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Transplantation and Cellular Therapy Jan 2023Although the possibility of first-line hematopoietic cell transplantation (HCT) from alternative donors in severe aplastic anemia (SAA) patients has been suggested...
Although the possibility of first-line hematopoietic cell transplantation (HCT) from alternative donors in severe aplastic anemia (SAA) patients has been suggested recently, transplantation strategies are still being investigated. We established a novel post-transplantation cyclophosphamide-based HCT protocol for patients with SAA in prior studies. We explores the effectiveness and safety of this HCT approach either as first-line or as salvage treatment in SAA patients. Outcomes of 71 consecutive young patients, who received HCT from unrelated or haploidentical donors, were retrospectively analyzed. According to their treatment before transplantation, the patients were classified into treatment-naive (TN) and relapsed or refractory (R/R) patients. The R/R patients were designated as such when a patient did not respond to previous immunosuppressive therapy or relapsed. We administered an antithymocyte globulin (ATG)-free, total body irradiation (TBI)-free conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine, all in an intravenous formula. We used a thorough post-transplantation prophylaxis regimen for GVHD, including post-transplantation cyclophosphamide (PTCy) and short-term methotrexate and long-term cyclosporine A. The median age of the cohort was 16 (95% confidence interval, 12-20) years at transplantation. Most patients (61 of 71) received HCT from haploidentical donors, and the others received HCT from unrelated donors. TN patients (n = 38) were younger and had a shorter time-to-transplant and lower HCT-specific comorbidity index than patients with R/R diseases (n = 33). The frequencies of graft failure, grade II-IV acute graft-versus-host disease (GVHD), and moderate-severe chronic GVHD were similar, at 5.3% versus 6.5% (P = .057), 8.3% versus 0% (P = .109), and 5.7% versus 0% (P = .199) between R/R and TN patients. With a median 42-month follow-up, the frequencies of overall survival (OS) and event-free survival (EFS) were higher in the TN group than in the R/R group (100% versus 84.8% [P = .013] and 86.8% versus 75.8% [P = .255], respectively). All patients who achieved successful engraftment showed full donor chimerism. Four patients, all in the R/R group, suffered from donor-type aplasia; of these, 2 died, 1 was salvaged with another transplantation, and the final one was still receiving transfusion at the last follow-up. Currently, 93.9% (62 of 66) of the patients are alive more than 12 months after transplantation; of these 93.5% (58 of 62) no longer receive immunosuppression, including 91.7% (33 of 34) of the TN group and 89.3% (25 of 28) in the R/R group. This novel TBI-free and ATG-free HCT protocol using a reduced-intensity conditioning regimen followed by modified PTCy achieved promising engraftment, minimal GVHD risk, and encouraging OS and EFS. Our study suggests that unrelated or haploidentical HCT with PTCy can be used as a first-line treatment for young patients with SAA. Nevertheless, further efforts are needed to explore possibilities for older patients and patients with a poor performance status.
Topics: Humans; Child; Adolescent; Young Adult; Adult; Anemia, Aplastic; Retrospective Studies; Transplantation Conditioning; Cyclophosphamide; Antilymphocyte Serum; Graft vs Host Disease; Unrelated Donors; Adaptor Proteins, Signal Transducing
PubMed: 36272527
DOI: 10.1016/j.jtct.2022.10.006 -
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 Proceedings Sep 2023Advances in immunosuppressive therapies and surgical techniques have led to a significant reduction in the incidence of rejection within 1 year after kidney...
BACKGROUND
Advances in immunosuppressive therapies and surgical techniques have led to a significant reduction in the incidence of rejection within 1 year after kidney transplantation. Immunologic risk is an important factor affecting graft functions and guiding the clinician in the selection of induction therapy. The aim of this study was to investigate graft functions based on serum creatinine levels, Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) and proteinuria levels, frequency of leukopenia, cytomegalovirus (CMV) and BK virus polymerase chain reaction (PCR) positivity in patients with low and high immunologic risk.
MATERIAL AND METHODS
This retrospective study included 80 renal recipients. Recipients were divided into 2 groups: patients at low immunologic risk who received basiliximab only and those with high immunologic risk who received low-dose (1.5 mg/kg for 3 days) antithymocyte globulin and basiliximab.
