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Neal S Young – 1st expert on this subject based on the ideXlab platform
retreatment with rabbit anti thymocyte Globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemiaBritish Journal of Haematology, 2006Co-Authors: Phillip Scheinberg, Olga Nunez, Neal S YoungAbstract:
The management of patients with severe aplastic anaemia (SAA) who do not have a matched sibling donor and fail a course of horse Anti-Thymocyte Globulin (h-ATG)/ciclosporin (CsA) is uncertain. Repeated courses of ATG-based immunosuppression are often employed; in children and increasingly in adults, alternative donor haematopoietic stem cell transplantation is an option. We analysed the success rate of retreatment with rabbit ATG (r-ATG)/CsA in 43 patients treated at our institution in the last 5 years; 22 were refractory (20 adults; two children) to h-ATG/CsA-based regimens and 21 (17 adults; four children) had relapsed after h-ATG/CsA-based regimens. The overall response rate was 30% in patients who were refractory to h-ATG and 65% in patients who had relapsed following h-ATG. The 1000-d survival in patients who responded to r-ATG was 90% compared with 65% in non-responders. Six patients developed a clonal haematological disorder; two were responders, two were non-responders and in two the evolution occurred before the response could be assessed at 3 months following r-ATG. Thirteen patients died; three were responders, six were non-responders and four patients died prior to 3 months when response was assessed. In our study, the response rate in refractory patients was inferior to what has been previously reported.
treatment of severe aplastic anaemia with combined immunosuppression anti thymocyte Globulin ciclosporin and mycophenolate mofetilBritish Journal of Haematology, 2006Co-Authors: Phillip Scheinberg, Olga Nunez, Colin O Wu, Neal S YoungAbstract:
Severe aplastic anaemia (SAA) can be successfully treated with immunosuppressive therapies or haematopoietic stem cell transplantation (HSCT). Response rates with horse Anti-Thymocyte Globulin (h-ATG) plus ciclosporin (CsA) are about 60-70%, and robust responders have an excellent long-term survival. We introduced a third immunosuppressive agent to standard h-ATG/CsA, mycophenolate mofetil (MMF), in an attempt to improve the response rate and survival, and to decrease the relapse rate and clonal evolution to myelodysplasia. A total of 104 consecutive patients with SAA were treated with h-ATG/CsA/MMF between May 1999 and June 2003 at the National Institutes of Health Clinical Center. The overall response rate at 6 months was 62%, with 24 (37% of responders) patients relapsing at a median of 389 d from ATG. Nine patients showed evidence of clonal evolution following ATG. After a median follow up of 42 months, the median survival among responders was not reached and among non-responders was 58 months. Over half of the relapses occurred during MMF administration. Despite a strong theoretical rationale for its use, MMF did not result in the improvement of response or relapse rates when compared with historical standard h-ATG/CsA.
Michael Haller – 2nd expert on this subject based on the ideXlab platform
low dose anti thymocyte Globulin preserves c peptide reduces hba1c and increases regulatory to conventional t cell ratios in new onset type 1 diabetes two year clinical trial dataDiabetes, 2019Co-Authors: Michael Haller, Desmond A. Schatz, Alice S Long, Lori J Blanchfield, Jay S Skyler, Jeffrey P Krischer, Brian N Bundy, Susan Geyer, Megan V Warnock, Jessica L MillerAbstract:
A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose Anti-Thymocyte Globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P
anti thymocyte Globulin g csf treatment preserves β cell function in patients with established type 1 diabetesJournal of Clinical Investigation, 2015Co-Authors: Michael Haller, Clive Wasserfall, Stephen E Gitelman, Peter A Gottlieb, Aaron W Michels, Stephen M Rosenthal, Jonathan J Shuster, Todd M Brusko, Maigan A Hulme, Clayton E MathewsAbstract:
BACKGROUND. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose Anti-Thymocyte Globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years). METHODS. A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m 2 ; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years. RESULTS. Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001–0.552, P = 0.050). A1c was lower in ATG/G-CSF–treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. CONCLUSIONS. Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease.
Irwin Walker – 3rd expert on this subject based on the ideXlab platform
addition of anti thymocyte Globulin to standard graft versus host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors final analysis of a randomised open laThe Lancet Haematology, 2020Co-Authors: Irwin Walker, Tony Panzarella, Stephen Couban, Felix Couture, Gerald M Devins, Mohamed Elemary, Genevieve GallagherAbstract:
Summary Background Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of Anti-Thymocyte Globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint. Methods This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative–reduced intensity conditioning. Patients were randomly assigned to receive Anti-Thymocyte Globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723 , status completed. Findings Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive Anti-Thymocyte Globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the Anti-Thymocyte Globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·60–7·60]; p=0·0016. At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·9–23·7) in the Anti-Thymocyte Globulin plus GVHD prophylaxis group compared with 17·5 (9·9–25·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·2–29·2) versus 31·3% (21·9–40·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·5–35·1) in the Anti-Thymocyte Globulin group and 41·3% (31·3–51·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 53·3% (95% CI 42·8–62·7) in the Anti-Thymocyte Globulin plus GVHD prophylaxis group compared with 70.6% (95% CI 60·6–78·6) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·35–0·90]; p=0·017. Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the Anti-Thymocyte Globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the Anti-Thymocyte Globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the Anti-Thymocyte Globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient died of Epstein-Barr virus hepatitis. Interpretation The results of this prespecified 24-month analysis suggest that pretreatment with Anti-Thymocyte Globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including a decrease in use of immunosuppressive therapy, chronic GVHD and its symptoms, depressive symptoms, and improved overall survival. Anti-Thymocyte Globulin could be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation. Funding Canadian Institutes of Health Research and Sanofi.