Optimizing Nursing Management of Hepatic Veno-Occlusive Disease

Optimizing Nursing Management of

Hepatic Veno-Occlusive Disease

Phyllis McKiernan, APN, MSN, OCN®

Advanced Practice Nurse

John Theurer Cancer Center

Michelle N. Rickard, DNP, CPNP-AC, CHPPN, BMTCN, CPON

Assistant Professor, College of Nursing

University of Tennessee Health Science Center

Jointly provided by USF Health and i3 Health

ACCREDITATION

USF Health is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s

Commission on Accreditation.

A maximum of 1.0 contact hour may be earned by learners who successfully complete this continuing nursing education activity.

No prerequisites are required for this activity.

INSTRUCTIONS TO RECEIVE CREDIT

In order to receive credit for this activity, participants must:

1. Participate in the live webinar

2. Complete and submit the posttest and activity evaluation via the link provided after the webinar

3. Download or print their Certificate of Credit

UNAPPROVED USE DISCLOSURE

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the

FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the

planners. Please refer to the official prescribing information for each product for discussion of approved indications,

contraindications, and warnings.

DISCLAIMER

The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the

independent medical/clinical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s

medical condition.

COMMERCIAL SUPPORT

This activity is supported by an independent educational grant from Jazz Pharmaceuticals Inc.

Disclosures

▶ Phyllis McKiernan has no commercial relationships

to disclose

▶ Michelle N. Rickard has no commercial

relationships to disclose

Learning Objectives

▶ Describe the pathophysiology of VOD

▶ Assess the risk for VOD in cancer patients

undergoing HSCT

▶ Evaluate evidence-based supportive care plans to

mitigate VOD in pediatric and adult patients with

cancer

VOD = veno-occlusive disease; HSCT = hematopoietic stem cell transplant.

VOD: Scope of the Problem

▶ Also known as sinusoidal obstruction syndrome

▶ Affects up to 60% of patients following HSCT

▶ Mortality rates: ◼ Severe VOD >80%◼ Moderate VOD >20%

▶ Associated with multiorgan failure

Dalle et al, 2016; Richardson et al, 2013.

Pathophysiology

▶ Endothelial cell activation due to

effects of conditioning regimen

▶ Gaps form between sinusoidal cells◼ Cellular debris, red blood cells, and

leukocytes accumulate in space of Disse

◼ Cells dissect from the endothelial lining

▶ Narrowing of sinusoidal lumen and

reduction in venous outflow

▶ Coagulation factor changes◼ Activation of fibrinolytic pathway

◼ Fibrosis and necrosis leads to further

blockage of the sinusoids

▶ Reduced hepatic outflow

Dalle et al, 2016; Mohty et al, 2015; Richardson et al, 2013.

Endothelial cell and

hepatocyte damage

Triggering of

multiple pathways

InflammationCytoskeletal

structure

Sinusoidal narrowing

VOD

Pathophysiology (cont.)

Mohty et al, 2015.

Risk Factors

PS = performance status.

Cheuk, 2012; Corbacioglu et al, 2017; Harper et al, 2017; Mohty et al, 2015.

Patient- and Disease-Related

Age Infant, small child, or elderly > older child/adult

Health status Comorbidities and poor performance status

Karnofsky PS <90%

Disease status Advanced > remissions

Previous treatmentAbdominal irradiation

Gemtuzumab

History of liver

disease

Hepatitis B or C

Cirrhosis

Hepatic fibrosis

Iron overload

Others Norethisterone; metabolic syndrome

Risk Factors (cont.)

HLA = human leukocyte antigen; IV = intravenous; GVHD = graft-versus-host-disease.

Cheuk, 2012; Corbacioglu et al, 2017; Dalle & Giralt, 2016; Harper et al, 2017; Mohty et al, 2015.

Transplant-Related

Type of HSCTAllogeneic > autologous

More than 1 HSCT

Grade of compatibility Unrelated or HLA-mismatched donors

Conditioning regimen

Myeloablative conditioning

Busulfan (oral vs IV)

Fludarabine

Melphalan

Total body irradiation

Disease status Active disease

Others

Non–T-cell depleted graft

Use of sirolimus

Acute GVHD

Cytokine activation

Risk Factors (cont.)

