Expired activity
Please go to the PowerPak homepage and select a course.

Examining the Evidence for Improving Outcomes in Veno-Occlusive Disease: Pharmacist Perspectives

INTRODUCTION

A hematopoietic stem cell transplant (HSCT) involves the administration of high-dose chemotherapy followed by the intravenous infusion of hematopoietic stem cells. These cells exhibit the capacity for self-renewal and yield daughter cells that reconstitute the active lymphohematopoietic system.1 HSCT utilizes higher and potentially more effective doses of chemotherapy for the treatment of otherwise incurable malignant and nonmalignant conditions. The selection of chemotherapy agents administered in the preparative regimen is dependent on the type of malignancy and the type of transplantation.

There are 3 types of HSCT: autologous HSCT (i.e., hematopoietic cells from the patient’s own marrow or peripheral blood), allogeneic HSCT (i.e., graft from a donor’s marrow, peripheral blood, or cord blood), and syngeneic HSCT (i.e., marrow or peripheral blood from an identical twin). In addition to marrow reconstitution, allogeneic transplantation potentially confers an immunologically mediated graft-versus-tumor effect that may prevent relapse of the primary malignancy. Syngeneic transplantation is rare but has the advantage that the identical twin is guaranteed to match the recipient, so there is no chance of graft-versus-host disease (GVHD).

Hematopoietic stem cells are rare, accounting for less than 0.01% of all cells found within the bone marrow.2 Because of the rarity of these progenitor cells, flow cytometry is used to identify cells that express the clusters of differentiation (CD) 34+ antigen. The number of collected CD34+ cells, along with negative lineage-specific markers, is used to determine the number of stem cells collected.3

Autologous HSCT was initially developed to optimize the dose intensity of chemotherapy being administered for a specific malignancy. Dose intensities of the preparative regimens used for HSCT are higher than those used for conventional chemotherapy in order to achieve an increased log kill of the malignant cell population. The infusion of autologous stem cells provides a rescue intervention after high-dose chemotherapy that would otherwise result in prolonged or permanent myelosuppression.

Allogeneic HSCT applies the same chemotherapy principles with the addition of donor immune effector cells. Ideally, the recipient’s immune system tolerates the engraftment of donor cells, which reconstitutes B-lymphocytes, T-lymphocytes, natural killer cell function, and myeloid lineage cells.4 The transplantation and reconstitution of the donor immune system provides a graft-versus-tumor effect or graft-versus-leukemia effect that can suppress the malignant clone for long-term disease control. Complications after allogeneic HSCT include GVHD, regimen-related toxicity, infection, bleeding, and relapse of original disease.

Regimen-related toxicities are specific complications associated with the chemotherapy conditioning regimen.5 One of the most prominent regimen-related toxicities is a clinical syndrome that is secondary to damage caused to the liver by the conditioning chemotherapy. This clinical syndrome has historically been called hepatic veno-occlusive disease (VOD) but has more recently been termed sinusoidal obstruction syndrome (SOS).6 This brief review will focus on the constellation of symptoms associated with hepatic VOD/SOS and historical and modern treatment approaches that are available for patients with this life-threatening disorder.

OVERVIEW OF VOD/SOS

VOD/SOS is a potentially fatal complication that occurs in 5% to 15% of patients who receive myeloablative therapy for HSCT.7 Rates of VOD/SOS are decidedly higher in pediatric patients, with the disorder reported to occur in upwards of 60% of patients, depending on the age of the patient and the conditioning regimen used. Risk factors for VOD/SOS can be globally divided into patient-associated or treatment-associated characteristics. Patient-related risks include factors such as older age, history of liver diseases, active hepatitis, prior treatment, or history of a previous HSCT.8,9 Treatment-related factors include transplant with an unrelated donor, select conditioning regimens (particularly those containing busulfan or total body irradiation), and GVHD prophylaxis that contains methotrexate or sirolimus.9-11 Select antineoplastic agents, such as inotuzumab ozogamicin and gemtuzumab ozogamicin, are known to cause VOD/SOS. Further, in patients who receive these agents and then go on to receive a subsequent HSCT, the risk for VOD/SOS post-transplant is increased.11

