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Expert Review of Hematology May 2017Post transplant cyclophosphamide (PT/Cy) in association to other immunosuppressive agents or alone has emerged as a promising pharmacological strategy in the setting of... (Review)
Review
Post transplant cyclophosphamide (PT/Cy) in association to other immunosuppressive agents or alone has emerged as a promising pharmacological strategy in the setting of allogeneic hematopoietic cell transplant (allo-HCT). Its safety profile and effectiveness in reducing GvHD (acute GvHD incidence comprised between 15 and 30%, chronic GvHD 20-30% in the haploidentical setting) contributed to the spreading of this technique all over the world. Areas covered: This review summarizes the use of PT/Cy in the setting of allo-HCT, both for oncological and non-malignant hematological diseases. Recent studies showed the feasibility of more intense conditioning regimens instead of the original NMAC. The use of peripheral blood stem cells instead of bone marrow as graft source (slightly increase of acute GvHD grade 2 but no differences in survival outcomes) was another significant variation to the original protocol. Later on, PT/Cy alone or in combination with other immunosuppressive agents (ATG, sirolimus, cyclosporine) were tested in the HLA-matched donor setting where lower GvHD rates are reported (acute GvHD grade 3 of 5-10% and chronic GvHD of 10-20%) Expert commentary: The best graft source and type of donor is still ongoing. Moreover, the research of the best pharmacological partner of PT/Cy remains an open question.
Topics: Acute Disease; Allografts; Antilymphocyte Serum; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Sirolimus
PubMed: 28395546
DOI: 10.1080/17474086.2017.1318054 -
Journal of Clinical Oncology : Official... Dec 2020
Topics: Antilymphocyte Serum; Hematologic Neoplasms; Humans; Research Design; Siblings; Tissue Donors
PubMed: 33104441
DOI: 10.1200/JCO.20.02841 -
Immunotherapy 2016Significant advances have been made in allogeneic hematopoietic cell transplantation by reducing toxicities and optimizing its efficacy. Antithymocyte globulin (ATG) is... (Review)
Review
Significant advances have been made in allogeneic hematopoietic cell transplantation by reducing toxicities and optimizing its efficacy. Antithymocyte globulin (ATG) is an important in vivo T-cell depletion strategy, which reduces the risk of graft-versus-host disease in HLA-matched or -mismatched donor allografting. ATG effectively targets alloreactive T cells at the expense of potentially increasing the risk of post-hematopoietic cell transplantation infections and delayed immune reconstitution. We summarize the targets, mechanisms, various preparations of ATG, the growing role of ATG in prevention of graft-versus-host disease in various transplant modalities as well as emerging data on pharmacokinetic modeling for individualized ATG dosing. Further research is needed to optimize the ATG administration while minimizing the toxicities.
Topics: Animals; Antilymphocyte Serum; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphocyte Depletion; T-Lymphocytes; Transplantation Conditioning; Transplantation, Homologous
PubMed: 26973125
DOI: 10.2217/imt.15.128 -
Nephrology, Dialysis, Transplantation :... Oct 2017Antithymocyte globulins (ATGs) are part of the immunosuppression arsenal currently used by clinicians to prevent or treat acute rejection in solid organ transplantation.... (Review)
Review
Antithymocyte globulins (ATGs) are part of the immunosuppression arsenal currently used by clinicians to prevent or treat acute rejection in solid organ transplantation. ATG is a mixture of non-specific anti-lymphocyte immunoglobulins targeting not only T cell subsets but also several other immune and non-immune cells, rendering its precise immunoglobulin composition difficult to appreciate or to compare from one preparation to another. Furthermore, several mechanisms of action have been described. Taken together, this probably explains the efficacy and the side effects associated with this drug. Recent data suggest a long-term negative impact on allograft and patient outcomes, pointing out the need to better characterize the potential toxicity and the benefit-risk balance associated to this immunosuppressive therapy within large clinical trials.
Topics: Animals; Antilymphocyte Serum; Graft Rejection; Humans; Immune Tolerance; Immunosuppressive Agents; Kidney Transplantation; Thymocytes
PubMed: 27798202
DOI: 10.1093/ndt/gfw368 -
Transplantation and Cellular Therapy Nov 2022Hitherto, the optimal timing of rabbit anti-thymocyte globulin (rATG) in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be...
