Grand Rounds Presentation

h-SOS on a post STEM Cell

Transplant Patient
September 07, 2016
Jay T. Datukan, MD
Moderator
Lordan G. Carreon
2nd Year Internal Medicine Resident

OBJECTIVES
Present a case Hepatic Sinusoidal
Obstruction Syndrome (HSOS) on a post
STEM Cell Transplant patient
Discuss current issues in the diagnosis,
prevention and management of HSOS

GENERAL DATA
JM
32/M
Guam
Single
American
Prosecution Lawyer

CHIEF COMPLAINT
For stem cell transplant

HISTORY OF PRESENT ILLNESS

Dx case of pre B Acute Lymphoblastic Leukemia (anemia) s/p
BFM protocol 2015 s/p chemotherapy with HyperCVAD (4
cycles) 2016 currently in remission
HyperCVAD
Induction therapy for Philadelphia chromosome negative acute
lymphoblastic leukemia in adults
Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin and
Dexamethasone alternating with high-dose methotrexate and
cytarabine

Admitted SLMC GC last June 4, 2016 for a haplo identical

stem cell transplant from his father

REVIEW OF SYSTEMS
General: no weight loss/gain, no heat/cold intolerance
Eyes: no blurring of vision, color blindness, discharge,
lacrimation, redness
Ears: no deafness, tinnitus, otorrhea, otalgia
Nose: no nasal obstruction, stuffiness, rhinorrhea
Mouth/Throat: no oral sores, tooth ache, sore throat
Respiratory/Cardiovascular: no cough, colds, difficulty of
breathing, phlegm production, chest pain, palpitations
Gastrointestinal: no abdominal pain, BM changes, vomiting,
melena, hematochezia
Skin/Musculoskeletal: no muscle pains, joint pains
Nervous: no change in sleeping pattern, involuntary
movements, seizures, dizziness disturbance of smell, vision,
paresthesias, difficulty chewing, facial weakness, difficulties in
speech and swallowing, paralysis, muscle wasting

PAST MEDICAL HISTORY

Fistula in ano s/p fistulotomy (102115)
No rheumatologic disease, no thyroid
disease, no blood dyscrasia, no DM, no
HPN
No intake of supplements or other drugs

PERSONAL and SOCIAL HISTORY

Denies smoking, drinking alcoholic
beverage, and illicit drug use
Prosecution lawyer in Guam
No travel history for the past 6 months

FAMILY HISTORY
No thyroid disease, rheumatologic
condition, HPN, DM, blood dyscrasia

PHYSICAL EXAM
General: Conscious, coherent, not in distress, comfortable in bed
Vital signs: BP 122/71 mm Hg, HR 71 RR 18cpm T 37.5, O2 99% at
room air
74.6 kg 176 cm BMI 24.08
Skin: Warm moist skin, no ecchymosis/skin changes, no pallor, no
jaundice
HEENT: Pink palpebral conjunctiva, anicteric sclerae, tonsils not
enlarged, non hyperemic posterior pharyngeal wall, Neck veins are not
engorged, thyroid not enlarged, non tender, no bruits, no CLADS
Chest: Symmetrical chest expansion
Heart: Adynamic precordium, regular rhythm; no heaves, lifts or thrills;
apex beat at the 5th intercostal space, MCL; no murmurs, distinct S1 and
S2
Abdomen: Abdomen flat, normoactive bowel sounds, soft, no
direct and indirect tenderness, no mass, no hepatosplenomegaly, no
CVA tenderness
Extremities: Pulses full and equal, no ROM limitations, no pedal edema

SALIENT FEATURES

SUBJECTIVE
Dx case of preB ALL s/p
Hyper CVAD
No intake of supplements
or other drugs
No skin lesion
Non smoker, denies illicit
drug use
No rheumatologic disease,
no thyroid disease, no
blood dyscrasia, no DM, no
HPN

OBJECTIVE
32 yo Male
BP 122/71 HR 71 RR 18 T 36.8
74.6 kg 176 cm BMI 24.08
Abdomen soft non tender
No hepatosplenomegaly
No pedal edema

