Dataset Information

Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis.

ABSTRACT: Posttransplantation thrombotic microangiopathy (TMA) is a multifactorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased with the use of a sirolimus plus tacrolimus (SIR/TAC) regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. The patients received either a sibling donor graft (n = 82) or a matched unrelated donor graft (n = 95). Within the first 100 days post-HCT, 30 patients (17%) were diagnosed with TMA, and an additional 9 patients (5%) were classified as probable TMA cases. The median time to onset of TMA was 4.6 weeks (range, 1.6-10.6 weeks). Thirty-four patients developed both TMA and aGVHD, with the majority (81%) developing aGVHD first. Multivariate analysis identified the following factors as associated with increased risk of TMA: day 14 serum sirolimus level ?9.9 ng/mL (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.13-4.27; P = .02), presence of previous aGVHD grade II-IV (HR, 3.04; 95% CI, 1.38-6.71; P < .01), and fully myeloablative conditioning (HR, 3.47; 95% CI, 1.60-7.53; P < .01). These risk factors for TMA suggest that when using a SIR/TAC regimen for GVHD prophylaxis, careful monitoring and adjustment of the sirolimus dosage is critical, particularly in patients with active aGVHD.

SUBMITTER: Shayani S

PROVIDER: S-EPMC3589900 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis.

Shayani Sepideh S Palmer Joycelynne J Stiller Tracey T Liu Xueli X Thomas Sandra H SH Khuu Tam T Parker Pablo M PM Khaled Samer K SK Forman Stephen J SJ Nakamura Ryotaro R

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20121015 2

Posttransplantation thrombotic microangiopathy (TMA) is a multifactorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased with the use of a sirolimus plus tacrolimus (SIR/TAC) regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. The patients received either a sibling donor graft ( ...[more]

PMID: 23078784

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Project description:Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

Project description:ObjectiveThe objective of this study was to evaluate the safety and efficacy of sirolimus (SRL) in the prevention of graft-versus-host disease (GVHD) in recipients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).MethodsRandomized controlled trials (RCTs) evaluating the safety and efficacy of SRL-based prophylaxis regimens in patients receiving allo-HSCT were obtained from PubMed, Embase, and the Cochrane database. Following specific inclusion and exclusion criteria, studies were selected and screened by two independent reviewers who subsequently extracted the study data. The Cochrane risk bias evaluation tool was used for quality evaluation, and RevMan 5.3 software was used for statistical analysis comparing the effects of SRL-based and non-SRL-based regimens on acute GVHD, chronic GVHD, overall survival (OS), relapse rate, non-relapse mortality (NRM), thrombotic microangiopathy (TMA), and veno-occlusive disease (VOD).ResultsSeven studies were included in this meta-analysis, with a total sample size of 1,673 cases, including 778 cases of patients receiving SRL-based regimens and 895 cases in which patients received non-SRL-based regimens. Our data revealed that SRL containing prophylaxis can effectively reduce the incidence of grade II-IV acute GVHD (RR = 0.75, 95% CI: 0.68∼0.82, p < 0.0001). SRL-based prophylaxis was not associated with an improvement of grade III-IV acute GVHD (RR = 0.78, 95% CI: 0.59∼1.03, p = 0.08), chronic GVHD (p = 0.89), OS (p = 0.98), and relapse rate (p = 0.16). Despite its immunosuppressant effects, SRL-based regimens did not increase bacterial (p = 0.68), fungal (p = 0.70), or CMV (p = 0.10) infections. However, patients receiving SRL-based regimens had increased TMA (p < 0.00001) and VOD (p < 0.00001).ConclusionsThis meta-analysis indicates that addition of sirolimus is an effective alternative prophylaxis strategy for II-IV aGVHD but may cause endothelial cell injury and result in secondary TMA or VOD events.

Dataset Information

Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis.

Publications

Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis.

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