RESUMEN

The annual number of human leukocyte antigen (HLA)-haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HCT) is increasing steadily. Comparative studies about haplo-HCT versus HCT with HLA-matched sibling donors (MSD-HCT) have been tried in acute myeloid leukemia and B-cell acute lymphoblastic leukemia/lymphoma (ALL). Few studies were reported in adult T-cell ALL (T-ALL). In this retrospective study, a total of 88 consecutive patients with T-ALL were enrolled who underwent MSD-HCT (n = 24) and haplo-HCT (n = 64) with antithymocyte globulin (ATG)-based graft versus host disease (GVHD) prophylaxis between 2010 and 2022. Median follow-up for survivors was similar (43.5 [range: 7-88] months for MSD-HCT versus 43.5 (range: 6-144) months in the Haplo-HCT group). The 100-day cumulative incidence of grade II to IV acute GVHD (aGVHD) was similar, 33% (95% confidence interval [CI], 16%-52%) after MSD-HCT versus 44% (95% CI, 31%-55%) after haplo-HCT, P = 0.52. The cumulative incidences of grade III-IV aGVHD were 8% (95% CI, 1%-23%) in the MSD-HCT group and 5% (95% CI, 1%-12%) in the haplo-HCT group (P = 0.50). The 2-year cumulative incidence of chronic GVHD (limited and extensive) in the haplo-HCT, 11% (95% CI, 5%-20%) was significantly lower than that in the MSD-HCT group (42% [95% CI, 21%-62%], P = 0.002). The cumulative incidence of 4-year relapse rates (44% versus 37%, P = 0.56) and non-relapse mortality (7% versus 21%, P = 0.08) did not differ between these two groups. There were also no differences in 4-year overall survival (46% versus 47%, P = 0.44) and progression-free survival (49% versus 42%, P = 0.45) between these two groups. On multivariate analysis, using busulfan/fludarabine (BU/Flu) conditioning regimen was found to be associated with worse clinical outcome. Our results suggested that ATG-based haplo-HCT platform could work as an alternative to MSD-HCT for adult patients with T-ALL. Compared with MSD-HCT, haplo-HCT might carry a low risk for cGVHD.

Asunto(s)

Suero Antilinfocítico , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Hermanos , Humanos , Adulto , Femenino , Masculino , Suero Antilinfocítico/uso terapéutico , Persona de Mediana Edad , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Adulto Joven , Estudios Retrospectivos , Trasplante Haploidéntico/métodos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Enfermedad Crónica

RESUMEN

We describe the epidemiology of cancer after kidney transplantation (KTx), investigating its risk factors and impact on therapeutic management and survival in KTx recipients (KTRs). The association between modification of immunosuppressive (IS) therapy after cancer and survival outcomes was analyzed. We collected data from 930 KTRs followed for 7 [1-19] years. The majority of KTRs received KTx from a deceased donor (84%). In total, 74% of patients received induction therapy with basiliximab and 26% with ATG. Maintenance therapy included steroids, calcineurin inhibitors, and mycophenolate. Patients with at least one cancer (CA+) amounted to 19%. NMSC was the most common tumor (55%). CA+ were older and had a higher BMI. Vasculitis and ADPKD were more prevalent in CA+. ATG was independently associated with CA+ and was related to earlier cancer development in survival and competing risk analyses (p = 0.01 and <0.0001; basiliximab 89 ± 4 vs. ATG 40 ± 4 months). After cancer diagnosis, a significant prognostic impact was derived from the shift to mTOR inhibitors compared to a definitive IS drug suspension (p = 0.004). Our data confirm the relevance of cancer as a complication in KTRs with ATG as an independent risk factor. An individualized choice of IS to be proposed at the time of KTx is crucial in the prevention of neoplastic risk. Finally, switching to mTORi could represent an important strategy to improve patient survival.

Asunto(s)

Inmunosupresores , Trasplante de Riñón , Neoplasias , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Italia/epidemiología , Adulto , Neoplasias/epidemiología , Factores de Riesgo , Basiliximab/uso terapéutico , Anciano , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Suero Antilinfocítico/uso terapéutico

