scholarly journals Cytomegalovirus Antigenic Mimicry of Human Alloreactive Peptides: A Potential Trigger for Graft versus Host Disease

2016 ◽  
Author(s):  
Charles Hall ◽  
Vishal Koparde ◽  
Max Jameson-Lee ◽  
Abdelrhman Elnasseh ◽  
Allison Scalora ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Hla Class I ◽  
Cross Reactivity ◽  
Unrelated Donor ◽  
Nucleotide Polymorphisms ◽  
Host Disease ◽  
Graft Versus Host ◽  
Human Cmv ◽  
Antigenic Mimicry

AbstractThe association between human cytomegalovirus (hCMV) reactivation and the development of graft-versus-host-disease (GVHD) has been observed in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n=50; matched related donor (MRD), n=27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) Database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV-derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive (≥6) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500nM) cross reactivity. Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, 29,658.8 ± 9038.5 were found to match MRD DRP alloreactive peptides and 52,910.2 ± 16121.8 matched MUD DRP peptides (Student’s T-test, p<0.001).In silicoanalysis revealed multiple high affinity, immunogenic CMV-Human peptide matches (IC50<500 nM) expressed in GVHD-affected tissue-specific manner (proteins expressed at ≥10 RPKM). hCMV+GVHD was found in 18 patients, 13 developing hCMV viremia before GVHD onset with a subset analysis of 7 instances of hCMV viremia prior to acute GVHD onset (n=3), chronic GVHD (n=2) and acute + chronic GVHD (n=2) indicating cross reactive peptide expression within affected organs. We propose that based on our analysis and preliminary clinical correlations that hCMV immune cross-reactivity may cause antigenic mimicry of human alloreactive peptides triggering GVHD.

Graft Versus Host Disease Prophylaxis with Everolimus and Tacrolimus in Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML) Receiving Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2886-2886 ◽  
Author(s):  
Uwe Platzbecker ◽  
Caroline Pabst ◽  
Alexander Kiani ◽  
Johannes Schetelig ◽  
Martin Wermke ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Clinical Signs ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: The use of a calcineurin-inhibitor in combination with methotrexate is the current standard in the prophylaxis of graft versus host disease (GVHD). Everolimus is a newly developed m-TOR inhibitor, which, besides a potent immunosuppressive action including the stimulation of regulatory CD4+foxp3+ T-cells (Tregs), seems to mediate anti-neoplastic effects in MDS and AML. Methods: We report results of a prospective study investigating for the first time a combination of everolimus (days 0–56) with tacrolimus (starting day 0) in 16 patients with MDS (RCMD n=3, RAEB-1 n=3, RAEB-2 n=3, CMMOL-1 n=1, CMMOL-2 n=1, MDS/AML n=1) or de novo AML (n=4) undergoing allogeneic myeloablative conditioning (busulfan 16 mg/kg over 4 days, fludarabine 120 mg/m² over 4 days) followed by a median of 7.0 x 106/kg CD34+ peripheral blood stem cells (PBSC) from related (n=2) or unrelated donors (n=14). It is of note that 5 unrelated donor/recipient pairs displayed one allel-mismatch whereas all others were matched in 10 out 10 HLA characters. The median age of the patients was 61 years (range 47–69) and the majority (n=7) of MDS patients were classified INT-2 or HIGH according to IPSS. Results: All patients engrafted a median of 14 days (platelets) and 17 days (neutrophils) after transplant. On day 21 and 56 after PBSCT the median number of CD4+foxp3+ cells in the blood was not significantly different from normal donors (patients, n=5: 3.2 and 2.3 x 104/ul, controls n=4: 3.7 x 104/ul) Nevertheless, the rate of acute GVHD was moderate with five patients (31 %) developing acute GVHD grade II and only one patient experiencing grade IV GVHD after cessation of immunosuppression due to thrombotic-thrombocytopenic purpura (TTP). Decrease of thrombocytes together clinical signs of TTP were seen in two additional patients while four patients developed VOD of the liver, which was fatal in one case. Extensive chronic GVHD was seen in 50 % of evaluable patients. Mucositis CTC grade III was observed in 5 patients only. The total day 100 mortality rate was 19 % and currently eleven out of sixteen patients (69%) are alive and in remission. Conclusion: Everolimus and tacrolimus are highly efficient in preventing GVHD after unrelated PBSCT in older patients with MDS and AML, which seems not to be mediated by an increase in Tregs. Nevertheless, side effects associated with thrombotic microangiopathy might be more prevalent compared to other regimens.

