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International Journal of Hematology Mar 2024The treatment of aplastic anemia (AA) has significantly advanced in the last 50 years, evolving from a fatal condition to one where survival rates now exceed 80-85%.... (Review)
Review
The treatment of aplastic anemia (AA) has significantly advanced in the last 50 years, evolving from a fatal condition to one where survival rates now exceed 80-85%. Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have become the primary treatments, with the latter widely adopted due to factors like the scarcity of compatible donors, patient age, comorbidities, and limited HSCT access. A therapy breakthrough was the introduction of antithymocyte globulin (ATG), with its effectiveness further boosted by cyclosporine. However, it took years to achieve another major milestone in management. Initially, treatments aimed to intensify immunosuppression following the success of the ATG-cyclosporine combination, but these methods fell short of expectations. A major turning point was combining immunosuppression with stem cell stimulation, surpassing the efficacy of IST alone. Earlier, growth factors had shown limited success in AA treatment, but thrombopoietin receptor agonists represented a significant advancement. Initially applied alone as salvage, these were later combined with IST, forming the most effective current regimen for medically managing SAA. Horse ATG is the preferred formulation combined with cyclosporine and eltrombopag. This progress in AA treatment offers improved outcomes for patients afflicted with this once-lethal disease.
Topics: Humans; Immunosuppressive Agents; Anemia, Aplastic; Cyclosporine; Antilymphocyte Serum; Immunosuppression Therapy; Treatment Outcome
PubMed: 38403842
DOI: 10.1007/s12185-024-03713-3 -
Transplantation Proceedings Apr 2024ABO-incompatible (ABOi) transplantation is a novel method transplantation method that carries a heightened risk of infection caused by the use of high immunosuppressant...
High-Dose Intravenous Immunoglobulin to Treat Anti-Thymocyte Globulin Induction-Related BK Virus and Cytomegalovirus Infection in Patients with ABO-Incompatible Kidney Transplantation.
BACKGROUND
ABO-incompatible (ABOi) transplantation is a novel method transplantation method that carries a heightened risk of infection caused by the use of high immunosuppressant doses. This elevated risk is particularly concerning for viral infections, such as cytomegalovirus (CMV) and the BK virus (BKV) increases. Herein, we present a case where high-dose intravenous immunoglobulin (IVIG) was effective in treating viral infections after transplantation.
METHODS
A 41-year-old man underwent an ABOi transplantation. The initial isoagglutinin titer was 1:32. The patient received 200 mg of rituximab, and 3 rounds of plasmapheresis were performed. Subsequently, renal function remained normal; however, 7 months later, the renal function declined, and BK nephropathy and CMV infection were diagnosed through biopsy and serologic tests. The FK level was reduced, and mycophenolate mofetil was discontinued. Although ciprofloxacin and leflunomide were administered, their effects were minimal. Therefore, high-dose IVIG (1 g/kg) was administered 5 times over 5 weeks, which led to a reduction in BK viral load and CMV infectivity in the serum.
CONCLUSIONS
High-dose IVIG may serve as a promising alternative treatment to mitigate early transplant rejection and BKV and CMV infections.
Topics: Humans; Kidney Transplantation; Male; Adult; Immunoglobulins, Intravenous; Polyomavirus Infections; BK Virus; Tumor Virus Infections; Cytomegalovirus Infections; Antilymphocyte Serum; ABO Blood-Group System; Immunosuppressive Agents; Blood Group Incompatibility
PubMed: 38388292
DOI: 10.1016/j.transproceed.2024.01.031 -
Frontiers in Immunology 2024The process of immunization following vaccination in humans bears similarities to that of immunization with allografts. Whereas vaccination aims to elicit a rapid...
INTRODUCTION
The process of immunization following vaccination in humans bears similarities to that of immunization with allografts. Whereas vaccination aims to elicit a rapid response, in the transplant recipient, immunosuppressants slow the immunization to alloantigens. The induction of CD4+CXCR5+ T follicular helper (Tfh) cells has been shown to correlate with the success of vaccine immunization.
METHOD
We studied a cohort of 65 transplant recipients who underwent histological evaluation concurrent with PBMC isolation and follow-up sampling to investigate the phenotypic profiles in the blood and allotissue and analyze their association with clinical events.
RESULTS
The proportion of circulating Tfh cells was heterogeneous over time. Patients in whom this compartment increased had lower CCR7-PD1+CD4+CXCR5+ T cells during follow-up. These patients exhibited more alloreactive CD4+ T cells using HLA-DR-specific tetramers and a greater proportion of detectable circulating plasmablasts than the controls. Examination of baseline biopsies revealed that expansion of the circulating Tfh compartment did not follow prior intragraft leukocyte infiltration. However, multicolor immunofluorescence microscopy of the grafts showed a greater proportion of CXCR5+ T cells than in the controls. CD4+CXCR5+ cells were predominantly PD1+ and were in close contact with B cells in situ. Despite clinical stability at baseline, circulating Tfh expansion was associated with a higher risk of a composite of anti-HLA donor-specific antibodies, rejection, lower graft function, or graft loss.