RESUMEN

The optimal treatment for patients with severe aplastic anemia (SAA) who fail an initial course of antithymocyte globulin (ATG) plus cyclosporine has not yet been established. We compared the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated immunosuppressive therapy (IST) (n = 33) for relapsed/refractory SAA between 2007 and 2022. In the IST group, patients were retreated with ATG (n = 16) or high-dose cyclophosphamide (n = 17). The overall response rate was 57.6% at 6 months and 60.6% at 12 months. In the allo-HSCT group, patients received a transplant from a matched sibling donor (n = 6), matched unrelated donor (n = 7), or haploidentical donor (n = 23). All patients achieved neutrophil engraftment, and there were no cases of primary graft failure. The cumulative incidences (CIs) of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 36.1% ± 0.7% and 13.9% ± 0.3% at day +100, respectively. The 4-year CI of chronic GVHD (cGVHD) was 36.2% ± 0.7%, with moderate to severe cGVHD at 14.9% ± 0.4%. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3, 6, and 12 months (63.9%, 83.3%, and 86.1%, respectively, p < 0.001). The estimated 4-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) was similar; however, the failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 56.6% ± 8.8%, p = 0.049). Of note, children in the HSCT cohort were all alive without treatment failures, exhibiting superior OS (100% vs. 50.0% ± 17.7%, p = 0.004) and FFS (100% vs. 50.0% ± 17.7%, p = 0.004) than children in the IST cohort. Subgroup analysis revealed that younger patients (age ≤ 35 years), especially children, and those with refractory SAA benefited more from HSCT. Therefore, for these patients, salvage HSCT may be more preferable than a second course of IST.

Asunto(s)

Anemia Aplásica , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores , Recurrencia , Humanos , Anemia Aplásica/terapia , Anemia Aplásica/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Femenino , Adolescente , Adulto , Enfermedad Injerto contra Huésped/etiología , Niño , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Adulto Joven , Preescolar , Persona de Mediana Edad , Resultado del Tratamiento , Suero Antilinfocítico/uso terapéutico , Suero Antilinfocítico/administración & dosificación , Trasplante Homólogo , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Terapia de Inmunosupresión/métodos , Estudios Retrospectivos , Ciclosporina/uso terapéutico , Ciclosporina/administración & dosificación

RESUMEN

OBJECTIVE: To document the results of outpatient hematopoietic stem cell transplantation (HSCT) from the peripheral blood (PB) of sibling donors without anti-thymocyte globulin (ATG) in the conditioning regimen. MATERIAL AND METHODS: Patients from a low-income population with severe AA who received a PB, unmanipulated sibling HLA-identical HSCT between 2000 and 2020 at a single institution were studied. Survival was the primary outcome. RESULTS: Forty-one transplants were performed. Time between diagnosis and transplant was five months (1-104). Median age was 37 (range, 4-61) years; 25 (61 %) recipients were males and 32 (78 %) had treatment failure, 9 (22 %) have not received treatment. ATG was administered in 5 (12.2 %) cases; the graft source was PB in 38 (92.7 %) transplants. Twenty-six (63.4 %) transplants were carried out in the outpatient setting. Infections developed in 14 (34.1 %) patients. Primary graft failure (GF) occurred in 3 (7.3 %) patients. The 15-year OS was 81 %, EFS was 77.4 %. Patients with high pre-HSCT transfusion burden had lower OS (p = 0.035) and EFS (p = 0.026). Previous treatment failure and age were not associated with lower OS (p = 0.115, p = 0.069) or EFS (p = 0.088, p = 0.5, respectively). CONCLUSIONS: HLA-identical T-cell replete outpatient HSCT from the PB of sibling donors for AA patients using ATG-free conditioning offers excellent long-term survival.

Asunto(s)

Anemia Aplásica , Suero Antilinfocítico , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Humanos , Masculino , Adulto , Femenino , Anemia Aplásica/terapia , Anemia Aplásica/mortalidad , Persona de Mediana Edad , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Niño , Preescolar , Suero Antilinfocítico/uso terapéutico , Adulto Joven , Acondicionamiento Pretrasplante/métodos , Hermanos , Pacientes Ambulatorios , Enfermedad Injerto contra Huésped/etiología , Resultado del Tratamiento

