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Monoclonal Antibody Mediated Treatment in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Ch. Michel Zwaan, Marry M. van den Heuvel-Eibrink
Meanwhile more data became available on the hepatotoxicity of GO, again showing that some patients developed clinical signs of VOD, which is thought to be due to CD33 expression in hepatic sinusoids and perhaps better described as “sinusoidal obstruction syndrome” (SOS) (23). Other factors involved may be the liver leukemia load or circulating soluble CD33 levels. A high incidence of VOD (in this particular single-center study as high as 64% of 14 patients) was noted among patients who were transplanted following reinduction with GO, mainly in patients who were transplanted shortly after GO treatment (24). This resulted in the recommendation to delay transplantation for at least 3.5 months following treatment with GO. However, in another series VOD also occurred in approximately 4% of patients without prior SCT history, as was also noted in the phase II studies described above (25). Several case reports suggest that defibrotide may be useful in preventing or treating GO-induced VOD, but no larger prospective or comparative studies have been performed (26,27).
Case 50
Published in Atul B. Mehta, Keith Gomez, Clinical Haematology, 2017
He has developed veno-occlusive disease. The peak incidence is in the first 2–3 weeks post-allogeneic bone marrow transplant (BMT) and overall incidence is 20%–25%. The cause is unknown, but important risk factors are pre-existing liver disease, a previous myeloablative transplant, large doses of previous cytoreductive chemotherapy or high-intensity pre-transplant conditioning. Treatment is largely supportive but defibrotide has been shown to be effective and steroids are valuable in selected patients. Recombinant tissue plasminogen activator has been successfully used to lyse the intrahepatic blood clot.
Adjuvant therapy in childhood cancer
Published in Brice Antao, S Irish Michael, Anthony Lander, S Rothenberg MD Steven, Succeeding in Paediatric Surgery Examinations, 2017
These symptoms and signs are consistent with veno-occlusive disease. Venoocclusive disease consists of the combination of rapid painful liver enlargement, more than 5% weight gain, ascites and hyperbilirubinaemia. It usually develops within 2 weeks of myeloablative therapy and haemopoietic stem cell transplant. Busulphan is one of the drugs used in myeloablative therapy that increases the risk of this complication. Veno-occlusive disease is in fact primarily due to hepatic sinusoidal injury and sinusoidal obstruction. Treatment is primarily supportive and the administration of defibrotide.
Cost-effectiveness analysis of defibrotide in the treatment of patients with severe veno-occlusive disease/sinusoidal obstructive syndrome with multiorgan dysfunction following hematopoietic cell transplantation in Spain
Published in Journal of Medical Economics, 2021
David Carcedo Rodriguez, Teresa Artola Urain, Anabelle Chinea Rodriguez, Estefanía García Torres, Marta González Vicent, Gonzalo Gutiérrez García, Alexandra Regueiro García, Marcos Calvo Hidalgo, Alba Villacampa
Several symptomatic measures, such as oxygen therapy, analgesia, paracentesis, and thoracentesis, as appropriate, can be used to reduce discomfort caused by massive ascites or pleural effusions11. In cases of suspected VOD/SOS, therapeutic interventions, such as optimizing hydroelectrolytic balance and restricting the supply of sodium by diuretics or using hemodialysis or hemofiltration when fluid accumulation and renal failure cannot be controlled, may be used. In some cases, VOD/SOS has been resolved with an intrahepatic portosystemic shunt or, more rarely, with liver transplantation12. In addition, defibrotide, a mixture of predominantly single-stranded polydeoxyribonucleotides, is approved in Europe for the treatment of severe hepatic VOD/SOS following HCT in adults and pediatric patients aged >1 month13. In vitro studies suggest that the mechanism of action of defibrotide involves two distinct elements: the protection of endothelial cells and the restoration of thrombotic-fibrinolytic balance13. The efficacy and safety of defibrotide for the treatment of VOD/SOS post-HCT have been demonstrated in a number of studies14–17. In a phase 3 study of defibrotide in patients with VOD/SOS with MOD, day 100 survival was 38% in defibrotide-treated patients and 25% in historical controls (23% estimated difference between groups; 95.1% confidence interval [CI] = 5.2–40.8; p = 0.0109, using a propensity-adjusted analysis)14.
Cost-effectiveness of defibrotide for treatment of severe veno-occlusive disease: it is time for evidence based economic evaluations
Published in Journal of Medical Economics, 2021
It is possible that many physicians using Defibrotide seriously believe that they do something good. Defibrotide clearly has some documented in vitro and in vivo activities. It has recently been shown to reduce endothelial leukocyte adhesion in vitro. Recent animal data suggest that Defibrotide can reduce T-cell-, neutrophil- and acute graft-versus-host disease‐associated tissue injury, thus could reduce acute graft-versus-host disease incidence and severity, hence survival after experimental allogeneic‐HSCT [19]. Still, these physicians hope to do something good; formal evidence is still lacking. Expectations are inherent to human activities, and in HSCT [19]. But “belief” does not suffice in the situation of VOD and HSCT. It does not justify the use of the drug nor its price. As it stands, the cost-effectiveness evaluation of Defibrotide is based on little more than expert opinion, hence level IV. It is more than irritating to have a drug in use for more than two decades without a proper prospective randomized double-blinded and placebo-controlled trial. There are near 50’000 HSCT performed per year in Europe alone [20]. Correct trials can be done. It is time to reconsider cost-effectiveness evaluations of orphan drugs. They should be based on formal medical and economic evidence, not on assumptions. The medical economists and the medical community should strive together to achieve this goal.
Recent developments with defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome
Published in Expert Opinion on Orphan Drugs, 2019
Christine Duncan, Justine Kahn, Stephan A. Grupp, Paul G. Richardson
A post-hoc analysis of the T-IND study investigated the impact of the timing of initiation of defibrotide following VOD/SOS diagnosis on patient outcomes. This analysis found that earlier initiation of defibrotide was associated with significantly higher day +100 survival in the overall post-HCT population (P ≤0.001); improved survival with early initiation was observed in pediatric patients (P <0.001) and suggested in adults (P = 0.055) [5]. A pooled analysis of the phases 2 and 3 studies and the T-IND study showed that among patients who achieved a complete response more than half of the patients required >3 weeks of persistent treatment with defibrotide (phase 2/3, 53.3%; T-IND, 60.3%) [67]. These analyses suggest that early initiation of defibrotide treatment and continued defibrotide therapy play an important role in outcomes.