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STUDY OBJECTIVE:

Basiliximab is an immunosuppressive monoclonal antibody used for rejection prevention following solid organ transplantation; the pharmacokinetics (PK) of basiliximab in this setting are known. Basiliximab may also be used for prophylaxis and treatment of graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic cell transplantation (HCT); however, the PK of basiliximab in this setting are not known. Clinical transplant providers expect variation in the volume of distribution and clearance after nonmyeloablative allogeneic transplantation (NMAT) compared with solid organ transplantation. Blood loss, organ site-specific antibody accumulation, and differences in blood product use during the two transplantation approaches may generate differences in basiliximab PK. Therefore, the objective of this study was to describe the PK of basiliximab after its addition to a minimally intense NMAT regimen, in conjunction with cyclosporine, for GVHD prophylaxis in patients with hematologic malignancies.

DESIGN:

Population PK analysis of a single-center, single-arm, phase II clinical trial.

SETTING:

Academic cancer research center.

PATIENTS:

Fourteen adults with hematologic malignancies (acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, myelofibrosis, or severe aplastic anemia) and undergoing NMAT with a fully HLA-matched (10 of 10 antigen matched) related or unrelated donor.

MEASUREMENTS AND MAIN RESULTS:

Basiliximab was used in conjunction with cyclosporine to deplete activated T cells in vivo as GVHD prophylaxis. We developed a novel competitive enzyme-linked immunosorbent assay (ELISA) method using recombinant interleukin-2 receptor alpha-chain (IL-2Ra) and a commercially available soluble sIL-2R ELISA kit to permit the quantification of serum basiliximab concentrations and characterization of the PK properties of the drug in this patient population. Using a nonlinear mixed effects model with NONMEM software, a one-compartment model with first-order elimination best described the PK, as covariate analysis using stepwise covariate modeling did not improve the base model.

CONCLUSION:

We suggest a one-compartment population model with first-order elimination to capture the PK profile for basiliximab for this patient population.

Aim: Recent randomized trials have failed to prove the benefit of steroid-free immunosuppression in liver transplantation for hepatitis C virus (HCV)-related cirrhosis. Furthermore, there is a lack of data on the use of basiliximab in living donor liver transplantation (LDLT). This pilot study evaluated the safety and efficacy of a steroid minimization protocol using basiliximab compared with standard immunosuppression. Methods: A single center, prospective cohort analysis was conducted to compare two immunosuppression regimens in adult recipients who underwent LDLT for HCV since 2004: calcineurin inhibitor/mizoribine/basiliximab (the St- group) and calcineurin inhibitor/mizoribine/steroid (the St+ group). Study end-points were rejection rates, recurrent HCV, patient survival and other adverse events up to 2years after transplantation. Results: A total of 27 consecutive patients were enrolled. Transplantation characteristics were similar between the two groups (14 St- and 13 St+) except ABO incompatible cases being more common in the St+ group. Rejection rates, recurrent HCV, patient survival, fibrosis stage and new-onset diabetes mellitus at 2years were comparable between the two groups. ABO incompatibility did not affect short- and long-term outcomes. Nine St- and seven St+ recipients underwent interferon and ribavirin therapy for recurrent HCV, with a sustained virological response rate of 33% and 29%, respectively. Conclusion: A steroid minimization protocol with basiliximab in adult LDLT for HCV is safe and affords equivalent rejection rates compared with standard immunosuppression. However, no significant differences are observed with respect to recurrent HCV, patient survival and metabolic complications.

Systemic infection is still a major concern in young children with liver transplantation. The approach of this study is to reduce the risk of systemic infections by avoiding intraoperative steroids (another class of immunosuppressive drugs) given in combination with basiliximab, cyclosporine and steroids in pediatric de novo liver transplant recipients. The treatment is compared to the same treatment regimen including intraoperative steroids with respect to rejection episodes.

IgA nephropathy (IgAN) is a histologically defined glomerulonephritis (renal biopsy) by the presence of deposits immunoglobulin A (IgA) in the renal mesangium (at least 1+) by immunofluorescence. The clinic allows excluding secondary forms (10-15%). Recurrence of this condition on the renal graft is time-dependent and confirmed in 25 to 50% of 10 years post-transplant.

The primary immunosuppressive induction regimens currently used in kidney transplantation are the anti-lymphocyte globulin (GAL) whose main target is human T lymphocytes (ATG, polyclonal) and monoclonal anti-CD25 antibodies (α chain of the interleukin receptor 2 in the surface of T lymphocytes). Due to their potent and prolonged immunosuppressive properties, the ATG may prevent or delay the recurrence on renal transplant.

The aim of this study was to evaluate the influence of induction therapy (ATG versus Basiliximab) in the cumulative incidence at 5 years of (IgAN) recurrence after a first kidney transplant.

This is a prospective, multicenter, randomized, open trial with a follow-up period of 5 years old.

