Experts share tips for treating patients with VOD with defibrotide, including strategies to ensure best possible outcomes.

VOD: Ensuring Best Outcomes

This is a synopsis of an Insights series featuring Mitchell S. Cairo, MD, of New York Medical College, and Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center.

Dr. Giralt explained defibrotide is a polydisperse oligonucleotide that protects endothelium through unclear mechanisms, restores thrombotic/fibrinolytic balance, reduces inflammatory mediators, and activates fibrinolysis. The phase 3 trial leading to FDA approval was a multi-center historical control study led by Dr. Paul Richardson. It compared defibrotide 25 mg/kg/day to best available therapy in severely affected VOD patients with multiorgan dysfunction. 102 received defibrotide, 32 comparator. Complete response rate at day 100 was 25% for defibrotide versus 9% controls. Day 100 survival was 38% versus 25%.

Pediatric response rates are markedly better. Notably, patients started on defibrotide within 48 hours of VOD diagnosis have significantly improved complete response (39%) and day 100 survival (61%). Many colleagues question if the 21-day FDA-approved course is necessary. Dr. Cairo explained Dr. Richardson’s seminal paper showed ~10% achieve complete response within a week, 10% more by day 14, 10-15% more by day 21. However, over 45% take 28-35+ days. Achieving complete response is critical, conferring 93% overall survival versus only 37% without. Some may need only 7-14 days, but extending therapy 28-35 days to achieve complete response optimizes outcome. As long as patients improve without progression, Dr. Giralt continues defibrotide until maximal response, monitoring closely after discontinuation to detect regression warranting restart.

Drs. Giralt and Cairo welcomed additional questions regarding VOD via email, hoping this discussion aids community colleagues in VOD diagnosis and management.

*Video synopsis is AI-generated and reviewed by OncLive editorial staff.

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Mitchell Cairo, MD, shares his standard-of-care approach to treating VOD and the role of defibrotide, the only FDA-approved drug for VOD.

Treating VOD: Standard-of-Care Approach

Dr. Giralt noted his center uses ursodeoxycholic acid for VOD prophylaxis, as recommended by British and American transplant societies. However, he asked Dr. Cairo to discuss current standard of care treatment for patients developing VOD.

Dr. Cairo responded supporting vital organ function is critical and cannot be overlooked before detailing specific VOD therapy. This includes meticulous fluid and electrolyte management, diuresis to control fluid overload, maintaining blood pressure and treating encephalopathy, respiratory failure, renal failure, or heart failure as needed with modalities like hemodialysis, continuous veno-venous hemofiltration, portal shunts, mechanical ventilation, and vasopressors. Patience is essential as patients improve minimally at first. Defibrotide is the only FDA-approved VOD therapy for patients with renal or pulmonary dysfunction. Earlier administration substantially improves survival and complete response rates.

Dr. Giralt concurred, emphasizing careful fluid/electrolyte management, rule-out of infection, adequate platelet monitoring if considering defibrotide, and avoiding outdated therapies like heparin or tissue plasminogen activator. He advocated starting defibrotide in high-risk patients early, even with subtle signs like exertional hypoxemia with weight gain and ascites, rather than waiting for multiorgan failure. Defibrotide has anticoagulant, profibrinolytic, anti-inflammatory and endothelial stabilizing effects, so earlier administration capitalizes on multiple mechanisms. With defibrotide's mild anticoagulation/fibrinolysis, the platelet count should be over 10,000-20,000 depending on comorbidities, with no concomitant systemic anticoagulation/thrombolytics. The earlier defibrotide is initiated, the higher likelihood of response.

Sergio Giralt, MD, leads a discussion on the importance of a multidisciplinary team approach in caring for patients with VOD.

A Multidisciplinary Approach to Managing VOD

Dr. Cairo emphasized that excellent multidisciplinary care is essential when diagnosing and managing transplant patients at risk for VOD. He asked Dr. Cairo to discuss the importance of a team-based approach.

Dr. Giralt responded that nurses and advanced practice providers are critical for safe care of the high transplant volume at his center. Key elements of multidisciplinary VOD care start with identifying high-risk patients so all clinicians have heightened vigilance. Nurses meticulously measure daily weights and intake/output to detect fluid retention early. Unexplained weight gain refractory to diuretics and sodium restriction warrants immediate action in a heavily pretreated patient. Radiology colleagues are essential for Doppler ultrasound diagnosis of VOD. Gastroenterology input helps exclude other potential causes of liver injury like graft-versus-host disease and infections. Even amoebic liver abscesses can mimic VOD. With high-risk patients, he advocates starting defibrotide at the earliest suggestion of VOD rather than waiting for overt disease.

Dr. Giralt agreed, highlighting the importance of ICU and nephrology colleagues particularly for patients with severe VOD and multiorgan failure. He noted that while excellent biomarkers are still lacking, serial ultrasound and Doppler assessments for portal flow slowing or ascites can prompt early defibrotide initiation in appropriate high-risk patients even before reversal of flow is seen. Close monitoring and a low threshold for treatment are key in patients at elevated baseline risk for VOD.

