Fast CMV and EBV Reactivations after Ruxolitinib for Graft-Versus-Host Disease Treatment

Introduction: Corticosteroid-refractory graft-versus-host disease (GVHD) remains a serious complication of hematopoietic stem cell transplantation (HSCT) with high morbidity and mortality rates. Unfortunately, no standard therapy exists for this setting. Ruxolitinib (ruxo), an oral selective Janus-associated kinase (JAK) inhibitor, achieved good results for corticoresistant acute and chronic GVHD in preclinical and clinical studies, with 80% overall response rates. Recent studies showed an increased risk of infections in patients treated with ruxo, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations. Patients and methods: In order to assess the efficacy and the safety of ruxo, we reviewed here the outcome of 57 patients who received ruxo for corticosteroid-refractory GVHD (in case of digestive tract involvement or in the absence of available ongoing clinical trials) or as a steroids-sparing medication. EBV and CMV reactivation risks were also assessed in the 137 consecutive patients received HSCT between January 1, 2012 and December 31, 2017 and who presented acute or chonic GVHD (57 of whom received ruxo). For this purpose, each reactivation were analyzed separately as a competing risk with death in a cause specific Cox model of survival after the first GVHD occurrence and the onset of ruxo therapy was coded as time dependent covariate. Results: The median age of 57 patients with ruxo was 55 years (range, 49 to 61). Indication for HSCT was acute myeloid leukemia for 25% patients, lymphoma for 30%, acute lymphoblastic leukemia for 11%, myeloproliferative neoplasm for 14% and myelodysplastic syndrome for 7%. Only 9% of this patients received ruxo before HSCT. Unrelated donor was used for 60% patients and main source of hematopoietic stem cells was peripheral stem cells (93%). T cell depletion with polyclonal anti-thymocyte globulin was performed for 89% of patients. Conditioning with high doses cyclophosphamide was used for 21% patients. A lymphopenia <1G/L persisted at day 100 for 42/51 patients evaluated. In these 57 patients, ruxo was given for 62 episode of GVHD (acute: 21 [which 95% for an acute grade III-IV GVHD]; chronic: 36; overlap syndrome: 5). Response rates to ruxo were 48% for acute GVHD, 60% for overlap syndrom and 58% for chronic GVHD. The overall GVHD related-death rate was 33% (19% for acute GVHD and 14% for chronic GVHD). Our median follow-up was 30 months (range, 9 to 42) after HSCT. Main non-infectious adverse events were cytopenias (17/57) and hepatic cytolysis (6/57) leading to discontinuation or tapering of ruxo in 12 patients. EBV reactivation (> 4 log or increasing viral charge of 0.5 log) occurred in 19 patients after ruxo with a 6-weeks cumulative incidence (6WCuI) of 22% (95CI [95% confidence interval]: 15-34). It was the first reactivation in 13 patients. CMV reactivation (> 3 log) occurred in 8 patients after ruxo with a 6WCuI of 4% (95CI: 7-25). It was the first reactivation in 3 patients (Figure 1). The distribution of first reactivation before ruxo and in the remaining 80 patients is shown in Table 1. Thus, 6WCuI of first EBV and CMV reactivation after the first episode of GVHD was 24% (95CI: 19-31) and 20% (95CI: 15-25) respectively. Finally, onset of ruxo coded as time dependent covariates retained a significant adverse prognostic value for the competing risks of death and first episode of EBV reactivation (HR [Hazard Ratio]: 2,657, p<0,05) as well as first episode of CMV reactivation (HR: 1,747, p<0,05) after first episode of GVHD. Discussion /Conclusion: Ruxo initiation coded as a time-dependent covariate was significantly associated with the overall risk of viral reactivation after the first episode of GVHD and the viral reactivations incidences after ruxo were similar with the incidence of reactivation at the onset of GVHD. Thus, it might be linked to the immuno-compromised state induced by both HSCT and GVHD. Furthermore, as we used ruxo for serious gastro intestinal GVHD, we could have selected patients with a more severe GVHD, requiring multiple immunosuppressive therapy, worsening immune reconstitution. To our knowledge it is the first study to assess the competing risk of CMV and EBV reactivation during ruxo treatment for GVHD. Given its effectiveness in corticoresistant GVHD, ruxo use must not be limited by the fear of viral reactivation at the light of our data, conditioned upon a close monitoring of viral loads in the first weeks. Disclosures No relevant conflicts of interest to declare.

