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The New England Journal of Medicine Jan 2022A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG)... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia.
METHODS
In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months.
RESULTS
Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome.
CONCLUSIONS
The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Antilymphocyte Serum; Benzoates; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hydrazines; Immunosuppression Therapy; Immunosuppressive Agents; Male; Middle Aged; Progression-Free Survival; Prospective Studies; Pyrazoles; Receptors, Thrombopoietin; Remission Induction; Young Adult
PubMed: 34986284
DOI: 10.1056/NEJMoa2109965 -
Transplantation May 2020With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated... (Review)
Review
With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.
Topics: Antilymphocyte Serum; Consensus; Graft Rejection; Humans; Immunosuppression Therapy; Isoantibodies; Kidney Transplantation; Societies, Medical; Tissue Donors
PubMed: 31895348
DOI: 10.1097/TP.0000000000003095 -
Blood Jan 2024B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells are the most potent treatment against multiple myeloma (MM). Here, we review the increasing body... (Review)
Review
B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells are the most potent treatment against multiple myeloma (MM). Here, we review the increasing body of clinical and correlative preclinical data that support their inclusion into firstline therapy and sequencing before T-cell-engaging antibodies. The ambition to cure MM with (BCMA-)CAR T cells is informed by genomic and phenotypic analysis that assess BCMA expression for patient stratification and monitoring, steadily improving early diagnosis and management of side effects, and advances in rapid, scalable CAR T-cell manufacturing to improve access.
Topics: Humans; Immunotherapy, Adoptive; Multiple Myeloma; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; Antilymphocyte Serum
PubMed: 38033289
DOI: 10.1182/blood.2023021221 -
British Journal of Haematology Jun 2020The prognosis in Myelodysplastic syndromes (MDS), although recently refined by molecular studies, remains largely based on conventional prognostic scores [International... (Review)
Review
The prognosis in Myelodysplastic syndromes (MDS), although recently refined by molecular studies, remains largely based on conventional prognostic scores [International Prognostic Scoring System (IPSS), revised IPSS], classifying patients into "lower risk" MDS (LR-MDS) and "higher risk" MDS (HR-MDS). In LR-MDS, treatment mainly aims at improving cytopenias, principally anaemia, while in HR-MDS it aims at delaying disease progression and prolonging survival. In LR-MDS without deletion 5q, anaemia is generally treated first by erythropoietic stimulating factors, while second line treatments are currently not approved [lenalidomide, hypomethylating agents (HMA), luspatercept] or rarely indicated (antithymocyte globulin). Lenalidomide has major efficacy in LR-MDS with deletion 5q. Allogeneic stem cell transplantation (allo-SCT) is sometimes considered in LR-MDS, and iron chelation can be considered when multiple red blood cell transfusions are required. Allo-SCT is the only potentially curative treatment for HR-MDS; however, it is rarely applicable. It is generally preceded by intensive chemotherapy (IC) or HMA in patients with excess of marrow blasts (especially if >10%). In other patients, HMA can improve survival. The role of new drugs, including venetoclax or, in case of specific mutations, IDH1 or IDH2 inhibitors, is investigated. IC is mainly indicated as a bridge to allo-SCT, in the absence of unfavourable karyotype.
Topics: Activin Receptors, Type II; Adult; Antilymphocyte Serum; Bridged Bicyclo Compounds, Heterocyclic; Erythrocyte Transfusion; Female; Humans; Immunoglobulin Fc Fragments; Lenalidomide; Male; Mutation; Myelodysplastic Syndromes; Recombinant Fusion Proteins; Sulfonamides
PubMed: 31568568
DOI: 10.1111/bjh.16206 -
American Journal of Transplantation :... Mar 2022The IgG-degrading enzyme derived from Streptococcus pyogenes (Imlifidase, Hansa Biopharma) is a novel agent that cleaves all four human subclasses of IgG and has... (Review)
Review
The IgG-degrading enzyme derived from Streptococcus pyogenes (Imlifidase, Hansa Biopharma) is a novel agent that cleaves all four human subclasses of IgG and has therapeutic potential for HLA desensitization in kidney transplantation and antibody-mediated rejection. Data from clinical trials in kidney transplantation demonstrated rapid degradation of anti-HLA donor-specific antibodies facilitating HLA-incompatible transplantation, which led to conditional approval of imlifidase by the European Medicines Agency for desensitization in kidney transplant recipients of a deceased donor with a positive cross match. Important considerations arising from the early experiences with imilfidase on kinetics of donor-specific antibodies after administration, timing of complementary therapeutic monoclonal or polyclonal IgG antibodies, and interference with cross match assays should be recognized as imlifidase emerges as a therapeutic agent for clinical transplantation.