WORKING DIAGNOSIS
Pre B ALL in remission

Course in the Ward

Underwent conditioning regimen:
Fludarabine 30mg/mm IV D-6 to D-2
Cyclophosphamide 14.5mg/kg IV on D-6
and D-5
Total body irradiation on D-1

D-1 prophylactic acyclovir 362.5mg IV

BID was started.
On D0 received CD34+ stem cells from
his father. No untoward incident noted

Course in the Ward

D+3 and +4 received
cyclophosphamide 50mg/kg (3,625mg)
IV per day with mesna 1450mg IV
D+5 started on tacrolimus 1 mg/tab 2
tabs po BID; mycophenolate mofetil
500mg/tab 2 tabs po BID, gcsf 300mcg
SQ and prophylactic itraconazole 200mg
OD
PE E/N

Baseline Laboratories
CBC: 10.3/ 32.4/ 3.42/ 3640/ 68-20-1-9-2/
164000/95-30-32
Blood Chemistry: Crea 0.63 UA 6.1 BUN
9 K 4 Mg 1.6 TB 0.49 CB 0.10 UB 0.39
ALP 89 TP 6.3 Alb 3.6 Glob 2.7
CXR: Interval regression of RLL linear
densities
12LECG: NSR, NSSTTWC
WA CT Scan: Liver not enlarged;

What happened through to the

patient? What are the
complications?

Complications

Graft Rejection
Hospital Acquired Infections
Elevated Bilirubin
Hemorrhagic Cystitis

Graft Rejection
D0 received stem cells from his father.
No untoward incident noted.
Serial CBC monitoring started due to
decreasing counts (RBC, WBC, PC)
Given routine irradiated PRBS and platelet
transfusion
Started on GCSF

D+13 still pancytopenic

Graft Rejection
D+13 still pancytopenic
HLA antibody to class I and II NEGATIVE
GCSF increased from 300 to 600 mcg daily
Tacrolimus was increased to 3 tabs BID
still neutropenic and noted to be septic

D+18 tacrolimus and (mycophenolate

mofetil discontinued
developed pseudomonas infection

Graft Rejection
D+19 pegfilgrastim 6mg SQ every 5
days
D+41 remains pancytopenic and
requires PRBC and platelet transfusion
developed pseudomonas infection
Platelets do not seem to be responding
adequately

Assessment:
Pre B ALL s/p 5 cycle chemo
s/p BMA Failed Engraftment;
s/p Haploid HSCT (6/11)

Hospital Acquired infection

D0 - fever of 37.9C several hours after
infusion of the stem cells
Started empirically with Piptaz 4.5 g/IVq8hr
CXR showed no new infiltrates
Blood CS grew E cloacae given . Amikacin 1
gram every 24 hours x 3 days
Afebrile since then

D+15 new onset fever T 38.8

Hospital Acquired infection

D+15 new onset fever T 38.8
Piptaz shifted to Meropenem and given once dose of
Vancomycin
Repeat Blood CS showed Pseudomonas Aeruginosa

D+20 persistently febrile

Ciprofloxacin and Andilafungin was added
Repeat Blood CS showed Stenotrophomonas
maltophilia (central line) and Pseudomonas
Auruginosa (Peri line).

Hospital Acquired infection

D+23 IJ central line removed sent for
cultures - Trenotrophopmonas
maltophilia
Meropenem, Anidulafungin and Vancomycin
shifted to Ceftazidime 2grams IV q8hours,
Tigecycline 50 mg IV q12h and fluconazole
200mg OD
Fever eventually resolved

Hospital Acquired infection

D+38 developed a temperature of 40C
Blood CS NG
CXR showed bilateral lung hazy and streaky densities
Sputum CS - Staphylococcus hemolyticus (contaminant)
HRCT - Interval progression of bilateral lung opacities
Ceftazidime, Tigecycline was shifted to Meropenem 1gm IV Q8, Vancomycin 1gm
IV q12 and Voriconazole 200mg IV q12. Ciprofloxacin 400mg IV every 12 hours
was continued

