scholarly journals Assessment of Individual versus Composite Endpoints of Acute Graft-versus-Host Disease in Determining Long-Term Survival after Allogeneic Transplantation

2019 ◽  
Vol 25 (8) ◽  
pp. 1682-1688
Author(s):  
John Magenau ◽  
Thomas Braun ◽  
Erin Gatza ◽  
Tracey Churay ◽  
Amanda Mazzoli ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Allogeneic Transplantation ◽  
Term Survival ◽  
Long Term Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Composite Endpoints ◽  
Acute Graft

Early Intervention with Mesenchymal Stromal Cells for Refractory Grade III-IV Graft Versus Host Disease In Children Results In Excellent Long Term Outcome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2336-2336
Author(s):  
Lynne Margaret Ball ◽  
Maria E. Bernardo ◽  
Jaap Jan Zwaginga ◽  
Maarten van Tol ◽  
Angela Cometa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Immune Suppression ◽  
Term Survival ◽  
Long Term Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory

Abstract Abstract 2336 Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with severe, steroid-refractory, acute graft-versus-host disease (aGVHD). However, long term comprehensive follow up data on pediatric patients is limited. We analyzed the outcome of 37 children receiving MSC for steroid-refractory aGvHD in two centers between January 2005 and December 2009 (characteristics see Table 1). A median of 2 infusions (range 1–13) were administered, with a median cell dose of 2×106/kg (range 0.9–3.0). MSC were from 3rd party HLA-mismatched donors (n=31), haploidentical relative (n=3) or both (n=3). (see Table 2) Fifteen children had either no (n=6) or partial (n=9) response to MSC. In this group, transplantation-related mortality (TRM) was 60%. Complete response (CR) was observed in 22 children, TRM being 14%. (p=0.005). Among the 28 patients with hematological malignancies, 5 relapsed, three with CR and two with PR. With a median follow-up of 2.3 years (range 7 months–4.7 years), overall survival was 62% with 87% versus 27% in patients who did or did not achieve CR after MSC respectively (p value <0.001). MSC after 2009 given at the time of steroid failure (median 8 days range 4 to 24) compared to pre 2009 (median 24 days range 5 to 85) (Maan-Whitney U = 65.5 two tailed p= 0.002) reduced fatal infections and was associated with a trend to better overall survival at 2 years post MSC infusion (p = 0.07). Although infections were evident at the time of immune suppression and mortality was high in NR/PR, response to MSC allows for reduction and eventual discontinuation of pharmacological immune suppression. Long term survival in responders is associated with eventual immune recovery, no late infections and persistent remission status. Treatment of steroid refractory aGVHD should aim to induce rapid stable control and early reduction of steroids to reduce TRM from viral reactivations. We conclude that MSC are ideal candidates for this purpose. Our results show that children responding to MSC treatment for severe steroid refractory GvHD have an excellent long term survival. Legend: ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; jMML = juvenile myelomonocytic leukemia; HLH = hemophagocytic lymphohistiocytosis; MSD = matched sibling donor; (m) MUD (mis) Matched unrelated donor; PBSC = peripheral blood stem cells; TBI = total body irradiation; CSA = Cyclosporine A; MTX = short course methrotrexate; ATG = anti-thymocyte globulin; HSCT = hematopoietic stem cell transplantation; DLI = donor lymphocyte infusion; GvHD = graft versus host disease; M=Male; F=Female. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Acute graft-versus-host disease: a bench-to-bedside update

Blood ◽  
2014 ◽  
Vol 124 (3) ◽  
pp. 363-373 ◽  
Author(s):  
Shernan G. Holtan ◽  
Marcelo Pasquini ◽  
Daniel J. Weisdorf
Keyword(s):  
Small Molecules ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Multiple Modalities ◽  
Graft Versus Host ◽  
The Past ◽  
Prevention And Treatment ◽  
Near Future ◽  
Acute Graft

Abstract Over the past 5 years, many novel approaches to early diagnosis, prevention, and treatment of acute graft-versus-host disease (aGVHD) have been translated from the bench to the bedside. In this review, we highlight recent discoveries in the context of current aGVHD care. The most significant innovations that have already reached the clinic are prophylaxis strategies based upon a refinement of our understanding of key sensors, effectors, suppressors of the immune alloreactive response, and the resultant tissue damage from the aGVHD inflammatory cascade. In the near future, aGVHD prevention and treatment will likely involve multiple modalities, including small molecules regulating immunologic checkpoints, enhancement of suppressor cytokines and cellular subsets, modulation of the microbiota, graft manipulation, and other donor-based prophylaxis strategies. Despite long-term efforts, major challenges in treatment of established aGVHD still remain. Resolution of inflammation and facilitation of rapid immune reconstitution in those with only a limited response to corticosteroids is a research arena that remains rife with opportunity and urgent clinical need.

