scholarly journals Children and Adults with Refractory Acute Graft-versus-Host Disease Respond to Treatment with the Mesenchymal Stromal Cell Preparation “MSC-FFM”—Outcome Report of 92 Patients

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1577 ◽  
Author(s):  
Halvard Bonig ◽  
Zyrafete Kuçi ◽  
Selim Kuçi ◽  
Shahrzad Bakhtiar ◽  
Oliver Basu ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Mononuclear Cells ◽  
Opportunistic Infections ◽  
Immunosuppressive Agents ◽  
Survival Rates ◽  
Third Party ◽  
Efficient Treatment ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.

Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells

The Lancet ◽  
2004 ◽  
Vol 363 (9419) ◽  
pp. 1439-1441 ◽  
Author(s):  
Katarina Le Blanc ◽  
Ida Rasmusson ◽  
Berit Sundberg ◽  
Cecilia Götherström ◽  
Moustapha Hassan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

scholarly journals Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2175-2182 ◽  
Author(s):  
Edward Seung ◽  
Neal Iwakoshi ◽  
Bruce A. Woda ◽  
Thomas G. Markees ◽  
John P. Mordes ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Mononuclear Cells ◽  
Autoimmune Diabetes ◽  
Third Party ◽  
Skin Allograft ◽  
Host Disease ◽  
Graft Versus Host ◽  
Islet Allografts ◽  
Hematopoietic Chimerism ◽  
Costimulatory Pathway

Abstract We describe a tolerance-based stem cell transplantation protocol that combines sublethal radiation with transient blockade of the CD40-CD154 costimulatory pathway using an anti-CD154 antibody. With this protocol, we established hematopoietic chimerism in BALB/c mice transplanted with fully allogeneic C57BL/6 bone marrow. The percentage of donor-origin mononuclear cells in recipients was more than 99%. In addition, all chimeric mice treated with anti-CD154 antibody remained free of graft-versus-host disease (GVHD) and accepted donor-origin but not third-party skin allografts. It was similarly possible to create allogeneic hematopoietic chimerism in NOD/Lt mice with spontaneous autoimmune diabetes. Pancreatic islet allografts transplanted into chimeric NOD/Lt mice were resistant not only to allorejection but also to recurrence of autoimmunity. We conclude that it is possible to establish robust allogeneic hematopoietic chimerism in sublethally irradiated mice without subsequent GVHD by blocking the CD40-CD154 costimulatory pathway using as few as 2 injections of anti-CD154 antibody. We also conclude that chimerism created in this way generates donor-specific allograft tolerance and reverses the predisposition to recurrent autoimmune diabetes in NOD/Lt mice, enabling them to accept curative islet allografts.

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

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5304-5304 ◽  
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.

scholarly journals A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment

Blood ◽  
1991 ◽  
Vol 77 (8) ◽  
pp. 1821-1828 ◽  
Author(s):  
PJ Martin ◽  
G Schoch ◽  
L Fisher ◽  
V Byers ◽  
FR Appelbaum ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Graft Versus Host Disease ◽  
Immunosuppressive Agents ◽  
Complete Response ◽  
Initial Therapy ◽  
Secondary Treatment ◽  
Glucocorticoid Treatment ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

We have reviewed results of secondary therapy in 427 patients with acute graft-versus-host disease (GVHD) who did not have a durable satisfactory response after primary treatment. At the beginning of secondary treatment, 320 patients (75%) had rash, 252 (59%) had liver dysfunction, and 228 (53%) had gut dysfunction. Secondary treatment was with glucocorticoids (n = 249), cyclosporine (n = 80), antithymocyte globulin (n = 114), or monoclonal antibody (n = 19) either singly (n = 390) or in combination (n = 37). Parameters of GVHD severity were recorded weekly, and responses were determined according to values at the initiation of tertiary treatment or, for patients without such treatment, using values on day 29 of secondary treatment or the last recorded values before death, whichever occurred first. Minimal criteria for improvement or deterioration were defined for each organ, but no attempt was made to define liver or gut outcome if another complication such as venocclusive disease or infectious enteritis was present. Improvement or resolution of GVHD in the respective organ was seen in 45% of patients with skin disease, 25% of patients with evaluable liver disease, and in 35% of patients with evaluable gut disease. Overall complete or partial responses were seen in 40% of patients. The highest complete response rate with secondary therapy (23%) was seen when GVHD recurred during the taper phase of primary glucocorticoid treatment and was managed by increasing the dose of glucocorticoids. Multivariate analyses were performed to identify patient, disease, or treatment factors associated with likelihood of complete response or overall improvement. A similar analysis was performed to identify covariates associated with time to treatment failure (defined as initiation of tertiary therapy or death not due to relapse of malignancy). Severe dysfunction in the skin, liver, and gut at the beginning of treatment was associated both with a decreased likelihood of complete response and an increased treatment failure rate. The times to treatment failure and the proportions of patients in various response categories were similar for primary and secondary treatment, suggesting that the potential efficacy of new immunosuppressive agents for treatment of acute GVHD can be assessed meaningfully in patients who have not responded adequately to initial therapy.