Reduced-intensity conditioning regimens (i.e., lower total doses of conditioning chemotherapy) for HSCT may decrease the risk of VOD/SOS post-HSCT, although VOD/SOS has still been reported in 2% to 9% of allogeneic transplant patients who received reduced-intensity conditioning.12 The use of busulfan, via both intravenous (IV) and oral administration, has been associated with VOD/SOS in myeloablative conditioning regimens.13 Pharmacokinetic monitoring of busulfan conditioning may modulate the risk of the development of VOD/SOS, although data are conflicting.14,15

Rarely, VOD/SOS has been reported in patients who have been exposed to pyrrolizidine alkaloids, an example of which is Symphytum officinale, more commonly known as comfrey.16 Comfrey is found in herbal products that are promoted for use in patients who have healing bone fractures, joint inflammation, wound healing, and gastrointestinal distress. The mechanism is believed to involve reactive metabolites that form pyrrole-protein adducts that cause widespread damage to hepatic sinusoidal endothelial cells.

VOD/SOS with multi-organ failure (MOF) is associated with a mortality rate typically in excess of 80%.9,11 Common signs and symptoms of VOD/SOS include painful hepatomegaly, ascites and/or weight gain, hyperbilirubinemia not attributed to other common post-HSCT complications such as sepsis, acute GVHD, and toxicity from other known hepatotoxic drugs. Ultrasonography reveals reversal of hepatic flow and increased portal congestion. Precise diagnostic criteria for VOD/SOS are listed in Table 1.6 A pathologic diagnosis can be obtained by a liver biopsy evaluating for characteristic changes to the hepatic sinusoids and loss of endothelial cell fenestrations. However, the risk/benefit ratio of biopsy must be weighed against the concern for hemorrhage in patients with impaired coagulation and who are often profoundly thrombocytopenic.

Table 1. Diagnostic Criteria for VOD/SOS in Adults and Children6
Criteria set Age groups Time of signs/symptoms onset Signs/symptoms
Baltimore (adopted for EBMT adult criteria as “classical”) Adult and pediatric patients ≤ 21 days post-HSCT Bilirubin ≥ 2 mg/dL plus 2 or more of the following: hepatomegaly, ascites, and weight gain > 5%
Modified Seattle Adult and pediatric patients ≤ 20 days post-HSCT 2 or more of the following: bilirubin ≥ 2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain > 2% (weight gain threshold > 5% sometimes used)
Late onset (adults) Adult patients > 21 days post-HSCT “Classical” VOD/SOS (Baltimore) or histologically proven VOD/SOS or 2 or more of the following: bilirubin ≥ 2 mg/dL, hepatomegaly, ascites, and weight gain > 5%; hemodynamic and/or ultrasound evidence of VOD/SOS
Pediatric Pediatric patients No time frame post-HSCT Either Baltimore (“classical”) or Seattle criteria with the following variations/exceptions: increased bilirubin from patient’s baseline for 3 consecutive days or bilirubin ≥ 2 mg/dL within 72 hours may replace the bilirubin levels specified for adults; weight gain on 3 consecutive days replaces the 2% weight gain in the Seattle criteria; weight gain > 5% above baseline (Baltimore criteria) is maintained as a criterion for children; addition of transfusion-refractory thrombocytopenia as one of the possible signs of VOD/SOS (≥ 2 still required for diagnosis)
EBMT, European Society for Blood and Marrow Transplantation; HSCT, hematopoietic stem cell transplant; VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome.

The pathophysiology of VOD/SOS encompasses a cascade of cellular injury, inflammation, deposition of cellular debris, hepatic sinusoidal congestion, hypoxia, hepatocyte tissue necrosis, and MOF.6,8 Unfortunately, this pathophysiologic process generally progresses rapidly prior to clinical symptomatology becoming evident in an affected patient. This process begins with toxic injury to sinusoidal cells of the endothelium and hepatocytes of zone 3 of the liver acinus; this insult induces downstream inflammatory and diffuse damage to the liver vasculature. The damage to hepatic endothelial cells results in reduced nitric oxide production and increased levels of matrix metalloproteinase, which may be associated with multiple prothrombotic biomarkers, which, in turn, exacerbates the inflammatory process. Damage to hepatic venular and sinusoidal endothelium leads to a local hypercoagulable state. Vasoactive peptides may cause vasoconstriction and platelet aggregation secondary to endothelial injury.

