Switching to Sirolimus-Based Immune Suppression After Liver Transplantation Is Safe and Effective: A Single-Center Experience

Harper, S.; Gelson, William; Harper, Ines; Alexander, Graeme; Gibbs, Paul

doi:10.1097/tp.0b013e3181fe131b

Cited by 41 publications

(47 citation statements)

References 31 publications

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“…The incidence of HAT related to sirolimus use varies in different reports. Molinari et al [78] reported a higher incidence of HAT in sirolimus group with CNI group but no HAT was reported in LT recipients on sirolimus in another study by Harper et al [79] . Similar results were reported by Fischer et al [80] , and they did notice no HAT following conversion of CNIs to everolimus.…”

Section: Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 99%

Review on immunosuppression in liver transplantation

Moini

Schilsky

Tichy

2015

WJH

203

159

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Section: Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 99%

Review on immunosuppression in liver transplantation

Moini

Schilsky

Tichy

2015

WJH

203

159

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“…Sirolimus is most commonly used to suppress the immune system and prevent rejection after kidney transplant; however, it is also used as an immune suppressant after other organ (liver, heart, and lung) and bone marrow transplants. [54][55][56][57][58][59] Sirolimus and other rapalogs associate with binding protein FKBP12, primarily blocking the mTORC1 complex with little to no activity against the mTORC2 complex. [60] Newer second-generation small molecule inhibitors of mTOR kinase that target both mTORCl and mTORC2 (mTORC1/2 inhibitors) are under development (see section 3.2).…”

Section: Rapalogsmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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“…Current work shows that sirolimus causes a significant decrease in acute rejection and improvement in patient and graft survival compared to azathioprine [21,22].…”

Section: Adjuvant Agentsmentioning

confidence: 99%

“…After induction therapy, whether this involves high-dose steroids that are then tapered off or an anti-thymocyte globulin preparation, maintenance therapy involves maintaining the program of conventional immunosuppression in order to prevent graft rejection [21]. Conventional maintenance therapy has evolved over the years and now includes multiple immunosuppressive agents that are given in non-toxic doses.…”

Section: Maintenance Strategymentioning

confidence: 99%