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Transplantation and Cellular Therapy Sep 2021Limited information is available on the efficacy of post-transplantation cyclophosphamide (PTcy) or thymoglobulin for graft-versus-host disease (GVHD) prophylaxis in...
Limited information is available on the efficacy of post-transplantation cyclophosphamide (PTcy) or thymoglobulin for graft-versus-host disease (GVHD) prophylaxis in mismatched unrelated donor (MMUD) transplants. We retrospectively compared outcomes of 76 adult patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who underwent 7/8 HLA-MMUD transplantation and received either PTcy (50 mg/kg on day 3 and 4) or thymoglobulin (total dose 4.5 mg/kg) for GVHD prophylaxis. In addition, tacrolimus and mycophenolate were used in both groups. Propensity score-based multivariable analyses (PSCA) were performed to adjust confounding effects of patient characteristics between both groups. Between January 2006 and June 2019, 25 patients received PTcy, and 51 received thymoglobulin. Median age of the population was 57 years, 78% of patients had AML, most common graft source was peripheral blood (96%), and 46% received myeloablative conditioning regimens. Median time to neutrophil (15 versus 11 days, P < .001) and platelet engraftment (21 versus 15 days, P = .002) was prolonged in the PTcy group. The cumulative incidence of grade III-IV acute GVHD at day 100 was similar (12% versus 19.6%, P = .38), whereas chronic GVHD at 1 year was lower with PTcy compared to thymoglobulin (16% versus 49%, P = .006). Using PSCA, no difference in survival, relapse, relapse-free survival, and GVHD-free relapse-free survival was seen between groups. However, thymoglobulin was associated with higher incidence of acute (hazard ratio [HR] = 2.63, P = .01) and chronic GVHD (HR = 4.43, P = .03), and non-relapse mortality (HR 3.38, P = .04) compared to PTcy. Our study demonstrated that PTcy resulted in significantly lower rates of acute and chronic GVHD and non-relapse mortality compared to thymoglobulin in 7/8 HLA-MMUD transplants for AML and MDS.
Topics: Adult; Antilymphocyte Serum; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Retrospective Studies; Unrelated Donors
PubMed: 34174469
DOI: 10.1016/j.jtct.2021.06.018 -
International Immunopharmacology Jul 2023Donor-specific anti-HLA antibody (DSA) is a significant obstacle to successful haploidentical hematopoietic stem cell transplantation (haplo-HSCT) and is associated with...
Donor-specific anti-HLA antibody (DSA) is a significant obstacle to successful haploidentical hematopoietic stem cell transplantation (haplo-HSCT) and is associated with poor engraftment rates. DSA strongly positive patients with a mean fluorescence intensity (MFI) over 5000 have a primary poor graft function (PGF) rate of over 60%. Currently, there is no consensus on the desensitization of DSA, and existing strategies are complex and have limited effectiveness. To address this issue, we conducted a retrospective study on 19 patients with strongly positive DSA (MFI over 5000) who underwent haplo-HSCT and were treated with intravenous immunoglobulin (IVIg)-based therapy. We also included 38 baseline-matched patients with DSA-negative as controls. Our findings revealed that the cumulative incidence of engraftment, PGF, graft-versus-host disease (GVHD), virus infection, overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) in the DSA strongly positive group after desensitization were comparable to those in the DSA negative group (P > 0.05). Our multivariable analysis showed that disease remission was a protective factor against PGF (P = 0.005, OR = 0.019, 95% CI 0.001-0.312). Subgroup analysis revealed that the desensitization efficacy was equal regardless of DSA type against HLA-I or II, and MFI value over 5000 or not. In conclusion, we propose a simple and effective DSA desensitization strategy based on immunoglobulin to ensure successful engraftment and improve patient prognosis.
Topics: Humans; Retrospective Studies; Transplantation, Haploidentical; Tissue Donors; Hematopoietic Stem Cell Transplantation; Immunoglobulins, Intravenous; Antilymphocyte Serum; HLA Antigens
PubMed: 37201405
DOI: 10.1016/j.intimp.2023.110299 -
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 -
Neurology Oct 2019To determine if autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) could be a salvage therapy for neuromyelitis optica spectrum disorder (NMOSD).
OBJECTIVE
To determine if autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) could be a salvage therapy for neuromyelitis optica spectrum disorder (NMOSD).