Inflammatory cytokine release from the injured tissue leads to structural deterioration of the sinusoidal endothelium.7 The demise of the hepatic vascular structure with increased metalloproteinase activity in the extracellular space causes widespread mutilation to the endothelial lining, which leads to accumulation of cellular/extracellular debris and platelets: this deposition results in widespread obstruction of the hepatic sinusoidal vasculature. Accumulation of this tissue within the vasculature leads to fibrotic changes to the sinusoids, tissue hypoxia, and subsequent cellular necrosis. These hemodynamic events can cause a downstream effect of portal hypertension, which may then progress to hepatorenal syndrome and MOF.

Patients with MOF often require renal replacement therapy, mechanical ventilation, and prudent measures to prevent infection and bleeding. Grading of VOD/SOS takes into account such factors as liver function tests, weight gain, renal function, and time to onset to differentiate mild, moderate, severe, and very severe VOD/SOS. A proposed grading system by the European Society for Blood and Marrow Transplantation (EBMT) is presented in Table 2.17

Table 2. European Society for Blood and Marrow Transplantation Severity Grading for VOD/SOS in Children, Adolescents, and Young Adults17
Clinical measure (highest grade with ≥ 2 symptoms) Mild Moderate Severe Very severe
Bilirubin (mg/dL) < 2 < 2 ≥ 2 Doubles in 48 hours
ALT/AST/GLDH ≤ 2 times normal > 2 and ≤ 5 times normal > 2 and ≤ 5 times normal > 5 times normal
Weight above baseline 2% - 5% 5% - 10% despite diuretic use > 10% > 10%
Renal function 1.5 - 1.9 times baseline at transplant 2 - 2.9 times baseline at transplant 3 times baseline at transplant or SCr > 4 mg/dL or eGFR < 35 mL/min or initiation of renal replacement therapy or anuria Persistent need for renal replacement therapy
Coagulopathy (not responsive to vitamin K administration; INR) < 1.5 1.5 - 1.9 > 2 Need for replacement of coagulation factors
Ascites Mild (minimal fluid by liver, spleen, or pelvis) Moderate (< 1 cm of fluid) Severe (fluid in all 3 regions with > 1 cm fluid in ≥ 2 regions) Requires paracentesis
Pulmonary function < 2 L oxygen < 2 L oxygen Non-invasive ventilation/invasive mechanical ventilation Invasive mechanical ventilation
Encephalopathy CAPD < 9 CAPD < 9 CAPD ≥ 9 CAPD ≥ 9
Persistent refractory thrombocytopenia < 3 days 3 - 7 days Not specified > 7 days
ALT, alanine transaminase; AST, aspartate transaminase; CAPD, Cornell Assessment of Pediatric Delirium; eGFR, estimated glomerular filtration rate; GLDH, glutamate dehydrogenase; INR, international normalized ratio; SCr, serum creatinine; VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome.

PREVENTION OF VOD/SOS

Therapeutic agents investigated for the prevention of VOD/SOS in HSCT patients include heparin, low-molecular-weight heparin, low-dose dopamine, prostaglandin E1, and ursodeoxycholic acid (ursodiol). However, evidence supporting these prophylactic approaches is limited. Additionally, heparin is associated with an increased risk of serious bleeding. Ursodiol has been evaluated for VOD/SOS prophylaxis in HSCT patients, but clinical results have been mixed.18-20 A systematic review evaluating 824 HSCT patients in 4 randomized trials and 2 historical controlled trials showed a reduction in transplant-related mortality but no overall survival benefit with ursodiol.18 However, a prospective, controlled study in 242 HSCT patients found no difference in the incidence of VOD/SOS with ursodiol prophylaxis.19 These conflicting results have limited the broad utilization of ursodiol as a standard prophylactic strategy against VOD/SOS in HSCT patients.

