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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 -
Haematologica May 2020
Topics: Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow; Cyclosporine; Granulocytes; Humans; Immunosuppression Therapy
PubMed: 32358076
DOI: 10.3324/haematol.2020.246512 -
Transplantation and Cellular Therapy Sep 2021Infection-related mortality (IRM) is the most common non-relapse-related cause of death reported after allogeneic hematopoietic cell transplantation (HCT). Information...
Infection-related mortality (IRM) is the most common non-relapse-related cause of death reported after allogeneic hematopoietic cell transplantation (HCT). Information on the incidence and timing of specific infective organisms and the risk factors for IRM is essential to developing prevention strategies. This report provides the first account of IRM in adults and children undergoing HCT in Australia. Between 2013 and 2018, 2705 adult and 689 pediatric first HCTs were identified from the Australasian Bone Marrow Transplant Recipient Registry database, associated with 1075 (39.7%) total overall deaths in adults and 134 (19.4%) in children. Demographics and causes of death, including infectious etiology and causative organisms, were extracted from the database for adults and children for analysis. At day +100 and 1 year post-HCT, IRM was the leading cause of early post-HCT mortality in adults, accounting for 6.2% and 9.8%, respectively; in children, IRM was the leading cause of post-HCT mortality at day +100 at 2.5% and the second highest cause of post-HCT mortality at 1 year post-HCT at 4.9%, following relapse at 5.8%. In adults, older age, transplantation not in a first complete remission (non-CR1), the use of antithymocyte globulin (ATG) or alemtuzumab, donor-positive/recipient-negative cytomegalovirus (CMV) serostatus, and acute graft-versus-host disease were significant risk factors for IRM. However, in children, age >5 years, acute lymphocytic leukemia as the primary disease, and mismatched unrelated or haploidentical donor source were predictive of IRM. Of the deaths in which an infectious etiology was reported in adults (52.4%), 49.3% were attributed to bacteria, 25.3% to fungus, 21.7% to viruses, and 3.6% to post-transplantation lymphoproliferative disorder (PTLD). The most common organisms were Pseudomonas spp, Enterococcus spp, Candida spp, Aspergillus spp, and CMV. In children where an infectious etiology was reported (64%), 13% were attributed to bacteria, 26% to fungus, 45% to viruses, and 16% to PTLD. This report highlights that IRM was the leading cause of death early post-HCT in Australia. Strategies to reduce IRM, such as individualized pre-transplantation infection risk assessment, rapid diagnostics, and prevention management strategies should be explored to determine whether these outcomes can be improved. In addition, improving the completeness and accuracy of reported data, particularly for infectious pathogens, could assist in directing management strategies to reduce IRM in HCT.
Topics: Aged; Antilymphocyte Serum; Australia; Child, Preschool; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Registries
PubMed: 34111574
DOI: 10.1016/j.jtct.2021.05.028 -
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 -
Neurology(R) Neuroimmunology &... Nov 2022Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat aggressive forms of multiple sclerosis (MS). This procedure is believed to...
BACKGROUND AND OBJECTIVES
Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat aggressive forms of multiple sclerosis (MS). This procedure is believed to result in an immune reset and restoration of a self-tolerant immune system. Immune reconstitution has been extensively studied for T cells, but only to a limited extent for B cells. As increasing evidence suggests an important role of B cells in MS pathogenesis, we sought here to better understand reconstitution and the extent of renewal of the B-cell system after aHSCT in MS.
METHODS
Using longitudinal multidimensional flow cytometry and immunoglobulin heavy chain (IgH) repertoire sequencing following aHSCT with BCNU + Etoposide + Ara-C + Melphalan anti-thymocyte globulin, we analyzed the B-cell compartment in a cohort of 20 patients with MS in defined intervals before and up to 1 year after aHSCT and compared these findings with data from healthy controls.
RESULTS
Total B-cell numbers recovered within 3 months and increased above normal levels 1 year after transplantation, successively shifting from a predominantly transitional to a naive immune phenotype. Memory subpopulations recovered slowly and remained below normal levels with reduced repertoire diversity 1 year after transplantation. Isotype subclass analysis revealed a proportional shift toward IgG1-expressing cells and a reduction in IgG2 cells. Mutation analysis of IgH sequences showed that highly mutated memory B cells and plasma cells may transiently survive conditioning while the analysis of sequence cluster overlap, variable (IGHV) and joining (IGHJ) gene usage and repertoire diversity suggested a renewal of the late posttransplant repertoire. In patients with early cytomegalovirus reactivation, reconstitution of naive and memory B cells was delayed.