Hitherto, the optimal timing of rabbit anti-thymocyte globulin (rATG) in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. We wanted to evaluate the effect of a new timing strategy of rATG in MSD-PBSCT patients on transplantation outcomes. In this prospective single-arm phase 2 clinical trial, 45 consecutive MSD-PBSCT patients were enrolled from February 1, 2019, to January 31, 2021. The rATG was administered intravenously at a total dose of 5 mg/kg from day -5 to day -2 before graft infusion (4d-ATG group). Thirty-seven MSD-PBSCT patients receiving rATG at the same total dose of 5 mg/kg from day -5 to day -4 before graft infusion from December 1, 2014, to January 31, 2019 served as historical control (2d-ATG group). No graft failure occurred in either group. In the 4d-ATG group, median timing to neutrophil and platelet engraftment was 12 days. The cumulative incidences (CI) of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) at day 100 were 37.8% and 4.4%. The 2-year CIs of severe chronic GVHD and extensive chronic GVHD were 2.2% and 9.6%. The rates of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation at day 180 were 24.4% and 37.8%, respectively. No patients died of non-relapse causes. Twenty-one patients relapsed at a median of 203 days after transplantation, and the 2-year cumulative incidence of relapse (CIR) was 51.4%. The 2-year probabilities of overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 72.4%, 48.6%, and 40.8%, respectively. There were no significant differences between the 4d-ATG group and 2d-ATG group with regard to timing of neutrophil and platelet engraftment, incidences of CMV reactivation, EBV reactivation, acute GVHD, chronic GVHD, probabilities of OS, and GRFS. The 2-year CIR was significantly increased, and the 2-year DFS was significantly reduced in 4d-ATG group compared with the control group (CIR: 51.4% versus 13.5%, P < .001; DFS: 48.6% versus 75.7%, P = .014). High CIR and worse DFS were noted in MSD-PBSCT receiving 4d-ATG regimen compared with historical control (2d-ATG regimen). Inappropriate rATG timing may increase the risk of relapse after MSD-PBSCT in patients with hematologic malignancies. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Topics: Humans; Peripheral Blood Stem Cell Transplantation; Antilymphocyte Serum; Siblings; Epstein-Barr Virus Infections; Prospective Studies; Herpesvirus 4, Human; Neoplasm Recurrence, Local; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Cytomegalovirus Infections
PubMed: 35973670
DOI: 10.1016/j.jtct.2022.08.012 -
American Journal of Hematology Jun 2023Immune severe aplastic anemia (SAA) is characterized by pancytopenia and immune-mediated bone marrow destruction. SAA may be treated with hematopoietic stem cell...
Immune severe aplastic anemia (SAA) is characterized by pancytopenia and immune-mediated bone marrow destruction. SAA may be treated with hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). However, 30% of patients treated with IST relapse. We previously reported a clinical trial of alemtuzumab in which more than half of 25 relapsed SAA patients (56%) responded hematologically. Here, we present long-term results of a total of 42 patients. Participants with SAA who had previously completed antithymocyte globulin (ATG)-based IST, but had relapsed, were enrolled on this study. Alemtuzumab was administered intravenously (IV) (n = 28) or subcutaneously (SC) (n = 14). The primary endpoint was hematologic response at 6 months. Secondary endpoints included relapse, clonal evolution, and survival. This trial was registered at clinicaltrials.gov (NCT00195624). Patients were enrolled over 9 years, with median follow-up of 6 years. Median age was 32 years, with 57% being female. At 6 months, 18 patients (43%) achieved response; 15 (54%) of those who received IV compared with 3 (21%) who received SC therapy. Six patients (14%) had durable long-term response without need for subsequent AA-directed therapy or HSCT at last follow-up. Nine patients had clonal evolution, with high-risk evolution occurring in 6. Overall survival was 67% at median follow-up of 6 years. Prolonged iatrogenic immunosuppression was observed as long as 2 years after alemtuzumab administration. Alemtuzumab induces responses in relapsed SAA, some of which are durable long-term. However, immunosuppression can persist for years, requiring long-term monitoring.
Topics: Humans; Female; Adult; Male; Immunosuppressive Agents; Cyclosporine; Alemtuzumab; Anemia, Aplastic; Treatment Outcome; Antilymphocyte Serum; Recurrence
PubMed: 37021397
DOI: 10.1002/ajh.26924 -
Immunotherapy Feb 2024Severe aplastic anemia (SAA) and very severe aplastic anemia (vSAA) are blood diseases of the bone marrow. If a suitable donor for bone marrow transplant as initial... (Review)
Review
WHAT IS THIS SUMMARY ABOUT?
Severe aplastic anemia (SAA) and very severe aplastic anemia (vSAA) are blood diseases of the bone marrow. If a suitable donor for bone marrow transplant as initial treatment is unavailable, standard immunosuppression is used. Standard immunosuppression treatment includes horse antithymocyte globulin (hATG) and cyclosporin A (CsA). This summary investigated the results of standard immunosuppression treatment (Group A) versus standard immunosuppression treatment with a medication called eltrombopag (Group B) in participants with SAA and vSAA. Eltrombopag is a medicine that improves the blood platelet level and is taken by mouth (orally).
WHAT WERE THE RESULTS OF THE STUDY?