RESUMEN

Eltrombopag combined with immunosuppressive therapy (IST) was superior to IST alone for severe aplastic anemia (SAA) in the previous studies. But in China, horse antithymocyte globulin (hATG) is not available, instead, we use rabbit ATG (rATG). Here, we compared the efficacy and safety of IST (rATG combined with cyclosporine) combined with or without eltrombopag for the first-line treatment of SAA and very severe aplastic anemia (VSAA). A total of 371 patients in ten institutions in China from April 1, 2017 to December 1, 2022 were enrolled. The overall response (OR) rate at 3 months (54.2% vs. 41%; P = 0.046), the complete response (CR) (31.3% vs. 19.4%; P = 0.041) and OR (78.3% vs. 51.1%; P < 0.0001) rates at 6 months were significantly higher with IST combined with eltrombopag than with IST alone in SAA patients. While in VSAA patients, the addition of eltrombopag to IST only increased the CR rate at 6 months (29.8% vs. 9.43%; P = 0.010). Liver injury increased significantly in groups treated with IST combined with eltrombopag (P < 0.05). Serious treatment-related toxicities were similar (P > 0.05). In patients with SAA, 3-year failure-free survival (FFS) of eltrombopag combined with IST group was significantly higher than that of IST group (70.7 ± 5.3% vs. 50.3 ± 3.9%; P = 0.007). In patients with VSAA, the addition of eltrombopag significantly improved 3-year overall survival (OS) (82.2 ± 5.7% vs. 57.3 ± 7.2%; P = 0.020). Our findings suggested that IST combined with eltrombopag could improve the hematological recovery of newly diagnosed SAA without increasing severe toxicities. But in VSAA, the addition of eltrombopag seemed to show no other improvement to efficacy except the CR rate at 6 months.

Asunto(s)

Anemia Aplásica , Suero Antilinfocítico , Benzoatos , Hidrazinas , Inmunosupresores , Pirazoles , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/mortalidad , Benzoatos/uso terapéutico , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Humanos , Hidrazinas/uso terapéutico , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Inmunosupresores/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Suero Antilinfocítico/administración & dosificación , Adulto Joven , Anciano , Estudios Retrospectivos , Quimioterapia Combinada , Niño , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Preescolar , Ciclosporina/uso terapéutico , Ciclosporina/administración & dosificación , China/epidemiología , Tasa de Supervivencia

Asunto(s)

Anemia Aplásica , Suero Antilinfocítico , Hemólisis , Inmunosupresores , Humanos , Suero Antilinfocítico/efectos adversos , Suero Antilinfocítico/uso terapéutico , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/inducido químicamente , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Hemólisis/efectos de los fármacos , Niño , Masculino , Femenino

RESUMEN

BACKGROUND: The optimal dose of rabbit anti-thymocyte globulin (r-ATG) in renal transplantation is still under debate. We previously reported that a low-dose r-ATG induction of 3 mg/kg can be used safely and effectively in low-risk kidney transplants with good results in the first year after transplantation compared to basiliximab induction. AIMS: The purpose of this study is to evaluate the long-term impact of this trial of low-dose r-ATG versus basiliximab on post-transplant outcomes (patient and graft survival, biopsy-proven acute rejection incidence [BPAR], infectious complications, and side effects). METHODS: Observational study (three-year follow-up) of a 12-month single-center, open-label RCT in de novo kidney allograft recipients assigned to receive either thymoglobulin or basiliximab before transplantation. RESULTS: Patients in the basiliximab group (BG) underwent more kidney transplant biopsies than patients in the low-dose r-ATG group (TG) (50 vs. 31.8%, p = 0.07). Although the 12-month cumulative incidence of BPAR was lower in BG, by the end of the three-year follow-up period this incidence was higher (22%) than in the low-dose TG (15%) (p = ns). Steroids were withdrawn more frequently in the TG group and sirolimus was most frequently indicated. Graft function and graft survival were higher in the low-dose TG than in the BG at three-year follow-up but not statistically significant. Patient survival was similar between groups (>90%). CONCLUSIONS: These three-year follow-up data confirm the efficacy and favorable safety aspects of the low-dose r-ATG (3 mg/kg) in low-risk kidney transplantation.

Asunto(s)

Suero Antilinfocítico , Basiliximab , Rechazo de Injerto , Inmunosupresores , Trasplante de Riñón , Proteínas Recombinantes de Fusión , Humanos , Basiliximab/uso terapéutico , Basiliximab/administración & dosificación , Trasplante de Riñón/efectos adversos , Suero Antilinfocítico/uso terapéutico , Suero Antilinfocítico/administración & dosificación , Masculino , Femenino , Estudios de Seguimiento , Persona de Mediana Edad , Adulto , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/uso terapéutico , Rechazo de Injerto/prevención & control , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Supervivencia de Injerto/efectos de los fármacos