D+38 IJ central line removed sent for cultures Trenotrophopmonas maltophilia

Meropenem, Anidulafungin and Vancomycin shifted to Ceftazidime 2grams IV
q8hours, Tigecycline 50 mg IV q12h and fluconazole 200mg OD

Hospital Acquired infection

On interim

intermittently febrile Tmax 39, his O2 sats range from 94-95%

on RA
Repeated Blood CS: +/- Pseudomonas Aeruginosa
Serial CXR showed progression of pneumonia

D+70
O2 sats noted to be ranging from 86% to 92%
Still febrile at 39-40C
Started on O2 via NC with increase in O2 demand warranting
use of BIPAP

Assessment:
1. Sepsis secondary to
a. Bacteremia (Pseudomonas
aeruginosa 8/20, 8/16, 8/14, 8/10, 8/2;
Enterococcus faecium 8/12;
Enterococcus faecium BNLAR 8/10;
Pseudomonas and Stenotrophomonas
maltophilia)
b. HAP
2. Impending Respiratory Failure sec to
HAP

Elevated Bilirubin
Noted progressive increase in weight D-1 74.6kg -> D+18 83kg
D+10 - abdominal pain progressive until referred to pain service D+18
D+58
Bilirubin 1st noted to be elevated (0.49 to 4.91)
WA UTZ showed hepatosplenomegaly, mild fatty liver changes
D+60
further increase in bilirubin (4.91 to 6.3)
Referred to GI service; A> Drug induced hepatitis
Reffered to hepatologist ; A> Hepatic sinusoidal obstruction syndrome
D+73
hepatosplenomegaly, with interval increase in size
26.5 cm (24.0)

CT Scan and UTZ WA of the patient

Radiology Department

Assessment:
Obstructive jaundice secondary to
Hepatic Sinuisoidal obstruction
syndrome sec to HSCT vs cholestasis
secondary to sepsis

Hepatic Sinusoidal Obstruction Syndrome (HSOS)

previously hepatic veno-occlusive disease (VOD)
hepatomegaly, right upper quadrant pain, jaundice, and
ascites
Those undergoing hematopoietic cell transplantation (HCT)
use of chemotherapeutic agents, ingestion of alkaloid toxins,
after high dose radiation therapy, or liver transplantation

resembles the Budd-Chiari (BC) syndrome clinically

HSOS - terminal hepatic venules and hepatic sinusoids
BC - hepatic veins and inferior vena cava

HSOS Pathogenesis
typically occurs in hematopoietic cell transplantation
begin with injury to the hepatic venous endothelium
preexisting liver disease increases the risk of developing
SOS
chronic hepatitis more susceptible to the cytoreductive regimen
abnormally express adhesion molecules and procoagulant factors

HSOS Pathogenesis
High power view of a reticulin stain of a
liver biopsy from a patient with sinusoidal
obstruction syndrome. There is prominent
perivenular fibrosis

Light micrograph of sinusoidal obstruction syndrome

in which venular occlusion has led to widespread
zonal liver disruption and centrilobular hemorrhagic
necrosis.
Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing
factors.McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas EDHepatology. 1984;4(1):11

HSOS Risk Factors

Preexisting liver disease (elevated serum aspartate
aminotransferase, AST)
Choice of conditioning therapy (higher
withcyclophosphamideand high doses of radiation,
lower with reduced intensity regimens)
Source of graft (allogeneic greater than autologous)
Patient age (higher rate in children <7 years)
Poor baseline performance status
Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study
of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic
Leukemia Working Party. Carreras E, Bertz H, Arcese W, Vernant JP, Toms JF, Hagglund H, Bandini G, Esperou H, Russell J, de
la Rubia J, Di Girolamo G, Demuynck H, Hartmann O, Clausen J, Ruutu T, Leblond V, Iriondo A, Bosi A, Ben-Bassat I, Koza V,

HSOS Clinical Features

develop signs and symptoms within the first three weeks,
later presentations have been reported
unexplained weight gain due to fluid and sodium retention, D3-6 post
transplant
abnormalities in liver biochemical tests
painful hepatomegaly with ascites
renal insufficiency (hepatorenal syndrome) and will require
hemodialysis
advance to multiorgan failure, hepatic encephalopathy,
and
death
Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.
McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RAAnn Intern Med.

