scholarly journals Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease Using Commercial Mesenchymal Stem Cell Products

2021 ◽  
Vol 12 ◽  
Author(s):  
Makoto Murata ◽  
Takanori Teshima
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Acute Gvhd ◽  
Eligibility Criteria ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Precise Position ◽  
A Prospective Study ◽  
Steroid Refractory ◽  
Acute Graft

Acute graft-versus-host disease (GVHD) is a life-threatening complication that can develop after allogeneic hematopoietic stem cell transplantation. In particular, the prognosis of patients with steroid-refractory acute GVHD is extremely poor. Ryoncil™ (remestemcel-L), a human bone marrow-derived mesenchymal stem cell (MSC) product, failed to show superiority over placebo in patients with steroid-refractory acute GVHD, but it was approved for use in pediatric patients in Canada and New Zealand based on the results of a subgroup analysis. Temcell®, an equivalent manufactured MSC product to remestemcel-L, was approved in Japan based on small single-arm studies by using a regulation for regenerative medicine in 2016. The efficacy of Temcell was evaluated in 381 consecutive patients treated with Temcell during the initial 3 years after its approval. Interestingly, its real-world efficacy was found to be equivalent to that observed in a prospective study of remestemcel-L with strict eligibility criteria. In this article, the potential of MSC therapy in the treatment of acute GVHD is discussed. A meticulous comparison of studies of remestemcel-L and Temcell, remestemcel-L/Temcell and ruxolitinib, and remestemcel-L/Temcell and thymoglobulin showed that the precise position of remestemcel-L/Temcell therapy in the treatment of acute GVHD remains to be determined.

scholarly journals Mesenchymal Stem Cell Therapy Overcomes Steroid Resistance in Severe Gastrointestinal Acute Graft-Versus-Host Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Kyoko Moritani ◽  
Reiji Miyawaki ◽  
Kiriko Tokuda ◽  
Fumihiro Ochi ◽  
Minenori Eguchi-Ishimae ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Graft Versus Host Disease ◽  
Lymphoblastic Leukemia ◽  
Steroid Resistance ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory ◽  
Acute Graft

The authors describe the high effectiveness of human mesenchymal stem cell (hMSC) therapy to treat steroid-refractory gastrointestinal acute graft-versus-host Disease (aGVHD) in a 15-year-old boy with acute lymphoblastic leukemia (ALL). He received allogeneic hematopoietic stem cell transplantation due to high-risk hypodiploid ALL. Around the time of engraftment, he developed severe diarrhea following high-grade fever and erythema. Although methylprednisolone pulse therapy was added to tacrolimus and mycophenolate mofetil, diarrhea progressed up to 5000~6000 ml/day and brought about hypocalcemia, hypoalbuminemia, and edema. Daily fresh frozen plasma (FFP), albumin, and calcium replacements were required to maintain blood circulation. After aGVHD was confirmed by colonoscopic biopsy, MSC therapy was administered. The patient received 8 biweekly intravenous infusions of 2×106hMSCs/kg for 4 weeks, after which additional 4 weekly infusions were performed. A few weeks after initiation, diarrhea gradually resolved, and at the eighth dose of hMSC, lab data improved without replacements. MSC therapy successfully treated steroid-refractory gastrointestinal GVHD without complications. Despite life-threatening diarrhea, the regeneration potential of children and adolescents undergoing SMC therapy successfully supports restoration of gastrointestinal damage. Even with its high treatment costs, SMC therapy should be proactively considered in cases where young patients suffer from severe gastrointestinal GVHD.

Treatment Options in Steroid-Refractory Acute Graft-Versus-Host Disease Following Hematopoietic Stem Cell Transplantation

2007 ◽  
Vol 41 (9) ◽  
pp. 1436-1444 ◽  
Author(s):  
Sara S Kim
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Treatment Options ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Pharmacologic Agents ◽  
Steroid Refractory ◽  
Acute Graft

