Abstract
Purpose
Defibrotide is an agent used to treat sinusoidal obstruction syndrome (SOS/VOD) in patients undergoing haemopoietic stem cell transplantation. The aim of this study was to evaluate the effectiveness of defibrotide used within institutional guidelines for the treatment of SOS/VOD in patients undergoing haemopoietic stem cell transplantation (HSCT).
Methods
Data for 23 patients was retrospectively reviewed to evaluate the effectiveness of defibrotide and the utility of response criteria to direct therapy as specified within institution guidelines. Patients met institutional criteria for a diagnosis of SOS/VOD based on predominantly Baltimore criteria and received defibrotide. Stabilisation or improvement in symptoms and biochemical markers was required for continuation of therapy with defibrotide.
Results
Overall, 14 patients responded to therapy. Survival at day 100 post HSCT was 70%. Median serum (total) bilirubin concentrations in all evaluable patients had decreased at days 5 and 10 (p < 0.001). There was a proportional reduction in median weight of 4% by day 5 and 6.6% by day 10 (p < 0.001). On cessation of defibrotide, there was a decrease in the proportion of patients exhibiting hepatomegaly (p = 0.02), ascites (p < 0.01) and requiring oxygen supplementation (p < 0.01), with 70% survival at day 100 post HSCT.
Conclusion
Defibrotide to treat SOS/VOD and continued based on attainment of early response was effective management of this condition. Defibrotide should be considered in any consensus protocol providing guidance on the management of SOS/VOD, with future studies considered to assess appropriate time points for response to therapy during treatment.
References
Carreras E (2015) How I manage sinusoidal obstruction syndrome after haemopoietic cell transplantation. Br J Haematol 168(4):481–491
Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A et al (2013) BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haemopoietic stem cell transplantation. Br J Haematol 163(4):444–457
Senzolo M, Germani G, Cholongitas E, Burra P, Burroughs AK (2007) Veno occlusive disease: update on clinical management. World J Gastroenterol 13(29):3918–3924
Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M et al (2015) Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 50(6):781–789
Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A et al (2010) Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant 16(2):157–168
Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M et al (2016) Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant 51(7):906–912
Ho VT, Revta C, Richardson PG (2008) Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies. Bone Marrow Transplant 41(3):229–237
McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED (1984) Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 4(1):116–122
Dalle JH, Giralt SA (2016) Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transplant 22(3):400–409
Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG et al (1987) Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 44(6):778–783
Shulman HM, Hinterberger W (1992) Hepatic veno-occlusive disease—liver toxicity syndrome after bone marrow transplantation. Bone Marrow Transplant 10(3):197–214
Palomo M, Diaz-Ricart M, Rovira M, Escolar G, Carreras E (2011) Defibrotide prevents the activation of macrovascular and microvascular endothelia caused by soluble factors released to blood by autologous hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 17(4):497–506
Pescador R, Capuzzi L, Mantovani M, Fulgenzi A, Ferrero ME (2013) Defibrotide: properties and clinical use of an old/new drug. Vasc Pharmacol 59(1–2):1–10
Richardson P, Riches ML, Keman NA, Brochstein J, Mineishi S, Termuhlen AM et al (2016) Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood 127(13):1656–1665
Richardson PG, Corbacioglu S, Ho VT-V, Kernan NA, Lehmann LE, Maguire C et al (2013) Drug safety evaluation of defibrotide. Expert Opin Drug Saf 12(1):123–136
Corbacioglu S, Kernan NA, Lehmann LE, Brochstein J, Revta C, Grupp SA et al (2012) Defibrotide for the treatment of heaptic veno-occlusive disease in children after hematopoietic stem cell transplantation. Expert Rev Haematol 5(3):291–302
Yakushijin K, Okamura A, Ono K, Kawano Y, Kawano H, Funakoshi Y et al (2009) Defibrotide therapy for patients with sinusoidal obstruction syndrome after hematopoietic stem cell transplantation. Rinsho Ketsueki Jpn J Clin Hematol 50(1):3–8
Richardson P, Linden E, Revta C, Ho VT-V (2009) Use of defibrotide in the treatment and prevention of veno-occlusive disease. Expert Review Haematology 2(4):365–376
Chopra R, Eaton JD, Grassi A, Potter M, Shaw B, Salat C et al (2000) Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol 111:1122–1129
Bearman SI, Anderson GL, Mori M, Hinds MS, Shulman HM, McDonald GB (1993) Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol 11(9):1729–1736
Sucak GT, Aki ZS, Yagci M, Yegin ZA, Ozkurt ZN, Haznedar R (2007) Treatment of sinusoidal obstruction syndrome with defibrotide: a single-center experience. Transplant Proc 39(5):1558–1563
Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, Dilloo D et al (2004) Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant 33(2):189–195
Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D et al (2002) 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 100(13):4337–4343
Bulley SR, Strahm B, Doyle J, Dupuis LL (2007) Defibrotide for the treatment of hepatic veno-occlusive disease in children. Pediatr Blood Cancer 48(7):700–704
Tsakiras DA (2006) Prophylaxis and treatment of hepatic veno-occlusive disease after pediatric stem cell transplantation. Haematologica 91(6):726B
Zhang L, Wang Y, Huang H (2012) Defibrotide for the prevention of hepatic veno-occlusive disease after hematopoietic stem cell transplantation: a systematic review. Clin Transpl 26(4):511–519
Gugliemelli T, Bringhen S, Palumbo A (2012) Update on the use of defibrotide. Expert Opin Biol Ther 12(3):353–361
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Coutsouvelis, J., Avery, S., Dooley, M. et al. Defibrotide for the treatment of sinusoidal obstruction syndrome: evaluation of response to therapy and patient outcomes. Support Care Cancer 26, 947–955 (2018). https://doi.org/10.1007/s00520-017-3915-1
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DOI: https://doi.org/10.1007/s00520-017-3915-1