DISCUSSION
Our detailed characterization of B-cell reconstitution after aHSCT in MS indicates a reduced reactivation potential of memory B cells up to 1 year after transplantation, which may leave patients susceptible to infection, but may also be an important aspect of its mechanism of action.
Topics: Antilymphocyte Serum; Carmustine; Cytarabine; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Immunoglobulin Heavy Chains; Melphalan; Multiple Sclerosis
PubMed: 36229189
DOI: 10.1212/NXI.0000000000200027 -
Blood Oct 2022Platelet transfusion and transplantation of allogeneic stem cells and solid organs are life-saving therapies. Unwanted alloantibodies to nonself human leukocyte antigens...
Platelet transfusion and transplantation of allogeneic stem cells and solid organs are life-saving therapies. Unwanted alloantibodies to nonself human leukocyte antigens (HLAs) on donor cells increase the immunological barrier to these therapies and are important causes of platelet transfusion refractoriness and graft rejection. Although the specificities of anti-HLA antibodies can be determined at the allelic level, traditional treatments for antibody-mediated rejection nonselectively suppress humoral immunity and are not universally successful. We designed HLA-Fc fusion proteins with a bivalent targeting module derived from extracellular domains of HLA and an Fc effector module from mouse IgG2a. We found that HLA-Fc with A2 (A2Fc) and B7 (B7Fc) antigens lowered HLA-A2- and HLA-B7-specific reactivities, respectively, in sera from HLA-sensitized patients. A2Fc and B7Fc bound to B-cell hybridomas bearing surface immunoglobulins with cognate specificities and triggered antigen-specific and Fc-dependent cytotoxicity in vitro. In immunodeficient mice carrying HLA-A2-specific hybridoma cells, A2Fc treatment lowered circulating anti-HLA-A2 levels, abolished the outgrowth of hybridoma cells, and prolonged survival compared with control groups. In an in vivo anti-HLA-A2-mediated platelet transfusion refractoriness model, A2Fc treatment mitigated refractoriness. These results support HLA-Fc being a novel strategy for antigen-specific humoral suppression to improve transfusion and transplantation outcomes. With the long-term goal of targeting HLA-specific memory B cells for desensitization, further studies of HLA-Fc's efficacy in immune-competent animal models are warranted.
Topics: Humans; Mice; Animals; Isoantibodies; HLA-B7 Antigen; HLA Antigens; Graft Rejection; Antilymphocyte Serum; HLA-A2 Antigen; Antibody-Producing Cells; Thrombocytopenia; Immunoglobulin G; Receptors, Antigen, B-Cell
PubMed: 36070233
DOI: 10.1182/blood.2022016376 -
BMJ Open Jan 2024Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or...
Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials.
INTRODUCTION
Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA.
METHODS AND ANALYSIS
Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a 'go/no-go' decision is made by evaluating the posterior probability of the events of interests.
ETHICS AND DISSEMINATION
The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication.
TRIAL REGISTRATION NUMBER
ACTRN12619001042134, ACTRN12619001043123.
Topics: Humans; Animals; Horses; Cyclosporine; Immunosuppressive Agents; Anemia, Aplastic; Bayes Theorem; Antilymphocyte Serum; Immunosuppression Therapy; Treatment Outcome; Clinical Trials, Phase II as Topic; Hydrazines; Benzoates; Thiophenes; Pyrazoles; Thiazoles
PubMed: 38238183
DOI: 10.1136/bmjopen-2023-076246 -
Transplantation and Cellular Therapy May 2021Allogeneic hematopoietic stem cell transplantation (HSCT) using fludarabine (Flu)-based conditioning regimens are being increasingly being used in patients with aplastic...
An Antithymocyte Globulin-Free Conditioning Regimen Using Fludarabine and Cyclophosphamide Is Associated with Good Outcomes in Patients Undergoing Matched Related Family Donor Transplantation for Aplastic Anemia.