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

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2918-2918 ◽  
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, 21 had complete responses, eight showed improvement, eight patients did not respond, two had stable disease and one patient was not evaluated due to short follow-up. Twenty 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.

Sirolimus Yields High Response Rates in Hematopoietic Allograft Recipients with Steroid-Refractory Acute Graft-Versus-Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2235-2235
Author(s):  
Joseph A. Pidala ◽  
Daanish Hoda ◽  
Norma Salgado-Vila ◽  
Jongphil Kim ◽  
Janelle Perkins ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Immunosuppressive Agents ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Maximum Decrease ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Abstract 2235 Poster Board II-212 Acute graft-versus-host disease (aGVHD) remains the major cause of morbidity and mortality in allogeneic hematopoietic cell transplant recipients. There is no consensus in regards to the best therapy for patients who fail to respond to, or do not tolerate, systemic glucocorticoids. We evaluate the efficacy of sirolimus in 34 pts, median age of 49 (23-67) years, with steroid-refractory (N=31) or steroid-intolerant (N=3) aGVHD. The diagnosis of aGVHD was established at a median of 34 (7-1042) days after transplantation, and confirmed by biopsy in all cases. Initial treatment of aGVHD consisted of prednisone up to 2 mg/kg. Sirolimus was initiated at a median of 9 (1-255) days after glucocorticoid initiation. A loading dose of sirolimus was administered to 19 (56%) of 34 pts, median 6 (3-8) mg, followed by maintenance therapy of 1-2 mg per day with doses adjusted to target therapeutic trough levels between 4 and 12 ng/ml; therapeutic levels were achieved in all cases. The overall response rate was 76%. Fifteen (44%) of the 34 pts achieved a CR after sirolimus initiation and without requiring additional immune suppressive agents. CR was achieved in 11/31 (42%) steroid-refractory patients, and in 2/3 (67%) steroid-intolerant patients. The median overall survival (OS) after initiation of sirolimus was 5.6 months, and one year OS was 44% (95% C.I. 27%-60%). Maximum decrease in dose of steroids over 12 weeks following sirolimus was a median of 50% (range 0-100%). Fourteen (42%) of 33 pts reached a dose < 20 mg of prednisone at a median of 4 months (95% CI: 3.5-13.5) after initiation of sirolimus. Seven (21%) of 34 pts were free from steroids after a median of 20 months (95% CI: 9.2-20.0) after initiation of sirolimus. Two pts were shown to be successfully liberated from all immunosuppressive agents without recurrent GVHD at 2.7 and 7.1 months after initiation of sirolimus, respectively. These data indicate the sirolimus is effective in controlling steroid-refractory aGVHD. Further studies are needed to determine the most appropriate timing for sirolimus after transplantation, whether prophylaxis, primary or secondary GVHD therapy. Disclosures: Off Label Use: Sirolimus for graft-versus-host disease.

Increased Plasma Indoleamine 2,3-Dioxygenase Activity Correlates with the Severity of Acute Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1985-1985
Author(s):  
Jinhuan Xu ◽  
Yicheng Zhang
Keyword(s):  
Graft Versus Host Disease ◽  
Mononuclear Cells ◽  
Healthy Controls ◽  
Rt Pcr ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Indoleamine 2,3 Dioxygenase ◽  
Blood Mononuclear Cells ◽  
Acute Graft