CONCLUSION
In otherwise stable patients post-transplant, circulating Tfh expansion can identify ongoing alloreactivity, detectable before allograft injury. Tfh expansion is relevant clinically because it predicts poor graft prognosis. These findings have implications for immune surveillance.
Topics: Humans; T-Lymphocytes, Helper-Inducer; T Follicular Helper Cells; Transplant Recipients; Leukocytes, Mononuclear; CD4-Positive T-Lymphocytes; Antilymphocyte Serum
PubMed: 38384450
DOI: 10.3389/fimmu.2024.1275933 -
Blood Cancer Journal Feb 2024The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC)... (Randomized Controlled Trial)
Randomized Controlled Trial
Post-transplant cyclophosphamide versus anti-thymocyte globulin after reduced intensity peripheral blood allogeneic cell transplantation in recipients of matched sibling or 10/10 HLA matched unrelated donors: final analysis of a randomized, open-label, multicenter, phase 2 trial.
The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679.
Topics: Humans; Antilymphocyte Serum; Unrelated Donors; Siblings; Quality of Life; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Retrospective Studies
PubMed: 38374026
DOI: 10.1038/s41408-024-00990-3 -
Cytotherapy Apr 2024Traditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease...
Impact of rabbit anti-thymocyte globulin (ATG) exposure on outcomes after ex vivo T-cell-depleted hematopoietic cell transplantation in pediatric and young adult patients.
BACKGROUND AIMS
Traditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft rejection leads to variable exposures. High exposures induce delayed CD4+immune reconstitution (CD4+IR) and greater mortality. We sought to determine the impact of rATG exposure in children and young adults receiving various types of EX-VIVO T-cell-depleted (EX-VIVO-TCD) HCT.
METHODS
Patients receiving their first EX-VIVO-TCD HCT (CliniMACS CD34+, Isolex or soybean lectin agglutination), with removal of residual T cells by E-rosette depletion (E-) between 2008 and 2018 at Memorial Sloan Kettering Cancer Center were retrospectively analyzed. rATG exposure post-HCT was estimated (AU*d/L) using a validated population pharmacokinetic model. Previously defined rATG-exposures, <30, 30-55, ≥55 AU*d/L, were related with outcomes of interest. Cox proportional hazard and cause-specific models were used for analyses.
RESULTS
In total, 180 patients (median age 11 years; range 0.1-44 years) were included, malignant 124 (69%) and nonmalignant 56 (31%). Median post-HCT rATG exposure was 32 (0-104) AU*d/L. Exposure <30 AU*d/L was associated with a 3-fold greater probability of CD4+IR (P < 0.001); 2- to 4-fold lower risk of death (P = 0.002); and 3- to 4-fold lower risk of non-relapse mortality (NRM) (P = 0.02). Cumulative incidence of NRM was 8-fold lower in patients who attained CD4+IR compared with those who did not (P < 0.0001). There was no relation between rATG exposure and aGVHD (P = 0.33) or relapse (P = 0.23). Effect of rATG exposure on outcomes was similar in three EX-VIVO-TCD methods.
CONCLUSIONS
Individualizing rATG dosing to target a low rATG exposure post-HCT while maintaining total cumulative exposure may better predict CD4+IR, reduce NRM and increase overall survival, independent of the EX-VIVO-TCD method.
Topics: Humans; Child; Young Adult; Antilymphocyte Serum; Retrospective Studies; T-Lymphocytes; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Transplantation Conditioning
PubMed: 38349310
DOI: 10.1016/j.jcyt.2024.01.004 -
Bone Marrow Transplantation May 2024
Impact of antithymocyte globulin usage and risk stratification for posttransplant lymphoproliferative disorders in aplastic anemia patients after allogeneic hematopoietic cell transplantation.
Topics: Humans; Anemia, Aplastic; Antilymphocyte Serum; Hematopoietic Stem Cell Transplantation; Lymphoproliferative Disorders; Male; Female; Adult; Middle Aged; Adolescent; Allografts; Transplantation, Homologous; Retrospective Studies; Aged; Young Adult; Risk Assessment; Child
PubMed: 38341498
DOI: 10.1038/s41409-024-02234-1 -
The Lancet. Haematology Mar 2024Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who...
BACKGROUND
Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who are 40 years or older. However, ATG requires in-hospital administration, is associated with infusion-related toxicities and has limited availability worldwide. In this study, we investigated the activity and safety of an ATG-free regimen of eltrombopag with cyclosporin A as a potential treatment for patients with severe aplastic anaemia who might not have access to or cannot tolerate horse-ATG.
METHODS
SOAR was a multicentre, single-arm phase 2 trial investigating eltrombopag and cyclosporin in adult (≥18 years) patients with severe aplastic anaemia who were treatment-naive and had an Eastern Cooperative Oncology Group performance status of less than 2. Participants were recruited from 20 hospitals in ten countries. Eltrombopag was initiated at 150 mg (100 mg in patients of Asian ethnicity) and cyclosporin at 10 mg/kg per day (adjusted to a trough of 200-400 μg/L) orally from day 1 to 6 months. The primary outcome was an overall haematological response rate by 6 months in the intention-to-treat population. This is the final report of the primary analysis period. The trial was registered with ClinicalTrials.gov, NCT02998645, and has been completed.
