasuhito Nannya ◽

Koichi Kashiwase ◽

Makoto Onizuka ◽

Fumihiro Azuma ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Histocompatibility Antigens ◽

Minor Histocompatibility Antigens ◽

Graft Versus Host ◽

Genome Wide ◽

Key Points ◽

Candidate Loci

Key Points GWAS can identify allele mismatch associated with aGVHD development. Three novel candidate loci for minor histocompatibility antigens significantly associate with aGVHD.

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Anaerobic Antibiotics and the Risk of Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-125080 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1992-1992

Author(s):

John Tanaka ◽

Rebecca Young ◽

Lisa Spees ◽

Kirsten Jenkins ◽

Anthony D. Sung ◽

...

Keyword(s):

Stem Cell ◽

Febrile Neutropenia ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Research Support ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Graft Versus Host ◽

Grade Ii

Background: The gut microbiota interacts extensively with the host immune system and thus may modify the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). During the post-transplant neutropenic period, the majority of allogeneic HSCT recipients receive empirical broad-spectrum antibiotics for febrile neutropenia. We hypothesized that receipt of an antibiotic regimen with an anaerobic spectrum of activity is associated with a higher risk of grade II-IV acute GVHD than receipt of a non-anaerobic antibiotic regimens. Methods: In this single-center retrospective cohort study, we evaluated associations between peri-transplant receipt of antibiotics with an anaerobic spectrum of activity and the risk and severity of GVHD among 877 adults who received an allogeneic HSCT between January 1, 2005 and December 31, 2016. We identified 609 patients who developed febrile neutropenia after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n=333) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, ceftazidime, or cefepime; n=276). Antibiotics received by patients between 7 days before and 28 days after allogeneic HSCT and GVHD diagnoses were verified via manual review of medication orders and provider notes in electronic medical records. Results: Receipt of anaerobic antibiotics was associated with an increased risks of grade II-IV acute GVHD (hazard ratio (HR): 1.41; 95% confidence interval (CI): 1.10-1.79; P=0.01) and acute GVHD mortality (HR: 1.87; 95% CI: 1.13, 3.11; P=0.02). This hazard was primarily associated with acute GVHD of the gut or liver (HR: 1.38; 95% CI: 1.06, 1.79; P=0.02). The association remained with even short (<7 days) courses of anaerobic antibiotics. Anaerobic antibiotic exposure was not associated with acute skin GVHD (HR: 0.97; 95% CI: 0.69, 1.37; P=0.88), chronic GVHD diagnosis (HR: 0.93; 95% CI: 0.70, 1.23; P=0.43), or chronic GVHD mortality (HR: 0.89; 95% CI: 0.44, 1.81; P=0.76). Conclusions: Receipt of anaerobic antibiotics for febrile neutropenia post-HSCT is associated with an increased risks of acute GVHD of the gut or liver and acute GVHD mortality. Limiting use of antibiotics with an anaerobic spectrum of activity after allogeneic HSCT may reduce acute GVHD incidence and mortality. Disclosures Sung: Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding. Martin:Novartis Pharmaceuticals: Other: research support; Jazz Pharmaceuticals: Other: research support.

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Role of Il-17 Varies at Different Periods After Hematopoietic Stem Cell Transplantation: Protection From Acute Graft-Versus-Host Disease and Exacerbation of Chronic Graft-Versus-Host Disease.

Blood ◽

10.1182/blood.v116.21.3741.3741 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3741-3741 ◽

Cited By ~ 1

Author(s):

Rie Kuroda ◽

Ryosei Nishimura ◽

Katsuaki Sato ◽

Hideaki Maeba ◽

Kazuhito Naka ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Immune Cells ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Graft Versus Host

Abstract Abstract 3741 Th17 is a newly identified T cell lineage that secretes the proinflammatory cytokine IL-17. Th17 cells have been shown to play a crucial role in mediating autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), arthritis, and colitis. Anti-IL-17 therapy for some autoimmune diseases in clinical settings has been started and promising results have been reported. However the role of IL-17 on developing acute and chronic GVHD in hematopoietic stem cell transplantation (HSCT) is not yet fully understood. Interaction between IL-17 and IL-17 receptor is complicated because IL-17 is produced in various kinds of immune cells other than CD4+ T-cells, and IL-17 receptors express on not only immune cells but also various epithelial cells, including lung and intestine, both of which are target organs of GVHD. To explore the role of host derived or donor derived IL-17 separately in acute GVHD, lethally irradiated wild type (WT) or IL-17 knockout (KO) Balb/c (H-2d) were given WT or IL-17 KO C57BL/6 (H-2b) bone marrow (BM) cells with WT splenocytes to induce acute GVHD. Infused cell number of WT splenocytes in this study induced acute GVHD, but not lethal in IL-17 WT host mice. In contrast, IL-17 KO host mice receiving WT BM plus WT splenocytes developed severe acute gut GVHD and finally half of them died (p<0.05). To exclude the possibility that alloreactivity of host IL-17 KO derived dentritic cells (DCs) could be much more than that of WT DCs, mixed leukocyte reaction (MLR) was performed using stimulators from WT or IL-17 KO DCs and responders from WT CD4+ T-cells. No significant differences were observed between WT DCs and IL-17 KO DCs in thymidine uptake and percentage of responder cells producing IFN-g or TNF-a. Taken together, host-derived IL-17 has a protective effect against acute GVHD. Moreover similar results were observed when IL-17 KO Balb/c mice were given BM cells from another strain B10.D2 plus splenocytes shown in the figure below (p<0.05). Next, we compared the development of chronic GVHD between the lethally irradiated WT Balb/c mice given IL-17 KO C57BL/6 BM cells or WT BM cells with low dose WT splenocytes to induce sublethal acute GVHD and chronic GVHD subsequently. After day 60 the mice receiving WT BM cells plus WT splenocytes experienced weight loss accompanied by skin histological changes (p<0.05, shown in the figure below), while mice receiving IL-17 KO BM plus WT splenocytes showed minimal signs of GVHD as well as mice receiving IL-17 KO BM or WT BM alone. Increased number of donor-BM derived IL-17 producing cells was observed in the mice showing chronic GVHD compared to BM control (p<0.05). Moreover, a significant increase of T-cell proliferation was observed by adding rIL-17 into MLR culture (p<0.05). These results suggest that donor BM derived IL-17 producing cells involved in the pathogenesis of chronic GVHD by exacerbating the alloimmune response in part. In conclusion IL-17, especially from host-derived, has a protective effect against acute GVHD. On the contrary, donor BM derived IL-17 exacerbates chronic GVHD. Neutralizing IL-17 would be a potent strategy only for preventing chronic GVHD, not for acute GVHD. Disclosures: No relevant conflicts of interest to declare.

