L Pi1, J Rooprai2, D S Allan3, H Atkins3, C Bredeson3, A J Fulcher3, C Ito4, T Ramsay5, W L Stanford4, M Sabloff3, G Christou6. 1. Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada; Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON, K1H 8M5, Canada. 2. Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON, K1H 8M5, Canada. 3. Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON, K1H 8M5, Canada; Division of Hematology, Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada; Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada. 4. Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd #3206, Ottawa, ON, K1H 8M5, Canada. 5. Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON, K1H 8M5, Canada; Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada. 6. Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON, K1H 8M5, Canada; Division of Hematology, Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada; Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada. Electronic address: grchristou@toh.ca.
Abstract
INTRODUCTION: Mouse double minute 2 protein (MDM2), a negative regulator of the p53 tumour suppressor gene, is frequently amplified in malignancies. MDM2 antagonists have shown efficacy in treating malignancies with MDM2 overexpression and can overcome chemoresistance in acute myeloid leukemia. We systematically evaluated the safety profile of MDM2 inhibitors in the treatment of solid organ and hematologic malignancies. MATERIALS AND METHODS: We searched Medline and EMBASE from January 1947 to November 2018 for prospective clinical studies, in English or French, investigating any MDM2 inhibitor in pediatric or adult cancers, and reporting dose and toxicity outcomes. Primary outcome was dose-limiting toxicity (DLT) and secondary outcome was death. RESULTS: The search yielded 493 non-duplicate citations. Eighteen studies of 10 inhibitors met inclusion criteria (total N = 1005 patients). Two-thirds of included studies did not define DLTs and the reporting of toxicities was highly variable. The most commonly reported DLTs were cytopenias, gastrointestinal toxicity, metabolic disturbances, fatigue and cardiovascular toxicity; there was one death attributed to treatment toxicity. CONCLUSION: MDM2 antagonists have been studied in a variety of malignancies with toxicities similar to other commonly used chemotherapy agents and may represent a safe adjuvant treatment for further study in in acute leukemia.
INTRODUCTION:Mousedouble minute 2 protein (MDM2), a negative regulator of the p53tumour suppressor gene, is frequently amplified in malignancies. MDM2 antagonists have shown efficacy in treating malignancies with MDM2 overexpression and can overcome chemoresistance in acute myeloid leukemia. We systematically evaluated the safety profile of MDM2 inhibitors in the treatment of solid organ and hematologic malignancies. MATERIALS AND METHODS: We searched Medline and EMBASE from January 1947 to November 2018 for prospective clinical studies, in English or French, investigating any MDM2 inhibitor in pediatric or adult cancers, and reporting dose and toxicity outcomes. Primary outcome was dose-limiting toxicity (DLT) and secondary outcome was death. RESULTS: The search yielded 493 non-duplicate citations. Eighteen studies of 10 inhibitors met inclusion criteria (total N = 1005 patients). Two-thirds of included studies did not define DLTs and the reporting of toxicities was highly variable. The most commonly reported DLTs were cytopenias, gastrointestinal toxicity, metabolic disturbances, fatigue and cardiovascular toxicity; there was one death attributed to treatment toxicity. CONCLUSION:MDM2 antagonists have been studied in a variety of malignancies with toxicities similar to other commonly used chemotherapy agents and may represent a safe adjuvant treatment for further study in in acute leukemia.
Authors: Varsha Ananthapadmanabhan; Thomas C Frost; Kara M Soroko; Aine Knott; Brianna J Magliozzi; Prafulla C Gokhale; Vijaya G Tirunagaru; Robert C Doebele; James A DeCaprio Journal: JCI Insight Date: 2022-07-08
Authors: Marina Y Konopleva; Christoph Röllig; Jamie Cavenagh; Dries Deeren; Larisa Girshova; Jürgen Krauter; Giovanni Martinelli; Pau Montesinos; Jonas A Schäfer; Oliver Ottmann; Mario Petrini; Arnaud Pigneux; Alessandro Rambaldi; Christian Recher; Rebeca Rodriguez-Veiga; David Taussig; Norbert Vey; Sung-Soo Yoon; Marion Ott; Susanne Muehlbauer; Benjamin M Beckermann; Olivier Catalani; Magali Genevray; Kirsten Mundt; Candice Jamois; Pierre Fenaux; Andrew H Wei Journal: Blood Adv Date: 2022-07-26