METHODS
Thirteen patients were enrolled in a prospective open-label cohort study (11 NMOSD aquaporin-4-immunoglobulin G [AQP4-IgG]-positive, 1 NMOSD without AQP4, and 1 NMOSD AQP4-IgG-positive with neuropsychiatric systemic lupus erythematosus [SLE]). Following stem cell mobilization with cyclophosphamide (2 g/m) and filgrastim, patients were treated with cyclophosphamide (200 mg/kg) divided as 50 mg/kg IV on day -5 to day -2, rATG (thymoglobulin) given IV at 0.5 mg/kg on day -5, 1 mg/kg on day -4, and 1.5 mg/kg on days -3, -2, and -1 (total dose 6 mg/kg), and rituximab 500 mg IV on days -6 and +1. Unselected peripheral blood stem cells were infused on day 0. AQP4-IgG antibody status was determined by Clinical Laboratory Improvement Amendments-validated ELISA or flow cytometry assays. Cell-killing activity was measured using a flow cytometry-based complement assay.
RESULTS
Median follow-up was 57 months. The patient with coexistent SLE died of complications of active lupus 10 months after HSCT. For the 12 patients with NMOSD without other active coexisting autoimmune diseases, 11 patients are more than 5 years post-transplant, and 80% are relapse-free off all immunosuppression ( < 0.001). At 1 and 5 years after HSCT, Expanded Disability Status Scale score improved from a baseline mean of 4.4 to 3.3 ( < 0.01) at 5 years. The Neurologic Rating Scale score improved after HSCT from a baseline mean of 69.5 to 85.7 at 5 years ( < 0.01). The Short Form-36 health survey for quality of life total score improved from mean 34.2 to 62.1 ( = 0.001) at 5 years. In the 11 patients whose baseline AQP4-IgG serostatus was positive, 9 patients became seronegative by the immunofluorescence or cell-binding assays available at the time; complement activating and cell-killing ability of patient serum was switched off in 6 of 7 patients with before and after HSCT testing. Two patients remained AQP4-IgG-seropositive (with persistent complement activating and cell-killing ability) and relapsed within 2 years of HSCT. No patient with seronegative conversion relapsed.
CONCLUSION
Prolonged drug-free remission with AQP4-IgG seroconversion to negative following nonmyeloablative autologous HSCT warrants further investigation.
Topics: Adult; Antilymphocyte Serum; Aquaporin 4; Autoantibodies; Cyclophosphamide; Female; Filgrastim; Hematologic Agents; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunosuppressive Agents; Male; Middle Aged; Neuromyelitis Optica; Progression-Free Survival; Recurrence; Rituximab; Salvage Therapy; Transplantation, Autologous; Young Adult
PubMed: 31578302
DOI: 10.1212/WNL.0000000000008394 -
Frontiers in Immunology 2023Idiopathic acquired aplastic anemia (AA) is considered an immune-mediated syndrome of bone marrow failure since approximately 70% of patients respond to...
Idiopathic acquired aplastic anemia (AA) is considered an immune-mediated syndrome of bone marrow failure since approximately 70% of patients respond to immunosuppressive therapy (IST) consisting of a course of anti-thymocyte globulin (ATG) followed by long-term use of ciclosporin. However, the immune response that underlies the pathogenesis of AA remains poorly understood. In this study, we applied high-dimensional mass cytometry on bone marrow aspirates of AA patients pre-ATG, AA patients post-ATG and healthy donors to decipher which immune cells may be implicated in the pathogenesis of AA. We show that the bone marrow of AA patients features an immune cell composition distinct from healthy donors, with significant differences in the myeloid, B-cell, CD4 and CD8 T-cells lineages. Specifically, we discovered that AA pre-ATG is characterized by a disease-specific immune cell network with high frequencies of CD16 myeloid cells, CCR6 B-cells, Th17-like CCR6 memory CD4 T-cells, CD45RACCR7CD38 CD8 T-cells and KLRG1 terminally differentiated effector memory (EMRA) CD8 T-cells, compatible with a state of chronic inflammation. Successful treatment with IST strongly reduced the levels of CD16 myeloid cells and showed a trend toward normalization of the frequencies of CCR6 B-cells, CCR6 memory CD4 T-cells and KLRG1EMRA CD8 T-cells. Altogether, our study provides a unique overview of the immune landscape in bone marrow in AA at a single-cell level and proposes CCR6 as a potential new therapeutic target in AA.