FINDINGS
54 patients were enrolled between May 11, 2017, and March 23, 2020. 34 (63%) patients were male and 20 (37%) were female. 22 (41%) were Asian, 22 (41%) were White, one (2%) was Native American or Alaska Native, one (2%) was Black or African American, and eight (15%) were other race or ethnicity. 35 patients (65%) completed 6 months of treatment with eltrombopag and cyclosporin and six (11%) completed the cyclosporin tapering period up to month 24. Overall haematological response rate by month 6 of treatment was 46% (25 of 54; 95% CI 33-60). The most reported adverse events were increased serum bilirubin (in 22 patients [41%]), nausea (16 [30%]), increased alanine aminotransferase concentration (12 [22%]), and diarrhoea (12 [22%]). Eight patients died on-treatment, but no deaths were considered related to the treatment.
INTERPRETATION
Eltrombopag and cyclosporin was active as front-line treatment of severe aplastic anaemia, with no unexpected safety concerns. This approach might be beneficial where horse-ATG is not available or not tolerated.
FUNDING
Novartis Pharmaceuticals.
Topics: Adult; Female; Humans; Male; Anemia, Aplastic; Antilymphocyte Serum; Benzoates; Cyclosporine; Hydrazines; Pyrazoles; Drug Therapy, Combination
PubMed: 38335978
DOI: 10.1016/S2352-3026(23)00395-2 -
Bone Marrow Transplantation May 2024Post-transplant cyclophosphamide (PTCY) has been introduced as graft-versus-host disease (GvHD) prophylaxis in mismatched and matched unrelated hematopoietic cell...
Graft-versus-host-disease prophylaxis with ATG or PTCY in patients with lymphoproliferative disorders undergoing reduced intensity conditioning regimen HCT from one antigen mismatched unrelated donor.
Post-transplant cyclophosphamide (PTCY) has been introduced as graft-versus-host disease (GvHD) prophylaxis in mismatched and matched unrelated hematopoietic cell transplant (HCT). However, data comparing outcomes of PTCY or ATG in patients undergoing a 1 antigen mismatched HCT for lymphoproliferative disease are limited. We compared PTCY versus ATG in adult patients with lymphoproliferative disease undergoing a first 9/10 MMUD HCT with a reduced intensity conditioning regimen from 2010 to 2021. Patients receiving PTCY were matched to patients receiving ATG according to: age, disease status at transplant, female to male matching, stem cell source and CMV serology. Grade II-IV acute GvHD at 100 day was 26% and 41% for the ATG and PTCY group, respectively (p = 0.08). Grade III-IV acute GvHD was not significantly different between the two groups. No differences were observed in relapse incidence, non-relapse mortality, progression-free survival, overall survival and GvHD-relapse-free survival at 1 year. The cumulative incidence of 1-year extensive chronic GvHD was 18% in the ATG and 5% in the PTCY group, respectively (p = 0.06). In patients with lymphoproliferative diseases undergoing 9/10 MMUD HCT, PTCY might be a safe option providing similar results to ATG prophylaxis. Due to the limited number of patients, prospective randomized trials are needed.
Topics: Humans; Transplantation Conditioning; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Female; Male; Middle Aged; Adult; Cyclophosphamide; Lymphoproliferative Disorders; Unrelated Donors; Antilymphocyte Serum; Aged
PubMed: 38331980
DOI: 10.1038/s41409-024-02225-2 -
Bone Marrow Transplantation Apr 2024Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment for myelofibrosis (MF). Relapse occurs in 10-30% and remains a major...
Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment for myelofibrosis (MF). Relapse occurs in 10-30% and remains a major factor for dismal outcomes. Previous work suggested that graft-versus-host disease (GVHD) might be associated with risk of relapse. This study included 341 patients undergoing their first (n = 308) or second (n = 33) alloHSCT. Anti-T-lymphocyte or antithymocyte globulin was used for GVHD prophylaxis in almost all patients. Median time to neutrophile and platelet engraftment was 13 days and 19 days, respectively. The cumulative incidence of acute GVHD grade II-IV was 41% (median, 31 days; range, 7-112). Grade III-IV acute GVHD was observed in 22%. The cumulative incidence of chronic GVHD was 61%. Liver was affected in 23% of acute GVHD cases and 46% of chronic GVHD cases. Severe acute GVHD was associated with high non-relapse mortality. The development of acute GVHD grade II and moderate GVHD was an independent factor for reduced risk for relapse after transplantation without increased risk for non-relapse mortality, while especially acute GVHD grade IV was associated with high non-relapse mortality. Last, we identified that ongoing response to ruxolitinib, accelerated-phase MF at time of transplantation and splenectomy prior to transplantation were independent predictors for relapse.
Topics: Humans; Primary Myelofibrosis; Neoplasm Recurrence, Local; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Antilymphocyte Serum
PubMed: 38321269
DOI: 10.1038/s41409-024-02220-7 -
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