Defibrotide, a profibrinolytic and anti-inflammatory drug, was first reported in the treatment of VOD/SOS in 1995.21 This was followed by the drug being made available by a compassionate use program until the drug was approved by the United States Food and Drug Administration (FDA) in 2016. Defibrotide has a particularly complex mechanism of action. Oligonucleotides have been observed to mimic heparin and interact with heparin-binding proteins, including basic fibroblast growth factor, a key angioprotective protein that promotes microvessel formation.22 Defibrotide appears to exert several anti-inflammatory and antioxidant effects through interaction with the endothelial cell membrane, as shown in an endothelial cell line of hepatic origin. Defibrotide was initially considered primarily an antithrombotic and profibrinolytic agent.23 Fibrinolysis was among the first pharmacologic actions of defibrotide observed in in vitro, animal, and clinical studies.24 Defibrotide has been further shown to reduce platelet adhesion and aggregate formation in humans and inhibit platelet activation; however, defibrotide has demonstrated no significant systemic anticoagulant effects in pharmacologic studies.25

The pharmacokinetics of defibrotide are notable in that its metabolism appears to be governed by degradation in plasma mediated by either nucleases, nucleosidases, deaminases, and/or phosphorylases that metabolize polynucleotides to eventually form free 2’-deoxyribose sugar and purine and pyrimidine bases. In vitro data demonstrate that defibrotide is not appreciably metabolized by human microsomal enzymes. Specific pharmacokinetic parameters of defibrotide are outlined in Table 3.21

Table 3. Defibrotide Pharmacokinetics21
Parameter Mean value
Half-life (hour) 0.7
Tmax (hour) 2
Cmax (mcg/mL) 17.3
Volume of distribution (L) 8.1 - 9.1
Clearance (L/hour) 10.4
AUC (mcg/mL/hour) 48.1
AUC, area under the curve.

Conventional treatment approaches using defibrotide have centered on early treatment to optimize the chance for the best outcomes,26,27 and observations from its use in this way led to the investigation of defibrotide in the setting of prophylaxis for patients undergoing HSCT. A phase III VOD/SOS prevention trial of defibrotide was conducted in pediatric patients undergoing HSCT who were considered high risk for VOD/SOS.28 This open-label, controlled study enrolled patients younger than 18 years old who had undergone myeloablative conditioning chemotherapy for either autologous or allogeneic HSCT and had 1 or more risk factors for VOD/SOS. A total of 356 patients were randomized to defibrotide 6.25 mg/kg IV every 6 hours starting on the same day as the pre-transplant conditioning regimen and continuing for 30 days post-HSCT (or for at least 14 days if hospital discharge occurred within 30 days) or to no prophylactic therapy. The primary endpoint of the trial was the presence of VOD/SOS at day +30 post-HSCT, which was judged by an independent monitoring committee. Patients in the control arm could receive defibrotide if they developed VOD/SOS.

The average patient age was 6.6 years. Approximately two-thirds of patients received an allogeneic HSCT and the mean duration of defibrotide therapy was 28.7 days in the treatment arm. Patients who received defibrotide had an incidence of VOD/SOS at +30 days post-HSCT of 12% and, for those receiving no prophylactic therapy, the incidence was 20%. The risk of VOD/SOS progression to MOF was 1% in the defibrotide arm and 6% in the control arm (p=0.169). Day +100 mortality was 25% in patients who developed VOD/SOS and 6% in those who did not (p<0.0001) in the entire study population, although the rates of day +100 mortality were not different between the defibrotide arm and control patients who developed VOD/SOS. Rates of overall and serious adverse events, as well as treatment discontinuations, were similar between the defibrotide and control groups. Despite the availability of this dataset, defibrotide is not currently approved as a prophylactic strategy for VOD/SOS in pediatric or adult patients undergoing HSCT. Prophylaxis in the adult population has not yet been established on the basis of prospective, randomized, controlled trials.29

CURRENT TREATMENT OF VOD/SOS

Supportive care in patients with VOD/SOS focuses meticulous attention on maintenance of intravascular volume and organ perfusion. Maintaining proper fluid balance and soliciting input from specialties such as critical care and hepatology are essential to preventing progression to MOF. Historically used treatments such as albumin, alteplase, heparin, or low-dose dopamine have not been validated in prospective randomized trials and are not generally recommended for routine use.8 Treatment decisions for VOD/SOS in the HSCT population focus on supportive care with pain management, minimizing hepatotoxin exposure, management of fluid overload, and prevention of hepato-renal syndrome.

Historical therapies used for VOD/SOS include methylprednisolone and tissue plasminogen activator (tPA).6,7 Data supporting methylprednisolone are limited to small retrospective studies, and its use is generally not recommended because of the risk of infections. Use of tPA with or without heparin has been evaluated in several small studies. One of the larger retrospective studies of tPA found a 25% day +100 survival, but the high rates of severe hemorrhage precluded widespread adoption of the drug in the treatment of VOD/SOS.