RESUMEN

ABSTRACT: It has been reported in prospective randomized trials that antithymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis has benefits in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with unrelated donors (UDs). However, the optimal GVHD prophylaxis strategy has been challenged recently by the increasing use of posttransplant cyclophosphamide (PTCY). We report from the European Society for Blood and Marrow Transplantation registry the outcomes of 960 patients with myelodysplastic neoplasms who underwent allo-HSCT from UD with PTCY or ATG as GVHD prophylaxis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). The disease characteristics were similar in both groups. Day 28 neutrophil engraftment was significantly better with ATG (93% vs 85%). Over a median follow-up of 4.4 years, the 5-year OS was 58% with PTCY, and 49% in the ATG group. The 5-year PFS was higher for PTCY at 53% vs 44% for ATG. Grade 2 to 4 acute GVHD incidence was lower when PTCY was used (23%), whereas there was no difference in the incidence of chronic GVHD at 5 years. Multivariable analyses confirmed better OS and PFS with PTCY with a hazard ratio (HR) for ATG of 1.32 (1-1.74) and a better PFS for PTCY with a HR for ATG of 1.33. This study suggests that GVHD prophylaxis using PTCY instead of ATG in this setting remains a valid option. Further prospective randomized studies would be essential to confirm these results.

Asunto(s)

Suero Antilinfocítico , Ciclofosfamida , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Donante no Emparentado , Humanos , Ciclofosfamida/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Persona de Mediana Edad , Femenino , Masculino , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/etiología , Adulto , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/mortalidad , Anciano , Adulto Joven , Trasplante Homólogo , Acondicionamiento Pretrasplante/métodos , Adolescente , Resultado del Tratamiento

Asunto(s)

Suero Antilinfocítico , Ciclofosfamida , Enfermedad Injerto contra Huésped , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/terapia , Suero Antilinfocítico/uso terapéutico , Ciclofosfamida/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Incidencia , Adulto , Anciano , Enfermedad Aguda , Trasplante de Células Madre Hematopoyéticas/métodos

RESUMEN

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acquired aplastic anemia (acquired AA) in young patients. The objective of the study was to compare patient outcomes after Cyclophosphamide and horse antithymocyte globulin (Cy-hATG) versus Fludarabine-cyclophosphamide and rabbit ATG (Flu-Cy-rATG) as part of conditioning regimen in allo-HSCT for acquired AA. RESEARCH DESIGN AND METHODS: Descriptive retrospective study conducted on patients with acquired AA who received allo-HSCT from HLA-matched sibling donors between January 2008 and August 2022 after conditioning regimen with Cy-hATG or Flu-Cy-rATG. RESULTS: A total of 121 patients were enrolled. Cumulative incidence of graft failure was 11.2% in Cy-hATG and 5.3% Flu-Cy-rATG group. There were no significant differences between the two groups in terms of acute GVHD, chronic GVHD, and transplant related mortality. Flu-Cy-rATG group was associated with significantly higher CMV and EBV reactivation(s) compared to Cy-hATG group (p = 0.008 and 0.035, respectively). After a median follow-up of 58 months, estimated overall survival, event-free survival, and graft rejection-free survival were not statistically different between the two groups. CONCLUSIONS: In high-risk population, Flu-Cy-rATG is associated with comparable outcomes to Cy-hATG in allo-HSCT from MSD. However, it seems to be associated with significant risk of viral infections.

Asunto(s)

Anemia Aplásica , Suero Antilinfocítico , Ciclofosfamida , Trasplante de Células Madre Hematopoyéticas , Hermanos , Acondicionamiento Pretrasplante , Vidarabina , Humanos , Anemia Aplásica/terapia , Anemia Aplásica/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Suero Antilinfocítico/uso terapéutico , Ciclofosfamida/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Masculino , Femenino , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Animales , Adolescente , Estudios Retrospectivos , Adulto , Caballos , Conejos , Niño , Trasplante Homólogo , Donantes de Tejidos , Adulto Joven , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Preescolar , Persona de Mediana Edad