Topics: Humans; Anemia, Aplastic; Bone Marrow; CD8-Positive T-Lymphocytes; Cyclosporine; Pancytopenia; Antilymphocyte Serum
PubMed: 38094307
DOI: 10.3389/fimmu.2023.1274116 -
Transplantation and Cellular Therapy Oct 2022Unmanipulated haploidentical hematopoietic stem cell transplantation (HCT) with post-transplantation cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis...
Comparison of Outcomes after Unrelated Double-Unit Cord Blood and Haploidentical Peripheral Blood Stem Cell Transplantation in Adults with Acute Myelogenous Leukemia: A Study on Behalf of Eurocord and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
Unmanipulated haploidentical hematopoietic stem cell transplantation (HCT) with post-transplantation cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis (haplo-PTCY) and unrelated double-unit umbilical cord blood transplantation (dUCBT) are feasible options for treating patients with high-risk acute myelogenous leukemia (AML). This study compared outcomes after dUCBT and haplo-HCT using peripheral blood stem cells (PBSCs) in adult patients with AML in complete remission (CR) who underwent transplantation in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers. In a population of adults with de novo AML in first or second CR, we compared outcomes after dUCBT (n = 165) and after haplo-PTCY PBSC (n = 544) performed between January 2013 and December 2018. Patients receiving in vivo antithymocyte globulin, Campath, or ex vivo T cell depletion were excluded. The median follow-up was 33 months for the haplo-PTCY arm and 52 months for the dUCBT arm. No statistically significant differences were observed between the 2 arms in the rates of grade II-IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 1.31; P = .18), grade III-IV acute GVHD (HR, 1.17; P = .56), chronic GVHD (HR, .86; P = .48), relapse (HR, 1.07; P = .77), nonrelapse mortality (NRM) (HR, .94; P = .77), leukemia-free survival (LFS) (HR, .99; P = .95), or overall survival (OS) (HR, .99; P = .97). Favorable cytogenetic risk was the sole factor predictive of lower relapse incidence (RI). Younger age at transplantation was associated with lower NRM and higher LFS and OS. Both dUCBT and haplo-PTCY with PBSCs can be considered valid approaches for adult AML patients in CR. New strategies should be investigated in both settings to define the most appropriate conditioning regimen and potentially decrease RI and NRM through better immune reconstitution and optimal supportive care.
Topics: Acute Disease; Adult; Alemtuzumab; Antilymphocyte Serum; Bone Marrow; Cyclophosphamide; Fetal Blood; Graft vs Host Disease; Humans; Leukemia, Myeloid, Acute; Peripheral Blood Stem Cell Transplantation; Recurrence
PubMed: 35830930
DOI: 10.1016/j.jtct.2022.07.006 -
Leukemia May 2024There is a high risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) from unrelated donors. Prophylaxis with rabbit...
There is a high risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) from unrelated donors. Prophylaxis with rabbit anti-thymocyte globulin (rATG) is standard in Europe but post-transplantation Cyclophosphamide (PTCy) is an emerging alternative. We analyzed outcomes of rATG (n = 7725) vs. PTCy (n = 1039) prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen-matched unrelated donors (MUD) between January 2018 and June 2021 in the EBMT database. The provided P-values and hazard ratios (HR) are derived from multivariate analysis. Two years after alloSCT, NRM in the PTCy group was 12.1% vs. 16.4% in the rATG group; p = 0.016; HR 0.72. Relapse was less frequent after PTCy vs. rATG (22.8% vs. 26.6%; p = 0.046; HR 0.87). Overall survival after PTCy was higher (73.1% vs. 65.9%; p = 0.001, HR 0.82). Progression free survival was better after PTCy vs. rATG (64.9% vs. 57.2%; p < 0.001, HR 0.83). The incidence of chronic GVHD was lower after PTCy (28.4% vs. rATG 31.4%; p = 0.012; HR 0.77), whereas the incidence and severity of acute GVHD were not significantly different. GVHD-free relapse-free survival was significantly higher in the PTCy arm compared to the rATG arm (2 y incidence: 51% vs. 45%; HR: 0.86 [95% CI 0.75-0.99], p = 0.035). In the absence of evidence from randomized controlled trials, our findings support a preference for the use of PTCy in adult recipients of peripheral blood alloSCTs from MUD.