Objective: To evaluate the treatment options in steroid-refractory acute graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. Data Sources: Literature was obtained by searching MEDLINE (1966–May 2007) and EMBASE (1980–May 2007). Study Selection and Data Extraction: All pertinent clinical trials, retrospective studies, case reports, and compassionate use studies were identified and evaluated for safety and efficacy of the pharmacologic agents. Data Synthesis: Steroid-refractory acute GVHD is associated with high rates of morbidity and mortality. Although various pharmacologic agents have been studied in the treatment of steroid-refractory acute GVHD, no treatments have been established as a salvage therapy. Preliminary data on different pharmacologic agents have been identified and evaluated for their efficacy and tolerability in the treatment of steroid-refractory acute GVHD. The effects of the pharmacologic agents varied significantly among patients: severity of the disease, involvement of different organs, and the patient's age seem to be the major factors that affect an individual's response to drug therapy. In addition, the treatments are further challenged by the high incidence of potentially fatal opportunistic infections that occur during the therapy. Conclusions: Selection of pharmacologic agents for the treatment of steroid-refractory acute GVHD should be based on the target organs, adverse drug reactions, and economic factors. Further studies with larger sample sizes are warranted to better understand the roles of these agents in the treatment of steroid-refractory acute GVHD.

Impact of highly conserved HLA haplotype on acute graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4664-4670 ◽  
Author(s):  
Satoko Morishima ◽  
Seishi Ogawa ◽  
Aiko Matsubara ◽  
Takakazu Kawase ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Extended Haplotypes ◽  
Hla Haplotypes ◽  
Acute Graft

Abstract Although the effects of human leukocyte antigen (HLA) locus matching on clinical outcome in unrelated hematopoietic stem cell transplantations have been characterized, the biologic implications of HLA haplotypes have not been defined. We demonstrated the genetic fixity of Japanese conserved extended haplotypes by multi–single nucleotide polymorphism analysis in 1810 Japanese donor-recipient pairs matching with HLA-A, -B, -C, -DRB1, and -DQB1 alleles. Three major Japanese conserved extended haplotypes (named HP-P1, HP-P2, and HP-P3) were essentially completely conserved at least in the 3.3-Mb HLA region from HLA-A to -DPB1, and extended far beyond HLA-A. The risk of acute graft-versus-host disease (GVHD) of these HLA haplotypes was assessed with multivariate Cox regression in 712 patients transplanted from HLA fully (HLA-A, B, C, DRB1, DQB1, and DPB1) matched unrelated donors. HP-P2 itself reduced the risk of grade 2 to 4 acute GVHD (hazard ratio [HR] = 0.63; P = .032 compared with HP-P2-negative), whereas HP-P3 tended to increase the risk (HR = 1.38; P = .07). Among 381 patients with HP-P1, HP-P1/P3 (HR = 3.35; P = .024) significantly increased the risk of acute GVHD compared with homozygous HP-P1. This study is the first to demonstrate that a genetic difference derived from HLA haplotype itself is associated with acute GVHD in allogeneic hematopoietic stem cell transplantation.

scholarly journals 2844. Butyrogenic Bacteria After Acute Graft vs. Host Disease Associate with the Development of Steroid Refractory GVHD

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S68-S68
Author(s):  
Jonathan L Golob ◽  
Martha M DeMeules ◽  
Tillie Loeffelholz ◽  
Z Z Quinn ◽  
Michael K Dame ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Electrical Resistance ◽  
Acute Gvhd ◽  
Host Disease ◽  
Direct Exposure ◽  
Increased Risk ◽  
Graft Vs Host Disease ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Background Steroid refractory acute graft- vs. -host-disease (GVHD) after hematopoietic cell transplantation (HCT) is highly morbid with limited treatment options. Murine studies show protection from GVHD with butyrate exposure but direct exposure of stem/progenitor cells to butyrate inhibits colonic stem cell proliferation. Methods Stool samples were collected weekly in a cohort of HCT recipients (n = 210) undergoing allogeneic transplant, and underwent 16S rRNA sequencing to determine the number and relative abundance of butyrogens. Dissociated primary human colonoid cell aggregates (200,000 per well) were plated onto collagen IV-coated transwells (0.4 µm pore size, 0.33 cm2, PET) in stem cell medium for 24 hours. From 24 hours onwards, the basal-lateral chamber was switched to differentiation medium; the apical chamber was Hanks Buffered Salt Solution (HBSS), HBSS with 10 mM butyrate sodium salt early (24 hours onwards) or late (72hours onwards). Trans-epithelial electrical resistance was measured daily. Results Retrospective chart review identified 27 recipients who developed acute GVHD of the gut, stratified to be either steroid refractory GVHD (failed to respond to 2 mg/kg of methylprednisolone) or responsive. The presence of butyrogens in the gut microbiome after the onset of severe acute GHVD of the gut associated with increased risk of steroid refractory GVHD (Figure 1; P < 0.05). Direct exposure of human colonic stem/progenitor cells to butyrate inhibits the development of trans-epithelial electrical resistance; exposure after differentiation had no inhibition of barrier formation (Figure 2; P < 0.05 by T-test). Conclusion Butyrogens may help prevent the development of acute GVHD of the gut, but once severe GVHD has developed may inhibit recovery due to the loss of crypt architecture exposing colonic stem cells to microbe-produced butyrate with impaired differentiation and cell replacement. Disclosures All Authors: No reported Disclosures.