Cheuk, 2012; Corbacioglu et al, 2017; Harper et al, 2017; Mohty et al, 2015.

Genetic

Macrophage-activating

syndromes

Hemophagocytic lymphohistiocytosis

Griscelli syndrome

Gene polymorphism

GSTM1

GSMTT1

Heparanase

OthersThalassemia

Osteopetrosis

▶ NOT Risk Factors◼ Race

◼ Sex

Pop Quiz Question 1

When do VOD symptoms typically occur following

HSCT?

a. Within 10 days

b. Within 30 days

c. Within 50 days

d. Within 70 days

Timing of VOD Onset in

HSCT Patients

PB = peripheral blood.

Dalle & Giralt, 2016.

Diagnostic Criteria:

Clinical Signs and Symptoms

Corbacioglu et al, 2017; Dignan et al, 2013.

Modified Seattle Criteria

By Day +20

post-HSCT at

least 2 of the

following:

Bilirubin >2 mg/dL

Right upper quadrant

pain or hepatomegaly

Weight gain of >2% from

baseline at conditioning

Baltimore Criteria

By Day +21

post-HSCT

bilirubin

>2 mg/dL + at

least 2 of the

following:

Ascites

Weight gain of >5% from

baseline at conditioning

Painful hepatomegaly

Diagnostic Criteria: Imaging/Histology

▶ Can be used in conjunction with clinical symptoms

▶ Ultrasound with Doppler measurements◼ Reversal portal vein flow

◼ Abnormal portal vein wave form

▶ CT or ultrasound◼ Hepatomegaly

◼ Gall bladder thickening

◼ Ascites

▶ Transjugular liver biopsy◼ Elevated transhepatic wedge pressure

◼ Elevated hepatic venous gradient pressure

◼ Histologic evidence of VOD

CT = computed tomography.

Dalle & Giralt, 2016; Mohty et al, 2016.

Diagnostic Criteria for Severe VOD

Carreras, 2015; Dalle & Giralt, 2016.

Renal dysfunction

Pulmonary infiltrates/

pneumonitis

Pleural effusion

Thrombocytopenia refractory to platelet

transfusion

Encephalopathy

Multiorgan failure

Syndromes not attributed to other

causes

Pop Quiz Question 2

Which of the following would you NOT recommend for

a patient experiencing multiorgan failure following

HSCT for VOD prophylaxis?

a. Unfractionated heparin

b. Low-molecular-weight heparin

c. tPA

d. Ursodeoxycholic acid

VOD Prophylaxis

tPA = tissue plasminogen activator.

Cheuk, 2012; Corbacioglu et al, 2016; Dalle & Giralt, 2016; Dignan et al, 2013; Mohty et al, 2015.

Agent Comments

Unfractionated heparin/

low-molecular-weight heparinHemorrhagic risk

tPAContraindicated in patients with

multiorgan failure

Ursodeoxycholic acid

Less liver toxicity and GVHD and

improved survival but no overall

reduction in VOD incidence

Defibrotide

Lower incidence of VOD, VOD with

renal failure, and GVHD in

randomized study

VOD Prophylaxis (cont.)

▶ Close monitoring of busulfan levels

▶ Avoid hepatotoxic concomitant drugs

▶ Reduced-intensity conditioning when appropriate

▶ Hyperfractionated TBI recommended

▶ Use of donors with the highest degree of

compatibility or use of T-cell depleted grafts

▶ Close monitoring of weight (≥once daily)◼ Maintenance of baseline weight should be goal

TBI = total body irradiation.

Cheuk, 2012; Corbacioglu et al, 2016; Dalle & Giralt, 2016; Dignan et al, 2013; Mohty et al, 2015.

Phase III Trial of Defibrotide for Severe

VOD and Multiorgan Failure

aDefined as renal and/or pulmonary dysfunction by Day +28 post-HSCT.

Richardson et al, 2016.

Adult and pediatric patients

with established VOD and

advanced multiorgan failure

(n=102)

Historical controls with

unequivocal diagnosis of

VOD and multiorgan failure

(n=32)

Primary end point:

Survival at

Day +100 post-HSCT

Secondary end points:

CR rate by

Day +100 post-HSCT

Survival at

Day +180 post-HSCT

Treatment with

defibrotide

25 mg/kg/d

Phase III Trial of Defibrotide for Severe

VOD and Multiorgan Failure (cont.)

