Subcutaneous Alemtuzumab May Be Useful in the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2983-2983
Author(s):  
David Gomez-Almaguer ◽  
Guillermo J. Ruiz-Arguelles ◽  
Oscar Gonzalez-Llano ◽  
Homero C. Gutierrez-Aguire ◽  
Olga G. Cantu-Rodriguez ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Background: Acute graft-versus-host disease (GvHD) is mediated by activated T lymphocytes. Alemtuzumab is an unconjugated, humanized IgG1 kappa monoclonal antibody which targets the CD52 antigen on T lymphocytes and other cells and has been used successfully in conditioning regimens for allogeneic transplantation to remove donor T cells so as to prevent GvHD. Patients and methods: Eighteen patients with steroid-refractory acute GvHD ≥ grade II were analyzed to evaluate the safety and efficacy of alemtuzumab. The patients received subcutaneous alemtuzumab 10 mg daily on days 1–5. The proportion of patients with grade II, III and IV were eight, eight and two, respectively. The main organ involved was the liver in four, gut in five, skin and liver in three, and skin and gut in three patients. Results: Fifteen out of 18 patients (83%) responded to alemtuzumab with 6 (33%) complete and 9 (50%) partial responses. All three unresponsive patients died of GvHD. Ten of 15 responders are alive at a median follow-up of 9 months (range 2–23) after alemtuzumab, with limited, extensive and no signs of chronic GvHD in 1, 4, and 5 patients, respectively. Fourteen patients (78%) developed some kind of infection; eleven of them developed cytomegalovirus reactivation. All patients tolerated alemtuzumab with minimal side effects; grade 3 neutropenia and thrombocytopenia were seen in six and four patients, respectively. Conclusions: Alemtuzumab is a well tolerated agent and has a beneficial effect in the treatment of steroid-refractory acute GvHD. Infections are common and anti-infective prophylaxis is mandatory.

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.

Early Onset of Acute Graft-Versus-Host Disease Indicating a Worse Prognosis in Terms of Chronic Graft-Versus-Host Disease and Survival Compared to Late Onset.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4979-4979
Author(s):  
Sang Kyun Sohn ◽  
Joon Ho Moon ◽  
Jong Gwang Kim ◽  
Yee Soo Chae ◽  
Yoon Young Cho ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Early Onset ◽  
Acute Gvhd ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Onset Time ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

Abstract Background: Acute graft-versus-host disease (GVHD) is an important risk factor for predicting chronic GVHD. The transplant outcome can be influenced by the onset time of acute GVHD in patients who received allogeneic stem cell transplantation (SCT) Methods: The medical records of one hundred six patients with hematological malignancies who received allogeneic transplantation were retrospectively reviewed. Results: Fifty four (39.7%) patients developed grade II to IV acute GVHD within D+30 after allogeneic SCT (<D+30 group) and 13 (9.6%) patients manifested acute GVHD after D+30 (≥D+30 group). The cumulative incidence of chronic GVHD was 81.5% and 53.8% in <D+30 group and ≥D+30 group, respectively.(p<0.001) On multivariate analysis, grade II to IV acute GVHD developed before D+30 and primary diagnosis of chronic myeloid leukemia were identified as independent variables predicting chronic GVHD. The overall survival rate was significantly lower in the <D+30 group than grade 0 or I group (p<0.001). But there was no statistical difference between the group with grade 0 or I and ≥D+30 group in terms of the incidence of chronic GVHD (p=0.295). Among the 54 patients with grade II to IV acute GVHD developed at before D+30, 26 (48.1%) patients developed into quiescent chronic GVHD and 20 (37%) patients progressive chronic GVHD. The quiescent chronic GVHD showed a better survival than progressive chronic GVHD (p=0.063). Conclusion: Acute GVHD of early onset (within D+30) was regarded as a worse prognostic indicator in terms of chronic GVHD and survival.

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.