Topics: Antilymphocyte Serum; Graft Rejection; HLA Antigens; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Tissue Donors
PubMed: 34467625
DOI: 10.1111/ajt.16828 -
Blood Reviews May 2021Treatment options for newly diagnosed aplastic anemia (AA) patient includes upfront allogeneic hematopoietic stem cell transplant (HSCT) or immunosuppressive therapy... (Review)
Review
Treatment options for newly diagnosed aplastic anemia (AA) patient includes upfront allogeneic hematopoietic stem cell transplant (HSCT) or immunosuppressive therapy (IST). With recent advances in supportive care, conditioning regimens and post-transplant immunosuppression the overall survival for HSCT approaches 70-90%. Transplant eligibility needs to be assessed considering age, comorbidities, donor availability and probability of response to immunosuppressive therapy (IST). Upfront HSCT should be offered to children and young adults with matched related donor (MRD). Upfront HSCT may also be offered to children and young adults with rapidly available matched unrelated donor (MUD) who require urgent HSCT. Bone marrow (BM) graft source and cyclosporine (CsA) plus methotrexate (MTX) as graft versus host disease (GVHD) prophylaxis are preferable when using anti-thymocyte globulin (ATG) based conditioning regimens. Alemtuzumab is an acceptable alternative to ATG and is used with CsA alone and with either BM or peripheral blood stem cells (PBSC). Cyclophosphamide (CY) plus ATG conditioning is preferable for patients receiving MRD transplant, while Fludarabine (Flu) based conditioning is reserved for older adults, those with risk factors of graft failure and those receiving MUD HSCT. For haploidentical transplant, use of low dose radiotherapy and post-transplant cyclophosphamide has resulted in a marked reduction in graft failure and GVHD.
Topics: Age Factors; Allografts; Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Methotrexate; Risk Factors; Transplantation Conditioning; Unrelated Donors; Vidarabine
PubMed: 33187812
DOI: 10.1016/j.blre.2020.100772 -
Hematology/oncology and Stem Cell... Jun 2022Hepatitis-associated aplastic anemia (HAAA) is a rare illness, characterized by onset of pancytopenia with a hypoplastic bone marrow that traditionally occurs within 6... (Review)
Review
Hepatitis-associated aplastic anemia (HAAA) is a rare illness, characterized by onset of pancytopenia with a hypoplastic bone marrow that traditionally occurs within 6 months of an increase in serum aminotransferases. HAAA is observed in 1% to 5% of all newly diagnosed cases of acquired aplastic anemia. Several hepatitis viruses have been linked to the disease, but in many cases no specific virus is detected. The exact pathophysiology is unknown; however, immune destruction of hematopoietic stem cells is believed to be the underlying mechanism. HAAA is a potentially lethal disease if left untreated. Management includes immunosuppression with antithymocyte globulin and cyclosporine and allogeneic hematopoietic stem cell transplantation.
Topics: Humans; Anemia, Aplastic; Antilymphocyte Serum; Hepatitis; Immunosuppression Therapy; Cyclosporine
PubMed: 33197413
DOI: 10.1016/j.hemonc.2020.10.001 -
American Journal of Orthodontics and... Sep 2019
Topics: Antilymphocyte Serum; Data Collection; Kidney Transplantation; Sensitivity and Specificity
PubMed: 31474255
DOI: 10.1016/j.ajodo.2019.06.006 -
Blood Reviews Nov 2023In search of an ideal partner or alternative to conventional immunosuppressive agents, rabbit anti-thymocyte globulin (ATG) and, more recently, post-transplant... (Review)
Review
In search of an ideal partner or alternative to conventional immunosuppressive agents, rabbit anti-thymocyte globulin (ATG) and, more recently, post-transplant cyclophosphamide (PT-Cy) have both emerged as valid and efficient options for preventing graft-versus-host disease (GvHD). To further reduce the risk of GvHD, strategies combining ATG and PT-Cy have recently been investigated. In a haploidentical setting, retrospective studies suggest that combining PT-Cy and ATG may result in a lower incidence of chronic GvHD without increasing the risks of infection or relapse, when compared to PT-Cy without ATG. In haploidentical or unrelated donor settings, adding reduced doses of PT-Cy to ATG may reduce the risk of acute and chronic GvHD and improve survival, particularly GvHD-free, relapse-free survival (GRFS), when compared to ATG without PT-Cy. Overall, the combination of PT-Cy and ATG is a safe and promising approach for patients with hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation (HSCT).
Topics: Humans; Antilymphocyte Serum; Retrospective Studies; Neoplasm Recurrence, Local; Cyclophosphamide; Graft vs Host Disease; Hematologic Neoplasms; Bronchiolitis Obliterans Syndrome; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning
PubMed: 37085459
DOI: 10.1016/j.blre.2023.101080 -
International Journal of Hematology Mar 2024Acquired aplastic anemia is an immune-mediated disease that targets hematopoietic stem cells, which is diagnosed by findings of peripheral blood pancytopenia and...
Acquired aplastic anemia is an immune-mediated disease that targets hematopoietic stem cells, which is diagnosed by findings of peripheral blood pancytopenia and hypocellular bone marrow. Although the diagnostic definition is simple, differential diagnosis from other overlapping hematopoietic disorders such as hypoplastic myelodysplastic syndrome and inherited bone marrow failure syndrome is not easy. Immune suppressive therapy and allogeneic hematopoietic stem cell transplantation are important treatment approaches for aplastic anemia, and both have advanced in recent years. This issue of Progress in Hematology covers four topics related to aplastic anemia: (1) laboratory markers to identify immune pathophysiology and their role on differential diagnosis and prognosis, (2) the path to combination therapy with horse anti-thymocyte globulin, cyclosporine A, and eltrombopag, (3) more than 60 years of history and recent trends in allogeneic HSCT, and (4) genetic testing for differential diagnosis from IBMFS and novel approaches to transplantation for children including fludarabine/melphalan-based conditioning.
Topics: Child; Humans; Anemia, Aplastic; Pancytopenia; Hematopoietic Stem Cell Transplantation; Cyclosporine; Antilymphocyte Serum
PubMed: 38310173
DOI: 10.1007/s12185-024-03715-1