Conversion to Rapamycin Immunosuppression for Malignancy After Kidney Transplantation

Manuelli, M.; Luca, Linda De; Iaria, Giuseppe; Tatangelo, Paola; Sforza, D.; Perrone, Luca; Bellini, Maria Irene; Angelico, Roberta; Anselmo, Alessandro; Tisone, Giuseppe

doi:10.1016/j.transproceed.2010.03.051

Cited by 39 publications

(22 citation statements)

References 9 publications

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“…However, results were biased by concomitant dose reduction or suspension of CsA. Other small series report success in reduction of PTLD progression when main drug in the ISR was switched for mTORi (21)(22)(23)(24). database showed a temporal association in the increased incidence of PTLD after TAC started to be used in pediatric kidney transplantation.…”

Section: Discussionmentioning

confidence: 99%

Association of Immunosuppressive Maintenance Regimens With Posttransplant Lymphoproliferative Disorder in Kidney Transplant Recipients

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Association of Immunosuppressive Maintenance Regimens With Posttransplant Lymphoproliferative Disorder in Kidney Transplant Recipients

et al. 2012

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“…This approach has been recently shown to improve PTLD in many cases, occasionally inducing a complete remission. [210][211][212][213] ALPS is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis. [135,214,215] Children with ALPS often present with lymphoproliferation (massive lymphadenopathy and/or splenomegaly) and autoimmune disease (most commonly autoimmune cytopenias).…”

Section: Lymphoproliferative Disordersmentioning

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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“…9 Similarly, in an observational study, 2 of 11 patients with nonmetastatic cancer lost their grafts due to chronic rejection after conversion to sirolimus. 10 On the other hand, escalation of immunosuppressive drug dose after rejection enhances the relapse of the primary tumor. In our series, almost one-third of the patients diagnosed with first NMSC developed either a recurrence or de novo primary tumor of a remote organ after tailored treatment for NMSC.…”

Section: Discussionmentioning

confidence: 99%

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et al. 2017

Exp Clin Transplant

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Objectives: We evaluated patients with nonmelanoma skin cancer after kidney transplant and the effects of immunosuppression reduction and switching to a mammalian target of rapamycin inhibitor drugs. Materials and Methods: Kidney transplant recipients were evaluated retrospectively from patient medical records (between January 2000 and December 2014). A 30% increase in serum creatinine was accepted as indicating renal failure progression. Results: Of 18 patients included (mean follow-up 98 ± 66 mo), 7 (38.8%) had squamous cell carcinoma, 7 (38.8%) had Kaposi sarcoma, and 4 (22.2%) had basal cell carcinoma. At cancer diagnosis, average serum creatinine was 1.6 ± 0.7 mg/dL and proteinuria was 410 ± 766 mg/d. Immunosuppression regimen was changed in 15 patients (83.3%), with new regimen being a single-drug (only prednisolone) in 4 patients, double-drug in 6 patients, and triple-drug protocol in 8 patients. Eight patients were switched to a mammalian target of rapamycin inhibitor-based double (4 patients) or triple (4 patients) regimen. During follow-up after starting new treatment (average 46 ± 50 mo), 6 patients (33.3%) had progressive kidney failure (0 were receiving triple regimen). Those that progressed were using mammalian target of rapamycin inhibitor-based drugs relatively less (33% vs 50%), although often receiving a single-drug immunosuppression treatment (50% vs 8.3%). Three patients (33.3%) had acute rejection (2 receiving double and 1 receiving single immunosuppression treatment). Five patients (27.7%) had local recurrence of the primary tumor. Mammalian target of rapamycin inhibitor use was relatively less common in patients with tumor relapse (20% vs 46%). One patient died (heart failure), and 1 with chronic rejection returned to dialysis. Conclusions: Mammalian target of rapamycin inhibitorbased drugs could reduce local recurrence rate in kidney transplant recipients with nonmelanoma skin cancers. Aggressive reduction and/or cessation of immunosuppressive drugs after skin cancer can lead to graft rejection.

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Conversion to Rapamycin Immunosuppression for Malignancy After Kidney Transplantation

Cited by 39 publications

References 9 publications

Association of Immunosuppressive Maintenance Regimens With Posttransplant Lymphoproliferative Disorder in Kidney Transplant Recipients

Association of Immunosuppressive Maintenance Regimens With Posttransplant Lymphoproliferative Disorder in Kidney Transplant Recipients

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

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