Marc J. Braunstein, MD, PhD
Veno-occlusive disease (VOD) stands out as a primary contributor to post-transplant mortality rates, particularly following hematopoietic stem cell transplant (HSCT). In light of this pressing issue, ongoing initiatives aimed at educating oncologists on the early detection of VOD symptoms are essential for enabling prompt diagnosis and the application of effective prevention and treatment approaches, as highlighted by Marc J. Braunstein, MD, PhD.
“VOD is a serious condition that poses a substantial risk of mortality, manifesting in about 15% of patients undergoing HSCT. Consequently, it is vital to maintain awareness and vigilance when treating patients exhibiting symptoms such as significant weight gain or refractory thrombocytopenia,” emphasized Braunstein, who serves as an associate professor in the Department of Medicine and co-director of the Hematology-Oncology System at New York University Grossman Long Island School of Medicine.
In his insightful discussion with OncLive®, Braunstein underscored the urgency of early VOD detection and management due to its swift escalation and potentially fatal consequences. He elaborated on critical risk factors linked to VOD and provided an overview of standard strategies for prevention and management of this condition across different clinical scenarios.
OncLive: How does VOD typically present, and what are the diagnostic criteria for this condition?
Braunstein: VOD, also known as sinusoidal obstruction syndrome, is a grave condition that frequently arises post-HSCT, particularly with allogeneic HSCT as opposed to autologous HSCT. It manifests as a systemic illness, although initial symptoms may be localized to the liver or lungs. The origin of VOD lies in endothelial and liver sinusoidal inflammation, which can trigger systemic issues that may escalate to multi-organ failure and even death. Thus, it is critical to maintain a high index of suspicion for VOD to guide further patient evaluation and timely intervention.
There are various diagnostic criteria utilized by different organizations for identifying VOD. The primary goal is to seek a constellation of symptoms that differentiates VOD from other similar conditions, such as graft-versus-host disease (GVHD) or infections. Key diagnostic criteria include assessing the extent of ascites, evaluating weight gain, and monitoring liver enzymes, particularly bilirubin levels. Imaging studies may also indicate liver enlargement or other liver damage indicators; ultimately, a liver biopsy remains the definitive method for diagnosing VOD.
What are some risk factors that contribute to the development of VOD, and how might these be mitigated?
Most patients undergoing HSCT will receive some form of prophylaxis for VOD. Nonetheless, heightened awareness of potential risk factors is essential for accurate identification of susceptible individuals. Specific risk factors include a prior history of liver or lung diseases, such as viral hepatitis or underlying lung conditions that can reduce lung diffusion capacity. Additional patient-specific factors contributing to increased VOD risk encompass older age and a poor baseline performance status prior to HSCT.
Moreover, total body irradiation has been identified as a factor that elevates the risk of developing VOD. Certain chemotherapeutic agents employed in the post-transplant phase, such as methotrexate and cyclophosphamide, can further exacerbate this risk. Careful consideration of these variables is vital when managing patients after transplantation, particularly during the immediate postoperative period where VOD is a concern.
What is the current consensus regarding the prevention and treatment of VOD post-HSCT in adult patients?
VOD emerges as the most prevalent cause of mortality in the post-transplant period, even surpassing GVHD; hence, maintaining comprehensive knowledge about VOD is crucial for effective prevention and treatment. All patients typically receive prophylactic treatment with ursodiol, intended to be continued for approximately 60 days after transplantation, which serves as the cornerstone of VOD prevention. Additionally, risk factors may be mitigated by avoiding gemtuzumab ozogamicin before HSCT, optimizing medication regimens to minimize hepatotoxic agents, and ensuring no untreated liver conditions, such as hepatitis, are present.
For treatment of VOD, the standard of care consists primarily of defibrotide (Defitelio). Different organizations categorize patients based on the severity of symptoms and organ dysfunction into mild, moderate, or severe designations; however, early intervention is preferable across all degrees of VOD. The mainstay of treatment remains defibrotide, supplemented by supportive measures to manage fluid overload and limit the use of unnecessary medications that may adversely impact liver function.
For cases of advanced VOD that do not respond to defibrotide, there is no established standard of care. However, some treatment guidelines suggest the consideration of steroids in these challenging situations.
What are some of the benefits and challenges of using defibrotide in clinical practice?
Defibrotide presents various advantages, including ease of administration for patients post-HSCT, particularly those who may struggle with oral medication intake, since it is delivered intravenously. The treatment is typically administered every six hours over a four-week period until resolution of VOD occurs. It is also generally well tolerated, even among seriously ill patients during the post-transplant phase, and has proven to be effective with a substantial body of research supporting its use in this scenario.