Acute Graft Versus Host Disease after Donor Lymphocyte Infusion: A Single Center Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5807-5807
Author(s):  
Fiona C. He ◽  
Daniel J. Weisdorf ◽  
Erica D. Warlick ◽  
Jeffrey S. Miller ◽  
Shernan G. Holtan ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Significant Risk ◽  
Donor Lymphocyte Infusion ◽  
Myelogenous Leukemia ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

Abstract Donor lymphocyte infusion (DLI) is an option for relapsed hematologic malignancies following allogeneic hematopoietic cell transplantation (HCT). We analyzed the incidence and manifestations of acute graft versus host disease (GVHD) in patients with malignant and non-malignant conditions treated with DLI. At the University of Minnesota, we gave 171 DLI to 120 patients from 1995-2013. The cumulative incidence of grade II-IV acute GVHD was 31.6% (CI 25-42%,n = 40); grade III-IV 23.3% (CI 16-32%,n = 29). GVHD after DLI (n = 46) included involvement of skin in 70% (n = 32), lower gastrointestinal (GI) 65% (n = 30), upper GI 43% (n = 20), and liver 35% (n = 16). Patients receiving chemotherapy prior to DLI (chemo-DLI) had more frequent acute GVHD and GI GVHD. Significant risk factors for grade II-IV acute GVHD included: age > 40, chemo-DLI, malignant disease, and time from HCT to DLI < 200 days. Response to treatment of acute GVHD at 8 weeks was complete in 40% and complete/partial in 52%. Patients developing GVHD had frequent disease response. In chronic myelogenous leukemia (CML) patients, responses were excellent (80%) with or without GVHD. The CR rate was 34% for non-CML malignancies; only 9% achieved CR without acute GVHD. Non-malignant diseases showed poor prognosis following acute GVHD and good prognosis without. Overall survival at 2 years for CML patients was similar (83% vs 79%, p = 0.89) with or without grade II-IV acute GVHD, but in non-CML malignancies survival was better in absence of acute GVHD (41% vs 22%, p = 0.04). We observed frequent, yet therapy-responsive acute GVHD following DLI. DLI often induced remission in CML, but less so for non-CML malignancies without chemo-DLI, particularly in absence of acute GVHD. Improvements in DLI efficacy and GVHD management are still needed. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3214-3219 ◽  
Author(s):  
Mary E. D. Flowers ◽  
Yoshihiro Inamoto ◽  
Paul A. Carpenter ◽  
Stephanie J. Lee ◽  
Hans-Peter Kiem ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Human Leukocyte ◽  
National Institutes Of Health ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

scholarly journals Butyrogenic bacteria after acute graft-versus-host disease (GVHD) are associated with the development of steroid-refractory GVHD

2019 ◽  
Vol 3 (19) ◽  
pp. 2866-2869 ◽  
Author(s):  
Jonathan L. Golob ◽  
Martha M. DeMeules ◽  
Tillie Loeffelholz ◽  
Z. Z. Quinn ◽  
Michael K. Dame ◽  
...  
Keyword(s):  
Stem Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Epithelial Monolayer ◽  
Graft Versus Host ◽  
Key Points ◽  
Colonic Stem Cells ◽  
Steroid Refractory ◽  
Acute Graft

Key Points The presence of butyrogenic bacteria after the onset of acute GVHD associates with subsequent steroid-refractory GVHD or chronic GVHD. Butyrate inhibits human colonic stem cells from forming an intact epithelial monolayer.

