Rapid Improvement in Jaundice Using Transdermal Isosorbide Tape as a Nitric Oxide Donor in Two Adult Patients with Transplantation-associated Microangiopathy Related to Graft-versus-host Disease

Abstract Syngeneic haematopoietic stem cell transplantation (HSCT) is a rare situation and is usually characterised by a high relapse rate because of the absence of graft versus leukaemia effect. We report results of syngeneic HSCT reported to the EBMT registry from 1975 to 2003. One hundred and 24 acute myeloid leukaemia (AML) and 104 acute lymphoblastic leukaemia (ALL) were reported comprising 150 adults and 78 children, 133 males and 95 females. The number of patients in first complete remission (CR1) was 137, comprising 93 AML (72 adults and 21 children) and 44 ALL (33 adults and 11 children). The number of patients in second complete remission (CR2) was 52 comprising 12 AML (9 adults and 3 children) and 40 ALL (11 adults and 29 children). The number of patients in more advanced disease (AD) was 39 comprising 19 AML (16 adults and 3 children) and 20 ALL (9 adults and 11 children). Total body irradiation was given to 36% of patients. Prophylaxis of graft versus host disease was given to 10% of patients. Source of stem cells was bone marrow for 81% of patients, peripheral blood for 18% and both for 1%. Outcome at 5 years showed for adult patients with AML in CR1 (n=72) a leukaemia free survival (LFS) of 56+/−7%, a relapse incidence (RI) of 37+/−7% and a non relapse mortality (NMR) of 11+/−5%. For adult patients with ALL in CR1 (n=33), LFS was 60+/−10%, RI 38+/−10% and NRM 3+/−3%. Outcome at 5 years showed for children with AML in CR1 (n=21) a LFS of 61+/−11%, a RI of 39+/−11% and a NMR of 0%. For children with ALL in CR2 (n=29), LFS was 46+/−10%, RI 52+/−10% and NRM 5+/−5%. Acute graft versus host disease (GVHD) was diagnosed in 12% of patients, 7% grade 1 and 5% grade ≥ 2. Chronic GVHD was observed in 2% of patients. These retrospective study indicates that syngeneic HSCT can lead to a high LFS in patients with acute leukaemia in CR1 and that GVHD is not a rare event. A graft versus leukemia effect is highly probable in syngeneic HSCT.

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Human Mesenchymal Stroma Cells (hMSCs) Expanded with Human Platelets Lysate Are Safe and Effective For the Treatment of Graft Versus Host Disease

Blood ◽

10.1182/blood.v112.11.1171.1171 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1171-1171 ◽

Cited By ~ 1

Author(s):

Martino Introna ◽

Ettore Biagi ◽

Chiara Capelli ◽

Agnese Salvadè ◽

Giovanna D’Amico ◽

...

Keyword(s):