Use of Peripheral Blood Grafts Is Associated with Increased Acute and Chronic Graft-Versus-Host Disease without Improved Survival after Unrelated Donor Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 443-443 ◽  
Author(s):  
Mary Eapen ◽  
Michael Haagenson ◽  
Brent Logan ◽  
Dennis Confer ◽  
Mary Horowitz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Treatment Failure ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Single Locus ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host

Abstract Data from the CIBMTR indicate that approximately 70% of unrelated donor hematopoietic stem cell transplants (HCT) in the U.S. utilize peripheral blood (PB) rather than bone marrow (BM) as a graft source. Comparative studies verifying its benefit, however, are lacking. We, therefore, performed a retrospective analysis comparing the results of 275 unrelated PB and 620 unrelated BM transplants in adults 18–60 years of age with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or chronic myeloid leukemia (CML), transplanted in 2000–2002. 73% of PB grafts were matched at HLA A, B, C (low resolution) and DRB1, 21% were mismatched at a single locus and 6% were mismatched at ≥ 2 loci. 69% of BM grafts were matched, 26% were mismatched at a single locus and 5% were mismatched at ≥ 2 loci. Median follow-up was 24 (range, 6–48) and 34 (range, 6–54) months for PB and BM recipients, respectively. Groups were similar except PB recipients were less likely to have CML, were more likely to have MDS and were transplanted more recently. Incidences of neutrophil recovery (95% vs. 90% at day 100, p=0.01) and platelets ≥20,000/ul (81% vs. 66%, at 1-year, p <0.0001) were significantly higher after PB than BM transplants. Incidences of grades 2–4 but not grades 3–4 acute graft-versus-host disease (GVHD) were significantly higher after PB than BM transplants (56% vs.45%, at day 100, p=0.003). Chronic GVHD was also significantly higher after PB transplants (54% vs. 39%, at 3 years, p<0.0001). Despite higher rates of grade 2–4 acute and chronic GVHD after PB transplantation, incidence of relapse was similar in the two groups for both early and advanced leukemia. In multivariate analysis, risks of treatment-related mortality (TRM), treatment failure (relapse or death) and overall mortality during the first 9 months after transplantation were similar. However, among patients surviving the first 9 months, subsequent risks of TRM (relative risk [RR] 1.90, 95% confidence interval [CI], 1.14–3.17, p=0.01) and treatment failure (RR 1.60, 95% CI 1.06–2.44, p=0.03) were significantly higher in the PB cohort. Three-year adjusted (from multivariate models) probabilities of leukemia-free survival were 29% and 31%, p=0.5, after PB and BM transplantation, respectively; corresponding probabilities of overall survival were 31% and 32%, p=0.8. While these data do not indicate a survival advantage with either stem cell source by disease or risk group, PB is associated with earlier engraftment. This advantage is offset by higher rates of grades 2–4 acute and chronic GVHD, leading to a higher risk of late adverse events. Randomized clinical trials are necessary to better define the relative risks and benefits of PB in the setting of unrelated donor HCT.