HSOS Diagnostic Criteria

HSOS Differential Diagnosis

Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.
McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RAAnn Intern Med.

HSOS Differential Diagnosis

Budd-Chiari syndrome
to obstruction of hepatic veins and inferior vena cava
demonstrated on UTZ with Doppler, CT, MRI
Acute graft-versus-host disease
have concurrent involvement of the skin and gastrointestinal tract
most definitive method to distinguish GVHD from SOS
Drug toxicity
calcineurin inhibitors (cyclosporine,tacrolimus,sirolimus),methotrexate,
azole antifungal agents,trimethoprim-sulfamethoxazole,ribavirin,
andbusulfan
Hepatic infections
CMV, VZV, EBV, HHV6, adenovirus and chronic Candidiasis
Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.
McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, Hardin BJ, Shulman HM, Clift RAAnn Intern Med.

HSOS Prevention
Minimizing exposure to hepatotoxic agents
avoid medications, supplements, and other substances that are commonly
associated with liver injury

Iron chelation for patients with liver dysfunction due to iron overload
Consider the preparative regimen
Pt. cirrhosis who receive myeloablative conditioning
Reduced intensity conditioning protocols like in those using busulfan

Consider choice of graft-versus-host disease prophylaxis

combination oftacrolimus,sirolimus, andmethotrexate vs
tacrolimus and methotrexate
BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following
haematopoietic stem cell transplantation. Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A, Veys P, Potter MN. Br J

HSOS Prophylaxis
variability in the use of pharmacologic prophylaxis for SOS among
transplant centers
Allogeneic HCT
- UDCA (12 mg/kg daily, divided in two doses) is started from the
day preceding the preparative regimen and continued for
the first
three months of transplantation
Autologous HCT
- Heparin (100 units/kg per day by continuous intravenous infusion)
is started on the first day of the preparative regimen and
continued until hematopoietic engraftment
BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following
haematopoietic stem cell transplantation. Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A, Veys P, Potter MN. Br J

HSOS Treatment
Supportive care is a key factor in the management of all
patients with SOS.
Daily weights and measures of fluid intake and output are critical to
maintaining euvolemia
Minimizing exposure to hepatotoxic agents
Pain Control
Paracentesis - for ascites that is associated with discomfort or
pulmonary compromise

HSOS Treatment
Supportive care is a key factor in the management of all
patients with SOS.
Daily weights and measures of fluid intake and output are critical to
maintaining euvolemia
Minimizing exposure to hepatotoxic agents
Pain Control
Paracentesis - for ascites that is associated with discomfort or
pulmonary compromise

HSOS Treatment
Defibrotide
treatment of adults and children with SOS with renal or
pulmonary dysfunction following hematopoietic cell
transplantation
20 to 30 percent of patients are expected to be alive beyond day
+100
6.25mg/kgis administered intravenously every six hours and
continued for a minimum of 21 days may be extended for a
maximum of 60 days
most common toxicities are hypotension, diarrhea, nausea,
vomiting, and epistaxis
no phase III randomized trials evaluating the use ofdefibrotidefor
the treatment of patients with SOS

HSOS Treatment
Liver transplantation
successfully performed in small numbers of patients with SOS
majority of patients not capable of undergoing such a rigorous surgical
procedure
patients at risk for recurrent malignancy are low-priority candidates for liver
transplant

BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following
haematopoietic stem cell transplantation. Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A, Veys P, Potter MN. Br J

Update on the patient

D+87 post HSCT

Currently intubated on AC mode
Worsening bilirubin level now at 40s
Pancytopenic, still requiring blood transfusion
Currently afebrile on multiple antbiotics, on one
pressor
Bad prognosis

Summary
HSOS is a formidable challenge both for patients
undergoing HSCT and for their physicians.
HSOS contributes considerably to transplantationrelated morbidity and mortality.
A high clinical index of suspicion is needed to
correctly and consistently identify patients with
HSOS
Prophylactic interventions are very critical
Therapeutic agents such as defibrotide still under
trial

Thank you for listening!