A BRIEF OVERVIEW OF VENO-OCCLUSIVE DISEASE

Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a serious and potentially life-threatening complication that is most often associated with patients receiving myeloablative therapy for hematopoietic stem cell transplantation (HSCT).^1-3 Broadly speaking, VOD/SOS is a narrowing of the hepatic sinusoids resulting from cellular and tissue injuries caused by the toxic effects of the chemotherapy and/or radiation therapy used for myelosuppression in HSCT. While rates of VOD/SOS vary from 5% to 15% in adults, VOD/SOS can occur in up to 60% of the pediatric HSCT population.^1-6 With high mortality rates in severe VOD/SOS (>80% when coupled with multiorgan dysfunction), prevention, early diagnosis, and treatment are critical to improving outcomes.^2,3,7 Supportive care (eg, fluid balance maintenance, pain management, eliminating concomitant hepatotoxic drugs) can help to prevent VOD/SOS or reduce progression to serious disease. Diagnostic and severity criteria differ between pediatric and adult populations. Presently, 1 drug, defibrotide, carries an US Food and Drug Administration (FDA)-approved indication for the treatment of VOD/SOS in children and adults.⁸

Given the complexity of treating HSCT patients in general, coupled with the elevated mortality rate associated with VOD/SOS, the collaborative efforts of the health care team are essential to help prevent, diagnose, and treat VOD/SOS. This program will focus on the detection, prevention, and treatment of VOD/SOS in both the pediatric and adult patient population with an emphasis on nurse-pharmacist collaborations.

Pathophysiology and Etiology

VOD/SOS is one of several transplant-related sequalae that affect the endothelium (eg, acute graft versus host disease, engraftment syndrome, transplant-associated microangiopathy).¹ The characteristic pathophysiological features of VOD/SOS include a range of processes—endothelial/hepatocyte damage, increased inflammation, decrease in cytoskeletal structure, cellular debris deposition, hepatic sinusoidal congestion/narrowing—that lead to hypoxia and necrosis of hepatic tissue.^9,10 Injury to the hepatic sinusoidal endothelium results in a breakdown of the endothelial barrier, which allows red blood cells into the perisinusoidal or Disse space (FIGURE 1).² As red blood cells and fluid accumulate and endothelial cohesion continues to deteriorate, endothelial cells and hepatocytes detach and embolize downstream, resulting in obstruction of the sinusoid, the defining characteristic of VOD/SOS.² Cellular damage to endothelial cells and hepatocytes triggers an inflammatory response mediated by several cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6).² Recently, researchers identified the involvement of angiopoietin-1 and -2 (Ang-1/2) via the tyrosine kinase Tie-2 receptor.¹¹ A range of agents can precipitate the initial injury to the endothelial cells and hepatocytes. In the oncology arena, these include busulfan (particularly high dose), cyclophosphamide, granulocyte colony-stimulating factor, calcineurin inhibitors, inotuzumab ozogamicin, or gemtuzumab ozogamicin.^12–14 Often, the presence of clinical symptoms lags behind cellular and tissue damage thus complicating diagnosis, treatment, and outcomes.

Epidemiology

Incidence rates for VOD/SOS differ substantially for the pediatric and adult HSCT populations. In adults, incidence of VOD/SOS ranges from 5% to 15%, while for children, the incidence can range from 20% to 30% and up to 60% for some pediatric populations.^1-6 The overall higher rates in pediatric populations may be related to a less developed metabolic system in children.¹ To add some perspective in regards to the numbers of patients affected, there were 22,013 HCTs in the US in 2020 that were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).¹⁵ Furthermore, 100-day post-diagnosis mortality rates due to VOD/SOS range widely (15.5% to 52.9%) with patient age, severity of disease, and numerous other factors affecting survival.^2,7 In more severe cases, mortality rates can exceed 80%.³