scholarly journals Eculizumab treatment in a patient with hematopoietic stem cell transplantation-associated thrombotic microangiopathy and steroid-refractory acute graft versus host disease

2015 ◽  
Vol 7 (4) ◽  
Author(s):  
Cristina Fernández ◽  
Ana Lario ◽  
Rafael Forés ◽  
Rafael Cabrera
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Thrombotic Microangiopathy ◽  
Acute Gvhd ◽  
Marrow Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Analytical Response ◽  
Acute Graft

A 30-year-old man with acquired aplastic anemia underwent an HLA-identical bone marrow transplant. He developed a grade III acute graft <em>versus</em> host disease (GVHD) refractory to various lines of treatment. On post-transplant day 196, he was diagnosed with stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and he received treatment with eculizumab 900 mg iv weekly for 4 doses followed by a single dose of 1200 mg 2 weeks later. After the first dose of eculizumab, the patient ceased to require transfusions and a progressive improvement in analytical parameters for microangiopathy was observed until their complete normalization. Coinciding with the improved of HSCT-TMA, the patient presented a clear response to his acute GVHD with disappearance of the diarrhea and bilirubin normalization. He was discharged eight weeks after the start of treatment. Unfortunately, one month later, the patient was readmitted for a GVHD relapse and he died two weeks later by an acute respiratory distress syndrome. In our case, the rapid clinical and analytical response to early treatment with eculizumab supports the implication of the complement in HSCT-TMA and suggests that the drug has a beneficial effect when used as coadjuvant therapy in acute GVHD.

scholarly journals Fecal Microbiota Transplantation for Treating Steroid-Refractory Acute Graft-versus-Host Disease of the Gut

2021 ◽  
Vol 96 (4) ◽  
pp. 358-362
Author(s):  
Sang Hoon Yeon ◽  
Myung-Won Lee ◽  
Deog-Yeon Jo ◽  
Bu-Yeon Heo ◽  
Jaeyul Kwon ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Fecal Microbiome ◽  
Graft Versus Host ◽  
Steroid Refractory ◽  
Acute Graft

Restoring the microbiota via fecal microbiota transplantation (FMT) can be an effective treatment for steroid-refractory acute graft-versus-host disease (GVHD) of the gut. Here, we report two adult patients who underwent FMT to treat steroid-refractory acute GVHD of the gut. The first patient was a 43-year-old man who underwent allogeneic hematopoietic stem cell transplantation (HSCT) with cells from a matched sibling donor. The second patient was a 70-year-old woman who underwent haplo-identical HSCT with cells from her son. Gut GVHD developed at 7 and 4 weeks after HSCT, respectively. After undergoing FMT, the clinical symptoms improved; the first patient had a complete response and the second patient had a partial response. Microbial analyses using RNA gene sequencing showed that a diverse fecal microbiome was recovered by 4 weeks after FMT. FMT should be considered an effective therapeutic option for managing steroid-refractory acute GVHD of the gut.