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Reconstitution of Regulatory T Cell Subpopulations After Allogeneic Hematopoietic Stem Cell Transplantation and Graft-Versus-Host-Disease

Blood ◽

10.1182/blood.v120.21.1948.1948 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1948-1948

Author(s):

Alienor Xhaard ◽

Helene Moins ◽

Marc Busson ◽

Maryvonnick Carmagnat ◽

Marie Robin ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

T Cell ◽

Malignant Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cd4 T Cell ◽

Effector Memory ◽

Hematopoietic Stem ◽

Graft Versus Host

Abstract Abstract 1948 Previous studies on the reconstitution of regulatory T cells (Treg) after allogeneic hematopoietic stem cell transplantation (HSCT) have shown a delayed reconstitution in patients (pts) with acute graft-versus-host-disease (GvHD) (Magenau, 2010) and an association between impaired Treg reconstitution and the development of extensive chronic GvHD (Matsuoka, 2010). However, no studies have analyzed naive (nTreg) versus memory (mTreg) Treg reconstitution in a longitudinal cohort with large numbers of pts. From 2006 to 2009, 165 consecutive pts were prospectively analyzed in our center post-HSCT. Fresh whole blood samples were obtained 3 (n=155), 6 (n=162), 12 (n=165) and 24 (n=94) months after HSCT and analyzed by flow cytometry to quantify CD4 T cells, including naive, activated, central memory and effector memory subsets (Sallusto, 1999), as well as Treg (CD4+ CD25+ CD127neg/lo), including nTreg (CD45RA+) and mTreg (CD45RAneg). The results are presented as median values of circulating cells. Median age was 41 years (range: 6–68). The indication for HSCT was malignant disease in 92%. The conditioning regimen was reduced-intensity (RIC) in 51%. The donor was an HLA-identical sibling in 56%. The source of stem cells was peripheral blood (PBSC), bone marrow (BM) and cord blood (CB) in 65%, 28% and 7%, respectively. All pts received cyclosporine as GvHD prophylaxis. GvHD was defined as acute if occurring before day 100 and chronic thereafter. Total Treg (tTreg) increased from 13/μL at 3 months to 44/μL at 24 months, but always remained inferior to healthy controls (HC) (66/μL). nTreg increased from 1.8/μL at 3 months to 4.8/μL at 24 months (HC: 24/μL). mTreg increased from 10.7/μL at 3 months to 33.3/μL at 24 months (HC: 42/μL). The CD4/Treg ratio remained stable at 12.6 at 3 months and 11.6 at 24 months while the nCD4/nTreg ratio increased from 17.4 at 3 months to 42.7 at 24 months, showing a larger expansion of naive cells in the CD4 T cell compartment than in the Treg compartment (Figure 1) and a larger expansion of memory cells in the Treg than within the CD4 cells. At 3 months post-HSCT, tTreg, nTreg and mTreg were significantly higher in PBSC recipients (18.4, 2.7 and 14.5/μL) than in BM (8.1, 0.9 and 6.5/μL) and CB recipients (6.5, 0.6 and 5.3/μL) (p=0.0001), respectively. Pts transplanted after a RIC regimen had significantly more tTreg and mTreg than pts transplanted after a standard regimen (17 and 14/μL, compared with 9.8 and 8/μL, p=0.004 and 0.008 respectively). Pts transplanted for an aplastic anemia had significantly fewer nTreg than pts transplanted for a malignant disease (0.4 and 1.9/μL, p=0.001). At 6 months post-HSCT, tTreg, nTreg and mTreg were significantly higher (p=≤0.01) in pts transplanted from an HLA-identical sibling (19.5, 1.9 and 17.2/μL) compared with pts transplanted from an unrelated donor (13.2, 1.2 and 11/μL). At 12 and 24 months post-HSCT, younger pts (≤15 years) had significantly more nTreg than older pts (9.8 and 28.7/μL compared with 2.1 and 4.2, p=0.001). In pts with previous acute GvHD, tTreg and mTreg were significantly lower at 3 (8.5 and 7.7/μL) and 6 months (14.6 and 12.5/μL) compared with pts without (15.6 and 13.8/μL at 3 months, p=0.005 and 21.3 and 18.2/μL at 6 months, p≤0.007), respectively. Absolute numbers of tTreg, nTreg and mTreg, and the frequencies of Treg relative to activated, effector memory and central memory CD4 T cells at 3, 6 and 12 months post-HSCT did not predict the occurrence of a later episode of chronic GvHD up to 2 years post-HSCT. In our population, total, naive and memory Treg reconstitution was delayed post-HSCT and remained below the normal range up to 2 years after HSCT. tTreg reconstitution post-HSCT was mostly due to mTreg expansion. RIC regimen and PBSC as source of stem cells were associated with a better short-term reconstitution. At 6 months, pts transplanted from siblings had a better reconstitution while nTreg long-term reconstitution was mainly influenced by recipient age (better if ≤15 years). While previous acute GvHD impaired Treg reconstitution, Treg subsets (absolute numbers and frequencies relative to CD4 T cell subsets) at 3, 6 and 12 months post-HSCT were unable to predict chronic GvHD in this large cohort of patients. We believe these data are of particular interest regarding the recently increasing number of Treg interventional studies in humans in the context of HSCT. Disclosures: No relevant conflicts of interest to declare.