Prediction of Chronic Lung Graft-Versus-Host Disease By Angiopoietin-2

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1175-1175
Author(s):  
Katharina Schmidt ◽  
Mark-Alexander Schwarzbich ◽  
Nicola Lehners ◽  
Sivaramakrishna P. Rachakonda ◽  
Christine Falk ◽  
...  
Keyword(s):  
High Risk ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Snp Genotyping ◽  
Nucleotide Polymorphisms ◽  
Host Disease ◽  
Graft Versus Host ◽  
Angiopoietin 2

Abstract Background: Severe chronic graft versus host disease (cGVHD) of the lung is a rare but often fatal complication of allogeneic stem cell transplantation (SCT). In order to identify patients at high risk of lung cGVHD prior to transplant, the aim of the present study was to test systematically candidate biomarkers for this purpose, thereby focusing on endothelial risk factors previously shown to be associated with the risk of refractory acute GVHD. These factors included angiopoietin-2 (ANG2), serum nitrates and asymmetric dimethylarginine (ADMA), as well as single nucleotide polymorphisms (SNPs) in the thrombomodulin gene (THBD). Methods: Patients were eligible if they were allo-grafted between June 2002 and December 2011 at our institution, and if their blood samples were available for nitrate, ANG2 and ADMA measurement at different landmarks (collected immediately before conditioning and on day +100 after allogeneic SCT). Concentrations of ANG2, ADMA and serum nitrates were quantified in patients’ sera by the multiplex protein array technology (Luminex). THBD SNP genotyping was performed using KASPar SNP Genotyping System v2.0 of K Bioscience in 384-well format. Cumulative incidence analysis of cause-specific hazards was performed. The occurrence of cGVHD was evaluated retrospectively by chart review applying clinical and histological criteria developed by the National Institute of Health’s consensus project (Filipovich et al., 2005). Results: Of a total sample of 329 eligible patients, 14 (4%) fulfilled the criteria for lung cGVHD. 19 out of 329 patients (6%) developed severe gastrointestinal cGVHD and 15 out of 329 patients (4%) developed sclerodermatous cGVHD. Elevated pre-transplant levels of ANG2 (> 1000 pg/ml) correlated with the incidence of lung cGVHD (p=0.037). In contrast, there was no association between pre-transplant levels of ANG2 and severe gastrointestinal cGVHD (p=0.684) or sclerodermatous cGVHD (p=0.242). Similarly, high ANG2 levels (> 4000 pg/ml) on day +100 after allogeneic SCT predicted lung cGVHD (p=0.009). Again, this effect was specific for lung cGVHD, as there was no association between high ANG2 levels on day +100 and sclerodermatous cGVHD (p=0.300) or severe gastrointestinal cGVHD (p=0.702). There was no correlation between lung cGVHD and antecedent acute GVHD (p=0.796). Moreover, no significant correlations between serum nitrates, ADMA and thrombomodulin-(THBD)-SNPs and the risk of lung cGVHD or any other manifestation of severe cGVHD could be identified. Conclusion: In contrast to other endothelial markers, elevated pretransplant and d +100 post-transplant ANG2 levels may be predictors of a high risk of lung cGVHD but not of gastrointestinal or sclerodermatous cGVHD. These preliminary results warrant validation by further studies. Moreover, this data suggests a different role of the endothelial component in the pathogenesis of acute vs chronic GVHD. Disclosures No relevant conflicts of interest to declare.

Chronic Graft-Versus-Host Disease after Tacrolimus Versus Cyclosporine for Graft-Versus-Host Disease Prophylaxis in Pediatric Patients Undergoing Matched Unrelated Donor Hematopoietic Stem Cell Transplantation. A Pediatric Blood and Marrow Transplant Consortium Study..

