Transcript Slide 1

NCCS Web Conference
3/23/11
Angela Smith, MD, MS
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Outline the etiology and management of stem
cell transplant (SCT) complications that may
early post transplant setting.
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Brief History and Overview of SCT
Potential Acute SCT Complications :
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Mucositis
Veno-occlusive Disease (VOD)
Pulmonary Hemorrhage
Graft-versus-Host Disease (GVHD)
Infection
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First successful related allogeneic bone marrow
transplant was performed at the University of
Minnesota in 1968.
Since then, we have performed thousands of
transplants and have pioneered many novel
therapies:
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Umbilical cord blood transplants
Transplant for metabolic disorders
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Delivery of high-dose chemotherapy +/radiation therapy to obliterate the bone
marrow and suppress the recipient’s immune
system.
Replacement of the abnormally functioning
bone marrow (or bone marrow derived) cells
with healthy hematopoietic cells.
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Overall Goals:
Eradicate any leukemic/cancer cells.
 Ablate the bone marrow and create space for donor
cells.
 Suppress the recipients immune system to prevent
rejection and GVHD.
 Augment the anti-tumor response. (graft-versusleukemia or graft-versus-tumor)
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Following transplant, the recipient immune
and blood-forming cell systems are
repopulated by normal donor-derived cells, all
of which are thought to derive from a common
primitive pluripotent stem cell.
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The stem cell is self-renewing and thus provides a
sustained source of its own cell population.
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The recipient becomes a “chimera” (a mythical
Greek beast that is part lion, part goat and part
snake) – an individual whose blood cells are of
foreign origin.
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Circulating RBC’s, platelets, leukocytes,
lymphocytes, monocyte/macrophage derived cells
(ex: osteoclasts, Kupffer cells, pulmonary alveolar
macrophages) and perhaps some glial cell
populations become donor in type.
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Neoplastic diseases – AML, ALL, CML, MDS,
lymphoma, neuroblastoma, other solid tumors.
Hematopoietic disorders – aplastic anemia,
Dyskeratosis Congenita, Fanconi anemia, PNH,
DBA, SDS, HLH, thalassemia, SCD.
Immunodeficiency states – SCID and related
disorders, Wiskott-Aldrich, CVID.
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Genetic diseases – In these cases, HCT provides
a normally functioning cell and/or a cellular
source for the deficient enzyme/protein.
Mucopolysaccharidoses/Mucolipidoses (Hurler
syndrome)
 Osteopetrosis
 Adrenoleukodystrophy
 Dystrophic Epidermolysis bullosa  collagen type
VII (major component of the basement membrane
anchoring fibrils; made and secreted by
keratinocytes and fibroblasts)
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Ultimate SCT outcome depends on many
variables:
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Underlying disease and it’s remission status
Health and age of the recipient
Conditioning intensity
Type of donor cells used
Development of GVHD
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Despite advances in therapy and supportive
care measures, transplant related complications
remain a major cause of morbidity and
mortality.
Acute phase – first 100 days post SCT.
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3 year male day +5 s/p matched sibling donor
(MSD) transplant for ALL.
Conditioning regimen: cytoxan, total body irradiation.
 GVHD prophylaxis: CSA, methotrexate.
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Mouth sores started on day +1 and have worsened.
Increasing oxygen requirement for last 24 hours.
Now with drooling, upper airway stridor,
retractions, pCO2=75, sats 88% on 100% O2 via
facemask.
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Inflammation and denudation of the mucous
membranes.
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Caused by chemotherapy, radiation and
neutropenia.
Severity depends on many factors:
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Occurs throughout the GI tract  mouth to anus.
Patient age, type of conditioning, GVH prophylaxis,
etc.
Allows a portal of entry for bacteria.
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Symptomatic Cares – bowel rest, pain control
with narcotics, platelet transfusion if bleeding.
Mouth Cares – helps prevent infection.
Airway management – may need intubation to
protect the airway until swelling/sloughing
resolve.
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Can be a difficult intubation as landmarks often hard
to identify.
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More commonly presents with airway
obstruction in small children.
More severe in patients receiving methotrexate
for GVHD prophy.
Increased risk of infections with oral flora 
need anaerobic antibiotic coverage if febrile.
Resolves with count recovery.
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2 year old male day +7 s/p UCBT for HLH
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Conditioning regimen: busulfan, cytoxan, ATG
GVHD Prophy: CSA, MMF
Progressive fluid retention – gained 2 kg.
Abdominal distention/pain with increasing
hepatomegaly and RUQ pain.