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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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Mesenchymal Stem Cells for Treatment of Severe Acute Graft-Versus-Host Disease.

Blood ◽

10.1182/blood.v108.11.5304.5304 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5304-5304 ◽

Cited By ~ 6

Author(s):

Katarina Le Blanc ◽

Francesco Frassoni ◽

Lynne Ball ◽

Edoardo Lanino ◽

Berit Sundberg ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Third Party ◽

Host Disease ◽

Graft Versus Host ◽

Acute Graft

Abstract Mesenchymal stem cells (MSC) from adult bone marrow have the capacity to differentiate into several mesenchymal tissues and inhibit T-cell alloreactivity in vitro. Within the EBMT MSC expansion consortium we have used MSC to treat grades III–IV acute graft-versus-host disease (GvHD) in 40 patients. The MSC dose was median 1.0 (range 0.4–9) 10^6 cells/kg body weight of the recipient. No side-effects were seen after MSC infusions. Nineteen patients received one dose, 19 patients received two doses, two patients received three and five doses respectively. MSC donors were in five cases HLA-identical sibling donors, 19 haploidentical donors and 41 third-party HLA-mismatched donors. Among the 40 patients treated for severe acute GvHD, 19 had complete responses, nine showed improvement, seven patients did not respond, four had stable disease and one patient was not evaluated due to short follow-up. Twenty-one patients are alive between six weeks up to 3.5 years after transplantation. Nine of these patients have extensive chronic GvHD. One patient with ALL has recurrent leukaemia and one patient has denovo AML of recipient origin. We conclude that MSC have immunomodulatory and tissue repairing effects and should be further explored as treatment of severe acute GvHD in prospective randomized trials.

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

Blood ◽

10.1182/blood.v108.11.447.447 ◽

2006 ◽

Vol 108 (11) ◽

pp. 447-447 ◽

Cited By ~ 1

Author(s):

Ann Mullally ◽

Cheng Li ◽

Haesook Kim ◽

Mehrdad Mohseni ◽

Edwin P. Alyea ◽

...