While patient health outcomes, mortality, and morbidity associated with VOD/SOS are paramount concerns, the burden of disease also extends to economic issues. A retrospective analysis demonstrates the economic burden of VOD/SOS. Cao et al determined that length of inpatient stay and total hospital costs increased in HSCT patients with VOD/SOS compared to patients without VOD/SOS.⁵ For pediatric patients (<17 years old), median length of stay was 73 days with VOD/SOS compared to 34 days without VOD/SOS (P < .001); and total median costs for pediatric patients were $374,656 with VOD/SOS compared to $148,414 without (P < .001). The adult patient group with VOD/SOS also experienced longer hospital stays with a median of 34 days versus 20 days for patients with and without VOD/SOS (P < .001) and increased median costs: $173,308 versus $59,353 for VOD/SOS and without VOD/SOS, respectively (P < .001). In addition, the presence of VOD/SOS correlated with a 6-fold increased odds of inpatient mortality compared to without VOD/SOS (odds ratio [OR] = 5.88; 95% confidence interval [CI]: 3.45-10.33).

Clinical Presentation/Diagnosis

The clinical presentation, and hence, diagnostic criteria can differ between pediatric and adult populations. Key aspects of the clinical presentation of VOD/SOS are rapid weight gain, hyperbilirubinemia, painful hepatomegaly, and ascites, which typically present within 21 days after transplant. Traditionally, 2 criteria (Modified Seattle and Baltimore) have been used to diagnose VOD/SOS, each with slight differences in data points. In the Modified Seattle criteria, the timeframe for diagnosis is within 20 days post-HSCT and 2 or more of the following must be present: bilirubin >2 mg/dL; hepatomegaly or right upper quadrant pain; weight gain >2% over baseline.¹⁶ For the Baltimore criteria, the diagnostic timeframe is within 21 days post HSCT and bilirubin level >2 mg/dL must be present along with 2 or more of the following: painful hepatomegaly; ascites; weight gain >5%.¹⁷ The Modified Seattle and Baltimore sets of criteria have been in use for over 30 years.

An updated set of diagnostic criteria, referred to as Cairo/Cooke, was published in 2020 by Cairo et al¹¹ and has been a valuable tool for clinicians. The Cairo/Cooke diagnostic criteria do not include time constraints for exhibiting VOD/SOS-related symptoms, account for the possibility of anicteric (not affected by jaundice) VOD/SOS, and also include new imaging criteria.¹¹ The 3 sets of criteria described (Modified Seattle, Baltimore, Cairo/Cooke) can all be applied to both children and adults (TABLE 1).^2,11,16,17

More recently, the European Society for Blood and Marrow Transplantation (EBMT) developed sets of diagnostic criteria for children and for adults.^1,18 For adults, the EBMT criteria distinguish between classical VOD/SOS where symptoms occur within 21 days post-HSCT and late-onset VOD/SOS, which presents beyond 21 days. The EBMT classical VOD/SOS criteria mirror those of the Baltimore criteria. For late-onset VOD/SOS, the criteria are classical VOD/SOS beyond day 21; or VOD/SOS proven by histology; or ≥ 2 classical criteria coupled with ultrasound or hemodynamic evidence of VOD/SOS (TABLE 2).¹⁸ The EBMT developed separate pediatric criteria since children tend to develop late-onset VOD/SOS more frequently than adults; anicteric VOD/SOS occurs more frequently in children; and hepatomegaly and ascites occur pre-HSCT in children. The EBMT VOD/SOS diagnostic criteria for children are listed in TABLE 3.¹ Clinicians should be aware that diagnostic criteria for VOD/SOS continue to evolve as clinical practice and technology advance.

Complications

One of the major complications of VOD/SOS is the development of multiorgan dysfunction (MOD) or multiorgan failure. Severe cases of VOD/SOS are often accompanied by MOD resulting in high mortality rates (estimated at approximately 80% or greater).¹⁹ Due to the involvement of multiple organs, VOD/SOS patients with MOD may require renal replacement therapy, mechanical ventilation, and measures to prevent infection and bleeding. A recent study suggests that up to 27% of deaths attributed to MOD were a result of underdiagnosed VOD/SOS.²⁰

PREVENTION OF VOD

With the substantial mortality rate of VOD/SOS, particularly in severe disease, efforts to prevent development of the condition are critical. If VOD/SOS can be prevented or the severity minimized, the impact of the condition can be lessened. Prevention efforts have mainly focused on A) minimizing risk factors; B) early identification and initiation of care; and C) preventive pharmacotherapy.