Creatinine has tripled in the last 2 days, UOP slowing
despite diuretics.
New O2 requirement.
Abdominal U/S – hepatomegaly, gallbladder sludge,
moderate ascites. Increased resistive indices in the
portal vessels, but flow is anterograde.
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AKA Sinusoidal Obstruction Syndrome (SOS)
Blockage of small intrahepatic veins by loose
connective tissue, fibrinogen and F VIII resulting on
post-sinusoidal obstruction and intrahepatic portal
hypertension.
Cause is unknown – likely sinusoidal endothelial
injury from chemo/radiation  local hypercoaguable
state  progressive occlusion of the hepatic venous
outflow  clinical manifestations.
Typically occurs within 3 weeks of SCT.
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Diagnosis  CLINICAL
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Abdominal U/S with doppler sometimes helpful.
Liver biopsy rarely indicated.
Severity
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Spectrum: mild  severe (progressive)
Mild = very common, easily treatable, mortality 3%.
Severe = life-threatening, difficult to treat, mortality
up to 98%!
 Death typically from renal and/or cardiopulmonary failure.
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Aggressive Fluid Management – diuretics +/colloid.
Ursodiol – to prevent cholestasis, more for
prophy.
ATIII – only if deficient.
NO systemic heparin – still used in some
centers, but carries a very real risk of lifethreatening bleeding.
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Defibrotide – **not currently FDA approved,
clinical trial is open**
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Large, single-stranded polydeoxyribonucleotide
Anti-thrombotic, anti-ischemic, anti-inflammatory
and thrombolytic effects without significant systemic
anticoagulant effects.
Complex mechanism of action.
Well-tolerated with few SE’s (1-9%)
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Flushing, nausea, abdominal discomfort.
Hypotension
Bleeding (rare)
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Identifying and treating VOD early is KEY!!
Life-threatening if severe.
Can cause progressive renal and respiratory
failure.
May require intubation secondary to
abdominal distention and/or pulmonary
edema.
May lead to renal failure requiring
hemodialysis.
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If using defibrotide to treat, remember that
there is a risk of bleeding and hypotension
with the drug.
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If either is significant and/or life-threatening,
defibrotide must be held.
Keep platelets >30K and INR <1.5
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16 year old male day +10 s/p matched
unrelated donor (MURD) BMT for
Dyskeratosis Congenita.
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Conditioning Regimen: campath, cytoxan,
fludarabine, TBI
GVHD Prophy: CSA, MMF
Progressive O2 requirement and respiratory
distress.
CXR with new bilateral patchy infiltrates.
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CXR -- Extensive
bilateral diffuse
pulmonary
consolidation with
sparing of the periphery
of the lungs.
BAL – Frank blood in
the airway that doesn’t
clear with lavage.
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Diagnosis: Respiratory distress/failure, CXR
findings, bloody BAL fluid.
Etiology: Multifactorial
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Thrombocytopenia/Coagulopathy
Endothelial injury
Vasculitis
?GVHD
Neutrophil influx into the lung
Infection
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Risk Factors:
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Intensive chemotherapy
Thoracic radiation and/or TBI
Pulmonary infection
Underlying disease – Hurler’s, dyskeratosis
congenita
Incidence 1-21%, Mortality >60%.
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Maintain Airway – usually requires intubation
and frequent suctioning.
Control Bleeding:
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Keep platelets ≥ 50-100K
activated Factor VII (90mcg/kg x 1-2 doses)
Methylprednisone (0.5-2g/day) – careful is infection
is suspected.
+/- DDAVP (0.3mcg/kg/day x 3 doses)
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Certain patients are more likely to have
hemorrhage:
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Hurler’s, Dyskeratosis Congenita, h/o fungal/viral
lung infection.
Treat EARLY and aggressively!
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10 year female day +33 s/p 1 antigen mismatched (i.e.
7/8) URD transplant for AML.
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Conditioning Regimen: cytoxan, TBI
GVHD Prophy: CSA, MMF
No major complications.
Engrafted on day +20, transitioning to oral CSA, but
some difficulty tolerating the pills.
New red, maculopapular rash covering 75% of her
body and involving the palms/soles. No
desquamation.
Also with 1 liter dark, watery stool output in the last 24
hours. No blood.
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Immune competent donor T cells attack
recipient epithelial tissues.
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Common targets: skin, gut, liver
3 stages
1) Injury to the host environment results in
release proinflammatory cytokines.
2) Donor T-cell activation, proliferation, and
differentiation.
3) Cellular and inflammatory attack on host
tissues.