Richardson et al, 2016.

End PointDefibrotide

(n =102)

Historical Control

(n=32)P Value

Survival by Day +100 (n) 39 8 –

Observed survival by Day +100 (%) 38.2 25 0.0109

95.1% CI 28.8-47.7 9.9-40.1 –

CR by Day +100 (n) 26 4 –

CR by Day +100 (%) 25.5 12.5 0.0160

95.1% CI 17-34 1-24 –

Survival by Day +180 (n) 33 8 –

Observed survival by Day +180 (%) 32.4 25 0.0669

95.1% CI 23.5-41.5 9.9-40.1 –

Defibrotide Treatment

Defitelio® prescribing information, 2016.

Dosing6.25 mg/kg baseline body weight every 6

hours to infuse over 2 hours

Administration 0.2 micron in-line filter

Duration

Recommended: 21 days minimum

May continue up to 60 days if VOD has not

resolved

Defibrotide Contraindications,

Warnings, and Precautions

▶ Concomitant use of defibrotide with

antithrombotic or fibrinolytic drugs is

contraindicated due to increased risk of

hemorrhage

▶ Delay the administration of defibrotide

until effects of previously administered

anticoagulant have abated


Defibrotide Contraindications,

Warnings, and Precautions (cont.)


Hypersensitivity Reactions

◼ Discontinue permanently if

patient has severe or life-

threatening reaction

(anaphylaxis)

◼ If patient has known

hypersensitivity to defibrotide or

any of its excipients do not

prescribe defibrotide

Hemorrhage

◼ Withhold defibrotide if persistent,

severe, or potentially life-

threatening bleeding occurs

◼ Treat cause of bleeding

◼ Administer supportive care

◼ Consider resuming treatment

after bleeding has stopped and

patient is hemodynamically

stable

◼ Discontinue if patient has

recurrent significant bleeding

Defibrotide Adverse Events


Adverse Event, n (%) Any Grade Grade 4/5

Hypotension 65 (37%) 12 (7%)

Diarrhea 43 (24%) 0

Vomiting 31 (18%) 0

Nausea 28 (16%) 0

Epistaxis 24 (14%) 0

Pulmonary alveolar hemorrhage 15 (9%) 12 (7%)

Gastrointestinal hemorrhage 15 (9%) 5 (3%)

Sepsis 12 (7%) 9 (5%)

Graft-versus-host disease 11 (6%) 7 (4%)

Lung infiltration 10 (6%) 5 (3%)

Pneumonia 9 (5%) 5 (3%)

Pulmonary hemorrhage 7 (4%) 4 (2%)

Infection 6 (3%) 4 (2%)

Hemorrhage intracranial 5 (3%) 4 (2%)

Hyperuricemia 4 (2%) 4 (2%)

Cerebral hemorrhage 3 (2%) 3 (2%)

Defibrotide Nursing Considerations

▶ Flush line immediately before and after

administration with 5% dextrose injection

or 0.9% sodium chloride

▶ Do not infuse with other IV drugs

concurrently within same IV line


Case Study 1: Adult Patient

▶ 73-year-old male

▶ Primary myelofibrosis◼ Diagnosed fall 2016

◼ JAK2V617F mutation-positive

◼ Splenomegaly

◼ Anemia

▶ Medical history◼ Coronary artery disease

◼ Arthritis

◼ Hypertension

◼ Hyperlipidemia

▶ Received ruxolitinib and demonstrated clinical

improvement

Case Study 1: Adult Patient (cont.)