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4984-4984
Author(s):  
Mark P. Atlas ◽  
Greg Yanik ◽  
Kirk R. Schultz ◽  
Rakesh K. Goyal
Keyword(s):  
Hematopoietic Stem Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Chronic graft versus host disease (GVHD) is a significant cause of morbidity and mortality in matched unrelated donor hematopoietic stem cell transplantation. Incidence of acute GVHD is a major risk factor for chronic GVHD. Calcineurin inhibitors form the backbone of graft versus host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation. When comparing cyclosporine to tacrolimus for GVHD prophylaxis, we previously reported a trend toward superiority of cyclosporine as prophylaxis against acute GVHD. We now analyze their effect on the incidence and severity of chronic GVHD. In a multi-institutional trial, we prospectively collected the clinical data on 141 evaluable patients receiving either cyclosporine/methotrexate or tacrolimus/methotrexate based prophylactic regimens for 6/6 matched unrelated donor, transplant. Conditioning regimens were fully ablative; no T-cell depletion was permitted; cord blood donors were excluded. Patients were required to receive either cyclosporine or tacrolimus, but the choice was per investigator preference. The two arms were reasonably balanced: 60.1% of patients received cyclosporine and 39.9% of patients received tacrolimus. Rates for acute GVHD were 60.4% for cyclosporine and 73.8% for tacrolimus (p = 0.086). Rates for chronic GVHD were 44.2% for cyclosporine and 47.3% for tacrolimus (p = 0.7). In the 61 patients with chronic GVHD, extensive disease was present in 82.9% of cyclosporine group and 80.8% of the tacrolimus group (p = 1.0) Those graded as moderate or severe comprised 80% of the cyclosporine group and 56% of the tacrolimus group (p = 0.46) and those both extensive and moderate or severe were 71.4% and 52%, respectively (p = 0.12). In pediatric matched unrelated donor transplantation, the incidence and severity of chronic graft versus host disease in patients receiving either tacrolimus/methotrexate or cyclosporine/methotrexate based regimens for prophylaxis of GVHD are not significantly different.

scholarly journals Bortezomib-Based Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Unrelated Donor Transplantation

2012 ◽  
Vol 30 (26) ◽  
pp. 3202-3208 ◽  
Author(s):  
John Koreth ◽  
Kristen E. Stevenson ◽  
Haesook T. Kim ◽  
Sean M. McDonough ◽  
Bhavjot Bindra ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Short Course

Purpose HLA-mismatched unrelated donor (MMUD) hematopoietic stem-cell transplantation (HSCT) is associated with increased graft-versus-host disease (GVHD) and impaired survival. In reduced-intensity conditioning (RIC), neither ex vivo nor in vivo T-cell depletion (eg, antithymocyte globulin) convincingly improved outcomes. The proteasome inhibitor bortezomib has immunomodulatory properties potentially beneficial for control of GVHD in T-cell-replete HLA-mismatched transplantation. Patients and Methods We conducted a prospective phase I/II trial of a GVHD prophylaxis regimen of short-course bortezomib, administered once per day on days +1, +4, and +7 after peripheral blood stem-cell infusion plus standard tacrolimus and methotrexate in patients with hematologic malignancies undergoing MMUD RIC HSCT. We report outcomes for 45 study patients: 40 (89%) 1-locus and five (11%) 2-loci mismatches (HLA-A, -B, -C, -DRB1, or -DQB1), with a median of 36.5 months (range, 17.4 to 59.6 months) follow-up. Results The 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22% (95% CI, 11% to 35%). One-year cumulative incidence of chronic GVHD was 29% (95% CI, 16% to 43%). Two-year cumulative incidences of nonrelapse mortality (NRM) and relapse were 11% (95% CI, 4% to 22%) and 38% (95% CI, 24% to 52%), respectively. Two-year progression-free survival and overall survival were 51% (95% CI, 36% to 64%) and 64% (95% CI, 49% to 76%), respectively. Bortezomib-treated HLA-mismatched patients experienced rates of NRM, acute and chronic GVHD, and survival similar to those of contemporaneous HLA-matched RIC HSCT at our institution. Immune recovery, including CD8+ T-cell and natural killer cell reconstitution, was enhanced with bortezomib. Conclusion A novel short-course, bortezomib-based GVHD regimen can abrogate the survival impairment of MMUD RIC HSCT, can enhance early immune reconstitution, and appears to be suitable for prospective randomized evaluation.