RESULTS
No significant differences were observed between the 2 risk groups in terms of first, third, sixth, and 12th-month creatinine levels, CKD-EPI, proteinuria levels, leukopenia frequency, and CMV and BK virus PCR positivity.
CONCLUSION
One-year graft survivals did not differ significantly between these 2 treatment modalities. The combined use of low-dose antithymocyte globulin and basiliximab in the induction treatment of patients with high immunologic risk seems promising in terms of graft survival, leukopenia frequency, and CMV and BK virus PCR positivity.
Topics: Humans; Basiliximab; Immunosuppressive Agents; Antilymphocyte Serum; Antibodies, Monoclonal; Retrospective Studies; Induction Chemotherapy; Graft Rejection; Graft Survival; Cytomegalovirus Infections; Renal Insufficiency, Chronic; Proteinuria; Recombinant Fusion Proteins
PubMed: 37414697
DOI: 10.1016/j.transproceed.2023.02.067 -
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 -
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 -
Clinical Pharmacokinetics Jan 2022Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely...
BACKGROUND
Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely empirical and the question of an individualized dose is still unresolved.
METHODS
Data from a prospective study in 17 kidney transplant patients were used to develop a model describing the dose-concentration-response relationship of rATG with T-lymphocyte subpopulation counts over time. The model was validated using an independent cohort of kidney transplant patients treated by rATG in the same center.
RESULTS
Pharmacokinetics of rATG was described using a two-compartment model integrating a third compartment and a target-mediated elimination for active rATG. The kinetics of CD3, CD4, CD8, and CD3CD56 cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3CD56-independent and CD3CD56-dependent rATG-mediated lymphocyte depletion, and a positive feedback. Elimination of rATG was influenced by age and body surface area, while its distribution was also influenced by body surface area. CD3 proliferation rate decreased with age and CD3CD56-mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3 count < 20 mm for at least 7 days and a CD4 count > 200 mm at 1 year, respectively. Simulations showed that increasing or decreasing the standard 6-mg/kg dose will impact both tolerance and efficacy, while a dose decrease may be beneficial in elderly patients.
CONCLUSIONS
Our results can be used to design prospective clinical trials testing dose individualization based on patients' characteristics.
CLINICAL TRIAL REGISTRATION
Eudract No. 2009-012673-35.
Topics: Aged; Antilymphocyte Serum; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Subsets; Prospective Studies; Receptors, IgG
PubMed: 34292526
DOI: 10.1007/s40262-021-01053-7 -
European Journal of Haematology Mar 2024Aplastic anemia (AA) is a rare bone marrow failure disorder that is treated with either allogeneic stem cell transplant or immunosuppressive therapy (IST) consisting of...
Aplastic anemia (AA) is a rare bone marrow failure disorder that is treated with either allogeneic stem cell transplant or immunosuppressive therapy (IST) consisting of antithymocyte globulin (ATG), cyclosporine (CSA), and eltrombopag. While outcomes are favorable in younger patients, older patients (>60) have significantly worse long-term survival. The dose of ATG is often reduced in older patients and those with multiple comorbidities given concerns for tolerability. The efficacy and safety of dose-attenuated IST in this population is largely undescribed. We performed a retrospective review of patients with AA treated with IST. Our analysis was confounded by changes in practice patterns and the introduction of eltrombopag. We identified 53 patients >60 years old, of which, 20 received dose-attenuated IST, with no statistically significant difference in overall survival between full and attenuated dose cohorts. Overall response rates in both cohorts were similar at 6 months at 71% and 68%. There were more documented infectious complications in the full dose cohort (13 vs. 3). This supports the consideration of dose-attenuated IST in older patients with concerns about tolerance of IST. Lastly, our data confirmed favorable outcomes of younger patients receiving IST, especially in combination with eltrombopag.
Topics: Humans; Aged; Middle Aged; Immunosuppressive Agents; Anemia, Aplastic; Treatment Outcome; Cyclosporine; Immunosuppression Therapy; Antilymphocyte Serum; Benzoates; Hydrazines; Pyrazoles
PubMed: 37929654
DOI: 10.1111/ejh.14131 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2022To observe the occurrence of immune dysfunction in children with aplastic anemia (AA) and the factors that may lead to immune dysfunction, analyze the relationship...