CLINICAL CASE #1: PEDIATRIC PATIENT

SL is a 1.5-year-old female diagnosed with metastatic stage 4 neuroblastoma, MYCN amplified anaplastic lymphoma kinase (ALK) negative, enrolled in ANBL1531 Arm B, s/p 6 induction cycles, second-look surgery, and is found to be in complete remission. She is admitted for the first of planned tandem high-dose chemotherapy and autologous stem cell rescue.

Patient received high-dose chemotherapy with cyclophosphamide and thiotepa x 3 days; prophylaxis for VOD/SOS with ursodeoxycholic acid (NOTE: this is off-label use); and anti-infective prophylaxis with acyclovir, sulfamethoxazole-trimethoprim, and fluconazole.

What risk factors does this patient have for developing VOD/SOS?

Minimizing Risk Factors

Minimizing risk factors begins with identification. Risk factors for VOD/SOS can be differentiated by patient factors and transplantation factors. Some of the common patient risk factors include young age (<1 year), preexisting liver condition, previous treatment with gemtuzumab ozogamicin or inotuzumab ozogamicin, previous abdominal radiation, pre-HSCT ferritin levels >950 ng/mL, and GSTM1 null genotype.^12,19 Common transplantation-related risk factors include allogeneic HSCT, high-intensity myeloablative regimens, total body irradiation (>12 Gy plus cyclophosphamide), and prophylaxis for graft-versus-host disease (GVHD) (TABLE 4).^12,19

The dose of busulfan, a frequently used drug in myeloablative regimens, can be a major factor in developing VOD/SOS. Recent studies identify higher cumulative busulfan exposure and greater busulfan maximum concentration (Cmax) as factors that increased the risk of VOD/SOS in children, thereby supporting pharmacokinetic monitoring of busulfan serum concentrations.^21,22

To minimize the potential for developing VOD/SOS, monitoring for signs and symptoms of disease is important. A number of steps, many of which are standard components of quality nursing care, can be taken to monitor for potentially developing VOD/SOS (TABLE 5).²³ Being aware of the symptoms used for diagnostic criteria and the typical time frame for the onset of symptoms can be critical for prompt identification of VOD/SOS.^23,24 Hepatomegaly and liver tenderness, weight gain, and edema tend to occur earlier post-HSCT, therefore, daily (or more frequent) monitoring for such changes are recommended.^23,24

Prompt Identification and Initiation of Supportive Care

Since identification of VOD/SOS generally occurs after classical symptoms appear, vigilant monitoring as described above is critical. In addition, some clinical signs may appear before classical symptoms. Roeker et al identified 3 potential early clinical predictors in adult HSCT patients: 1) acute kidney injury (defined as an increase in creatinine by ≥0.3 mg/dL or ≥50% over 48 hours); 2) refractoriness to platelet transfusion (defined as requiring platelet transfusions on 2 consecutive days for a consistent transfusion goal and without a rise of ≥10,000/µL); and 3) higher trough levels of tacrolimus.²⁵ In the 7 days prior to VOD/SOS diagnosis, patients who developed VOD/SOS compared to non-VOD/SOS patients were more likely to have signs of acute kidney injury (61% vs 33%, P < .0001); more likely to become refractory to platelet transfusion (48% vs 24%, P < .0001); and demonstrated higher tacrolimus trough levels (7 days before VOD/SOS diagnosis: median 8.8 ng/mL vs 7.3 ng/mL, P = .0002; day of diagnosis: median 9.3 ng/mL vs 7.2 ng/mL, P < .0001).²⁵ Although these clinical clues have not been validated in a larger cohort of patients, they can provide insights on patient progression to overt disease.