Extracorporeal photopheresis and anticytokine therapy in the treatment of steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in children

2016 ◽  
Vol 7 (1) ◽  
pp. 58-64
Author(s):  
Andrey V Kozlov ◽  
Julia G Fedukova ◽  
Tatzana A Bykova ◽  
Ivan S Moiseev ◽  
Marya A Estrina ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Extracorporeal Photopheresis ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Anticytokine Therapy ◽  
Steroid Refractory ◽  
Acute Graft

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is used widely in the management of children with hematological, oncological and inherited diseases. Study to compare efficiency of steroid-refractory acute graft versus host disease treatment (extracorporeal photopheresis (ECP) vs anticytokine therapy) was conducted in Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of Saint Petersburg. Sixty four children were included in the analysis. Patients were divided into two groups: first “group with ECP” (n = 31; 50,5 %) ("ECP group") and second - "group without ECP" (n = 33; 49,5 %). Treatment in the second group consisted of anticytokine therapy (etanercept (n = 12), infliximab (n = 9), daclizumab (n = 8)) and alemtuzumab (n = 4). Ten-year overall survival (OS) of children with steroid-refractory acute graft versus host disease was 39 % without difference in OS between ECP and anticytokine therapy (5-year OS 40 % vs 35 %, p = 0,34). Response rate to the therapy was also the same in both groups (68 % after ECP and 70 % after anticytokine therapy, p = 0,77). Difference in cumulative incidence of relapse in "ECP group" and "group without ECP" was not statistically significant (18 % and 7 %, respectively, p = 0,2). In conclusion, ECP and anticytokine therapy are equally effective in the treatment of children with steroid-refractory acute graft versus host disease and are associated with the same cumulative incidence of relapse.

scholarly journals Ruxolitinib for Steroid-Refractory Acute Graft-Versus-Host Disease: A Single Centre Retrospective Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4878-4878
Author(s):  
Yuan Suo ◽  
Jiapei Liu ◽  
Yiming Sun ◽  
Qiaoyuan Wu ◽  
Hua Jin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retrospective Study ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Second Line ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Background Acute graft-versus-host disease (aGVHD) is the major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation(allo-HSCT). But only 40% of the patients will respond to first-line therapies Corticosteroids. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, reduces the incidence and severity of GVHD while preserving graft-versus-leukemia effects in preclinical models. The retrospective study evaluated the efficacy of ruxolitinib compared with other second-line therapies for steroid-refractory aGVHD (SR-aGVHD) in a single-center. Methods A total of 90 patients who developed SR-aGVHD after HSCT were evaluated in this retrospective study.They were treated with ruxolitinib (n=45) or other salvage-therapies (n=45) including MTX, basiliximab, etanercept and MSC at our institution. The primary endpoint was the overall response rate (ORR) at Day 28. Additional endpoints included overall survival (OS), cumulative incidence rates of failure-free survival (FFS), relapse, non-relapse mortality (NRM) and cGVHD. Treatment failure was defined as 1) addition of new systemic therapy for aGVHD, 2) NRM, 3) relapse, 4) progression of hematologic disease. FFS and OS were calculated from the day of starting the use of second-line treatments for aGVHD. Results The median age was 34 years (range 14-69). At the time of enrollment 25 patients had grade Ⅱ disease, 39 with grade Ⅲ disease, 26 with grade IV disease. The skin was involved in 54.4%, lower gastrointestinal (GI) tract in 78.9% and liver in 20.2%. With a median follow-up of 1.33 years, the ORR at day 28 was higher in ruxolitinib group than non-ruxolitinib group (62.2% [95% CI, 47.5%-77.0%] vs. 26.7% [95% CI, 13.2%-40.1%], P=0.001) (Table 1). The 1-year OS was 64.4 % and 45.5% in the two groups, respectively (P=0.0382). Ruxolitinib treatment also improved the 1-year cumulative incidence of FFS (57.8% vs. 26.6%, P=0.002), while the 1-year cumulative incidence of relapse did not differ significantly (9.6% vs. 20.0%, P=0.195). The 1-year cumulative incidence of NRM was lower in the ruxolitinib group than the non-ruxolitinib group (24.4% vs. 45.3%, P=0.023). The 1-year and 3-year cumulative incidence of cGVHD were 17.8% vs. 33.3% and 26.8% vs. 44.4% between the ruxolitinib group and non-ruxolitinib group (P=0.10 and P=0.04). Conclusions Our study demonstrated that ruxolitinib is effective than other second-line treatments in patients with SR-aGVHD due to the higher response rates and the improvement of prognosis. Furthermore, ruxolitinib could reduce the incidence and severity of chronic GVHD in aGVHD patients. Keywords: Ruxolitinib; Steroid-refractory; Acute graft-versus-host disease; Haploidentical hematopoietic stem cell transplantation Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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