Defibrotide is the only treatment that is approved by the FDA for the treatment of adult and pediatric patients with VOD/SOS with renal or pulmonary dysfunction associated with or following HSCT.23 The approved dosing for defibrotide is 6.25 mg/kg every 6 hours given as a 2-hour IV infusion. Treatment duration is a minimum of 21 days. If, after 21 days, signs and symptoms of VOD have not resolved, treatment is continued until resolution.21

A series of phase I and II trials of defibrotide were published to provide insight into potential activity of this agent in patients with VOD/SOS. Efficacy was measured in terms of complete response (CR), which was defined as reduction of total bilirubin to less than 2 mg/dL, resolution of MOF, and survival at day +100. Four phase I, I/II, and II trials evaluated a total of 296 patients with and without MOF.30-34 Dosing of defibrotide ranged from 5 to 60 mg/kg/day IV with CR as the primary measure of efficacy. The rate of CR ranged from 36% to 55% in the trials, and each trial reported an absence of significant defibrotide-associated serious toxicities. These experiences spurred further development of the drug.

A phase III trial of defibrotide for treatment of VOD/SOS with MOF enrolled 102 adults and children at 35 centers in the United States, Canada, and Israel.35 The investigators chose to forego a traditional phase III, randomized design due to ethical concerns regarding the high mortality risk of VOD/SOS with MOF coupled with emerging phase I/II evidence of improved clinical outcomes with defibrotide. The control group that was utilized as a comparator was selected by an outside medical review committee: the control group was screened from approximately 7000 historical controls with VOD/SOS and MOF. Eligibility for both groups required unequivocal diagnosis of VOD/SOS based on the Baltimore criteria or biopsy and MOF determined by specific clinical indications of renal and/or pulmonary dysfunction. For selection of cases for the control arm, the medical review committee evaluated the charts of 123 patients with possible hepatic VOD/SOS with MOF from the screened historical controls treated at study sites before defibrotide availability. The control arm ultimately consisted of 32 patients with unequivocal VOD/SOS-associated MOF. The primary study endpoint was rate of overall survival at day +100 post-HSCT. Defibrotide was dosed at 6.25 mg/kg IV every 6 hours for at least 21 days.

Pediatric patients comprised slightly less than half of the active treatment arm. The majority of patients received prophylaxis with either ursodiol, low-dose dopamine, or both. Results demonstrated a day +100 survival of 38.2% in defibrotide-treated patients and 25% in historical controls. At day +180 post-HSCT, the rate of overall survival was 32.4% in the defibrotide arm and 25% in the historical controls. CR, defined as total bilirubin less than 2 mg/dL and resolution of MOF, occurred in 25.5% of defibrotide-treated patients and 12.5% of historical controls. The most common adverse events were hypotension and diarrhea, and no significant difference in bleeding was found between the arms.

An expanded-access treatment Investigational New Drug protocol was conducted to determine the efficacy of defibrotide in patients with VOD/SOS, both with and without MOF.36 The primary outcome for analysis was overall survival at day +100 post-HSCT. The total population included 1154 patients enrolled at 101 institutions across the United States from 2007 to 2016, with 1137 patients meeting criteria for VOD/SOS. In all, 756 HSCT or non-transplant-associated chemotherapy patients were diagnosed with VOD/SOS by either Baltimore or modified Seattle criteria and received treatment with defibrotide 6.25 mg/kg IV every 6 hours prior to approval of the drug in 2016. The Kaplan-Meier estimated survival at day +100 was 61.1% for the total cohort of patients and 51.9% for patients who were determined to have VOD/SOS with MOF. Treatment-related adverse events in both cohorts included diarrhea and hypertension, and 20.6% of patients had a toxicity that was possibly related to defibrotide.

A nonpharmacologic approach to the treatment of VOD/SOS is the insertion of a transjugular intrahepatic portosystemic shunt (TIPS). This invasive procedure aims to decompress the portal circulation and relieve ascites in some patients with VOD/SOS. However, clear clinical benefit has not been realized and specific expertise is required to conduct the procedure, which may not be widely available at all centers.37

Treatment guidelines for the management of VOD/SOS have been published within the last decade. The British Committee for Standards in Haematology, in conjunction with the British Society for Blood and Marrow Transplantation, specified measures for prophylaxis and treatment of VOD/SOS.38 Both ursodiol and defibrotide (in pediatrics) were recommended as reasonable treatment strategies for prophylaxis. The only firm drug therapy treatment recommendation was for defibrotide, although the guidelines stated that methylprednisolone could be considered while weighing the risk of infection. The guidelines endorsed standard supportive care measures, such as proper fluid balance management.