Supportive measures are important aspects in caring for VOD/SOS patients and in patients with a high risk of developing VOD/SOS. Having the most training in such measures and having the most direct patient contact, nursing staff will generally provide the supportive care responsibilities. Ní Chonghaile and Wolownik summarized a list of recommended supportive care measures, which can be a helpful resource (TABLE 6).²³ Maintaining fluid and sodium balance would be 1 of the more critical measures to take since fluid retention and ascites are 2 of the early indicators of VOD/SOS. Other measures, such as positioning the patient comfortably and maintaining skin integrity, should not be downplayed as they can improve patient well-being and prevent adverse sequelae.

Preventive Therapy: Brief Overview

Preventive pharmacotherapy has been attempted with numerous agents, including heparin, low-molecular-weight heparin (LMWH), antithrombin III (ATIII), prostaglandin E1 (PGE1), pentoxifylline, ursodeoxycholic acid (UDCA), and defibrotide.²⁶ In general, due to inconsistent or insufficient evidence, no single agent has established sufficient efficacy to obtain FDA approval as preventive therapy for VOD/SOS.²⁷

Heparin and UDCA: Limited Data Supporting Use

Heparin and LMWH have been studied alone or in combination with other agents for the prevention of VOD/SOS. Such studies continue to be conducted in efforts to find particular scenarios where heparin may be useful as a preventive agent or strategy. A recently published retrospective study by Sola et al found some benefit with low-dose unfractionated heparin in adult HSCT undergoing myeloablative regimens where 3% (95% CI: 2.0-4.0) of 514 patients developed VOD/SOS by 100 days.²⁸ Overall, systematic reviews and meta-analyses suggest that heparin and LMWH do not aid in the prevention of developing VOD/SOS and may increase risk of bleeding.^27,29

Somewhat more promising results have been observed with UDCA, a secondary bile acid used to treat primary biliary cirrhosis. Two systematic reviews share similar summaries in that limited, low-quality evidence seems to suggest that UDCA may be efficacious in preventing VOD/SOS and in reducing mortality due to VOD/SOS.^27,30 However, due to the relatively small number of clinical trial participants, lack of high-quality evidence, and lack of a standardized prophylactic regimen, UDCA is not recommended in the prevention of VOD/SOS in the US and is not indicated.²⁷ On the other hand, a US-based initiative, the HCT Committee of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) and the Supportive Care Committee of the Pediatric Blood and Marrow Transplant Consortium (PBMTC), published guidelines that do recommend UDCA for the prophylaxis of VOD/SOS in children and adolescents.³¹ In addition, international groups and societies (the British Committee for Standards in Haematology [BCSH], British Society for Blood and Marrow Transplantation [BSBMT], Italian Society of Stem Cell Transplant [Gruppo Italiano Trapianto di Midollo Osseo], PALISI Network, and EBMT) have recommended the use of UDCA for VOD/SOS prophylaxis based on published evidence and the drug’s safety profile.^32-34

Defibrotide

As the only drug with an FDA-approved indication for VOD/SOS (as discussed below), defibrotide has also attracted interest as a preventive agent. Defibrotide is a mixture of oligonucleotides derived from porcine intestinal tissue with protective effects on endothelial cells.^35-37 Mixed clinical results with defibrotide have not provided sufficient evidence to warrant an indication for prophylaxis of VOD/SOS.²⁷ Similar to UDCA, the clinical data has led to the off-label prophylactic use of defibrotide in certain instances.

Pediatric Patients: Efficacy and Safety

Stronger evidence seems to support a role for defibrotide in the prophylaxis of VOD/SOS in children. In the open-label, phase 3 study in children <18 years old by Corbacioglu et al, patients were randomized to receive no prophylaxis or defibrotide (25 mg/kg/day via 4 intravenous [IV] infusions at 6.25 mg/kg IV over 2 hours).³⁸ Defibrotide regimen was initiated on the day that HSCT preconditioning regimens began. Incidence of VOD/SOS in the control group was 20% (35/176) compared to 12% (22/180) for a risk difference of -7.7% (95% CI: -15.3 to -0.1), although the rates of VOD/SOS-associated mortality at 100 days post-HSCT did not differ between the groups.³⁸ While the lowered risk of developing VOD/SOS has led to recommendations for the prophylactic use of defibrotide in children by several international professional societies and working groups,^32-34 defibrotide is not approved for the prophylaxis of VOD/SOS in children and such use would be considered off-label.