Compared to Group A, more participants in Group B showed increased blood cell level to a normal range without SAA or vSAA and faster treatment response. Side effects were similar in both groups even with the addition of eltrombopag for Group B. Participants in both groups reported feeling well after 6, 12 and 24 months. Differences in the participant-reported scores (overall health, physical, emotional, and social) between Group A and Group B were minimal.
WHAT DO THE RESULTS OF THE STUDY MEAN?
Immunosuppression treatment (hATG plus CsA) with eltrombopag benefited participants with SAA and vSAA and could be the new standard for SAA in persons who cannot undergo bone marrow transplant. At this time, eltrombopag is only approved in specific countries to treat the condition under study that is discussed in this summary. NCT02099747 (RACE study).
Topics: Humans; Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Benzoates; Immunosuppressive Agents; Treatment Outcome
PubMed: 38088156
DOI: 10.2217/imt-2023-0200 -
Haematologica Feb 2019
Topics: Aged; Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Humans; Immunosuppressive Agents; Standard of Care; Surveys and Questionnaires
PubMed: 30705112
DOI: 10.3324/haematol.2018.207167 -
Frontiers in Immunology 2024Acquired aplastic anemia (AA) is an immune-mediated bone marrow (BM) failure where marrow disruption is driven by a cytotoxic T-cell-mediated autoimmune attack against... (Review)
Review
Acquired aplastic anemia (AA) is an immune-mediated bone marrow (BM) failure where marrow disruption is driven by a cytotoxic T-cell-mediated autoimmune attack against hematopoietic stem cells. The key diagnostic challenge in children, but also in adults, is to exclude the possible underlying congenital condition and myelodysplasia. The choice of treatment options, either allogeneic hematopoietic cell transplantation (alloHCT) or immunosuppressive therapy (IST), depends on the patient's age, comorbidities, and access to a suitable donor and effective therapeutic agents. Since 2022, horse antithymocyte globulin (hATG) has been available again in Europe and is recommended for IST as a more effective option than rabbit ATG. Therefore, an update on immunosuppressive strategies is warranted. Despite an improved response to the new immunosuppression protocols with hATG and eltrombopag, some patients are not cured or remain at risk of aplasia relapse or clonal evolution and require postponed alloHCT. The transplantation field has evolved, becoming safer and more accessible. Upfront alloHCT from unrelated donors is becoming a tempting option. With the use of posttransplant cyclophosphamide, haploidentical HCT offers promising outcomes also in AA. In this paper, we present the state of the art in the management of severe AA for pediatric and adult patients based on the available guidelines and recently published studies.
Topics: Humans; Anemia, Aplastic; Hematopoietic Stem Cell Transplantation; Adult; Child; Immunotherapy; Antilymphocyte Serum; Immunosuppressive Agents; Treatment Outcome; Animals
PubMed: 38646536
DOI: 10.3389/fimmu.2024.1378432 -
Frontiers in Endocrinology 2022Management of Graves' orbitopathy remains a challenge. Our previous case report has shown promising results for rabbit antithymocyte globulin (rATG) in the treatment of...
OBJECTIVE
Management of Graves' orbitopathy remains a challenge. Our previous case report has shown promising results for rabbit antithymocyte globulin (rATG) in the treatment of Graves' orbitopathy.
DESIGN
We present the response of 7 individuals with active moderate-to-severe steroid-resistant Graves' orbitopathy to rATG, representing preliminary results from a prospective single-center study.
METHODS
rATG was administered intravenously at a dose of 0.8-1.0 mg/kg daily (cumulative dose of 150-200 mg). The primary outcome measures at weeks 24 and 48 were ≥2-point reduction in Clinical Activity Score from baseline, a proptosis response, a diplopia response, and improvement of distant best-corrected visual acuity and mean retinal sensitivity. Key secondary outcomes included stabilization of ganglion cell complex thickness, a decrease of retinal nerve fiber layer in OCT, and a reduction in CD4/CD8 ratio and TRAb at 48 weeks.
RESULTS
An improvement in clinical activity score was observed in all patients, with disease inactivation in 3 cases. Proptosis reduction equal to or greater than 2 mm was noted for 8 of 10 eyes. Diplopia improved in three of 6 patients. There was an improvement in best-corrected visual acuity (from 0.69 to 0.78) and mean retinal sensitivity (from 20.8 to 23.5 dB). In addition, there was a long-lasting improvement in CD4/CD8 ratio in 6 patients. Two patients experienced adverse events (influenza and serum sickness).
CONCLUSION
rATG therapy offers a long-lasting improvement in moderate-to-severe steroid-resistant Graves' orbitopathy with improvement in functional vision (reduction of diplopia, improvement of visual acuity, retinal sensitivity, and VEP pattern). The therapy is well-tolerated.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT05199103.
Topics: Antilymphocyte Serum; Diplopia; Exophthalmos; Graves Ophthalmopathy; Humans; Prospective Studies
PubMed: 35615718
DOI: 10.3389/fendo.2022.871009