▶ Unrelated donor identified◼ 10/10 HLA match

◼ Female

◼ ABO: Donor O+, recipient B+

◼ Bone marrow

▶ Renal insufficiency◼ Elevated potassium and uric acid 1 week prior to transplant

◼ Responded to IV fluids and rasburicase


◼ Fludarabine 30 mg/m2

Day -6 thru -2

◼ Busulfan 130 mg/m2 Day

-3 and -2

◼ rATG 4 mg/kg Day -3 thru

-1

◼ Received 1.67 x 10e6/kg

CD34-positive cells

◼ Serum creatinine

1.0 mg/dL

◼ Bilirubin 0.8 mg/dL

◼ Weight 74 kg

◼ Tacrolimus

◼ Mycophenolate mofetil

◼ Sirolimus

Nonmyeloablative

Conditioning

GVHD

ProphylaxisDay 0


◼ Weight 85 kg


◼ Pulmonary edema

◼ Weight 91 kg

◼ Anasarca


◼ Dyspnea

◼ Diagnosed VOD

◼ Furosemide drip

◼ Defibrotide initiated: 6.25

mg/kg every 6 hr

Day +6 Day +10


◼ Improved bilirubin

◼ Dialysis for fluid overload

◼ Improvement in weight

◼ Dyspnea resolved Continued Defibrotide

for 21-Day Course

◼ Weight 71 kg

◼ Pancytopenic – possible

graft failure unrelated to

VOD

◼ Afebrile

◼ No dialysis


Started 14-Day

Course of Defibrotide Day +39

Case Study 2: Pediatric Patient

▶ 12-year-old female

▶ Acute lymphocytic leukemia◼ Initially diagnosed at 8 years of age

◼ Relapsed at 11 years of age

▶ Medical history◼ Avascular necrosis of bilateral hip

– Anticipating hip replacements after recovery from HSCT

◼ Abnormal liver enzymes– History of moderate elevation in liver enzymes. Resolve prior to

transplant

Case Study 2: Pediatric Patient (cont.)

▶ Haploidentical donor (mother)◼ 8/10 HLA Match

◼ T-cell depleted

◼ ABO: Donor B+, recipient B+

◼ Peripheral stem cells

◼ Donor received G-CSF for mobilization

G-CSF = granulocyte-colony stimulating factor.


rATG = rabbit antithymocyte globulin; PTLPD = posttransplant lymphoproliferative disease.

◼ Heparin drip (VOD

prophylaxis on admission)

◼ rATG

◼ Busulfan

◼ Cyclophosphamide

(MESNA)

◼ Fludarabine

◼ Thiotepa

◼ Melphalan

◼ Mycophenolate mofetil

Conditioning GVHD Prophylaxis

Pop Quiz Question 3

Which of the following is associated with a lower risk

for VOD in this patient?

a. Busulfan IV

b. T-cell depletion

c. Normal liver enzymes

d. All of the above


PO = taken orally.

◼ Weight 48.4 kg

◼ Bili 0.8 mg/dL

◼ Weight 50.1 kg

◼ Bili 1.0 mg/dL

◼ Furosemide 40 mg/d PO

added

◼ Weight 49.8 kg

◼ Bili 1.4 mg/dL

◼ Furosemide 40 mg/d PO

Day 0 Day +6Day +4

Dry weight (prior to transplant admit) 49.6 kg


◼ Weight 52.8 kg

◼ Bili 1.8 mg/dL

◼ Right flank pain (6/10)

◼ Furosemide drip started

◼ Weight 54 kg

◼ Bili 2.2 mg/dL

◼ Continued right flank pain

(8/10)

◼ Ultrasound image of liver

shows reversal of portal

venous flow

◼ Heparin stopped

◼ Defibrotide initiated 12

hours after heparin

withheld

Day +12 Day +13


PO = taken orally.

◼ Furosemide drip stopped

◼ Transitioned to

furosemide 20 mg PO

BID with PRN for

increased weights

◼ Elevated creatinine 3.2

mg/dL

◼ Improvement in weight

◼ Weaned from oxygen

◼ Weight 48.7 kg

◼ Bili 0.6 mg/dL

◼ No longer requires

furosemideStarted 14-Day

Course of Defibrotide

Day +32Day +23

Future Considerations

▶ Prevention◼ Increase use of reduced-intensity conditioning regimens

◼ Decrease toxicity of myeloablative conditioning regimens– Order of medications

– Hyperfractionated TBI

◼ HLA compatible donors

◼ Ursodeoxycholic acid

◼ Chelation for iron overload prior to HSCT

◼ Prophylaxis with defibrotide for high-risk patients

Carreras, 2015; Mohty et al, 2016.

Future Considerations (cont.)