Emerging Data in Adult Patients

Defibrotide has also been investigated for the prophylaxis of VOD/SOS in adults. The HARMONY trial (NCT02851407) studied IV defibrotide (25 mg/kg/day) or best supportive care in HSCT patients at high risk for developing VOD/SOS in both pediatric and adult populations.³⁹ Most recent results demonstrated no statistical differences between groups for primary (VOD/SOS-free survival by day 30) and key secondary endpoints.⁴⁰ The VOD/SOS-free survival by 30 days post HSCT as estimated by Kaplan-Meier analysis was 67% (95% CI: 58% to 74%) in the defibrotide cohort versus 73% (95% CI: 62% to 80%) for the best supportive care group (P = .85). Similarly, VOD/SOS-free survival by 100 days was not different between groups—50% (95% Cl: 26% to 70%) versus 57% (95% Cl: 37% to 73%) for defibrotide and best supportive care groups, respectively (P = .81).⁴⁰ The study stopped enrolling patients even prior to the reporting of preliminary results.⁴¹

Interest in defibrotide as a prophylactic remains. A recently published systematic review and meta-analysis suggests defibrotide may lower the incidence of VOD/SOS in adult and pediatric populations compared to control groups (heparin prophylaxis or standard care) with a calculated relative risk of 0.30 (95% CI: 0.12-0.71, P = .006).⁴²

CURRENT TREATMENT OF VOD

Supportive Care Measures

When treating patients with VOD/SOS, supportive care measures are critical for minimizing complications and optimizing patient outcomes.⁴³ The Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees published a series of papers outlining guidelines for supportive care measures in children and adolescents with VOD/SOS.^31,44,45 Supportive care measures are also key to adult patient outcomes. Administering supportive care measures are the province of nursing staff.⁴⁶ The training, education, and clinical knowledge of nurses establish them as the experts in this area. A paramount goal of supportive care is maintaining renal and pulmonary function through fluid and electrolyte management.^23,24TABLE 6 provides a list common supportive care measures provided by nurses to patients with VOD/SOS.²³

CLINICAL CASE #2: ADULT HSCT

GA is a 58-year-old man with acute myeloid leukemia (AML) refractory to induction chemotherapy now undergoing allogeneic HSCT.

The patient failed to achieve remission with induction with daunorubicin/cytarabine/gemtuzumab ozogamicin, so he subsequently received venetoclax and azacitidine for 6 cycles and achieved a complete remission. The patient had a 10 of 10 human leukocyte antigen (HLA)–matched unrelated donor identified and was referred to allogeneic HSCT.

The patient received conditioning chemotherapy with busulfan (3.2 mg/kg) IV Q24H x 4 days on days -7 through -4 and cyclophosphamide (60 mg/kg) on days -3, -2 with stem cells infused on day 0. On day +3, the patient was noted to have an increase in total bilirubin from a baseline of 0.7 mg/dL to 2.2 mg/dL. Additionally, the patient noted right upper quadrant pain and has gained 2.3 kg of weight since admission to the hospital. These signs and symptoms suggest development of VOD/SOS.

What would be the recommended VOD/SOS treatment regimen for this patient?

Defibrotide

Currently, defibrotide is the only FDA-approved drug therapy for the treatment of VOD/SOS in children and adults. The specific mechanism(s) of action of defibrotide, a mixture of mostly single-stranded oligodeoxyribonucleotides (ODNs) derived from porcine intestinal mucosa, in VOD/SOS is not completely understood.^35-37 Through a combination of antithrombic, profibrinolytic, anti-inflammatory, antioxidant, and anti-ischemic properties, defibrotide provides protective effects on the hepatic endothelium.^35,37,47 Interactions between defibrotide and endothelial cell membranes appear to contribute to defibrotide’s activity.⁴⁸ Some of defibrotide’s effects may be attributed to action as an adenosine receptor agonist, inhibiting plasminogen activator inhibitor type 1 (PAI-1) activity, enhancing production of prostaglandins I2 and E2 (PGI2/E2), and reducing the production of several cytokines, including IL-6, vascular endothelial growth factor (VEGF), thromboxane A2 (TXA2), and TNF-α.^35,37