However, the principal drawback of defibrotide lies in its cost. It is often not included on many formularies, and while vital to centers performing HSCT, particularly for allogeneic procedures, the expenses associated may create access challenges for some patients.
What knowledge gaps or areas for improvement in the diagnosis, prevention, or management of VOD still need to be addressed?
Improving care for patients suffering from VOD remains a crucial focus, especially as this serious condition does not always receive the same level of emphasis as GVHD in post-transplant care. A critical unmet need is the development of improved markers for the early risk stratification and identification of patients on the cusp of developing VOD. The onset of VOD symptoms may overlap with those of other diseases, such as GVHD, engraftment syndrome, or Budd-Chiari syndrome, also complicating accurate VOD diagnosis. Emerging markers, including ICAM1 and angiopoietin-2, show promise in identifying patients at risk of VOD onset or those recovering from prior episodes.
In addition to this, the availability of alternative treatment agents beyond ursodiol or defibrotide would enhance management options. Current interventions have high efficacy rates for prevention and treatment but introducing additional therapeutic options, along with careful management of steroid use in an immunocompromised post-transplant environment, presents a significant challenge. Overall, both diagnostic and therapeutic approaches require improvement and refinement.
Lastly, enhancing educational efforts regarding VOD is essential. While high-throughput tertiary care centers, which treat HSCT patients, operate with a high acuity towards conditions like VOD, there remains a pressing need to educate healthcare professionals in other settings. These practitioners should be equipped with the knowledge to promptly recognize VOD signs and symptoms, facilitating timely intervention.
Dr Braunstein ophthalmologist
**Interviewer:** Today, we have the pleasure of speaking with Dr. Marc J. Braunstein, a renowned expert in hematology-oncology from New York University Grossman Long Island School of Medicine. Dr. Braunstein, thank you for joining us. Your recent article highlights the critical issue of veno-occlusive disease (VOD) in patients post-hematopoietic stem cell transplant (HSCT). Can you tell us what makes VOD such a pressing concern in this patient population?
**Dr. Braunstein:** Thank you for having me. VOD is indeed a major concern following HSCT, particularly allogeneic transplants. It manifests in approximately 15% of patients and is associated with significant mortality rates. The condition occurs due to endothelial and liver inflammation, which can lead to multi-organ failure and death if not identified and managed early. Raising awareness among oncologists about the symptoms and urgency of VOD is crucial for improving patient outcomes.
**Interviewer:** You mentioned early detection is vital. What are some of the key symptoms and diagnostic criteria for VOD that doctors should be aware of?
**Dr. Braunstein:** VOD symptoms can initially be localized to the liver or lungs, but they can escalate to systemic manifestations. Clinicians should look for signs like significant weight gain, ascites, and elevated liver enzymes, particularly bilirubin levels. While there are various diagnostic criteria, imaging studies can show liver enlargement, and a liver biopsy remains the definitive method for diagnosis.
**Interviewer:** What risk factors should healthcare providers consider that might contribute to the development of VOD?
**Dr. Braunstein:** Good question. Several risk factors heighten the risk of VOD, including prior liver or lung conditions, older age, and poor performance status before HSCT. The use of total body irradiation and certain chemotherapy agents, like methotrexate and cyclophosphamide, also increases susceptibility. Being aware of these factors can help us target specific patients who may require closer monitoring.
**Interviewer:** In terms of prevention and management, what does the current consensus suggest for VOD post-HSCT?
**Dr. Braunstein:** Prophylaxis is essential, with many patients receiving ursodiol shortly after HSCT. This is typically continued for about 60 days. Additionally, it’s crucial to manage risk factors, avoid hepatotoxic medications when possible, and treat underlying liver conditions. For patients who develop VOD, the mainstay of treatment is defibrotide, which has shown effectiveness and is well tolerated, although its cost can present access issues for some.
**Interviewer:** what advantages and challenges have you observed with the use of defibrotide in clinical practice?
**Dr. Braunstein:** Defibrotide is beneficial as it can be administered intravenously, which is particularly useful for patients who may struggle with oral medications. It’s generally well tolerated and effective, but the high cost can be a barrier to access, especially in centers where it may not be readily available. We must navigate these challenges while ensuring patients receive the care they need.
**Interviewer:** Thank you, Dr. Braunstein, for shedding light on this critical issue. Your insights are invaluable for improving care for HSCT patients at risk of VOD.
**Dr. Braunstein:** Thank you for having me. It’s important that we continue to educate and raise awareness about these conditions to ultimately enhance patient outcomes.