RESUMEN

PURPOSE: Currently 80% of lung transplant centers use induction immunosuppression. However, there is a lack of standardization of induction protocols within and across lung transplant centers. This study explores the association of two different induction immunosuppression strategies used at our center [single dose rabbit antithymocyte globulin (rATG) vs. alemtuzumab] compared to no induction with immunologic and clinical outcomes after lung transplantation. METHODS: A total of 174 consecutive lung transplant recipients (LTR) between 2016 and 2019 were included in the analysis. Twenty nine LTR (16.7%) received no induction, 22 LTR (12.6%) received alemtuzumab, 123 LTR (70.6%) received a single dose of rATG; 1.5 mg/kg within 24 h of transplant for induction. All LTR had a negative flow cytometry crossmatch on the day of the transplant. All LTR were assessed for de novo HLA donor-specific antibodies (DSA) development and clinical outcomes, including the risk of acute cellular rejection (ACR), antibody-mediated rejection (AMR), chronic lung allograft dysfunction (CLAD), and overall survival post-transplant. RESULTS: The median lung allocation score (LAS) was significantly higher in LTR that did not receive Induction immunosuppression (76; range = 35.3-94.3) compared to induction with rATG (41.6; range = 31.6-91) and alemtuzumab (51; range = 33.1-88.2) (p < 0.001). De novo HLA DSA were detected in 50/174 (28.7%) LTR within 12 months post-transplant. They were detected in 13/29 (44.8%) LTR without induction immunosuppression compared to 28/123 (22.8%) and 9/22 (40.9%) LTR with rATG and alemtuzumab induction, respectively (p = 0.02). The percent freedom from ACR rates between LTR who received alemtuzumab induction was significantly higher compared to LTR who received rATG or no induction at 1 (p = 0.02), 2 (p = 0.01) and 3 (p = 0.05) years post-transplant. In addition, the overall 1-year survival rates were significantly higher in LTR who received rATG or alemtuzumab induction compared to LTR without induction immunosuppression (p = 0.02). CONCLUSION: Induction immunosuppression strategies utilizing rATG or Alemtuzumab have unique and contrasting benefits in LTR. Combination of alemtuzumab induction and a lower dose of maintenance immunosuppression may reduce the incidence of ACR in LTR. Single-dose rATG or alemtuzumab induction immunosuppression may also improve the 1 year overall LTR survival compared to no induction.

Asunto(s)

Alemtuzumab , Suero Antilinfocítico , Rechazo de Injerto , Terapia de Inmunosupresión , Trasplante de Pulmón , Humanos , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Masculino , Persona de Mediana Edad , Femenino , Suero Antilinfocítico/uso terapéutico , Alemtuzumab/uso terapéutico , Adulto , Terapia de Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Animales , Anciano , Estudios Retrospectivos , Supervivencia de Injerto , Conejos , Resultado del Tratamiento , Antígenos HLA/inmunología , Isoanticuerpos/sangre

RESUMEN

We retrospectively analyzed high-risk ALL patients in CR1 receiving total body irradiation based conditioning regimen with ATLG (n = 74) or PTCy (n = 73) for GVHD prophylaxis. The 3-year OS and LFS were similar in both groups: 65 and 60% in the ATLG group and 64 and 67% in the PTCy group (p = 0.9 and 0.5, respectively). CIR and NRM rate at three years was 12 and 21% after PTCy and 19 and 20% after ATLG (p = 0.4 and p = 0.9, respectively). Acute GvHD grades II-IV and grades III/IV at 100 days was 46 and 19% after PTCy and 33 and 10% after ATLG (p = 0.08 and p = 0.9, respectively). Chronic GvHD of all grade at two years was higher after PTCy: 55% versus 26% (p < 0.001). Based on the propensity score matching (PSM) analysis, aGvHD grades II-IV was trending higher in the PTCy group compared to the ATLG group (p = 0.07). In contrast to the PSM analysis, on multivariate analysis the receipt of PTCy compared with ATLG was associated with a reduced CIR (p = 0.026). Our retrospective single-center analysis shows a lower incidence of acute and chronic GvHD while displaying similar LFS and OS after ATLG compared to PTCy in TBI based allogeneic stem cell transplantation for high-risk ALL.

Asunto(s)

Suero Antilinfocítico , Ciclofosfamida , Enfermedad Injerto contra Huésped , Humanos , Enfermedad Injerto contra Huésped/prevención & control , Femenino , Masculino , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Suero Antilinfocítico/uso terapéutico , Suero Antilinfocítico/administración & dosificación , Adolescente , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Acondicionamiento Pretrasplante/métodos , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo/métodos , Adulto Joven , Niño , Aloinjertos