Efficacy, Safety, and Outcomes Data for VOD With Multiorgan Failure

When VOD/SOS progresses to MOD, the mortality rate can exceed 80%. An open-label, phase 3 study of defibrotide using a historical control group provided efficacy, safety, and outcomes. Pediatric and adult HSCT patients (n = 102, median age 21 years, age range 0 to 72 years) with VOD/SOS and advanced MOD received defibrotide at standard dosing and administration (ie, 25 mg/kg/day in 4 divided doses administered by 2-hour IV infusion every 6 hours).⁴⁹ Historical controls were pulled from 6857 medical charts of HSCT patients resulting in 32 patients with VOD/SOS with MOD. Compared to historical controls, treatment with defibrotide improved survival at 100 days post-HSCT (primary endpoint): 25% for historical control cohort; 38.2% for defibrotide cohort; 23% difference (95.1% CI: 5.2% to 40.8%, P = .0109). In addition, defibrotide improved complete response (secondary endpoint—difference of complete response by day +100 post-HSCT and survival at day +180 post-HSCT): 12.5% for historical control cohort; 25.5% for defibrotide cohort; 19% difference (95.1% CI: 3.5% to 34.6%, P = .0160).

Efficacy, Safety, and Outcomes Data for VOD Without Multiorgan Failure

Multiple clinical studies (phase 1, phase 2, and expanded access trials) from the late 1990s to the mid 2010s contributed to the efficacy and safety data that lead to the approval of defibrotide for VOD/SOS.^7,50-53 Earlier studies would use doses that ranged from 5 mg/kg/day to 60 mg/kg/day until the recommended dose of 25 mg/kg/day was established. The systematic review by Richardson et al, comprehensively summarizes the efficacy data of defibrotide.⁵⁴ The established endpoint of day +100 survival was compared across the studies and reviewed in a pooled analysis. Patients in the clinical trials included children and adults. For all patients (with or without MOD) at a dose of 25 mg/kg/day of defibrotide, the estimated day +100 survival was 54% (95% CI: 48% to 59%, P < .01). In the subgroup of patients without MOD (2 5 mg/kg/day dose), the estimated day +100 was 71% (95% CI: 67% to 75%) and for the subgroup of patients with MOD (25 mg/kg/day dose) the estimated day +100 was 44% (95% CI: 35% to 52%, P < .01). The pooled pediatric subgroup (25 mg/kg/day) had an estimated day +100 survival of 68% (95% CI: 61% to 74%, P = .05) and the adult subgroup (25 mg/kg/day) had an estimated day +100 survival of 48% (95% CI: 38% to 57%, P< .01). Due to variability in reporting of adverse events, that aspect of the studies was not analyzed in the same manner.⁵⁴ Overall, consistent with the drug’s prescribing information, the most common adverse events associated with defibrotide are hypotension, diarrhea, nausea, vomiting, and epistaxis.³⁶

Practical Administration and Pearls

The recommended administration and dosing of defibrotide for both children and adults is via IV infusions every 6 hours at dose of 6.25 mg/kg administered over 2 hours for a minimum of 21 days.³⁶ Similar to the mechanism of action, the specific metabolic pathway of defibrotide is not fully elucidated, but a range of plasma exonucleases, nucleotidases, deaminases, and phosphorylases are suspected to be involved.^36,37 Drug-drug interactions are not expected with defibrotide as the drug has not been shown to induce or inhibit common hepatic metabolizing enzymes of the cytochrome P450 (CYP450) system and is also not known to be a substrate of common drug influx and efflux transporters.^36,37