Pentostatin Therapy for Steroid-Refractory Acute Graft Versus Host Disease: Identifying Those Who May Benefit

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3136-3136
Author(s):  
Brittany Knick Ragon ◽  
Alison M Gulbis ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Partial Response ◽  
Graft Versus Host Disease ◽  
Term Survival ◽  
Graft Versus Host ◽  
Baseline Characteristics ◽  
Third Line ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Patients with steroid-refractory acute graft versus host disease (aGVHD) have dismal outcomes. Historically, anti-thymocyte globulin has been used in this setting with prior reports demonstrating that even when patients respond, long-term survival occurs in only 5% of patients (Arai et al, 2012). Unfortunately, no therapy has been shown to improve outcomes for this high-risk group. Pentostatin, a potent adenosine deaminase inhibitor, was previously tested in a phase 1/ 2 study in steroid-refractory aGVHD and demonstrated an overall survival (OS) of 25% with a median follow-up of < 3 months (m). We performed a retrospective review of patients receiving pentostatin for steroid-refractory aGVHD with the goal of characterizing long-term outcomes. Methods: All patients transplanted at MD Anderson Cancer Center from January, 2006 to December, 2014 who received at least one dose of pentostatin for steroid-refractory aGVHD were included in this analysis. Pentostatin was dosed at 1.5 mg/m2 on days 1-3 and repeated every two weeks as indicated. Patients who received the drug as GVHD prophylaxis, upfront therapy, beyond third-line, for classic chronic GVHD or following relapse were excluded. Primary endpoints included day 28 response and OS. Results: A total of 60 patients received pentostatin as second (n=22) or third line (n=38) treatment for steroid-refractory aGVHD. The median age was 52 years (range, 2-70). First dose of pentostatin was administered at a median 69 days post-transplant (27-595) with a median of 3 doses provided (range, 1-9). A majority of patients had steroid-refractory lower GI (78%) and/or liver (43%) GVHD. Baseline characteristics described in table 1. The median time from initiation of steroids to pentostatin was 15 days (range, 4-172). OS at 18 m after pentostatin initiation was 21%, with median follow-up of 19 m (range, 7-77).A total of 22 (37%) patients died before day 28 and were considered non-responders. Day 28 response rate was 33% with 20 patients achieving a complete (n=11) or partial response (n=9). Pentostatin administration <10 days following initiation of steroid was the only predictor for day 28 response (HR 2.2, 95% CI 1.2-4.3, p=0.02). The median survival was 25 and 341 days in non-responders and responders, respectively. Landmark analysis starting on day 29 after pentostatin is shown in figure 1. Predictors for OS on multivariate analysis at 18 m included: day 28 complete/partial response (CR/PR) as a time dependent variable (HR 0.3, 95% CI 0.1-0.7, p=0.005), liver GVHD (HR 2.2, 95% CI 1.2-4.1, p=0.007), and age >60 (HR 1.9, 95% CI 0.99-3.6, p=0.05). Within our analysis, patients destined for early mortality within 30 days of pentostatin exhibited all these features: liver GVHD, receipt of pentostatin >100 days from transplant, and age >60, with an OS of 35% at 30 days compared to 72% in the absence of these features (p=0.001). Conclusions: Patients with steroid refractory aGVHD have dismal outcomes. However, long-term survival does occur, especially when additional therapy is administered promptly. Novel strategies to identify patients who are destined to fail upfront therapies are likely to improve outcomes. We identified that earlier dosing of pentostatin after recognition of steroid refractoriness improved response rates. Further, patients without liver GVHD and who were ≤60 had better OS, identifying those who will benefit most from this therapy. Conversely, pentostatin should be avoided in patients >60 with liver GVHD as these patients had extremely high mortality with two-thirds dying by day 30. Table 1. Baseline characteristics at pentostatin initiation. Variable Patients (N=60) Preparative Regimen Intensity  Non-myeloablative (%) 22 (37)  Ablative (%) 38 (63) Overall GVHD Grade  2 (%) 11 (18)  3 (%) 21 (35)  4 (%) 28 (47) Skin GVHD Stage  0 (%) 48 (80)  1 (%) 4 (7)  2 (%) 5 (8)  3 (%) 3 (5) Lower GI GVHD Stage  0 (%) 12 (20)  1 (%) 10 (17)  2 (%) 6 (10)  3 (%) 11 (18)  4 (%) 20 (33)  Unknown (%) 1 (2) Liver GVHD Stage  0 (%) 33 (55)  1 (%) 4 (7)  2 (%) 9 (15)  3 (%) 6 (10)  4 (%) 7 (11)  Unknown (%) 1 (2) Number of GVHD sites  1 (%) 40 (67)  2 (%) 15 (25)  ≥3 (%) 5 (8) Day 28 Response  CR (%) 11 (18)  PR (%) 9 (15)  No Response (%) 11 (18)  GVHD Progression (%) 5 (9)  Died by Day 28 (%) 22 (37)  Progression of Malignancy (%) 2 (3) Figure 1. OS, starting at day 29, stratified by response. Figure 1. OS, starting at day 29, stratified by response. Disclosures Alousi: Therakos, Inc: Research Funding.

scholarly journals Long-Term Follow-Up of a Pilot Study Using Placenta-Derived Decidua Stromal Cells for Severe Acute Graft-versus-Host Disease