Sergio Giralt, MD, leads a discussion on the importance of a multidisciplinary team approach in caring for patients with VOD, from recognizing early signs to treating and monitoring the disease.

Mitchell Cairo, MD, and Sergio Giralt, MD, provide insights about the challenges in diagnosing VOD and the need to educate physicians.

Challenges in Diagnosing VOD

Dr. Giralt noted colleagues at smaller transplant centers feel radiologists are uncomfortable diagnosing VOD or reversed portal venous flow, posing a major challenge. He asked Dr. Cairo what other challenges clinicians face.

Dr. Cairo responded the first is overcoming naysayers who still do not believe VOD occurs post-transplant, despite 80-90% historical mortality without treatment. Second is understanding VOD pathophysiology including prothrombotic sinusoidal endothelial damage, capillary leakage, and subsequent clinical findings like hepatomegaly, pain, fluid retention, ascites, jaundice, and portal hypertension. This facilitates early VOD diagnosis. Finally, some delay diagnosis for days, though early recognition is key to enable effective therapy.

Dr. Giralt agreed, asking about radiology expertise. Dr. Cairo responded the needed Doppler ultrasound skills are basic and objective for hepatology and transplant, with quantitative criteria like velocity and flow direction, though interobserver variability exists. Specialized radiologists may overcall benign abnormalities. The learning curve is short for motivated clinicians. Dr. Giralt advised being present to guide radiologists on needed images and flow measurements. Dr. Cairo stressed any practitioner caring for transplant patients should learn to perform and interpret Doppler assessments for VOD. Though false positives occur, benefits outweigh harms. Dr. Giralt advocated direct communication between treating clinician and radiologist to clarify findings and facilitate learning on both sides.

Mitchell Cairo, MD, and Sergio Giralt, MD, provide insights about the challenges in diagnosing VOD and the need to educate physicians about risk factors for VOD, its pathophysiology, and the importance of early detection.

A review of the diagnostic criteria for veno-occlusive disease for pediatric and adult patients.

Diagnosing VOD

Dr. Giralt noted one problem is differing diagnostic criteria for VOD leading to variable reported incidence. He asked Dr. Cairo to discuss diagnostic criteria, especially how they differ between children and adults and between the US and Europe.

Dr. Cairo responded the criteria are a moving target but he has published consensus criteria intended for both children and adults. Easy pathognomonic signs are biopsy showing VOD/SOS or portal hypertension without other cause, but these are rarely done. Currently, VOD is a clinical syndrome, with evolving criteria as new tests emerge. Today, he recommends diagnosis if a patient has 2+ of 7 criteria not explained by other causes: elevated bilirubin (though 20% are anicteric), weight gain, hepatomegaly, right upper quadrant pain, and Doppler evidence of reversed portal venous flow. Key inexpensive, non-invasive studies are liver ultrasound, assessing size and ascites, paired with Doppler assessing flow and resistance. In future, elastography assessing liver stiffness may help diagnosis. Dr. Cairo co-authored 2020 consensus criteria for VOD diagnosis in Blood Journal that transplant clinicians should reference.

Dr. Giralt emphasized the importance of context when evaluating VOD risk, asking Dr. Cairo whether his threshold for diagnosing VOD changes with patient risk factors. Dr. Cairo responded clinicians should be vigilant with any patient receiving conditioning therapy, but heighten suspicion with those having previous gemtuzumab or obinutuzumab, pre-existing liver disease, high ferritin, or intensive regimens putting them at 10-20% VOD risk versus baseline 1-2%. However, even low-risk patients can sporadically develop SOS.

Experts discuss the risk factors associated with VOD and which high-risk patients should be monitored for signs and symptoms of this disease.

VOD Risk Factors

Dr. Giralt discussed risk factors and current incidence of VOD in 2024 among post-hematopoietic cell transplant (HCT) patients. He noted reported VOD incidence ranges from 2% to 14%, with the highest risk groups being pediatric patients receiving autologous transplant for neuroblastoma with high-dose or triple alkylator therapy, and those with osteosarcoma. More common predisposition factors are previous exposure to gemtuzumab ozogamicin or obinutuzumab, heavy pretreatment such as a second autologous or allogeneic transplant, previous autologous transplant, preexisting liver disease or high ferritin levels from transfusions, and high-dose busulfan and cyclophosphamide or total body irradiation conditioning regimens. Specific associations exist between VOD and busulfan-based therapies and tacrolimus-based graft-versus-host disease prophylaxis. In summary, those at highest risk for VOD are patients with preexisting liver damage, those receiving intense conditioning regimens, and patients at particularly high baseline risk including those with neuroblastoma getting tandem transplants or osteosarcoma.