The EBMT published an expert position statement on the diagnosis, grading, and treatment of VOD/SOS in children, adolescents, and young adults.17 Several recommendations about what defines platelet refractoriness, hepatomegaly, and ascites were clarified. Liver biopsy and ultrasound findings in the liver were not recommended for routine use in diagnosing VOD/SOS in this population. The use of ursodiol was endorsed as a routine measure for prophylaxis in this population. Defibrotide for prophylaxis was recommended for specific populations deemed to be at high risk for the development of VOD/SOS. Defibrotide was recommended for treatment of VOD/SOS for patients who met the diagnostic criteria for VOD/SOS.

THE ROLE OF THE PHARMACIST IN IMPROVING OUTCOMES IN VOD/SOS

A pharmacist on an HSCT medical team has an important and dynamic role to play. The accreditation agency for HSCT—a collaboration of the Foundation for the Accreditation of Cellular Therapy (FACT) and the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and the EBMT (JACIE) (commonly known as FACT-JACIE)—has listed pharmacists as key personnel within the HSCT team; as such, HSCT pharmacists are required to complete 10 hours of relevant continuing education annually. Recently, the American Society for Blood and Marrow Transplant (ASBMT), the Hematology/Oncology Pharmacy Association, the American College of Clinical Pharmacy, and the National Marrow Donor Program have endorsed a Clinical Pharmacist Role Description created by the Pharmacist Special Interest Group of ASBMT.39 The EBMT has adopted similar standards. This role description includes core competencies related to medication management, chemotherapy and medication counseling, symptom management, therapeutic drug monitoring, discharge and transitions of care planning, policy and guideline development, patient and family education, and evidence-based program development and evaluation.40 Specific pharmacist activities, including medication management, direct patient care activities, transition planning, education, and research activities, were detailed. These skills have direct implications for patients with suspected VOD/SOS.

The pharmacist collaborates with other HSCT team members to evaluate the overall clinical status of HSCT patients to assess for risk of VOD/SOS. By paying close attention to the fluid status of patients at risk for VOD/SOS by tracking ins and outs, daily patient weights, and trending laboratory abnormalities, as well as evaluating new sources of pain, the pharmacist contributes to identifying early worrisome signs and symptoms of emerging VOD/SOS.

The pharmacist also has a critical role in ruling out any drug-related causes of hyperbilirubinemia that could mimic VOD/SOS. Commonly used drugs in HSCT such as azole antifungal agents, immunosuppressant agents, and other medications that carry a risk of hepatotoxicity can obscure the diagnosis of VOD/SOS and a pharmacist will need to help clarify these findings. While some of these agents can be discontinued or substituted with other agents, allogeneic HSCT patients will still require immunosuppressant therapy regardless of a VOD/SOS diagnosis. Therapeutic drug monitoring can be used for agents such as cyclosporine, tacrolimus, methotrexate, and sirolimus to help guide their proper dosing. HSCT pharmacists are particularly well-suited to manage these therapies.

Immunosuppressive agents typically have myriad drug-drug interactions, mostly as a result of cytochrome P450 (CYP) 3A4-mediated metabolism, that will require ongoing analysis and monitoring.41 Given the large number of drugs routinely used in HSCT, such as antibacterial drugs, antifungal agents, and antihypertensives, the risk of drug-drug interactions looms large. The HSCT pharmacist maintains a primary role in mitigating the potential risks of toxicity when these agents are used concurrently. Further, these agents can be both hepatotoxic and nephrotoxic, thereby exacerbating the severity of VOD/SOS. Minimizing the impact of potentially hepatotoxic and nephrotoxic drugs is crucial in managing this group of patients to prevent progression to MOF. Pharmacist expertise in pharmacokinetics is also useful in providing guidance for patients receiving busulfan-containing conditioning regimens that require pharmacokinetic dose adjustment.