Keyword(s):

Stem Cell ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Histocompatibility Antigens ◽

Single Nucleotide ◽

Hematopoietic Stem ◽

Minor Histocompatibility Antigens ◽

Sibling Pairs ◽

Graft Versus Host ◽

Genome Wide

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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Mesenchymal Stem Cells for Treatment of Refractory Chronic Graft-Versus-Host Disease.

Blood ◽

10.1182/blood.v110.11.4968.4968 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4968-4968

Author(s):

Weng Jianyu ◽

Xin Du ◽

Xiang Peng ◽

Zhang Xiumin ◽

Suijin Wu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Immunosuppressive Agents ◽

Steroid Resistant ◽

Host Disease ◽

Graft Versus Host

Abstract Refractory extensive chronic graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation (SCT) is associated with high mortality [Margolis J., SeminOncol 2000].However, conventional therapies including steroids are often unsuccessful in those patients with multiorgan involvement and are associated with significant therapy-related complications and poorly life quality. Mesenchymal stem cells (MSCs) have immunomodulatory effects [Tse WT et al., Transplantation 2003; Spees JI et al.,Proc Natl Acad Sci USA 2003]. Recently MSCs have been given intravenously to treat seven steroid resistant acute GVHD patients and one patient with chronic GVHD. MSCs effects in chronic GVHD is rarely known, although this successfully experience suggests that MSCs have been well tolerated and had a powerful immunosuppressive effects on acute GVHD. [Katarina Le Blanc et al., Lancet 2004; Olle Ringden., Transplantation 2006 ]. Here, we present our experience of using MSCs for treatment of Thirteen patients with refractory chronic GVHD. Between May 2005 and March 2007, thirteen patients (8 male, 5female) with hematological malignancies with a median age of 26(range:15 to 40) years who had received peripheral stem cells from sibling donors. All patients developed steroid resistant or extensive chronic GVHD, with progressive involvement of the skin(13), liver(10), oral mucosa(12),ocular glands(12), and thrombocytopenia (1) when the immunosuppressive agents were taped after five to twenty-four months. The MSC dose was median 1.0 ×106 cells/kg body weight of the recipient. In all, thirteen patients had at least received one dose, seven patients received more than two doses. MSC donors were in seven cases HLA-identical siblings, six unrelated mismatched donors. No side-effects were seen after MSCs infusions. All patients have responded after follow-up of the median time 15 months. One patient with moderate cGVHD had a complete responses, and discontinued all of the immunosuppressive agents without relapse more than 18.4 months after MSC infusion. Three moderate and two patients with severe chronic GVHD improved to mild degree, and six severe turned to moderate degree. Complete resolution was seen in gut(2/3), liver(5/10), skin(5/13), oral(6/12) and eye(2/12). One patient responded in skin, liver, oral mucose and eye, but developed in lung (bronchiolitis obliterans, BO) score of 2 which are considered severe chronic GVHD. Mean follow-up periods was 27m (rang: 14 to48m), Leukemia free survival(LFS)rate were 85%(11/13), and the overall survival (OS)rate were 92.3%(12/13). Our experience suggests that MSC infusion is a safe and effective adjunct therapy for refractory extensive chronic GVHD with resistance to conventional therapy. But more prospective, controlled studies with MSCs for treatment of GVHD should be performanced to evaluate this new treatment exactly.

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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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Single Nucleotide Polymorphism (SNP) Approach of Multiple Candidate Pathways Predicting the Risk of Acute / Chronic Graft-Versus-Host Disease or Transplant Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation: Potential Involvement of Nuclear Factor Kappa-B (NFKB), Platelet-Derived Growth Factor (PDGF) and Transforming Growth Factor-Beta (TGF-β) Pathway with Chronic Graft-Versus-Host Disease Graft-Versus-Host Disease.