Topics: Humans; Cyclophosphamide; Graft vs Host Disease; Antilymphocyte Serum; Male; Middle Aged; Female; Adult; Hematologic Neoplasms; Unrelated Donors; Hematopoietic Stem Cell Transplantation; Immunosuppressive Agents; Transplantation, Homologous; Aged; Young Adult; Transplantation Conditioning; Adolescent; Survival Rate; Follow-Up Studies; Retrospective Studies
PubMed: 38538862
DOI: 10.1038/s41375-024-02225-7 -
Blood Advances May 2024Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplant (HSCT) but hampers...
Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplant (HSCT) but hampers posttransplant immune reconstitution. We hypothesized that in patients receiving haploidentical CD3/CD19-depleted grafts, these double-edged effects could be better balanced by attaining high ATLG serum concentrations before transplant but as low as possible on the day of transplant. Therefore, we moved the start of ATLG application to day -12 and determined serum concentrations of T-cell-specific ATLG in pediatric patients treated with 3 established dosing regimens (15, 30, or 60 mg/kg). Corresponding mean T-cell-specific ATLG serum concentrations at day 0 were 1.14, 2.99, or 12.10 μg/mL, respectively. Higher ATLG doses correlated with higher peak levels at days -8 and -7 and reduced graft rejection, whereas lower ATLG doses correlated with significantly faster posttransplant recovery of T and natural killer cells. The rate of graft-versus-host disease remained low, independent of ATLG doses. Moreover, in vitro assays showed that ATLG concentrations of 2.0 μg/mL and lower only slightly reduced the activity of natural killer cells, and therefore, the function of such effector cells might be preserved in the grafts. Pharmacokinetic analysis, compatible with linear first-order kinetics, revealed similar half-life values, independent of ATLG doses. Hence, the day on which a desired ATLG serum level is reached can be calculated before HSCT. Our retrospective study demonstrates the relevance of dosing and time of administration of ATLG on engraftment and immune recovery in ex vivo CD3/CD19-depleted haploidentical HSCT.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Child; CD3 Complex; Male; Child, Preschool; Female; Antigens, CD19; Adolescent; Antilymphocyte Serum; Graft vs Host Disease; Immune Reconstitution; Infant; Transplantation, Haploidentical; T-Lymphocytes; Lymphocyte Depletion
PubMed: 38290133
DOI: 10.1182/bloodadvances.2023011016 -
Scientific Reports Aug 2023Anti-thymocyte globulin (ATG) is currently the most widely prescribed induction regimen for preventing acute rejection after solid organ transplantation. However, the...
Anti-thymocyte globulin (ATG) is currently the most widely prescribed induction regimen for preventing acute rejection after solid organ transplantation. However, the optimal dose of ATG induction regimen in Asian kidney recipients is unclear. Using the Korean Organ Transplantation Registry, we performed a retrospective cohort study of 4579 adult patients who received renal transplantation in South Korea and divided them into three groups according to the induction regimen: basiliximab group (n = 3655), low-dose ATG group (≤ 4.5 mg/kg; n = 467), and high-dose ATG group (> 4.5 mg/kg; n = 457). We applied the Toolkit for Weighting and Analysis of Nonequivalent Groups (TWANG) package to generate high-quality propensity score weights for intergroup comparisons. During four-year follow-ups, the high-dose ATG group had the highest biopsy-proven acute rejection rate (basiliximab 20.8% vs. low-dose ATG 22.4% vs. high-dose ATG 25.6%; P < 0.001). However, the rates of overall graft failure (4.0% vs. 5.0% vs. 2.6%; P < 0.001) and mortality (1.7% vs. 2.8% vs. 1.0%; P < 0.001) were the lowest in the high-dose ATG group. Our results show that high-dose ATG induction (> 4.5 mg/kg) was superior to basiliximab and low-dose ATG induction in terms of graft and patient survival in Asian patients undergoing kidney transplant.
Topics: Adult; Humans; Antilymphocyte Serum; Basiliximab; Immunosuppressive Agents; Kidney Transplantation; Antibodies, Monoclonal; Retrospective Studies; Graft Rejection; Graft Survival; Allografts
PubMed: 37532735
DOI: 10.1038/s41598-023-39353-6 -
JAMA Network Open Apr 2022Patient-specific human leukocyte antigen (HLA) genomic loss (HLA loss) is one of the reputed mechanisms of leukemia immune escape and relapse after haploidentical...