When defibrotide is selected as a treatment option for VOD/SOS patients, the pharmacist can assure adherence to the proper dosing and administration of the drug, as specified by the package labeling. Monitoring for known toxicities such as hypotension, diarrhea, and the potential for hemorrhage necessitate close follow-up. Avoidance of concurrent therapy known to increase the risk of bleeding, such as any anticoagulant therapy, any antiplatelet therapy, or commonly used agents such as non-steroidal anti-inflammatory agents and salicylates that impair platelet function, is required. 

Importantly, the pharmacist is charged with stewardship of drug therapy resources. For example, pharmacists can recommend that the HSCT team round the total defibrotide dose to the nearest 200-mg vial when the total dose is within 5% to 10% of a 200-mg dosing increment, with deference to institutional dose-rounding policies. The labeling of the drug states that up to 4 doses may be prepared at a time, with the 3 future doses being refrigerated after preparation. This practice, coupled with dose rounding, may provide an opportunity to conserve drug vials and prevent waste. An HSCT pharmacist provides additional value in helping to draft and review order set templates (paper or electronic medical records) that encompasses all aspects of a drug order for defibrotide. Issues such as dosing, the 2-hour administration time, using an in-line filter, and proper dilution of the drug for stability can be addressed with this approach.

Finally, for patients who recover from VOD/SOS, the pharmacist plays a key role in helping to guide medication selection during the inpatient recovery period and to assist transitions of care to the outpatient setting by reviewing discharge medications and educating patients and family members appropriately. The HSCT pharmacist is tasked with monitoring, evaluating, and reporting transplant-related outcomes with respect to medication usage to the HSCT program leadership. This offers an opportunity to provide a sober assessment of the evidence for use of all agents that have been used as prophylactic and treatment agents for VOD/SOS to promote evidence-based decision-making.