Abstract Abstract 1985 Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism, which plays an important role in the induction of immune tolerance. To evaluate the expression level of IDO in the patients receiving hematopoietic stem cell transplantation (HSCT) and to identify the possible correlation between IDO activity and acute graft-versus-host disease (aGVHD), we collected blood samples from 96 patients before and after HSCT and 10 healthy volunteers served as controls. The expression of IDO mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells of the patients and healthy controls. Reverse-phase high-performance liquid chromatography (HPLC) was performed to analyze the level of kynurenine (Kyn) and tryptophan (Trp) in plasma. The IDO activity was calculated as the ratio of kyn to trp. Plasma IFNgama was measured by standard ELISA. RT-PCR showed that IDO mRNA was detected in 65 of 85(65/85, 76.5%) patients with aGVHD; in patients without aGVHD, only 1 of them express IDO mRNA (1/11, 9.1%); none of 10 healthy volunteers was positive for the IDO expression. The plasma IDO activity was much higher in aGVHD group than those without aGVHD(4.49¡À0.46 vs. 1.69¡À0.9, respectively; p < 0.0001) or the healthy controls(4.49¡À0.46 vs. 1.77¡À0.22, respectively; p < 0.0001). Patients with severe aGVHD (grade III/IV) had significantly higher IDO activity than those with mild aGVHD (grade I/II) (6.74¡À0.58 vs. 2.17¡À0.79, respectively; p < 0.0001). IDO activity was decreased following effective treatment of aGVHD, while fluctuation of plasma IDO was also observed upon the recurrence of aGVHD. The plasma IDO activity was correlated with the IFNgama level(r=0.8816). Conclusion: The IDO mRNA was expressed in blood mononuclear cells from patients with aGVHD. The plasma IDO activity was elevated in aGVHD and correlated with severity of aGVHD. In combination with plasma IFNgama, IDO may serve as a potential biomarker for the diagnosis and evaluation of aGVHD following HSCT; intervention of IDO pathway may also provide an alternative way to overcome the steroids resistant aGVHD. Keywords: acute graft-versus-host disease, Indoleamine 2,3-dioxygenase, hematopoietic stem cell transplantation Disclosures: No relevant conflicts of interest to declare.

scholarly journals Third-party regulatory T cells prevent murine acute graft-versus-host disease

2018 ◽  
Vol 33 (5) ◽  
pp. 980-989 ◽  
Author(s):  
Jung-Yeon Lim ◽  
Keon-Il Im ◽  
Yunejin Song ◽  
Nayoun Kim ◽  
Young-Sun Nam ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

scholarly journals A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment

Blood ◽  
1991 ◽  
Vol 77 (8) ◽  
pp. 1821-1828 ◽  
Author(s):  
PJ Martin ◽  
G Schoch ◽  
L Fisher ◽  
V Byers ◽  
FR Appelbaum ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Graft Versus Host Disease ◽  
Immunosuppressive Agents ◽  
Complete Response ◽  
Initial Therapy ◽  
Secondary Treatment ◽  
Glucocorticoid Treatment ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract We have reviewed results of secondary therapy in 427 patients with acute graft-versus-host disease (GVHD) who did not have a durable satisfactory response after primary treatment. At the beginning of secondary treatment, 320 patients (75%) had rash, 252 (59%) had liver dysfunction, and 228 (53%) had gut dysfunction. Secondary treatment was with glucocorticoids (n = 249), cyclosporine (n = 80), antithymocyte globulin (n = 114), or monoclonal antibody (n = 19) either singly (n = 390) or in combination (n = 37). Parameters of GVHD severity were recorded weekly, and responses were determined according to values at the initiation of tertiary treatment or, for patients without such treatment, using values on day 29 of secondary treatment or the last recorded values before death, whichever occurred first. Minimal criteria for improvement or deterioration were defined for each organ, but no attempt was made to define liver or gut outcome if another complication such as venocclusive disease or infectious enteritis was present. Improvement or resolution of GVHD in the respective organ was seen in 45% of patients with skin disease, 25% of patients with evaluable liver disease, and in 35% of patients with evaluable gut disease. Overall complete or partial responses were seen in 40% of patients. The highest complete response rate with secondary therapy (23%) was seen when GVHD recurred during the taper phase of primary glucocorticoid treatment and was managed by increasing the dose of glucocorticoids. Multivariate analyses were performed to identify patient, disease, or treatment factors associated with likelihood of complete response or overall improvement. A similar analysis was performed to identify covariates associated with time to treatment failure (defined as initiation of tertiary therapy or death not due to relapse of malignancy). Severe dysfunction in the skin, liver, and gut at the beginning of treatment was associated both with a decreased likelihood of complete response and an increased treatment failure rate. The times to treatment failure and the proportions of patients in various response categories were similar for primary and secondary treatment, suggesting that the potential efficacy of new immunosuppressive agents for treatment of acute GVHD can be assessed meaningfully in patients who have not responded adequately to initial therapy.

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