Defibrotide TMA Prophylaxis Pilot Trial

Summary

Thrombotic microangiopathy (TMA) is a common complication in the stem cell transplant population. Certain populations within the hematopoietic stem cell transplant (HSCT) population are at a higher risk than others. Defibrotide is an endothelial stabilizing agent which may prevent the endothelial damage that triggers TMA in HSCT patients. The feasibility, safety, and efficacy of defibrotide prophylaxis in a pediatric transplant population is unknown. Twenty five patients age 0 to 30 years receiving autologous or allogeneic hematopoeitic stem cell transplant who meet TMA high risk criteria will be enrolled. Patients will receive Defibrotide for 28-35 days starting before conditioning, and will be closely monitored for any adverse events up through 6 months post-transplant. The feasibility of administering defibrotide will be evaluated as well as incidence of TMA.

Timeline

Start

2018-05-01

Primary completion

2020-07-31

Completion

2020-07-31

Publications

• Background Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Min WS, Park CW. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010 Oct 27;90(8):918-26. doi: 10.1097/TP.0b013e3181f24e8d.
• Background Choi CM, Schmaier AH, Snell MR, Lazarus HM. Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and treatment. Drugs. 2009;69(2):183-98. doi: 10.2165/00003495-200969020-00004.
• Background Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, Boelens JJ, Hewitt A, Schrum J, Schulz AS, Muller I, Stein J, Wynn R, Greil J, Sykora KW, Matthes-Martin S, Fuhrer M, O'Meara A, Toporski J, Sedlacek P, Schlegel PG, Ehlert K, Fasth A, Winiarski J, Arvidson J, Mauz-Korholz C, Ozsahin H, Schrauder A, Bader P, Massaro J, D'Agostino R, Hoyle M, Iacobelli M, Debatin KM, Peters C, Dini G. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012 Apr 7;379(9823):1301-9. doi: 10.1016/S0140-6736(11)61938-7. Epub 2012 Feb 23.
• Background Corti P, Uderzo C, Tagliabue A, Della Volpe A, Annaloro C, Tagliaferri E, Balduzzi A. Defibrotide as a promising treatment for thrombotic thrombocytopenic purpura in patients undergoing bone marrow transplantation. Bone Marrow Transplant. 2002 Mar;29(6):542-3. doi: 10.1038/sj.bmt.1703414. No abstract available.
• Background Jodele S, Dandoy CE, Myers KC, El-Bietar J, Nelson A, Wallace G, Laskin BL. New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Transfus Apher Sci. 2016 Apr;54(2):181-90. doi: 10.1016/j.transci.2016.04.007. Epub 2016 Apr 25.
• Background Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, Myers K, Grimley M, Bleesing J, El-Bietar J, Wallace G, Chima RS, Paff Z, Laskin BL. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014 Jul 24;124(4):645-53. doi: 10.1182/blood-2014-03-564997. Epub 2014 May 29.
• Background Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, Lane A, Meller J, Medvedovic M, Chen J, Davies SM. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016 Feb 25;127(8):989-96. doi: 10.1182/blood-2015-08-663435. Epub 2015 Nov 24.
• Background Kim SS, Patel M, Yum K, Keyzner A. Hematopoietic stem cell transplant-associated thrombotic microangiopathy: review of pharmacologic treatment options. Transfusion. 2015 Feb;55(2):452-8. doi: 10.1111/trf.12859. Epub 2014 Sep 11.
• Background Kojouri K, George JN. Thrombotic microangiopathy following allogeneic hematopoietic stem cell transplantation. Curr Opin Oncol. 2007 Mar;19(2):148-54. doi: 10.1097/CCO.0b013e3280148a2f.
• Background Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood. 2011 Aug 11;118(6):1452-62. doi: 10.1182/blood-2011-02-321315. Epub 2011 May 19.
• Background Obut F, Kasinath V, Abdi R. Post-bone marrow transplant thrombotic microangiopathy. Bone Marrow Transplant. 2016 Jul;51(7):891-7. doi: 10.1038/bmt.2016.61. Epub 2016 Mar 14.
• Background Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D, Elias AD, Antin JH, Soiffer R, Spitzer T, Avigan D, Bearman SI, Martin PL, Kurtzberg J, Vredenburgh J, Chen AR, Arai S, Vogelsang G, McDonald GB, Guinan EC. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood. 2002 Dec 15;100(13):4337-43. doi: 10.1182/blood-2002-04-1216. Epub 2002 Aug 1.
• Background Rosenthal J. Hematopoietic cell transplantation-associated thrombotic microangiopathy: a review of pathophysiology, diagnosis, and treatment. J Blood Med. 2016 Sep 2;7:181-6. doi: 10.2147/JBM.S102235. eCollection 2016.
• Background Uderzo C, Bonanomi S, Busca A, Renoldi M, Ferrari P, Iacobelli M, Morreale G, Lanino E, Annaloro C, Volpe AD, Alessandrino P, Longoni D, Locatelli F, Sangalli H, Rovelli A. Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation. 2006 Sep 15;82(5):638-44. doi: 10.1097/01.tp.0000230373.82376.46.
• Background Uderzo C, Fumagalli M, De Lorenzo P, Busca A, Vassallo E, Bonanomi S, Lanino E, Dini G, Varotto S, Messina C, Miniero R, Valsecchi MG, Balduzzi A. Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation. Bone Marrow Transplant. 2000 Nov;26(9):1005-9. doi: 10.1038/sj.bmt.1702648.
• Background Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, Socie G. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011 Jun 1;29(16):2230-9. doi: 10.1200/JCO.2010.33.7212. Epub 2011 Apr 4.
• Background Yeates L, Slatter MA, Bonanomi S, Lim FLWI, Ong SY, Dalissier A, Barberi W, Shulz A, Duval M, Heilmann C, Willekens A, Hwang WHY, Uderzo C, Bader P, Gennery AR. Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation. Bone Marrow Transplant. 2017 May;52(5):762-764. doi: 10.1038/bmt.2016.351. Epub 2017 Jan 16. No abstract available.
• Higham CS, Shimano KA, Melton A, Kharbanda S, Chu J, Dara J, Winestone LE, Hermiston ML, Huang JN, Dvorak CC. A pilot trial of prophylactic defibrotide to prevent serious thrombotic microangiopathy in high-risk pediatric patients. Pediatr Blood Cancer. 2022 May;69(5):e29641. doi: 10.1002/pbc.29641. Epub 2022 Mar 6.

Drugs

Indications