Excellent Long-Term Survival of Patients with Steroid-Refractory and Steroid-Dependent Acute Graft-Versus-Host Disease after Extracorporeal Photochemotherapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1244-1244
Author(s):  
Hildegard T. Greinix ◽  
Robert M. Knobler ◽  
Nina Worel ◽  
Margit Mitterbauer ◽  
Axel Schulenburg ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Complete Response ◽  
Graft Versus Host ◽  
Steroid Dependent ◽  
Grade Ii ◽  
Grade Iii ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Despite posttransplantation immunosuppressive therapy, acute graft-versus-host disease (GVHD) remains a major cause of sickness and death. Second-line therapies for steroid-refractory acute GVHD have been used with limited success. Extracorporeal exposure of peripheral blood mononuclear cells to the photosensitizing agent 8-methoxypsoralen and UV-A radiation (ECP) has been shown to be effective in the treatment of selected diseases mediated by T cells. We have reviewed the responses and long-term outcome of 59 hematopoietic stem cell transplant (HSCT) patients treated from 1996 to 2003 with ECP for steroid-refractory acute GVHD, defined as progression or no improvement of acute GVHD after a minimum of 4 (range, 4–49, median 17) days of treatment with prednisone (n=37) or steroid-dependent acute GVHD, defined as flare-up of GVHD during prednisone taper (n=22). Patients received HSCT from 17 related and 42 unrelated donors. In 28 cases an HLA-mismatch between recipient and donor was present. Prior to ECP, grade III–IV GVHD was observed in 23 patients (39%) and grade II GVHD in 36 (61%). Organs involved included skin in 97% of patients, liver in 39%, and GI tract in 17%. Treatment consisted of ECP on two consecutive days per week (=1 cycle) for a median of 7 (range, 1–45) cycles administered within a median of 3 (range, 0.5–31) months in addition to cyclosporine A and prednisone. Three months after initiation of ECP complete resolution of GVHD was achieved in 82% of patients with cutaneous, 61% with liver, and 61% with gut involvement. Complete responses were obtained in 86% of patients with grade II, 55% of patients with grade III, and 30% of patients with grade IV acute GVHD. Probability of transplant-related mortality (TRM) at 4 years after HSCT is 15% in patients with complete response to ECP compared to 88% in patients not responding completely. After a median follow-up of 46 (range, 9–45) months since discontinuation of ECP, 28 (47%) patients are alive including 22 without chronic GVHD. Probability of survival (OS) at 4 years after HSCT is 59% in patients with complete response to ECP compared to 11% in patients not responding completely. Besides response to ECP only organ involvement and grade of GVHD at start of ECP, and ability to timely taper steroids during ECP had a significant impact on both TRM and OS. Thus, ECP is an effective adjunct therapy for acute steroid-refractory and steroid-dependent GVHD. Our long-term results demonstrate durability of responses without adverse events.

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.

CCR5 Expression On Circulating Blood DC Post-Allogeneic Hemopoietic Cell Transplant Is Highly Predictive for the Development of Clinically Significant Acute Graft Versus Host Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2251-2251
Author(s):  
Mary M Sartor ◽  
Jenny Lau ◽  
David J Gottlieb ◽  
Kenneth F Bradstock
Keyword(s):  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Chemokine Receptors ◽  
Acute Gvhd ◽  
Ccr5 Expression ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ccr7 Expression ◽  
Grade Ii ◽  
Acute Graft