Mitchell Cairo, MD, and Sergio Giralt, MD, offer an overview of veno-occlusive disease, an endothelial damage syndrome, and its prognosis.

VOD Overview

Dr. Sergio Giralt, Professor of Medicine at Weill Cornell Medical College, Deputy Division Head of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center, and attending physician in the Adult BMT Service at Memorial Sloan Kettering Cancer Center, welcomed Dr. Mitch Cairo, Cancer Center Director and Transplant Director at Westchester Medical Center and Professor of Pediatrics, Medicine and other departments at New York Medical College, to discuss treatment options for patients with veno-occlusive disease (VOD) and how to best manage these patients. They also discussed the latest in clinical research and the impact on future treatment options.

Dr. Giralt provided an overview of VOD, also known as hepatic sinusoidal obstruction syndrome (SOS), including its pathophysiology and primary patient population affected. He noted VOD was described over 100 years ago as a cirrhosis of the liver occurring in patients in South Africa after ingesting wild berries called Senecio. The first description in the transplant setting was by Hillard Lazarus after mitomycin C therapy. VOD has various reported incidences between 13-17%, recently 2-3%. Dr. Giralt stated VOD is part of a spectrum of endothelial damage syndromes including VOD, idiopathic pneumonia syndrome, fluid overload, capillary leak syndrome, and thrombotic microangiopathy. Patients are predisposed to chemotherapy-induced endothelial damage. Once the hepatic endothelium is damaged, it causes prothrombotic events within the capillaries, eventually causing small clots, portal hypertension, flow reversal, and disruption of liver function. For colleagues, VOD is an endothelial damage syndrome after high-dose chemotherapy in predisposed patients, ranging from mild to severe. Severe VOD with multiorgan failure can rapidly lead to death if not treated appropriately.

Treatment outcome comparisons in randomized controls trials (RCTs) vs observational studies can yield different results.

Distortions in observational studies may occur because of differences in factors other than those being studied (confounders).

RCTs minimized confounder effects by random assignment to each treatment group.

Observational study methods intending to control for confounders are available.

Here we present the first US representative, real-world observational study using a confounder minimizing method to compare tumor lysis syndrome (TLS) associated morbidities in patients with hematological malignancies at risk of TLS following rasburicase monotherapy vs allopurinol monotherapy.

We have previously found rasburicase significantly and more rapidly reduces uric acid exposure compared to allopurinol in patients with or at risk of TLS.

In 2021, 266 oncologists from US physician practices, academic and non-academic hospitals, and outpatient clinics provided anonymized information for 715 randomized liquid-tumor patients treated in the past year for hyperuricemia (HU) risk and TLS potential.

From this group, 282 rasburicase and allopurinol patients without spontaneous TLS or TLS before HU treatment were propensity score (PS) matched for TLS-risk using eleven predictive covariates: acute renal failure, age, anti-cancer regimen, creatinine, gender, lactate dehydrogenase, perceived risk, renal disease, tumor type, uric acid, and white blood cell count.

Matched patients met with the 1:1, nearest neighbor, caliper matching requirements using calipers of width equal to 0.2 of the standard deviation of the logit of the PS (d score) on the covariates, regardless of whether they later developed post-HU treatment TLS.

The overall PS was almost 0.6 before matching but near zero afterward.

No covariate exhibited a large imbalance ([d] > .25), nor did the overall relative imbalance difference of the groups (0.077) before and after matching. There was significant improvement in the density of overall standardized differences before and after.

TLS- associated mortality was significantly less likely among rasburicase patients (2.1% vs 7.1% [P-value =0.047]) (71% Reduction).

Analyzing the 63-patients subset who developed TLS after HU treatment, TLS-associated fatalities were even less likely among rasburicase patients, 3 of 36 rasburicase TLS patients vs. 10 of 27 allopurinol TLS patients [P-value = 0.005].

PS matching successfully corrects before and after overall covariate and individual baseline covariate imbalances

Rasburicase compared with allopurinol significantly reduces TLS- associated mortality.

Cairo M, Gallagher JR, Barnes Y et al. Primary Comparison of Nationally Representative Samples of Rasburicase vs Allopurinol Post-Hyperuricemia Monotherapy in Hematological Malignancies: Significant Reduction in Tumor Lysis Syndrome Mortality with Rasburicase Abstract presented at: 2022 Society of Hematologic Oncology, September 28-October 1, 2022; Abstract # MDS-065 https://clml-soho2022.elsevierdigitaledition.com/302/index.html

Dr Cairo reviews results from a real-world observational study comparing the incidence of tumor lysis syndrome (TLS)-associated fatalities between rasburicase monotherapy and allopurinol monotherapy.

Comparison of Nationally Representative Samples of Rasburicase vs Allopurinol Post-Hyperuricemia Monotherapy in Hematological Malignancies: Significant Reduction in Tumor Lysis Syndrome Mortality with Rasburicase

Mitchell S. Cairo, MD

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