Patients in the ATG arm will receive 5 antilymphocyte globulin infusions Fresenius® (rabbit immunoglobulin antilymphocyte human T-Fresenius® said ATG) from Day 0 to Day + 4 post-transplant (day 0 one dose of 4mg / kg, day 1 one dose of 4mg/kg, day2 one dose of 4mgkg, day 3 one dose of 3 m/kg and day 4 and one final dose of 3 mg/kg) and the patients in the anti-CD25 arm will receive 2 doses of 20 mg of basiliximab (Simulect®) pn day 0 and day 4 after the graft. The maintenance immunosuppressive therapy is left to the discretion of the center.

The primary endpoint will be the clinical and histological recurrence of IgAN defined by the presence of mesangial deposits of IgA (at least 1) by immunofluorescence on a biopsy of the graft triggered by the onset of proteinuria 1g/j and/or microalbuminuria greater than 300 mg / day.

BACKGROUND:

Induction therapy with IL-2 receptor antagonist (IL2-RA) is recommended as a first-line agent in low immunological risk kidney transplant recipients. However, the role of IL2-RA in the setting of tacrolimus-based immunosuppression has not been fully investigated.

AIMS:

To compare different induction therapeutic strategies with 2 doses of basiliximab vs. no induction in low immunologic risk kidney transplant recipients as per KFSHRC protocol.

METHODS:

Prospective, randomized, double blind, non-inferiority, controlled clinical trial

EXPECTED OUTCOMES:

1. Primary outcomes: Biopsy-proven acute rejection within first year following transplant 2.

SECONDARY OUTCOMES:

a. Patient and graft survival at 1 year b. eGFR at 6 months and at 12 months c. Emergence of de novo donor-specific antibodies (DSAs)

TRIAL REGISTRATION:

The study has been prospectively registered at clinicaltrials.gov (

NTC:

04404127). Registered on 27 May 2020.

BACKGROUND:

Cyclosporine exposure, as estimated by the area under the curve (AUC), predicts outcomes in renal transplantation. Cyclosporine concentration at two h post-dose (C(2)) has been shown to be the most reliable, single-point surrogate marker for AUC. The objective of this study was to measure renal function beyond month 2 post-transplant using two different C(2) maintenance targets in combination with enteric-coated mycophenolate sodium (EC-MPS), corticosteroids, and basiliximab induction.

METHODS:

In this open-label, multicenter trial, renal transplant recipients entered one of two randomized groups at day 61 post-transplant: group A (higher-C(2) range) or group B (lower-C(2) range).

RESULTS:

Patients (164) were recruited, and 141 patients were entered the randomized groups (group A, n = 66; group B, n = 75). At 12 months, the mean calculated creatinine clearance was significantly greater in group B than in group A (79.2 vs. 71.0 mL/min, p < 0.05). Biopsy-proven acute rejection occurred in 14.7% patients in group B and in 24.2% patients in group A (n.s.). During the 12-month trial, 17.7% patients discontinued EC-MPS because of adverse events. Group B (44.0%) had fewer serious adverse events when compared with group A (62.1%; p = 0.04). Overall patient and graft survival were 99.4% and 95.7% respectively. Among 99 high-risk patients (i.e., African-American race, previous transplant, PRA >35% or >4 HLA mismatches), mean creatinine clearance at 12 months was 65.6 mL/min and biopsy-proven rejection occurred in 20.2% patients.

CONCLUSIONS:

Low cyclosporine C(2) levels are associated with improved renal function compared with higher C(2) levels when used in conjunction with EC-MPS, steroids and basiliximab induction. EC-MPS with low cyclosporine C(2) levels, corticosteroids and basiliximab provides excellent renal function with good efficacy even in high-risk patients.

Basiliximab, a chimeric interleukin-2 receptor (IL-2-R) antagonist, was evaluated in 17 patients with steroid-refractory acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Patients were transplanted from a related (n = 6) or unrelated (n = 11) HLA-identical donor because of acute lymphoblastic leukemia (n = 4), acute myeloid leukemia (n = 3), chronic myeloid leukemia (n = 7), myelodysplastic syndrome (n = 1), non-Hodgkin's lymphoma (n = 1), and multiple myeloma (n = 1). Basiliximab was given at a dose of 2 x 20 mg on 2 consecutive days after steroid-refractory acute GVHD had developed. Basiliximab was repeated on day 8 in cases of persistent GVHD. A median of four basiliximab infusions (range 1-12) were given to these patients. None had infusion-associated or cytokine-related side-effects after basiliximab. Twelve of 17 patients (71%) responded to basiliximab, 9/17 (53%) had a complete response (CR) of acute GVHD and 3/17 (18%) had a partial response (PR). Five of 17 patients (29%) did not respond. Chronic GVHD developed in 8/13 evaluable patients and only 2/8 had responded to basiliximab before. Five of 13 evaluable patients have no signs of chronic GVHD and all five had a CR or PR after basiliximab. This is the first report on the safety of basiliximab in patients with steroid-refractory acute GVHD. Our data suggest that basiliximab is effective in a substantial proportion of these patients.

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