OBJECTIVE
To observe the occurrence of immune dysfunction in children with aplastic anemia (AA) and the factors that may lead to immune dysfunction, analyze the relationship between the expression of granulocyte colony stimulating factor (G-CSF) and immune dysfunction.
METHODS
A total of 34 children with AA treated in our hospital from December 2016 to September 2018 were selected. All the children received immunosuppressive therapy (IST) for 6 months. According to whether the children had immune dysfunction after 6 months of treatment, they were divided into occurrence group and non occurrence group. General information and laboratory indices were compared between the two groups, and serum G-CSF level was tested, the relationship between serum G-CSF level and immune dysfunction in AA children after treatment with IST was observed and analyzed.
RESULTS
After treatment with IST for 6 months, 12 cases developed immune dysfunction (35.29%). Serum interferon (IFN)-γ level of the occurrence group was higher but G-CSF level was lower than those of the non occurrence group (P<0.05), while the difference of other baseline data was not statistically significant (P>0.05). Multiple regression analysis showed that overexpression of serum IFN-γ and low expression of G-CSF were both the influencing factors of immune dysfunction in AA children after IST treatment (OR>1, P<0.05). ROC curve was drawn, and the result showed that the area under the curve (AUC) of serum G-CSF level predicted the risk of immune dysfunction after IST was 0.843>0.80, when the index cut-off value was set at 6.614 pg/ml, the predictive value was ideal.
CONCLUSION
AA children have a higher risk of immune dysfunction after IST, which may be related to the low expression of serum G-CSF. The detection of serum G-CSF expression can be considered to predict the risk of immune dysfunction in AA children after IST, so as to guide early clinical intervention.
Topics: Anemia, Aplastic; Antilymphocyte Serum; Child; Cyclosporine; Granulocyte Colony-Stimulating Factor; Humans; Immunity; Immunosuppressive Agents
PubMed: 35680811
DOI: 10.19746/j.cnki.issn.1009-2137.2022.03.025 -
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 -
British Journal of Haematology Oct 2023When human leucocyte antigen-matched related donors are available, haematopoietic stem cell transplantation (HSCT) in children with severe aplastic anaemia (SAA)...
Human leucocyte antigen-matched related haematopoietic stem cell transplantation using low-dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia.
When human leucocyte antigen-matched related donors are available, haematopoietic stem cell transplantation (HSCT) in children with severe aplastic anaemia (SAA) represents the standard of care. Cyclophosphamide (Cy) 200 mg/kg and anti-thymocyte globulin (ATG) are frequently administered, but to-date, no standard conditioning regimen exists. In this study, we investigated the efficacy of a unified HSCT conditioning protocol consisting of low-dose Cy 80 mg/kg, fludarabine and ATG. Data were reviewed from children aged ≤14 years with either acquired SAA or non-Fanconi anaemia inherited bone marrow failure syndrome (IBMFS) between 2011 and 2022 at various Saudi institutions. Graft-versus-host disease (GVHD) prophylaxis included mycophenolate mofetil and calcineurin inhibitors. HSCT was performed in 32 children (17 females and 15 males). Nine patients had deleterious mutations (two ERCC6L2, two ANKRD26, two TINF2, one LZTFL1, one RTEL1 and one DNAJC21). Four patients had short telomeres. All 32 patients engrafted successfully. At 3 years post-transplant, the event-free survival was 93% and overall survival was 95%. Two patients experienced secondary graft failure or myelodysplastic syndrome. A low probability of GVHD was observed (one acute GVHD II and one mild chronic GVHD). These data highlight how HSCT using low-dose Cy as part of a fludarabine-based regimen is safe and effective in SAA/non-Fanconi anaemia IBMFS.
Topics: Male; Female; Humans; Child; Antilymphocyte Serum; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Fanconi Anemia; HLA Antigens; Histocompatibility Antigens Class II; Transplantation Conditioning; DNA Helicases
PubMed: 37491781
DOI: 10.1111/bjh.19004