Bone Marrow ◽

Graft Versus Host Disease ◽

Pediatric Patients ◽

Human Platelets ◽

Adult Patients ◽

Third Party ◽

Host Disease ◽

Graft Versus Host ◽

Grade Iii

Abstract Background Very recently, encouraging results indicate that third party human mesenchymal stromal cells (hMSCs) are a rapidly available therapeutic tool for the treatment of severe (grade III–IV), steroid resistant, acute graft versus host disease (aGVHD). In the clinical experience published so far, hMSCs have been expanded in Fetal Bovine Serum (FBS), which may constitute a problem for its antigenicity and as a possible vehicle of animal pathogens. We have established a highly efficient protocol for the in vitro expansion, under strict GMP compliance, of bone marrow derived hMSCs using human platelets lysate (PL) in place of FBS (Capelli C. et al.: BMT, 2007). In this study, upon Ethical Committee approval and patient’s informed consent, hMSCs were administered on a compassionate basis for the treatment of refractory GVHD. Methods hMSCs were prepared from washouts of bags and filters, left over at the end of the standard filtration procedures of the bone marrow harvests from third party HLA mismatched healthy donors. Cells were grown in the presence of DMEM with 5% PL obtained from the Blood Bank of our Hospitals. In a short period of time (10–33 days), low density seeding of unmanipulated cells (100–200/cm2), obtained from 7 bone marrow harvests allowed to prepare large quantities of hMSCs (median 115×106, range: 67–375), with only one in vitro passage. Twenty-three frozen bags of hMSCs (each containing approximately 1×106/kg of recipient body weight) have been quarantined until the completion of quality tests, including viability, phenotype, absence of detectable bacteria, fungi, mycoplasma or endotoxin, according to European Pharmacopea guidelines. Differentiation to osteogenic and chondrogenic cells as well as the immunosuppressive potential of these cells was confirmed when tested in mixed lymphocyte reaction (MLR). Q banding and clonogenic assays were performed for each batch and never showed abnormalities of karyotype or autonomous growth in vitro. Results Two adult and 4 pediatric patients were treated for aGVHD (grade II–IV) and 2 adults for extensive chronic GVHD (cGVHD) between January and July 2008, using 12 hMSCs bags that had completed quarantine. Before hMSCs, second or third line treatments had been given to patients with aGVHD, including Etanercept (n= 5), Mycophenolate Mofetil (MMF, n= 4) and Extracorporeal Photopheresis (ECP, n= 3), Rituximab (1 patient). Patients with cGVHD were previously treated with ECP and MMF (n= 2), Imatinib (n= 1) and Etanercept (n= 1). Each infusion contained a median dose of 1×106/kg (range, 0.7–1.2×106) hMSCs. For patients with aGVHD, a single infusion was performed in 4 pediatric patients while 1 and 3 infusions were performed in 2 adult patients. The 2 patients with cGVHD received 1 and 4 infusions, respectively. All infusions were very well tolerated with no immediate or late adverse events according to WHO common criteria. Among pediatric patients with aGVHD, 3 complete and 1 partial responses were registered and all patients are alive and in complete hematologic remission. A complete response was observed in 1 adult with grade III cutaneous aGVHD although the patient rapidly relapsed and died of leukemia progression. No response was observed in the other adult patient who died of progressive grade IV gut and liver aGVHD. The 2 adult patients with cGVHD had both a partial response and are alive. Conclusions These data show that large numbers of third party hMSCs can be expanded in vitro with PL containing medium and stored for immediate use in patients with GVHD. Moreover, the clinical results and the toxicity profile confirm those reported with hMSCs expanded in FBS containing media.

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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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Intestinal derivation for digestive complications of graft versus host disease in adult patients: a case series and review of the literature

Trends in Transplantation ◽

10.15761/tit.1000302 ◽

2021 ◽

Vol 14 (3) ◽

Author(s):

Christophe Desprez ◽

Sylvie François ◽

Sylvain Thepot ◽

Christopher Nunes Gomes ◽

Norbert Ifrah ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Case Series ◽

Adult Patients ◽

Review Of The Literature ◽

Host Disease ◽

Graft Versus Host

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ATTENUATION OF LETHAL GRAFT-VERSUS-HOST DISEASE BY INHIBITION OF NITRIC OXIDE SYNTHASE1

Transplantation Journal ◽

10.1097/00007890-199701150-00018 ◽

1997 ◽

Vol 63 (1) ◽

pp. 94-100 ◽

Cited By ~ 20

Author(s):

Rosemary A. Hoffman ◽

Natascha C. N??ssler ◽

Susan L. Gleixner ◽

Guisheng Zhang ◽

Henri R. Ford ◽

...

Keyword(s):

Nitric Oxide ◽

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host

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Oral Complications of Chronic Graft-Versus-Host Disease

JNCI Monographs ◽

10.1093/jncimonographs/lgz007 ◽

2019 ◽

Vol 2019 (53) ◽

Cited By ~ 6

Author(s):

Jane M Fall-Dickson ◽

Steven Z Pavletic ◽

Jacqueline W Mays ◽

Mark M Schubert

Keyword(s):

Graft Versus Host Disease ◽

Adult Patients ◽

High Dose ◽

Term Survival ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Oral Complications ◽

Mucosal Involvement ◽

Clinically Significant

Abstract The increasing clinical indications for hematopoietic stem cell transplantation (HSCT) and improved clinical care throughout and following HSCT have led to not only long-term survival but also to an increasing incidence and prevalence of graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT, with increasing incidence in pediatric patients as well. Oral cGVHD specifically has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to significantly decreased caloric intake, oral infections, and increased health service utilization, and may thus affect overall health and survival. The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids, and calcineurin inhibitors. This review of oral complications of cGVHD presents the clinical significance of oral cGVHD to HSCT survivors, our current understanding of the pathobiology of oral cGVHD and gaps in this evidence, and the global targeted interdisciplinary clinical research efforts, including the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Current challenges regarding the management of oral cGVHD and strategies to advance our scientific understanding of this clinically significant chronic oral disease are presented.

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