Intrahepatic Portosystemic Shunt/Hepatic Transplantation for Select Patients

In addition to pharmacological therapy, a surgical approach to treating VOD/SOS is transjugular intrahepatic portosystemic shunt (TIPS), a procedure also used in the treatment of portal vein thrombosis in hepatic disorders.⁵⁵ The TIPS procedure uses a stent to create a pathway between the portal and systemic circulatory systems to alleviate portal pressure by at least 20%.⁵⁶ Due to limited expertise and a paucity of published data, there are no clear recommendations on the use of TIPS in VOD/SOS.³²

NURSE AND PHARMACIST COLLABORATION TO IMPROVE OUTCOMES

Nurses will have the most frequent interactions with patients at risk of developing VOD/SOS and, therefore, will play critical roles in identifying symptoms of VOD/SOS, providing supportive care for patients with VOD/SOS, and administering recommended treatments. Pharmacists, as stewards of drug resources, will work with nursing and other members of the health care team to ensure efficient and accurate dosing of defibrotide as well as other drugs used in the HSCT regimen. Caring for patients undergoing HSCT requires intensive technical expertise beyond standard nursing and pharmacy care. The Foundation for the Accreditation of Cellular Therapy (FACT) along with the Joint Accreditation Committee of the International Society for Cellular Therapy and the EBMT (ISCT-EBMT or JACIE), collectively referred to as FACT-JACIE, provide detailed accreditation standards for HSCT therapy with roles for nurses and pharmacists including 10 hours of continuing education in cellular therapy for pharmacists and requirements for nurses to be trained in age-specific treatment of HSCT patients.⁵⁷ A Hematopoietic Clinical Pharmacist role was recently described by the Pharmacist Special Interest Group of the American Society for Blood and Marrow Transplantation (ASBMT) with support from the ASBMT and other organizations.⁵⁸

Common nursing interventions in the treatment of patients with VOD/SOS include closely monitoring fluid input/output; administering fluids to maintain renal perfusion; administering diuretics to maintain net negative fluid status; administering defibrotide at appropriate dose and schedule; maintaining comfort with use of analgesics and physical comfort measures (eg, loose clothing, warm soaks); and providing blood product support and correction of coagulopathies. Common pharmacist interventions in the treatment of patients with VOD/SOS include monitoring serum blood levels of immunosuppressants; avoiding concomitant hepatotoxic drugs when possible (made difficult with need for potentially hepatotoxic antifungals); monitoring for drug-drug interactions, particularly those involving CYP450 enzymes; and minimizing fluid intake by reducing volume of IV medications as much as possible. For drug-drug interactions, a helpful resource is The Flockhart Cytochrome P450 Drug-Drug Interaction Table maintained by the Indiana University School of Medicine.⁵⁹ Resources for determining how concentrated IV medications can be prepared include the package inserts of each drug and Trissel’s Stability of Compounded Formulations.⁶⁰

Identification of Risk Factors and Signs/Symptoms of Disease

Identifying the risk factors and signs/symptoms of VOD/SOS is key to effectively manage HSCT patients. Rapid changes in patient status, particularly weight gain, can occur that may signal development of VOD/SOS. With the most frequent patient contact, nurses will typically have the most current information on patient status and will be able to enlist the support of the health care team as needed.⁶¹ Nurses will have prominent roles in pretransplant assessment including baseline monitoring (eg, the patient’s weight and abdominal girth) prior to initiating conditioning therapy.^23,24 As conditioning therapy commences, several parameters should be measured and monitored closely, including vital sign monitoring every 4 hours, twice daily patient weight and abdominal girth, fluid/electrolyte balance/replacement daily, daily assessment for presence of right upper quadrant pain, and skin changes (TABLE 5).^23,24

Treatment Selection (Patient, Disease, and Regimen Characteristics)

Many conditioning regimens exist for patients preparing for HSCT, which can influence the risk of developing VOD/SOS. Myeloablative regimens involving total body irradiation or higher-dose busulfan are associated with increased risk of VOD/SOS. Other drugs may also increase VOD/SOS risk such as methotrexate and sirolimus (used for GVHD prophylaxis) and the immunotherapy antineoplastics, inotuzumab ozogamicin and gemtuzumab ozogamicin.¹⁹ Since prior exposure to these drugs as well as patient factors (ie, age, liver disease, active hepatitis) can impact VOD/SOS risk, well-documented patient history is important.

