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Oncology Briefings™: Updates in Pediatric Hepatic Veno-Occlusive Disease: Integrating Novel Therapeutic Strategies to Overcome Posttransplant Obstacles PER Pulse™ Recap

PER Pulse Recap

PER Pulse™ Recap


This first of 3 PER Pulse™ Recaps highlights key points presented in Oncology Briefing: Optimizing Treatment Strategies for Chemotherapy-Induced Nausea and Vomiting (CINV).

Diagnosis of and Risk Factors for Veno-Occlusive Disease

Pediatric hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is an ominous complication of hematopoietic stem cell transplantation (HSCT). The development of VOD is associated with patient morbidity, and can progress to become life-threatening in approximately 30% to 50% of cases.1 The severe form of VOD, which is associated with multiorgan dysfunction, may carry a mortality rate of greater than 80%.2 Current diagnostic and management approaches for VOD in the pediatric population are highly variable in clinical practice.3 As diagnostic and management approaches for VOD continue to evolve, awareness of new evidence and clinical guidelines may help to optimize outcomes for patients undergoing HSCT. Dr Stephan Grupp, director of the Cancer Immunotherapy Frontier Program and CCCR director of Translational Research at Children's Hospital of Philadelphia, provides his insights on current and evolving diagnostic approaches for VOD. He also shares his perspectives on patient- and disease-related risk factors for the development of VOD following transplant, including risk factors specific to the pediatric population, such as low weight, age younger than 1 to 2 years, being treated for neuroblastoma, and being treated for nonmalignant conditions such as hemophagocytic lymphohistiocytosis or osteopetrosis. This segment will also address evidence pertaining to the use of different imaging techniques in the diagnosis of VOD.4-7

References

  1. Carreras E, Diaz-Beyá M, Rosiñol L, et al. The incidence of veno-occlusive disease following allogenic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade. Biol Blood Marrow Transplant. 2011;17(11):1713-1720.
  2. Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127(13):1656-1665.
  3. Skeens MA, McArthur J, Cheifetz IM, et al. High variability in the reported management of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(10):1823-1828.
  4. Mohty M, Malard F, Abecassis M, et al. 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. 2015;50(6):781-789.
  5. Dignan FL, Wynn RF, Hadzic N, et al. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol. 2013;163(4):444-457.
  6. Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transplant. 2016;22(3):400-409.
  7. Reddivalla N, Chane S, Robinson A, et al. Using ultrasound elastography to diagnose sinusoidal obstruction syndrome in pediatric bone marrow transplant patients. Presented at: the 2017 American Society of Pediatric Hematology/Oncology Annual Meeting; April 26-29, 2017; Montreal, Canada. Abstract e26591.


This second of 3 PER Pulse™ Recaps highlights key points presented in Oncology Briefings™: Updates in Pediatric Hepatic Veno-Occlusive Disease: Integrating Novel Therapeutic Strategies to Overcome Posttransplant Obstacles.

VOD Risk Stratification and Data Pertaining to the Use of Prophylaxis

Severe VOD is established with the emergence of multiorgan failure, which carries a mortality rate that may exceed 80%. Preclinical assessment has shown that defibrotide has a protective effect on endothelial cells. It also affects endothelial cells by reducing their procoagulant activity and increasing their fibrinolytic properties.1 These preclinical data and other early clinical studies led to the development of a phase III, open-label, randomized, controlled trial of defibrotide for prophylaxis of VOD in pediatric patients who had undergone myeloablative conditioning before HSCT. These patients were noted to have at least 1 risk factor for VOD. Patients who received defibrotide prophylaxis had a lower incidence of VOD by day 30 post-HSCT relative to those who received best supportive care (12% vs 20%; P =.0507, log-rank test; P =.0488, Z test for competing risk analysis).1 Dr Grupp shares his insights on these data, as well as ongoing investigation into the potential of defibrotide for VOD prophylaxis,2 as well as other agents that have been studied for prophylaxis of VOD, including ursodeoxycholic acid and antithrombin III.3

References

  1. Corbacioglu S, Cesaro S, Faraci M, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in pediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012;379(9823):1301-1309.
  2. Study Comparing Efficacy and Safety of Defibrotide vs Best Supportive Care in the Prevention of Hepatic Veno-Occlusive Disease in Adult and Pediatric Patients. NCT02851407.  https://www.clinicaltrials.gov/ct2/show/NCT02851407. Updated June 12, 2017. Accessed June 12, 2017.
  3. Haussmann U, Fischer J, Eber S, et al. Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy. Haematologica. 2006;91(6):795-800.

3 of 3
PER Pulse™ Recap

This third of 3 PER Pulse™ Recaps highlights key points presented in Oncology Briefings™: Updates in Pediatric Hepatic Veno-Occlusive Disease: Integrating Novel Therapeutic Strategies to Overcome Posttransplant Obstacles.

Treatment Approaches and Counseling Strategies for Patients With VOD

A key phase III trial of defibrotide for the treatment of patients with severe VOD and multi-organ failure used a historical control arm methodology for ethical reasons to assess the influence of defibrotide on day 100-plus post-HSCT survival.1 A 23 % improvement in survival was noted, with hypotension being the most common adverse event (AE) in both groups. No difference in common hemorrhagic AEs was observed.1

Prior to its approval in the United States for the treatment of VOD with renal or pulmonary dysfunction following HSCT, defibrotide was made available through a treatment protocol study of patients who had VOD with or without multiorgan failure.2 Interim results from this study showed that 50.3% of patients were alive at Day+100 post-HSCT. In the pediatric (≤16 years old) subgroup, 54.5% of patients were alive at day 100, while 44.9% of adult patients were alive at day 100.2 For patients with multiorgan failure, 45.3% were alive at day 100. Hypotension was the most commonly reported treatment-related AE.2

Dr Grupp provides his assessment of these studies pertaining to the use of defibrotide in patients with VOD. He also addresses data pertaining to the timing of treatment initiation, adverse events seen with the use of defibrotide, and counseling strategies for patients who may be candidates for this treatment option. He also provides commentary on other options that have been used in the treatment of VOD, such as methylprednisolone,3 as well as supportive care measures for patients with VOD.  

References

  1. Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127(13):1656-1665.
  2. Richard PG, Smith AR, Triplett BM, et al. Defibrotide for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome: interim results from a treatment IND study. Biol Blood Marrow Transplant. 2017;23(6):997-1004.
  3. Myers KC, Lawrence J, Marsh RA, et al. High-dose methylprednisolone for veno-occlusive disease of the liver in pediatric hematopoietic stem cell transplantations recipients. Biol Blood Marrow Transplant. 2013;19(3):500-503.




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