REFERENCES

  1. Copeland EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354(17):1813-26.
  2. Murphy WJ. Making a better hematopoietic stem cell – timing is everything. N Engl J Med. 2018;378(1):89-91.
  3. Blau HM, Daley GQ. Stem cells in the treatment of disease. N Engl J Med. 2019;380(18):1748-60.
  4. Sarantopoulos S. Allogeneic stem-cell transplantation – a T-cell balancing act. N Engl J Med. 2018;378(5):480-2.
  5. Pallera AM, Schwartzberg LS. Managing the toxicity of hematopoietic stem cell transplant. J Support Oncol. 2004;2(3):223-37.
  6. Fan CQ, Crawford JM. Sinusoidal obstruction syndrome (hepatic veno-occlusive disease). J Clin Exp Hepatol. 2014;4(4):332-46.
  7. Valla DC, Cazals-Hatem D. Sinusoidal obstruction syndrome. Clin Hepatol Gastroenterol. 2016;40(4):378-85.
  8. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85(11):3005-20.
  9. McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118(4):255-67.
  10. Barker CC, Butzner JD, Anderson RA, et al. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric haematopoietic stem cell transplant patients. Bone Marrow Transplant. 2003;32(1):79-87.
  11. Corbacioglu S, Jabbour EJ, Mohty M. Risk factors for development of and progression of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Biol Blood Marrow Transplant. 2019;25(7):1271-80.
  12. Lewis C, Kim HT, Roeker LE, et al. Incidence, predictors, and outcomes of veno-occlusive disease/sinusoidal obstructive syndrome after reduced-intensity allogeneic hematopoietic cell transplantation. Biol Bone Marrow Transplant. 2020;26(3):529-39.
  13. Ruutu T, van der Werf S, van Biezen A, et al. Use of busulfan in conditioning for allogeneic hematopoietic stem cell transplantation in adults: a survey by the Transplant Complications Working Party of the EBMT. Bone Marrow Transplant. 2019;54(12):2013-9.
  14. Bartelink IH, Lalmohamed A, van Reij EM, et al. Association of busulfan exposure with survival and toxicity after haematopoietic cell transplantation in children and young adults: a multicenter, retrospective cohort analysis. Lancet Haematol. 2016;3(11):e526-36.
  15. Palmer J, McCune JS, Perales MA, et al. Personalizing busulfan-based conditioning: considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant. 2016;22(11):1915-25.
  16. Yang XQ, Ye J, Li X, et al. Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: pathogenesis, clinical manifestations, diagnosis, treatment and outcomes. World J Gastroenterol. 2019;25(28):3753-63.
  17. Mahadeo KM, Bahwa R, Abdel-Azim H, et al; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation. Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syndrome: an international expert position statement. Lancet Haematol. 2020;7(1):e61-72.
  18. Tay J, Tinmouth A, Fergusson D, et al. Systematic review of controlled clinical trials on the use of ursodeoxycholic acid for the prevention of hepatic veno-occlusive disease in hematopoietic stem cell transplantation. Biol Bone Marrow Transplant. 2007;13(2):206-17.
  19. Essell JH, Schroeder MT, Harman GS, et al. Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998;128(12 Pt 1):975-81.
  20. Park SH, Lee MH, Lee H, et al. A randomized trial of heparin plus ursodiol vs heparin alone to prevent hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2002;29(2):137-43.
  21. Richardson PG, Grupp SA, Pagliuca A, et al. Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome with multiorgan failure. Int J Hematol Oncol. 2017;6(3):75-93.
  22. Richardson PG, Triplett BM, Ho VT, et al. Defibrotide sodium for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Exp Rev Clin Pharmacol. 2018;11(2):113-24.
  23. Defitelio (defribotide sodium) injection [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2016.
  24. Richardson PG, Carreras E, Iacobelli M, Nejadnik B. The use of defibrotide in blood and marrow transplantation. Blood Adv. 2018;2(12):1495-509.
  25. Aziz MT, Kakadiya PP, Kush SM, et al. Defibrotide: an oligonucleotide for sinusoidal obstruction syndrome. Ann Pharmacother. 2018;52(2):166-74.
  26. Pagliuca A. The importance of early intervention in the treatment of hepatic veno-occlusive disease. Int J Hematol Oncol. 2019;8(2):IJH15.
  27. Roeker LE, Kim HT, Glotzbecker B, et al. Early clinical predictors of hepatic veno-occlusive disease/sinusoidal obstruction syndrome after myeloablative stem cell transplantation. Biol Bone Marrow Transplant. 2019;25(1):137-44.
  28. Corbacioglu S, Cesaro C, Faraci M, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomized controlled trial. Lancet. 2012;379(9823):1301-9.
  29. Picod A, Bonnin A, Battipaglia G, et al. Defibrotide for sinusoidal obstruction syndrome/veno-occlusive disease prophylaxis in high-risk adult patients: a single-center experience study. Biol Blood Marrow Transplant. 2018;24(7):1471-5.
  30. Richardson PG, Elias AD, Krishman A, et al. Treatment of severe hepatic veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood. 1998;92(3):737-44.
  31. Richardson PG, Murakami C, Jin Z, et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood. 2002;100(13):4337-43.
  32. Chopra R, Eaton JD, Grassi A, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of a European compassionate use study. Br J Haematol. 2000;111(4):1122-9.
  33. Richardson PG, Soiffer RJ, Antin JH, et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multi-organ failure after stem cell transplantation: a multicenter, randomized dose-finding trial. Biol Bone Marrow Transplant. 2010;16(7):1005-17.
  34. Kernan NA, Richardson PG, Smith AR, et al. Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following non-transplant associated chemotherapy: final results from a post hoc analysis of data from an expanded-access program. Pediatr Blood Cancer. 2018;65(10):e27269.
  35. 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):1656-65.
  36. Kernan NA, Grupp S, Smith AR, et al. Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Br J Haematol. 2018;181(6):816-27.
  37. Richardson P, Aggarwal S, Topaloglu O, et al. Systemic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS). Bone Marrow Transplant. 2019;54(12):1951-62.
  38. Fignan FL, Wynn RF, Hadzic N, et al; Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol. 2013;163(4):444-57.
  39. Clemmons AB, Alexander M, DeGregory K, Kennedy L. The hematopoietic cell transplant pharmacist: roles, responsibilities, and recommendations from the ASBMT Pharmacy Special Interest Group. Biol Blood Marrow Transplant. 2018;24(5):914-22.
  40. Langebrake C, Admiraal R, van Maarseveen E, et al; EBMT Working Group. Consensus recommendations for the role and competencies of the EBMT clinical pharmacist and clinical pharmacologist involved in hematopoietic stem cell transplantation. Bone Marrow Transplant. 2020;55(1):62-9.
  41. Indiana University School of Medicine. Flockhart Drug Interaction Table. https://drug-interactions.medicine.iu.edu/MainTable.aspx. Accessed February 14, 2020.

Back to Top