RESUMEN

Introduction: Anti-Thymocyte Globulin (ATG) is a cornerstone in immune suppression for solid organ transplantation. The treatment is a delicate balance between complications arising from over-immunosuppression such as infections and cancer versus rejection stemming from under-immunosuppression. CD3+ T-lymphocyte measurements are frequently employed for treatment monitoring. However, this analysis is costly and not always accessible. The aim of this study was to investigate whether the total count of lymphocytes could replace CD3+ T-lymphocyte measurements based on data from our transplantation center combined with a review of the literature. The hypothesis was that the total lymphocyte count could serve as a diagnostic surrogate marker for CD3+ T-lymphocytes. Methods: A retrospective cohort study was conducted, including patients who underwent kidney and/or a pancreas transplantation and received ATG as induction therapy or for rejection treatment. The inclusion criterium was that the total lymphocyte count and CD3+ T-lymphocyte measurements were measured simultaneously on the same day. Additionally, PubMed and Embase were searched up to 18/10/2023 for published studies on solid organ transplantation, ATG, T-lymphocytes, lymphocyte count, and monitoring. In the retrospective cohort study, a total of 91 patients transplanted between 2016 and 2023, with 487 samples, were included. Results: Total lymphocyte counts below 0.3 x 109/L had a high sensitivity (86%) as a surrogate marker of CD3+ T-lymphocytes below 0.05 x 109/L, but the specificity was low (52%) for total lymphocyte counts above 0.3 x 109/L as a surrogate marker for CD3+ T-lymphocytes above 0.05 x 109/L. A review of the literature identified seven studies comparing total lymphocyte counts and CD3+ T-lymphocytes in ATG monitoring. These studies supported the use of a low total lymphocyte count as a surrogate marker for CD3+ T-lymphocytes and an indicator to omit ATG treatment. However, there was no consensus regarding high total lymphocyte counts as an indicator for continued treatment. Discussion: Results supports that the total lymphocyte count can be used to omit ATG treatment when below 0.3 x 109/L whereas the CD3+ T-lymphocyte analysis should be reserved for higher total lymphocyte counts to avoid ATG overtreatment.

Asunto(s)

Suero Antilinfocítico , Rechazo de Injerto , Inmunosupresores , Humanos , Suero Antilinfocítico/uso terapéutico , Recuento de Linfocitos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Linfocitos T/inmunología , Trasplante de Riñón/efectos adversos , Anciano , Trasplante de Páncreas , Complejo CD3 , Trasplante de Órganos/efectos adversos

RESUMEN

The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.

Asunto(s)

Abatacept , Suero Antilinfocítico , Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Corazón , Interleucina-6 , Linfocitos T Reguladores , Animales , Masculino , Ratones , Abatacept/farmacología , Abatacept/uso terapéutico , Aloinjertos/inmunología , Suero Antilinfocítico/farmacología , Suero Antilinfocítico/uso terapéutico , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Trasplante de Corazón/efectos adversos , Inmunosupresores/farmacología , Interleucina-10/metabolismo , Interleucina-10/inmunología , Interleucina-6/metabolismo , Depleción Linfocítica , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos

RESUMEN

This study aimed to assess the efficacy of dual T-cell suppression using individually tailored doses of antithymocyte globulin (ATG) and attenuated dose of post-transplant cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We conducted a retrospective analysis of 78 adults with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT using intravenous busulfan and fludarabine conditioning. Thirty-two patients received attenuated ATG/PTCy, while 46 patients received ATG (7.5 mg/kg) as GVHD prophylaxis. The 100-day cumulative incidence of grade III-IV (9.7% vs. 32.4%, P = 0.018) acute GVHD, as well as 2-year moderate-severe chronic GVHD (13.9% vs. 43.9%, P = 0.018) in the ATG/PTCy group were significantly lower than those in the ATG group. The 2-year overall survival was comparable between the two groups. However, 2-year GVHD-free, relapse-free survival in the ATG/PTCy group was significantly higher compared to that in the ATG group (38.9% vs. 21.7%, P = 0.021). Moreover, during post-engraftment period, the ATG/PTCy group exhibited lower incidences of life-threatening bacterial (12.5% vs. 37%, P = 0.033) and viral infection (0% vs. 17.4%, P = 0.035) than the ATG group. In conclusion, the combination of individually tailored ATG and low-dose PTCy appears to be a promising strategy in haplo-HSCT.

Asunto(s)

Suero Antilinfocítico , Ciclofosfamida , Enfermedad Injerto contra Huésped , Depleción Linfocítica , Linfocitos T , Acondicionamiento Pretrasplante , Trasplante Haploidéntico , Humanos , Suero Antilinfocítico/administración & dosificación , Suero Antilinfocítico/uso terapéutico , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Masculino , Femenino , Adulto , Persona de Mediana Edad , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/etiología , Estudios Retrospectivos , Linfocitos T/inmunología , Depleción Linfocítica/métodos , Trasplante Haploidéntico/métodos , Acondicionamiento Pretrasplante/métodos , Adulto Joven , Trasplante de Células Madre de Sangre Periférica/métodos , Adolescente , Síndromes Mielodisplásicos/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico

RESUMEN

PURPOSE: Kidney transplantation has a survival benefit for people with human immunodeficiency virus (HIV) and end-stage kidney disease, however increased rates of rejection remain an issue. Questions remain regarding the impact of induction immunosuppression therapy and antiretroviral (ARV) choice on long-term outcomes. METHODS: We performed a multicenter retrospective analysis of outcomes in recipients with HIV who received kidneys from donors without HIV transplanted between 2004 and 2019. The association between induction and ARV regimens and long-term outcomes including rejection, graft, and recipient survival over 5 years was investigated using Cox regression modeling. RESULTS: Seventy-eight kidney transplants (KT) performed in 77 recipients at five US transplant centers were included, with median follow up of 7.1 (4.3-10.7) years. Overall recipient and graft survival were 83% and 67%, respectively. Rejection occurred in 37% (29/78). Recipients with rejection were more likely to be younger, recipients of deceased donor organs, and Black. Receipt of rabbit anti-thymocyte globulin (rATG) induction without protease-inhibitor (PI)-based ARVs was associated with 83% lower risk of rejection (adjusted hazard ratio (aHR) 0.17 (95% CI 0.05-0.63), p =.007) and a non-statistically significantly lower risk of graft failure (aHR 0.18 (0.03-1.16), p =.07) when compared to those who received other induction and ARV combinations. CONCLUSIONS: In this multicenter retrospective study, we found a trend toward lower rejection and improved graft survival among those who received both rATG for induction and PI-sparing ARVs.

Asunto(s)

Suero Antilinfocítico , Rechazo de Injerto , Supervivencia de Injerto , Infecciones por VIH , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Masculino , Femenino , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/mortalidad , Adulto , Persona de Mediana Edad , Suero Antilinfocítico/uso terapéutico , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/cirugía , Antirretrovirales/uso terapéutico , Quimioterapia de Inducción/métodos , Receptores de Trasplantes/estadística & datos numéricos , Resultado del Tratamiento , Terapia de Inmunosupresión/métodos

RESUMEN

In αß T-cell/CD19 B-cell depleted hematopoietic stem cell transplantation (αßhaplo-HSCT) recipients, antithymocyte globulin (ATG; Thymoglobulin) is used for preventing graft rejection and graft-versus-host disease (GVHD). The optimal dosing remains to be established, however. Here we present the first comparative analysis of 3 different ATG dosing strategies and their impact on immune reconstitution and GVHD. Our study aimed to evaluate the effects of 3 distinct dosing strategies of ATG on engraftment success, αß+ and γδ+ T cell immune reconstitution, and the incidence and severity of acute GVHD in recipients of αßhaplo-HSCT. This comparative analysis included 3 cohorts of pediatric patients with malignant (n = 36) or nonmalignant (n = 8) disease. Cohorts 1 and 2 were given fixed ATG doses, whereas cohort 3 received doses via a new nomogram, based on absolute lymphocyte count (ALC) and body weight (BW). Cohort 3 showed a 0% incidence of day 100 grade II-IV acute GVHD, compared to 48% in cohort 1 and 27% in cohort 2. Furthermore, cohort 3 (the ALC/BW-based cohort) had a significant increase in CD4+ and CD8+ naïve T cells by day 90 (P = .04 and .03, respectively). Additionally, we found that the reconstitution and maturation of γδ+ T cells post-HSCT was not impacted across all 3 cohorts. Cumulative ATG exposure in all cohorts was lower than previously reported in T cell-replete settings, with a lower pre-HSCT exposure (<40 AU*day/mL) correlating with engraftment failure (P = .007). Conversely, a post-HSCT ATG exposure of 10 to 15 AU*day/mL was optimal for improving day 100 CD4+ (P = .058) and CD8+ (P = .03) immune reconstitution without increasing the risk of relapse or nonrelapse mortality. This study represents the first comparative analysis of ATG exposure in αßhaplo-HSCT recipients. Our findings indicate that (1) a 1- to 2-fold ATG to ATLG bioequivalence is more effective than previously established standards, and (2) ATG exposure post-HSCT does not adversely affect γδ+ T cell immune reconstitution. Furthermore, a model-based ATG dosing strategy effectively reduces graft rejection and day 100 acute GVHD while also promoting early CD4+/CD8+ immune reconstitution. These insights suggest that further optimization, including more distal administration of higher ATG doses within an ALC/BW-based strategy, will yield even greater improvements in outcomes.

Asunto(s)

Suero Antilinfocítico , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Linfocitos T , Enfermedad Injerto contra Huésped/prevención & control , Suero Antilinfocítico/uso terapéutico , Suero Antilinfocítico/administración & dosificación , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Niño , Masculino , Femenino , Adolescente , Preescolar , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Enfermedad Aguda , Lactante , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo

RESUMEN

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.