Abstract Abstract 2251 Poster Board II-228 Introduction: Dendritic cells (DC) are central to the development of acute graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT). We previously showed that the activation status, as assessed by CMRF-44 antigen expression, of blood CD11c+ myeloid DC is highly associated with the severity of acute GvHD, and that activated DC may be detected in the circulation prior to clinical presentation of GvHD (Transplantation 2007;83: 839–846). Because DC migration is tightly regulated by the interaction between chemokine receptors on DC and their ligands, we investigated the relationship between the severity of acute GvHD and the expression of the chemokine receptors CCR5 and CCR7 on CD11c+myeloid and CD11c- plasmacytoid from the peripheral blood of 32 patients post alloHCT. Methods: Peripheral blood was collected twice weekly up to day 100 post transplant from 22 patients who received transplants from matched siblings, 10 from unrelated donors. Nineteen transplants were performed with myeloablative conditioning, 13 with reduced intensity conditioning. The expression of each chemokine receptor on CD11c+ and CD11c- DC was calculated using multiparameter flow cytometry. The percentage of CD11c+ DC expressing a given receptor was added to the percentage of CD11c- DC expressing the same receptor to give a maximum score that could vary from 0 to 200%. Results: Eleven of 32 patients developed moderate to severe acute GvHD (grade II-IV), the remaining 21 patients developed either no GvHD or only grade I GvHD. The percentage of DC expressing either CCR5 or CCR7 was correlated with the development of acute GvHD. CCR7 expression was detected in 13 of 32 patients post-HCT with a median of 2.3% of DC positive (range 0 to 39%). CCR7 expression on DC showed no association with the severity of acute GvHD (p=1.0). In contrast, higher CCR5 expression was detected on DC in patients developing grade II-IV GvHD (median 98.0%, SEM 9.1%) than in those with grade 0-I GvHD (median 5.2%, SEM 5.1%) p<0.0001. All eleven patients with grade II-IV GvHD expressed CCR5 at a level of >35% of myeloid and plasmacytoid DC. Only two of 21 patients with grade I GvHD expressed CCR5 at the same level (66% and 94%). Most importantly, the expression of CCR5 preceded the development of moderate to severe GvHD in all patients by a median of 19 days (range 2 to 47 days, SEM 4.3 days). Using a receiver operator curve analysis, CCR5 expression above 35% demonstrated a sensitivity of 100% and a specificity of 90.5% for predicting grade II-IV GvHD. Conclusion: Expression of CCR5 on circulating DC post allo-HCT predicts for the development of moderate to severe GvHD, and detection could allow earlier therapeutic intervention prior to the development of clinical GVHD, if these findings are confirmed in a larger study Disclosures: No relevant conflicts of interest to declare.

scholarly journals Quantitative assessment of posttransplant host-specific interleukin-2- secreting T-helper cell precursors in patients with and without acute graft-versus-host disease after allogeneic HLA-identical sibling bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 841-848
Author(s):  
T Nierle ◽  
D Bunjes ◽  
R Arnold ◽  
H Heimpel ◽  
M Theobald
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Interleukin 2 ◽  
T Helper ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

Recent studies in mice and humans have emphasized an important contribution of host-reactive minor histocompatibility antigen (mH)- specific lymphokine-secreting donor T-helper cells (Th) for the induction of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). By using limiting dilution (LD) and clonal specificity analyses, we investigated in 14 patients with and without acute GVHD after non-T-depleted HLA-identical sibling BMT whether posttransplant host-reactive mH-specific interleukin-2 (IL-2)- secreting Th are involved in the development of clinically significant acute GVHD and the establishment of tolerance. At different time intervals posttransplant (I, days 0 through 45; II, days 45 through 90; III, days 90 through 180), host-specific IL-2-secreting Th-precursors (Th-p) were quantitatively assessed in six patients during clinically apparent grade II-III acute GVHD. Frequencies of responding Th-p ranged from 1/13,000 to 1 4,000. The presence of host-specific Th-p was significantly correlated with the development of grade II-III acute GVHD (P = .0003 by Fisher's exact test). The detectability of host- specific Th-p preceded the clinical onset of grade II-III acute GVHD. Host-specific Th-p were no longer detectable after the clinical resolution of grade II-III acute GVHD. No subsequent chronic GVHD was observed in these patients. However, prolonged occurrence of host- specific Th-p was accompanied by clinically persisting acute GVHD and the onset of secondary chronic GVHD. In patients with no acute GVHD (grade 0) (n = 7) and grade I (n = 1) acute GVHD, host-specific Th-p were not detectable at all. We conclude that host-reactive Th are critically involved in the development and maintenance of acute GVHD and may contribute to the establishment of tolerance after genotypically HLA-identical sibling BMT.

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