Prevention and Early Recognition of Veno-Occlusive Disease Is Key to Reducing Post-Transplant Mortality

As veno-occlusive disease (VOD) is one of the leading causes of mortality following hematopoietic stem cell transplant (HSCT), ongoing efforts to educate oncologists on recognizing early signs and symptoms of the condition are necessary to facilitate timely identification and implementation of effective prevention and treatment strategies, according to Marc J. Braunstein, MD, PhD.

“VOD is a serious condition. It can [be associated with] a very high rate of mortality, and it tends to manifest in up to 15% of patients undergoing HSCT. [Therefore], it’s important to always have it front and center in our minds when treating a patient who has signs and symptoms of weight gain or refractory thrombocytopenia,” said Braunstein, an associate professor in the Department of Medicine and the co-director of the Hematology-Oncology System at New York University Grossman Long Island School of Medicine in New York.

In an interview with OncLive®, Braunstein highlighted the critical need for early identification and management of VOD due to its rapid progression and potential fatality; noted key risk factors for VOD; and detailed standard prevention and management strategies for this disease in various clinical settings.

OncLive: How does VOD typically present, and what are the diagnostic criteria for this condition?

Braunstein: VOD—sometimes called sinusoidal obstruction syndrome—is a serious condition that can be seen after HSCT, particularly with allogeneic HSCT more so than autologous HSCT. It’s a systemic disease, although it may only present in the liver or lungs initially. It [originates from] inflammation in the endothelium and liver sinusoids that can lead to systemic inflammation and, ultimately, multi-organ failure and death, at worst. Accordingly, it’s important to have a high index of suspicion to determine whether you’re going to further work up the patient and intervene.

[Regarding] clinical appearance, VOD typically [appears] within 1 to 3 weeks of HSCT. The symptoms result from injury to the endothelium in the liver, and that can initially present as weight gain. One of the earliest signs in blood work may be low platelets or thrombocytopenia that is refractory to platelet transfusions. The patient may also have symptoms related to liver damage, including enlargement of the liver, jaundice, and fluid accumulation. If left undiagnosed, [VOD] can progress fairly rapidly to multi-organ failure or even death.

There are various diagnostic criteria [for VOD] that are used by various organizations. Ultimately, what we’re looking for is the constellation of symptoms that distinguishes the diagnosis as VOD as opposed to things that [present similarly], such as graft-vs-host disease [GVHD] or infection. The typical criteria are looking at the degree of ascites, weight gain, and liver enzymes, such as bilirubin levels. Some of the criteria also involve imaging that may suggest enlargement of the liver or other findings suggestive of liver damage. Ultimately, a liver biopsy would be diagnostic of VOD.

What are some risk factors that contribute to the development of VOD, and how might these be mitigated?

Almost all of our patients will receive some form of prophylaxis for VOD, but we always want to be aware of identifying this condition with a higher index of suspicion in patients who have risk factors. Some of those [risk factors] may include a history of prior liver or lung disease, such as viral hepatitis in the past or an underlying lung condition that leads to reduced lung diffusion capacity. Those are higher risks in patients. Other patient-specific factors that have been associated [with VOD] would include older age and poor performance status at baseline going into HSCT.

Then there are the transplant-related factors, namely the conditioning regimen [patients received]. Patients who underwent mild myoablative conditioning, particularly with certain alkylators—a typical one might be busulfan [Busulfex]—can also increase the risk of VOD. Prior treatment, such as with the antibody-drug conjugate gemtuzumab ozogamicin [Mylotarg], is known to increase the risk of VOD. This is something to potentially avoid or be aware of if the patient has received gemtuzumab ozogamicin proximal to HSCT. There are also certain other GVHD prophylactic agents that can be associated with increased risk.

[Additionally], total body irradiation can be associated with increased risk for VOD. Certain alkylating agents that might be used in the post-transplant period, such methotrexate and cyclophosphamide, [as well as] other chemotherapies, can increase the risk. These are the things we want to consider when treating a patient following transplant in the immediate period when you’re concerned about a patient potentially having VOD.

What is the current consensus regarding the prevention and treatment of VOD post-HSCT in adult patients?

VOD is the most common cause of death in the post-transplant period, more so than GVHD; therefore, it’s important to be knowledgeable about this [condition] and try to prevent it as well as treat it. All our patients go on prophylaxis with ursodiol, and they’ll stay on that for approximately 60 days after transplant. That is the main preventative agent. We can also try to modify some of the risks. [This includes] avoiding gemtuzumab ozogamicin, if we can, prior to HSCT; optimizing medications to avoid hepatotoxic medications; and making sure they don’t have any untreated liver conditions such as hepatitis.

In terms of treatment, the standard of care [SOC] to manage VOD is defibrotide [Defitelio]. Some organizations stratify patients into mild, moderate or severe [disease categories] based on the degree of symptoms and organ dysfunction, but we want to intervene as early as possible, [irrespective of] whether they have mild or more advanced [VOD]. The mainstay of treatment is using defibrotide [along with] supportive measures to avoid volume overload and minimize unnecessary medications that may also impair liver function.

For patients who are refractory to defibrotide with more advanced VOD, there really isn’t a SOC, but some societies say to give steroids in that setting.

What are some of the benefits and challenges of using defibrotide in clinical practice?

Some of the advantages of defibrotide are that it is relatively easily dosed for patients following HSCT [who] may have issues with oral intake, as it is intravenous. It’s administered every 6 hours and can be given for 4 weeks until resolution of VOD. It is generally well tolerated, even in patients who may be quite sick in that post-transplant period. It can be very effective, and it’s well studied in this setting.

The disadvantages primarily center [around] cost. It may not be on a formulary, and although it’s important to have at a center that’s performing HSCTs, especially for allogeneic transplants, it is costly. That might be a barrier [to access].

What knowledge gaps or areas for improvement in the diagnosis, prevention, or management of VOD still need to be addressed?

We always want to think about how we can improve care for these patients, especially with a condition that can be so severe but doesn’t necessarily get as much attention as GVHD in the post-transplant setting. The first unmet need is having better markers for risk stratification and identification of patients developing VOD early on. The symptoms and signs [of VOD] can overlap with those of other diseases such as GVHD, engraftment syndrome, or even Budd-Chiari [syndrome], which is thrombosis in the liver circulation. All of these can impair our ability to make an accurate diagnosis of VOD. Some better markers are emerging, such as ICAM1 or angiopoietin-2, [which could be used to identify] a patient who is on the verge of VOD or even recovering from it after their intervention.

Having additional agents available beyond ursodiol or defibrotide would be valuable. Fortunately, those [agents] tend to have a high effort rate of efficacy for prevention and treatment, respectively, but having steroids as the next line of therapy can be challenging in the post-transplant setting when patients are immunocompromised. That may worsen when you when you give various steroids after transplant. Diagnostic-wise and treatment-wise, there’s still room for improvement.

The last thing would be general education about these conditions. Most tertiary care, high-throughput centers that [treat] patients following HSCT have a high acuity for conditions like VOD. However, in places where the patient may be treated by other team members who are not as familiar with VOD, it’s important to continue education [about its] signs and symptoms so they can identify it as quickly as possible.