scholarly journals Less Chronic Graft-Versus-Host Disease, Immunosuppressive Therapy and Better Survival after Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplant Recipients: Longer Follow-up of a Multicentre Cell Therapy Transplant Canada Randomized Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 875-875
Author(s):  
Jean Roy ◽  
Tony Panzarella ◽  
Stephen Couban ◽  
Félix Couture ◽  
Gerald M. Devins ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Control Group ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
To Receive

Background: We previously reported that pretreatment with rabbit anti-thymocyte globulin (ATG) decreases the use of immunosuppressive therapy (IST) and occurrence of chronic graft-versus-host disease (GVHD) 12 months after allogeneic stem cell transplantation from unrelated donors. We hypothesized these benefits would persist beyond 12 months with a positive clinical impact on patients. Methods: Phase 3, multicentre, open-label, randomized controlled trial at 10 centres in Canada and one in Australia. Patients aged 16-70 years with a hematological malignancy, a matched (HLA-A, B, C and DRB1) or 1-antigen/allele mismatched unrelated donor were eligible. Myeloablative, nonmyeloablative or reduced intensity conditioning regimens were permitted according to center clinical preference. Patients were randomized to receive or not to receive rabbit ATG (Thymoglobulin®, Sanofi Canada) as part of their conditioning. GVHD prophylaxis included either cyclosporine or tacrolimus plus methotrexate or mycophenolate mofetil. The ATG arm received 0.5, 2.0, 2.0 mg/kg of ATG on days -2, -1 and +1, respectively. Analyses were on a modified intention-to-treat basis for patients actually transplanted. Primary endpoint was freedom from all systemic IST without resumption up to 24 months after transplantation. Secondary endpoints included survival, relapse, non-relapse mortality, incidence and symptoms of chronic GVHD according to Lee scale and quality of life using different questionnaires including the Center for Epidemiologic Studies Depression (CES-D) scale. We also aimed to evaluate the recently described endpoints of graft-versus-host disease and relapse-free survival (GRFS) and chronic graft-versus-host disease and relapse-free survival (CRFS) in each cohort. This trial was registered at ISRCTN (#29899028) and clinicaltrials.gov (#NCT01217723). Results: Between 06/2010 and 07/2013, 203 patients were randomized and 196 available for end-points analysis, including 99 patients in the ATG group and 97 in the No ATG (control) group. Datalock was performed on April 1, 2019. The cumulative incidence of chronic GVHD at 24 months was significantly lower in ATG recipients (26.3% versus 41.2%, p=0.032). Similarly, more than twice patients in the ATG group were free from IST at 24 months (adjusted OR of 3.49 [95% CI : 1.60-7.60]; p = 0.002). Most patients retained the same IST status from 12 to 24 months (74.7% in the ATG and 81.4% in the control group). Symptoms of chronic GVHD were also significantly less prevalent in patients receiving ATG, with scores by Lee scale of 13.57 (SE : 1.47) versus 19.90 (SE : 2.15); p=0.017. In contrast, we observed no difference in non-relapse mortality (ATG : 21.2% versus No ATG : 30.9%; p=0.14) and relapse (ATG : 16.2% versus No ATG : 17.5%; p=0.73). Of note, there was no increase in relapse in those receiving either myeloablative or non-myeloablative conditioning (Gray's test p = 0.66 and 0.29, respectively). ATG had a positive impact on survival (Figure 1), with an overall survival at 12 months of 74.8% (SE : 4.4) compared with 64.9% (SE : 4.8) in the control group (adjusted HR 0.56 [95% CI : 0.35-0.90; p=0.017). This benefit of ATG on survival persisted at 24 months, with 70.7% of patients in the ATG group and 53.6% in the control group being alive (p=0.018). GRFS at 12 and 24 months were significantly better in the ATG group, with 45.4% and 37.4% of patients alive and free of ever having had GVHD versus 24.7% and 17.5%, respectively (p = 0.0034). CRFS led to similarly better results in ATG recipients at 12 (57.6%) and 24 (48.5%) months (p=0.01; Figure 2). Depressive symptoms were less frequently reported in the ATG group, the mean CES-D scores being 10.39 (SE : 1.29) compared with 14.63 (SE : 1.48) in the No ATG group (p=0.034). There were no statistically significant differences in other patient-reported outcomes. Conclusions: Pretreatment with rabbit ATG in combination with standard acute GVHD prophylaxis provides long term benefits consisting of decreases in chronic GVHD incidence, use of IST, depression and improved survival. Our trial is the first to demonstrate both a survival advantage and improvement in quality of life in patients receiving ATG for chronic GVHD prophylaxis. Our data support that ATG should be included in the preparative regimens of all unrelated donor transplant recipients receiving standard acute GVHD prophylaxis. Disclosures Roy: Celgene: Consultancy, Honoraria, Research Funding; ExCellThera: Patents & Royalties: Royalties from sales of UM171, Research Funding; Amgen Canada: Honoraria; Janssen Canada: Honoraria; Sanofi Canada: Research Funding. Foley:Celgene: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau. Kuruvilla:Janssen: Research Funding; Roche: Research Funding; BMS: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Amgen: Honoraria; Astra Zeneca: Honoraria; BMS: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Merck: Honoraria; Novartis: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria. Lee:AstraZeneca: Research Funding; Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Popradi:Sanofi Canada: Consultancy, Honoraria. Walker:Kiadis Pharma: Other: Grant funding via institution (as a principal investigator). OffLabel Disclosure: Rabbit ATG (Sanofi) for chronic GVHD prophylaxis.