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Incidence:
30 - 50% MSD recipients
 50 - 70% URD recipients
 30% single UCBT recipients
 60% double UCBT (increase grade II)
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Donor source
 HLA disparity
 Sex mismatch
 Parity
 Older age
 CMV status compared to
recipient
 Source – PBSC > BM,
double UCB > single UCB
 Cell dose, T cell depletion
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Recipient factors
 Older age
 CMV positive serostatus
 Previous SCT
 Use of TBI
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Most commonly involved organ.
Maculopapular rash, +/- pruritic/painful.
May have epidermal necrosis and/or bullae.
DDx: drug allergy, viral exanthem, SJS,
chemoradiotherapy effect.
Dx: Biopsy
Diffuse erythroderma
with desquamation
Blister Formation
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Patients with stage IV skin GVHD are best
treated like a burn patient.
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Pay meticulous attention to skin and wound care,
nutrition, and infection control.
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Lower GI disease: profuse, watery diarrhea;
crampy abdominal pain.
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Grade IV = intestinal bleeding, ileus.
Upper GI disease: anorexia, intractable
nausea/vomiting.
DDx: chemoradiotherapy effects, mucositis,
infection (c.diff, CMV, adeno)
Dx: Biopsy
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Potential Issues:
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Fluid Management
 Fluid and protein losses often hard to keep up with.
 Need accurate recording of stool output.
 Replace stool output.
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Bleeding
 Keep platelets 50-100K.
 Correct coagulopathy.
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Concomitant Infection  CMV common.
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Least common, hardly ever seen in the absence
of skin/gut involvement.
SSx: cholestatic jaundice.
DDx: hepatic VOD, infection, drug toxicity
(CSA, etc)
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Supportive cares as previously outlined
Immune Suppression  depends on grade of
aGVHD
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ALL patients receive prophylaxis.
 CSA  weekly levels, goal 200-400.
 MTX or MMF or steroids
Prophylaxis
MTX/MMF/MP + CSA
Mild GVHD
Moderate
Severe
CSA
CSA
CSA
Topical Steroids
Topical Steroids
Topical Steroids
Prednisone
High Dose MP
ATG
Steroid
Taper
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Skin > Gut >>> Liver
Commonly occurs between days 30-60 post
SCT.
Extreme susceptibility to INFECTION!!
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Infection is the major cause of death in patients with
GVHD.
Treated with increased immune suppression.
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16 year old male day +22 s/p UCBT for
relapsed AML.
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Conditioning regimen: cytoxan, fludarabine, TBI
GVHD prophy: CSA, MMF
Persistent fevers with acute onset of
hypotension, respiratory distress and
coagulopathy.
Not yet engrafted (WBC < 0.1).
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Presentation of infections in the post SCT
setting are unique.
Quick onset
 Severe and often prolonged course
 Serious infections often occur with “common,
benign” organisms.
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Line Infections – CONS, alpha-hemolytic strep.
Pneumonia
Sepsis/DIC – gram negative rods
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**Especially common in those receiving ATG or
Campath**
CMV – pneumonitis, colitis, retinitis
EBV – PTLD, mono-like illness
Adeno – diarrhea, pneumonitis, colitis, liver
failure
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HHV-6 – rash, marrow suppression, graft
failure, pneumonitis, encephalitis
HSV – stomatitis
VZV – zoster, pneumonitis
Influenza/RSV – pneumonia
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Candida spp
Aspergillus spp
Other – Rhizopus, Mucor, Histoplasma,
Blastomycoses.
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Frequent monitoring – culture with fevers,
follow viral DNA PCR’s.
Aggressive antibiotics/antivirals/antifungals.
Supportive care – mechanical ventilation,
pressors, fluids, IVIG.
If documented fungal infection prior to
engraftment, consider granulocyte infusions.
**Regardless of whether or not an infection
documented, if fever is present, antimicrobials
will be continued until engraftment and
resolution of fever**
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Antifungals (until day +100)
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Fluconazole – Routine risk patients
Voriconazole – High risk patients
 SAA, FA, AML/MDS
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Levaquin – Streptococcus
HEPA filtered air systems/laminar airflow
rooms, isolation rooms
Hand washing, oral hygiene
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Onset, severity and duration of infections in
immune compromised patients are unique.
Patients receiving ATG or Campath are at very
high risk for viral infections (early and late).
Heavily pre-treated patients (AML) and those who
had prolonged neutropenia prior to SCT (FA, SAA,
MDS) are at very high risk for fungal infections.
Prophylaxis, pre-emptive therapy and early
treatment are key!