Allogeneic hematopoietic stem cell transplantation (HSCT) using fludarabine (Flu)-based conditioning regimens are being increasingly being used in patients with aplastic anemia (AA). We describe an antithymocyte globulin (ATG)-free conditioning regimen consisting of Flu and cyclophosphamide (Cy) in patients undergoing matched related donor (MRD) HSCT for AA. Between 2004 and 2019, 212 patients underwent MRD HSCT using Flu (30 mg/m/day for 6 days) and Cy (60 mg/kg/day for 2 days) for conditioning. The graft source was peripheral blood stem cells in all patients. Graft-versus-host disease (GVHD) prophylaxis consisted mainly of cyclosporine and methotrexate, although 41 patients received post-transplantation Cy as part of a study. Engraftment occurred in 91% of patients at a median of 16 days, whereas 4 patients (1.8%) experienced primary graft failure and 15 (7.1%) died before achieving engraftment. Toxicity was minimal. The incidence of grade II-IV acute GVHD (aGVHD) was 27.9%, and that of grade III-IV aGVHD was 11.3%. Chronic GVHD occurred in 41.6%. 80% were free of immunosuppression at 60 months and long-term complications were seen in 8.4%. At a median of 46 months, 158 patients were alive and well, with a 5-year overall survival (OS) of 75.3 ± 3.0%. The 5-year OS was 80.6 ± 4.1% for patients age <20 years (n = 93), 74.5 ± 4.6% for those age 20 to 40 years (n = 91), and 59.7 ± 9.5% for those age >40 years (n = 28) (P = .11). Patients classified as low risk had better OS compared with those at high risk (93.2 ± 2.9% versus 65.7 ± 4.1%; P = .000). Factors affecting OS on multivariate analysis included aGVHD (P = .02) and graft failure (P = .000). This large series using Flu/Cy for conditioning before MRD HSCT confirms good outcomes in patients with AA, with excellent outcomes in low-risk patients. Suitable modifications are needed to improve outcomes in high-risk patients.
Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Cyclophosphamide; Humans; Retrospective Studies; Vidarabine; Young Adult
PubMed: 33965181
DOI: 10.1016/j.jtct.2021.01.029 -
Blood Advances Aug 2019Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining...
Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.
Topics: Adult; Aged; Antilymphocyte Serum; Female; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hospitalization; Humans; Lymphatic Irradiation; Male; Middle Aged; Prognosis; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Unrelated Donors; Young Adult
PubMed: 31427277
DOI: 10.1182/bloodadvances.2019000297 -
Transplantation and Cellular Therapy Aug 2023Donor-specific anti-HLA antibodies (DSAs) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective...
Treatment With the Combination of Rituximab and Intravenous γ Globulin Is Effective in Promoting Engraftment in Donor-Specific Antibody Positive Patients Receiving Myeloablative Conditioning Haploidentical Stem Cell Transplantation.
Donor-specific anti-HLA antibodies (DSAs) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective procedures are needed for those who demand urgent transplantation and have no other donor options. We here retrospectively analyzed 13 patients with DSAs successfully treated with desensitization of rituximab and intravenous γ globulin (IVIg) before HaploSCT from March 2017 to July 2022. All 13 patients had DSA mean fluorescence intensity >4000 of at least 1 loci before desensitization. Of the 13 patients, 10 patients were with the initial diagnosis of malignant hematological diseases, and 3 were diagnosed with aplastic anemia. Patients were treated with 1 (n = 3) or 2 (n = 10) doses of rituximab (375 mg/m for 1 dose). All patients receive the same total dose of 0.4 g/kg of IVIg within 72 hours before haploidentical stem cell administration to neutralize the remaining DSA. All patients achieved neutrophil engraftment, and 12 patients achieved primary platelet engraftment. The patient with primary platelet engraftment failure received purified CD34-positive stem cell infusion nearly 1 year after transplantation and achieved platelet engraftment thereafter. The estimated 3-year overall survival is 73.4%. Although further studies on larger numbers of patients are needed, it is clear that the combination of IVIg and rituximab is an effective way to clear DSA and has a strong effect on promoting engraftment and survival for patients with DSA. It is a practical and adaptable combination of treatment options.
Topics: Humans; Rituximab; Immunoglobulins, Intravenous; gamma-Globulins; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Antibodies; Antilymphocyte Serum
PubMed: 37178922
DOI: 10.1016/j.jtct.2023.05.005