Blood ◽

10.1182/blood.v114.22.2221.2221 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2221-2221

Author(s):

Dong Hwan (Dennis) Kim ◽

Jina Yun ◽

Jee Hyun Kong ◽

Chul Won Jung ◽

Ahmed Galal ◽

...

Keyword(s):

Nitric Oxide ◽

Growth Factor ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Transforming Growth Factor ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Cytokine Activation

Abstract Abstract 2221 Poster Board II-198 Background: Acute graft-versus-host disease (GVHD) was known to be involved in the Th1 cytokine activation and alloreactive T-cell cytotoxicity, while the pathogenesis of chronic GVHD is yet revealed fully although in which Th2 cytokine activation or transforming growth factor (TGF) mediated pathway was suggested to be involved. The current study is a hypothesis generating study in order to identify potential predictive surrogate associated with the risk of acute or chronic GVHD in addition with transplant outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). Methods: The current study was performed to identify genetic surrogates predicting the risk of acute / chronic GVHD, relapse free survival, non-relapse mortality and overall survival in 394 pairs transplanted at the Princess Margaret Hospital, Toronto, ON, Canada. In addition, the predictive markers for organ specific incidence of acute / chronic GVHD were also evaluated (i.e. for skin/liver/gut acute GVHD or skin, eye, oral, lung or liver chronic GVHD). Total of 261 single nucleotide polymorphisms (SNPs) in 56 genes were determined for donor/recipients' genotypes using MALDI-TOF based platform, involving in the pathways of 1) cytokines (i.e. IL1A, IL1B and its receptor, IL1R1, IL2 & IL2RA, IL4 & IL4R, IL6 & IL6R, IL8, IL10 & IL10RA, RB, IL12A/BandIL12RB1, IFNG & IFNGR1/2, TNFTI/II/II), 2) NFKB (NFKB1/2/A, NFKBIA/B, IKB, IKK1, IKBKB, RelB), 3) apoptosis (FAS, TRAIL & TRAILR1), 4) endothelium nitric oxide regulation (EDN1, NOS1/2A/3), 5) PDGF (PDGFB/C/D & PDGFRA/B), 6) TGF-β (TGFB1/2 & TGFBR1/2/3, TGFRB1), 7) Toll-like receptor (TLR4/5), 8) NOD2/CARD15 and 9) prostaglandin-endoperoxide synthase (PTGS1/2). The candidate genotypes have been selected by choosing the SNPs in non-synonymous SNPs in exon region with minor allele frequency of > 0.05 to 0.1. Results: Followings are the lists of recipients' and donors' genotypes with p-value<0.05 thus associating with clinical outcomes following allogeneic HSCT: In summary, the risk of chronic GVHD was significantly associated with SNP of the genes involved in the pathway of NFKB, PDGF, TGF-β, and some of cytokines (esp. type II, IL6 & IL4), while that of acute GVHD associates with the genotypes in the pathway of TNF and apoptosis. In addition, survival after allogeneic transplantation was associated with the genotypes in NOS (nitric oxide synthase, endothelial nitric oxide synthesis pathway), IL-2 and TGF pathway. Conclusion: Because of complex nature of GVHD pathogenesis, multiple candidate pathway SNPs has been explored targeting SNPs in the pathway of cytokines, NFKB, apoptosis, endothelium nitric oxide regulation, NOD2/CARD15, PDGF, PTGS1/2, TGF-β and TLR. Different involvements were noted of TGF-β, PDGF or NFKB with chronic GVHD versus TNF and apoptosis-associated SNPs with acute GVHD. Further study will help us to reach more clear conclusion which genotype is the predictor of the risk of GVHD. Disclosures: No relevant conflicts of interest to declare.

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The Bidirectional Relationship Between Cytomegalovirus Replication and Graft-Versus-Host Disease - a Retrospective Single Center Study.