scholarly journals Cytomegalovirus Antigenic Mimicry of Human Alloreactive Peptides: Exploring Cross-Reactivity As a Potential Trigger for Graft Versus Host Disease

2017 ◽  
Vol 23 (3) ◽  
pp. 1
Author(s):  
Charles E. Hall ◽  
Vishal N. Koparde ◽  
Maximilian Jameson-Lee ◽  
Abdelrhman Elnasseh ◽  
Allison F. Scalora ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cross Reactivity ◽  
Host Disease ◽  
Graft Versus Host ◽  
Potential Trigger ◽  
Antigenic Mimicry

Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 548-551 ◽  
Author(s):  
Mats Remberger ◽  
Dietrich W. Beelen ◽  
Axel Fauser ◽  
Nadezda Basara ◽  
Oliver Basu ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Increased Risk ◽  
Unrelated Donors

AbstractThe long-term follow-up of a study including 214 patients receiving either peripheral blood stem cells (PBSCs) or bone marrow (BM) from an HLA-A, -B, and -DR–compatible unrelated donor is presented. Median follow-up was 4.4 (2.3-7.3) and 5.0 (0.7-8.4) years in the 2 groups, respectively. Cumulative incidence of overall chronic graft-versus-host disease (GVHD) was similar in the 2 groups (78% vs 71%), while extensive chronic GVHD was significantly more common in the PBSC group compared with the BM group (39% vs 24%, P = .03). The 5-year transplant-related mortality (TRM) was 37% in the PBSC group and 35% in the BM controls (P = .7), and overall survival was 42% in both groups. The relapse incidences were 26% and 27% in the 2 groups, respectively, resulting in a disease-free survival of 41% in both groups. In conclusion, PBSCs from HLA-compatible unrelated donors results in similar outcome compared to BM but implies an increased risk for extensive chronic GVHD.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 370-370
Author(s):  
Alexander I. Ngwube ◽  
Niketa C. Shah ◽  
David Jacobsohn ◽  
Edward Dela Ziga ◽  
Shalini Shenoy
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Low Incidence ◽  
One Year

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 &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 &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 &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

scholarly journals Hydroxychloroquine for the prevention of acute graft-versus-host disease after unrelated donor transplantation

2003 ◽  
Vol 9 (11) ◽  
pp. 714-721 ◽  
Author(s):  
H Khoury ◽  
K Trinkaus ◽  
M.J Zhang ◽  
D Adkins ◽  
R Brown ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft
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