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Alpha/Beta T-Cell and B-Cell Depletion HLA-Haploidentical Hematopoietic Stem Cell Transplantation Is an Effective Treatment for Children/Young Adults with Acute Leukemia

Blood ◽

10.1182/blood-2018-99-117136 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2169-2169

Author(s):

Pietro Merli ◽

Mattia Algeri ◽

Giuseppina Li Pira ◽

Michela Falco ◽

Daniela Pende ◽

...

Keyword(s):

Young Adults ◽

Stem Cell ◽

Board Of Directors ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

Preparative Regimen

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children/young adults with acute leukemia (AL) either relapsed or at high-risk of treatment failure and in urgent need of an allograft. A novel method of graft manipulation based on the selective, negative depletion of αβ T and B cells has been recently developed. We published the results of a prospective trial (ClinicalTrial.gov identifier: NCT01810120) enrolling 80 children with AL transplanted until September/2014 using this approach (Locatelli, Blood 2017). In the present analysis, we update those results, evaluating also additional patients given haplo-HSCT after that date. Patients and methods: Analyzed are 111 children with AL enrolled in the trial; median age is 10 years (range 0.9-22.2). Eighty-two (74%) and 29 (26%) patients had acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), respectively; they were transplanted between 09/2011 and 05/2018. All children were transplanted in complete morphological remission and received a fully myeloablative preparative regimen. Details on patients' characteristics, as well as on the number of HSC and lymphocyte subsets infused, are shown in Table 1. The donor was mainly chosen according to immunological criteria, giving priority to NK-cell alloreactivity, evaluated according to the killer immunoglobulin-like receptor (KIR)/KIR-Ligand mismatch in graft-versus-host direction model, KIR B haplotype, higher B-content score and size of NK alloreactive subset. Anti-T lymphocyte globulin (ATLG Grafalon®, Neovii Biotech) was administered at a dose of 12 mg/Kg from day -5 to -3 for preventing graft rejection and graft-versus-host disease (GvHD). Moreover, to reduce the risk of EBV-related post-transplant lymphoproliferative disorder (PTLD), on day -1, patients received rituximab (200 mg/m2) for in vivo depletion of both donor and recipient B cells. No patient was given any post-transplantation pharmacological GvHD prophylaxis. Results: Median follow-up of surviving patients is 47 months (range: 2 months - 7.7 years). All patients but two successfully engrafted and the median time to neutrophil and platelet recovery was 13 (range 9-22) and 11 (range 8-20) days, respectively. Acute GvHD occurred in 28 patients; it was of grade I and grade II severity in 9 and 19 patients, respectively. Skin was the sole organ involved in all patients but one, who had gut involvement. The cumulative incidence of grade I-II acute GvHD was 25% (95% confidence interval, CI, 17-33). Four out of the 91 patients at risk developed chronic GvHD, in all cases of limited severity, the cumulative incidence of this complication being 5% (95% CI, 1-9). Six patients died for transplant-related complications, this resulting into a 5-year cumulative incidence of transplant-related mortality (TRM) of 6% (95% CI, 2-11). Twenty-three patients relapsed at a median time of 186 days (range 60-1012) after transplantation, the 5-year cumulative incidence of relapse being 24% (95% CI, 16-33). The 5-year probability of overall and leukemia free survival (LFS) were both above 70%, as shown in Figure 1A and 1B, respectively. The 5-year probability of LFS in children with ALL and AML was 69% (95% CI, 57-79) and 73% (95% CI, 52-86), respectively (Figure 1C). Use of total body irradiation (TBI) during the preparative regimen was associated with better patient's outcome (Figure 1D), since it protected against the risk of leukemia recurrence [18% (95% CI, 10-28) vs. 45% (95% CI, 22-66) in patients who did or did not receive TBI, respectively, p<0.01]. The correlation between use of TBI and better outcome remained significant in multivariable analysis, with a hazard ratio of 0.35 (95% CI, 0.16- 0.78, p=0.01) for LFS. The median CD3+ cell count on day +90, +180 and +360 were 247, 659 and 1380/mcl, respectively. Conclusions: This study, reporting long-term outcome of a large population of children/young adults with AL, confirms that αβ T- and B-cell depleted haplo-HSCT is an effective option for patients in need of an urgent allograft and lacking an HLA-identical donor. While TRM is impressively low, the main cause of treatment failure is leukemia recurrence, whose incidence can be lowered by the use of TBI during the conditioning regimen. The remarkably low risk of chronic GvHD renders the approach attractive also in terms of patient's quality of life. Figure 1 Figure 1. Disclosures Locatelli: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

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