Blood ◽

10.1182/blood.v114.22.2236.2236 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2236-2236

Author(s):

Nathan Cantoni ◽

Hans H Hirsch ◽

Nina Khanna ◽

Dominik Heim ◽

Joerg Halter ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Time Dependent ◽

Cmv Infection ◽

Graft Versus Host ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Cmv Reactivation ◽

Multiple Episodes

Abstract Abstract 2236 Poster Board II-213 Cytomegalovirus (CMV) infection and graft-versus host disease (GVHD) are important complications after allogeneic HSCT with a clear link. Multiple studies show that GVHD and its treatment put patients at risk for CMV reactivation. Data on CMV infection as a cause of GVHD, in contrast, are controversial. The association of pre-transplant CMV serology with GVHD development and reduced rates of chronic GVHD after preemptive CMV treatment are indicative of such an association. However, analyses of the direct impact of CMV infection on GVHD are rare; a recent small study found no effect of CMV replication on subsequent development of acute GVHD (Wang et al, BMT 2008). We analyzed in a single centre study the association of CMV reactivation with acute GVHD in 517 patients treated between 1993 and 2008. 59% of patients were male, median age was 42 years (range 16 to 70). Diagnoses were AML (31%), ALL (16%), CML (15%), MDS/MPN (13%), lymphoma (21%), and other (4%). Conditioning regimens were Cy/TBI ±/- etoposide (49%), Cy/Bu (17%), fludarabine and TBI (16%), or others (18%). GVHD prophylaxis consisted of CyA/MTX (78%) or CyA/MMF (21%). Donors were HLA-identical siblings (65%), other family members (4%), or unrelated donors (31%). We made use of a standardized CMV policy over the last decades. CMV reactivation was monitored using real-time polymerase chain reaction or pp65 antigenemia assay weekly in patients without infection, twice weekly in patients with CMV replication. CMV was preemptively treated with gancyclovir or foscarnet. To determine the correlation of CMV infection with acute GVHD, we used a stringent Cox regression model, in which CMV replication was modeled as a time-dependent covariate becoming positive on the day of the first detection of CMV and negative on the first negative assay thereafter. Multiple episodes of CMV replication were considered. Acute GVHD was modeled as a time-dependent covariate in models with CMV infection as endpoint. Hazard ratios (HR) were adjusted for patient age, disease, disease stage, donor type, stem cell source, conditioning regimen and GVHD prophylaxis. The analysis was restricted to the time from transplant to day 100. CMV reactivation was detected at least once in 16% (84/517) of patients at a median of 33 (range 1-95) days after HSCT. Median duration of CMV reactivation was 8.5 days (range 2-62). 19 patients showed multiple episodes of CMV replication. Donor and recipient serostatus significantly influenced the day 100 cumulative incidence of CMV infection: D-/R- (N=173) 6%; D±/R- (N=61) 10%; D±/R± (N=128) 25%; and D-/R± (N=99) 37%, p<0.001. The cumulative incidence for any acute GVHD (grade I-IV) was 67% (95% CI 56-78%) with a median onset time at day 14 (range day 5-94); the cumulative incidence for severe acute GVHD (grade II-IV) was 48% (95% CI 40-56%). When both endpoints (CMV, GVHD) were combined, 150 patients (29%) experienced neither GVHD nor CMV reactivation, 281 (54%) GVHD only, 19 (4%) CMV reactivation only, and 67 (13%) both CMV reactivation and GVHD. Of the 67 patients with both GVHD and CMV, 46 (69%) developed GVHD prior to CMV reactivation, 17 (25%) developed GVHD during CMV reactivation, and 4 (6%) developed GVHD after CMV reactivation. Cox modeling revealed that presence of GVHD grade II-IV increased the risk of CMV infection (HR 1.61, 95% CI 1.03-2.52, p=0.04). Similarly, patients were at increased risk of developing acute GVHD during phases of CMV replication (grades I-IV: HR 2.23, 95% CI 1.39-3.81, p=0.001; grades II-IV: HR 2.00, 95% CI 1.08-3.72, p=0.03). GVHD grade was not influenced by concomitant CMV reactivation (median grade II, in patients with or without CMV reactivation). The overall proportion of GVHD that occurred during phases of CMV replication was small (3% versus 64% occurring in CMV non replicating patients). Even if GVHD occurring after resolution of CMV reactivation was additionally taken into account, the majority of GVHD occurred without preceding CMV infection (63% versus 4%). These data describe the complex relationship between CMV infection and GVHD. We confirm previous studies that GVHD (and GVHD therapy) can induce CMV infection. We describe as well that patients with active CMV replication have a significantly higher risk of developing GVHD compared to patients without CMV replication. However, the proportion of GVHD that could be linked to CMV reactivation was small in this population with a low overall incidence of CMV reactivation. Disclosures: No relevant conflicts of interest to declare.