▶ Early diagnosis and intervention◼ Update criteria for diagnosis

◼ Separate criteria for adult vs pediatric patients

◼ Classic vs late-onset VOD

▶ Identification of patients at risk for severe VOD◼ Kinetics of symptoms – when symptoms first appear to

diagnosis

◼ High number of risk factors

◼ Multiorgan involvement/failure

◼ Doubling of bilirubin from baseline within 48 hours

▶ Improved imaging


Future Considerations (cont.)

▶ Combination therapy with defibrotide◼ Low-molecular-weight heparin

◼ N-acetylcysteine

◼ Antithrombin III

◼ Novel antithrombotics

▶ Genetic polymorphisms to individualize conditioning

regimens

▶ Identification of biomarkers◼ Endothelial injury


Key Takeaways

▶ VOD affects many patients undergoing HSCT

▶ Can progress to multiorgan failure and death in

patients posttransplant

▶ Early diagnosis and prompt treatment is key to

preventing multiorgan failure and improving patient

outcomes

▶ Transplant centers should develop diagnostic

criteria and clinical pathways for VOD treatment

based on current evidence to guide management

Audience Q&AsUse the Questions section of your Control Panel

to submit questions to the faculty.

To receive CE credit visit:

www.i3health.com/VOD

References

Carreras E (2015). How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol, 168(4):481-491.

DOI:10.1111/bjh.13215

Chalandon Y, Roosnek E, Mermillod B, et al (2004). Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell

transplantation. Biol Blood Marrow Transplant, 10(5):347-354.

Cheuk DL (2012). Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: prophylaxis and treatment controversies. World

J Transplant, 2(2):27-34. DOI:10.5500/wjt.v2.i2.27

Corbacioglu S, Carreras E, Ansari M, et al (2017). Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in

pediatric patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplantation.

[Epub ahead of print] DOI:10.1038/bmt.2017.161

Corbacioglu S, Carreras E, Mohty M, et al (2016). Defibrotide for the treatment of hepatic veno-occlusive disease: final results from the

International Compassionate-Use Program. Biol Blood Marrow Transplant, 22(10):1874-1882. DOI:10.1016/j.bbmt.2016.07.001

Coppell JA, Richardson PG, Soiffer R, et al (2010). Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical

course, and outcome. Biol Blood Marrow Transplant, 16(2):157-168. DOI:10.1016/j.bbmt2009.08.024

Dalle JH & Giralt SA (2016). Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Risk factors and stratification,

prophylaxis, and treatment. Biol Blood Marrow Transplant, 22(3):400-409. DOI:10.1016/j.bbmt.2015.09.024

Defitelio® (defibrotide) prescribing information, 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208114lbl.pdf

Dignan F, Gujral D, Ethell M, et al (2007). Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality

from veno-occlusive disease. Bone Marrow Transplant, 40(1):79-82.

Dignan FL, Wynn RF, Hdzic N, et al (2013). BCSH/BSBMT guidelines: diagnosis and management of veno-occlusive disease (sinusoidal

obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol, 163(4):444-457. DOI:10.111/bjh.12558

Harper JL & Corbacioglu S (2016). Veno-occlusive hepatic disease. Available at: http://emedicine.medscape.com/article/989167-overview

Mohty M, Malard F, Abecassis M, et al (2016). Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive

disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow

Transplant, 51(7):906-912. DOI:10.1038/bmt.2016.130

References

Mohty M, Malard F, Abecassis M, et al (2015). Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives – a

position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant, 50(6):781-789.

DOI:10.1038/bmt2015.52

Myers KC, Dandoy C, El-Bietar J, et al (2015). Veno-occlusive disease of the liver in the absence of elevation in bilirubin in pediatric patients

after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant, 21(2):379-381. DOI:10.1016/jbbmt.2014.09.026

Richardson PG, Ho VT, Cutler C, et al (2013). Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: Novel insights to

pathogenesis, current status of treatment, and future directions. Biol Blood Marrow Transplant, 19(1):S88-S90.

DOI:10/1016/j.bbmt.2012.10.023

Richardson PG, Riches ML, Kernan NA, et al (2016). Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-

organ failure. Blood, 127(13):1656-1665. DOI:10.1182/blood-2015-10-676924

Optimizing Nursing Management of Hepatic Veno-Occlusive Disease

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