2019 ◽  
Vol 25 (10) ◽  
pp. 1965-1969 ◽  
Author(s):  
Behnam Sadeghi ◽  
Mats Remberger ◽  
Britt Gustafsson ◽  
Jacek Winiarski ◽  
Gianluca Moretti ◽  
...  
Keyword(s):  
Pilot Study ◽  
Graft Versus Host Disease ◽  
Stromal Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Long Term Follow Up ◽  
Acute Graft

The Disease Status at Transplant Is the Major Factor Association with the Long Term Survival of HLA Haploidentical Peripheral Blood Stem Cells Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5107-5107
Author(s):  
Binyi Wu ◽  
Lanxiao Wu ◽  
Kunyuan Guo ◽  
Chaoyang Song ◽  
Dingan Yan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cells ◽  
Term Survival ◽  
Long Term Survival ◽  
Graft Versus Host ◽  
Blood Stem Cells ◽  
Stem Cells Transplantation

Abstract Objective: To evaluate the factors effecting the long term survival of refractory leukemia patients who received the therapy of HLA haploidentical peripheral blood stem cells transplantation. Methods: To analysis the factors effecting long term survival of refractory leukemia patients who underwent HLA haploidentical peripheral blood stem cells transplantation. The HLA mismatched locus between the donors and patients, the disease status of patients at transplant, the grafted mononucleaer cells number, and the occurrence of GVHD, the age of patients and other factors were considered and analyzed by data reduction SSP11. From July, 1998 to May, 2004, 30 Patients with refractory leukemia patients including 13 cases of acute non-lymphocytes leukemia, 10 cases of acute lymphocytes leukemia, 6 cases chronic myeloid leukemia and 1 cases of non-Hodgkin lymphoma underwent HLA haploidentical peripheral blood stem cells transplantations. The median age was 25 years old (3– 52 years old). Twelve patients received stem cells from parents, four from daughter and son, and the other from sibling donors. Twelve patients received three HLA locus mismatched stem cells, thirteen patients received two HLA mismatched donors stem cells, and five patients received one HLA mismatched donors stem cells. The conditioning regime consisted of fludara (25mg/m2 X5d), busufan (4mg/kg X4d) and cyclophosphamide ( 60mg/kg X2d). Median dose of rabbit anti-human lymphocyte globulin (5mg/kg X5d) was added in the in some patients. A mean of 6.0 x 108 /kg (3–9 x108 /kg) mono-nucleated cells was grafted. The mean CD34+ cells number was 5.5 x106 /Kg (3–6.5 x106/kg). Results: Twenty-nine patients were successfully grafted and one failed to graft. The mean time of white cell count more than 1x109/L was 13 days (10–18 days) and 12 days (9–16) respectively. Severe acute graft versus host disease occurred in six patients, and four died. Seven patients suffered from intensive chronic graft versus host disease. Nine patients relapsed and died. The mean relapse time was 10 months (3 months to 24 months). Four patients died from intensive chronic graft versus host disease. Fourteen patients are still disease free survival with high karnofsky performs. The relapse of leukemia was the main cause of death. Five the patients less than 20 year’s old age are still disease free survival with high karnofsky performs scores. Conclusion: HLA haploidentical peripheral blood stem cells transplantation may be an effect therapy for refractory leukemia. Although graft versus leukemia effect may be strong in HLA haploidentical blood stem cells transplantation, leukemia relapse is still the main cause to death. We suggest that for these patients with leukemia who can not find full matched donor perform related HLA mismatched peripheral blood stem cells transplantation as earlier as to get the better long term outcome.

Association between Regimen Related Toxicity and Acute-Graft-Versus-Host Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5017-5017
Author(s):  
Edward A. Copelan
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Tissue Injury ◽  
Critical Factor ◽  
Allogeneic Transplantation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Grade 3 ◽  
Acute Graft

Abstract Tissue injury resulting from preparative therapy for transplantation is integral to the development of acute graft-versus-host disease (GVHD) according to current theory. If toxicity to normal tissues is a critical factor in the pathophysiology of GVHD, greater degrees of regimen related toxicities should be associated with a higher incidence and greater severity of GVHD. We analyzed 438 patients who underwent allogeneic transplantation from related (n=360) or unrelated (78) donors and who survived > 100 days following transplantation. Patients had received preparative regimens of BuCy (n=340) or BuCyVP16 (n=98). Median age was 36 (range 4–66). There were 263 males and 175 females. This cohort survived a median of 35 months (range 3 months to 20 years). Sixty-eight of these patients had developed (Bearman) grade 3-4 regimen related toxicities. These patients had a 50% incidence of acute GVHD > grade II and a 26% incidence of developing GVHD ≤ grade II, compared to significantly lower incidences of 33% (P=.01) and 14% (P=.02) respectively in the group experiencing < grade 3 regimen related toxicity. Exclusion of patients whose GVHD prophylactic regimens were significantly altered because of toxicity did not significantly influence these results. This data suggest that patients who develop severe regimen related toxicity are significantly more likely to develop severe acute GVHD, supporting a potential pathophysiologic role for tissue injury in the development of acute GVHD.

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