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The Use of Bone Marrow Graft for Hematopoietic Stem Cell Transplantation From Matched Unrelated Donors After Reduced Intensity Conditioning Regimen Improves Survival : Analysis of the Societe Française De Greffe De Moelle Et De Therapie Cellulaire.

Blood ◽

10.1182/blood.v114.22.873.873 ◽

2009 ◽

Vol 114 (22) ◽

pp. 873-873

Author(s):

Andrea Toma ◽

Marie-Lorraine Balère-Appert ◽

Jean-Michel Boiron ◽

Pierre Bordigoni ◽

Gerard Socie ◽

...

Keyword(s):

Stem Cells ◽

Multivariate Analysis ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity Conditioning Regimen ◽

Unrelated Donors ◽

Grade Ii

Abstract Abstract 873 The use of peripheral blood stem cells (PBSC) for hematopoietic stem cell transplantation (HSCT) is associated with a higher risk of chronic graft versus host disease (GvHD) but its impact on survival is not clear since it may favor a greater graft versus leukemia (GvL) effect. However, in the context of HSCT from unrelated donors (UD), the balance between GvH and GvL may differ from the context of sibling donors and thus the use of PBSC may be deleterious. In this retrospective study, we analyzed 103 patients from the french registry who received a graft from an UD after a reduced intensity conditioning regimen (RIC) to evaluate the role of various parameters including the source of stem cells on the outcome. Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The median age was 46 years (18-67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. The conditioning regimen was Fluda/TBI 2Gys for 26 patients, Bu/Fluda/ATG for 24 patients, Fluda/Melph for 16 patients and others for 37 patients. Overall, anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The source of stem cells was PBSC for 65 patients and bone marrow (BM) for 38 patients. The median follow up of the cohort is 61,3 months (1,2-113,7). The results showed that 95% of patients engrafted. Five patients did not engraft (4 in the BM group and 1 in the PBSC group). Acute GvHD grade II to IV and grade III/IV occurred in 47% and 19% of patients, respectively. The risk of developing chronic GvHD was 49% at 2 years. Overall survival (OS) was 36% at five years. The median disease free survival (DFS) was 55 months among the 36 patients alive. We performed univariate and multivariate analysis of factors susceptible to impact on GvHD and survival. The multivariate analysis included the impact of HLA mismatch, disease status, diagnosis, source of stem cells, patient's and donor's ages. This multivariate analysis performed on the global population shows a trend towards an improved OS with the use of BM instead of PBSC. However, when focusing the multivariate analysis on the 71 patients transplanted with a 10/10 match donor, the most potent factor influencing the outcome is the use of BM which is associated with an improved OS (p=0.03) and DFS (p=0.02), less acute GvHD grade II-IV (p=0.05), or grade III/IV (p=0.05) and less chronic GvHD (p=0.05). These results suggest that the use of BM as the source of stem cells should be reconsidered in the context of matched UD after RIC transplantation. Disclosures: No relevant conflicts of interest to declare.

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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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