Asunto(s)

Anemia Aplásica , Trasplante de Células Madre Hematopoyéticas , Neutrófilos , Humanos , Anemia Aplásica/terapia , Anemia Aplásica/mortalidad , Anemia Aplásica/sangre , Adulto , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adolescente , Adulto Joven , Anciano , Recuento de Leucocitos , Suero Antilinfocítico/uso terapéutico , Tasa de Supervivencia , Trasplante Homólogo , Acondicionamiento Pretrasplante , Aloinjertos

RESUMEN

BACKGROUND: Patients undergoing heart transplants are at risk of rejection which can have significant morbidity and mortality. Induction immunosuppression at the time of transplant reduces the early risk and has additional benefits. The induction agent of choice within our program was changed from rabbit antithymocyte-globulin (rATG) to basiliximab, so it was necessary to evaluate whether this had any impact on patient outcomes. OBJECTIVES: Our primary objective was to describe rejection, infection, and other outcomes in adult heart transplant patients at the University of Alberta Hospital in Edmonton, Canada. METHODS: This study was a nonrandomized, retrospective cohort study. RESULTS: Sixty-three patients were included with median ages 50 years versus 54 years. More female patients received rATG (20% vs. 42.4%). The most common indication for transplant in both cohorts was ICM (63.3% vs. 57.6%). Patients who received rATG had significantly higher PRA (0% vs. 43%, p < .001). Acute rejection episodes were similar between basiliximab and rATG at 3 months (16.7% vs. 15.1%; p = 1.0) and 6-months (30.0% vs. 18.1%; p = .376). Infections were not statistically different with basiliximab compared to rATG at 3-months, 43.3% vs. 63.6% and at 6-months 60.0% vs. 66.7%). There were no fatalities in either group. CONCLUSIONS: Our study did not demonstrate differences in rejection with basiliximab compared to rATG. Mortality did not differ, but basiliximab-treated patients had fewer infections and infection-related hospitalizations than those treated with rATG. Larger studies with longer durations are needed to more completely describe the differences in rejection and infectious outcomes.

Asunto(s)

Anticuerpos Monoclonales , Suero Antilinfocítico , Basiliximab , Rechazo de Injerto , Trasplante de Corazón , Inmunosupresores , Proteínas Recombinantes de Fusión , Humanos , Basiliximab/uso terapéutico , Femenino , Masculino , Trasplante de Corazón/efectos adversos , Persona de Mediana Edad , Estudios Retrospectivos , Proteínas Recombinantes de Fusión/uso terapéutico , Rechazo de Injerto/prevención & control , Rechazo de Injerto/etiología , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/inmunología , Suero Antilinfocítico/uso terapéutico , Inmunosupresores/uso terapéutico , Adulto , Estudios de Seguimiento , Anticuerpos Monoclonales/uso terapéutico , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Pronóstico , Factores de Riesgo , Complicaciones Posoperatorias , Anciano , Terapia de Inmunosupresión/métodos

RESUMEN

The KDIGO guideline for acute rejection treatment recommends use of corticosteroids and suggests using lymphocyte-depleting agents as second line treatment. Aim of the study was to determine the current practices of detection and treatment of TCMR of kidney allografts amongst European kidney transplant centres. An invitation was sent through ESOT/EKITA newsletters and through social media to transplant professionals in Europe for taking part in the survey. A total of 129 transplant professionals responded to the survey. There was equal representation of small and large sized transplant centres. The majority of centres treat borderline changes (BL) and TCMR (Grade IA-B, IIA-B) in indication biopsies and protocol biopsies with corticosteroids as first line treatment. Thymoglobulin is used mainly as second line treatment for TCMR Grade IA-B (80%) and TCMR IIA-B (85%). Treatment success is most often evaluated within one month of therapy. There were no differences observed between the large and small centres for the management of TCMR. This survey highlights the common practices and diversity in clinics for the management of TCMR in Europe. Testing new therapies for TCMR should be in comparison to the current standard of care in Europe. Better consensus on treatment success is crucial for robust study designs.

Asunto(s)

Rechazo de Injerto , Trasplante de Riñón , Humanos , Rechazo de Injerto/diagnóstico , Europa (Continente) , Encuestas y Cuestionarios , Linfocitos T/inmunología , Inmunosupresores/uso terapéutico , Corticoesteroides/uso terapéutico , Biopsia , Suero Antilinfocítico/uso terapéutico