Strategies to Prevent, Reduce, and Manage Adverse Effects

Prompt initiation of defibrotide is generally recommended in the cases of suspected or confirmed VOD/SOS as better outcomes were observed when therapy is initiated close to the day of diagnosis.⁶² With earlier initiation, adverse outcomes from VOD/SOS may be mitigated. In addition, supportive care measures, primarily provided by nurses, would also contribute to the prevention and management of adverse effects (TABLE 6).²³ Management of ascites would include reducing fluid and sodium intake, administering diuretics, and/or paracentesis when indicated.^23,24 A range of other nursing roles include care of venous access devices, pain management, observing for signs of sepsis, and reducing patient distress and isolation.⁴⁶

Appropriate Dosing and Administration

The prescribing information for defibrotide recommends a dosage of 6.25 mg/kg as a 2-hour infusion given every 6 hours for a minimum of 21 days.³⁶ Therapy may continue beyond 21 days if VOD symptoms persist. With renal impairment a common comorbidity in VOD/SOS, investigators studied the pharmacokinetics in VOD/SOS on dialysis or end-stage renal disease (ESRD). Dialysis had no significant effect on defibrotide peak plasma concentration, exposure, or clearance. While peak plasma concentrations and areas under the curve (AUC) increased in patients with ESRD (35%-37% and 50%-60%, respectively), drug accumulation did not appear to occur, and no dose adjustments were recommended for dialysis or ESRD.⁶³

Pharmacists can also oversee how the defibrotide drug supply is managed in order to reduce costs without sacrificing patient care. Encouraging dose rounding (within institutional policies and procedures) and preparing up to 4 doses for a single patient from a vial (per labeling) may conserve product and reduce drug costs. Pharmacists should also ensure the proper preparation of defibrotide IV infusions in dextrose 5% or normal saline so that is diluted to a concentration between 4 mg/mL to 20 mg/mL.³⁶ Ensuring that defibrotide is administered with a 0.2 micron inline filter as directed would be an area of nurse-pharmacist collaboration.³⁶

Challenges in Managing Patients at Risk or With VOD

Patients undergoing HSCT therapy already experience the stress of their underlying cancer diagnosis. Adding to the stress (both physical and psychological) is a complicated and complex regimen that can include radiation therapy, high-dose chemotherapy, and surgical procedures. Compounding the issue is the risk of developing VOD/SOS, one of the most serious potential adverse health outcomes that HSCT patients can encounter. Managing the psychosocial support that patients and their families need is one of the many responsibilities that nurses often provide.^23,24,46 Nurses are also typically at the center of coordinating patient care. Communication between all members of the health care team is critical in the prevention and management of VOD/SOS. For example, when fluid intake should be restricted, communication and coordination with pharmacy is important so that drug solution volumes are reduced as needed. The effect of reduced nurse staffing levels on providing quality patient care should also not be overlooked.

SUMMARY

VOD/SOS is a serious medical condition that can arise from treatments associated with HSCT. In severe cases of VOD/SOS, such as when associated with MOD, mortality rates can be quite high (up to 80% in some populations). Since no drugs have been approved with an indication for VOD/SOS prophylaxis, patient monitoring and supportive care measures can help identify and mitigate aspects of VOD/SOS. With the potential for morbidity and mortality, collaboration between professionals on the health care team (including nurses and pharmacists) is essential to aid in the prevention and treatment of VOD/SOS. Nurses and pharmacists are integral to the care and treatment of patients with VOD/SOS with specific, complementary roles. To date, FDA-approved drug therapy for the treatment of VOD/SOS is limited to a single agent—defibrotide, which is administered intravenously. Through the application of patient monitoring, supportive care measures, and early initiation of pharmacological treatment, the risks associated with VOD/SOS may be mitigated. Clinicians should be aware of the risk factors, signs, symptoms, and treatment regimens of VOD/SOS to better serve patients undergoing HSCT.

References

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