Assessment of Patient-Specific Human Leukocyte Antigen Genomic Loss at Relapse After Antithymocyte Globulin-Based T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplant.
IMPORTANCE
Patient-specific human leukocyte antigen (HLA) genomic loss (HLA loss) is one of the reputed mechanisms of leukemia immune escape and relapse after haploidentical hematopoietic stem cell transplant (HSCT). However, clinical characteristics and prognosis of this distinct relapse type in the setting of haploidentical HSCT based on antithymocyte globulin (ATG) T-cell-replete conditioning are still unknown, especially for patients with lymphoid leukemia.
OBJECTIVE
To identify the incidence of and patient characteristics associated with HLA loss at hematologic cancer relapse after ATG-based haploidentical HSCT and to assess overall survival after HLA loss at relapse.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective and multicenter case series study used data from medical records to identify patients who experienced relapse of hematologic cancer after receipt of ATG-based haploidentical HSCT. The study included 788 consecutive patients aged 8 to 70 years with lymphoid or myeloid leukemia who received ATG T-cell-replete haploidentical HSCT at the Zhejiang Cooperative Group for Blood and Marrow Transplantation between May 1, 2012, and May 31, 2021.
EXPOSURES
Relapse after ATG-based haploidentical HSCT.
MAIN OUTCOMES AND MEASURES
Incidence, risk factors, and postrelapse overall survival among patients with HLA loss at hematologic cancer relapse after receipt of haploidentical HSCT. Logistic regression analysis was used to identify characteristics associated with the likelihood of HLA loss, and Kaplan-Meier and Cox regression analyses were performed to evaluate postrelapse survival.
RESULTS
A total of 788 patients who received haploidentical HSCT for hematologic cancer were identified, 180 of whom experienced relapse after HSCT. Of those, 106 evaluable patients (median age, 30.9 years [range, 8.3-64.6 years]; 54 female [50.9%] and 52 male [49.1%]) were screened for HLA loss, which was detected in 54 patients (50.9%). Patients with HLA loss experienced relapse later than those without HLA loss (lymphoid group: median, 323 days [range, 98-2056 days] vs 151 days [range, 57-2544 days]; P = .01; myeloid group: median, 321 days [range, 55-1574 days] vs 223 days [range, 68-546 days]; P = .03). Among patients with lymphoid leukemia, those with minimal residual disease positivity before hematologic relapse (odds ratio [OR], 28.47; 95% CI, 1.99-407.98; P = .01), those with chronic graft-vs-host disease (OR, 27.68; 95% CI, 1.40-546.88; P = .03), and those with more than 180 days between HSCT and relapse (OR, 6.91; 95% CI, 1.32-36.22; P = .02) were more likely to lose unshared HLA at relapse, whereas male patients (OR, 0.03; 95% CI, 0.003-0.32; P = .04) were more likely to preserve their HLA genome at relapse. Patients with myeloid leukemia had different factors associated with HLA loss, including underweight status (OR, 0.10; 95% CI, 0.02-0.60; P = .01) and acute graft-vs-host disease (OR, 4.84; 95% CI, 1.14-20.53; P = .03). The receipt of preemptive donor lymphocyte infusion among patients with minimal residual disease recurrence did not postpone hematologic cancer relapse in those with HLA loss (median, 322 days [range, 204-1030 days]) compared with no receipt of donor lymphocyte infusion (median, 340 days [range, 215 days to not available]; P > .99).
CONCLUSIONS AND RELEVANCE
In this study, HLA loss at leukemia relapse occurred frequently after receipt of ATG-based haploidentical HSCT. The identification of risk factors associated with HLA loss would help to prompt screening, avoid potentially harmful infusions of donor T cells, and develop alternative therapeutic strategies.
Topics: Adolescent; Adult; Aged; Antilymphocyte Serum; Child; Female; Graft vs Host Disease; HLA Antigens; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Male; Middle Aged; Neoplasm, Residual; Recurrence; Retrospective Studies; T-Lymphocytes; Young Adult
PubMed: 35385089
DOI: 10.1001/jamanetworkopen.2022.6114