Transcript Early complications of haematopoietic stem cell transplantation Gan Gin Gin University Malaya Medical Centre.

Early complications
of haematopoietic stem cell
transplantation
Gan Gin Gin
University Malaya Medical Centre
outline
1)Toxicities of conditioning regimen
• Cardiac
• Ora-pharyngeal mucositis
• Hemorrhagic cystitis
• CNS
2) Others CNS complications
3) Thrombosis including Hepatic veno-occlusive
disease
4) Respiratory problems
5) Engraftment failure
Factors associated with early
complications
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Comorbidities
underlying disease
Age
Pre-transplant chemotherapy
type & conditioning regimens of transplant
Regimen related toxicity
cardiac
• Cardiac events 5-10%
• Cardiac failure, cardiac
tamponade, arrythmias
• Stem cell infusion–
bradycardia ?DMSO or
cell debris during thawing
• Cyclophosphamide–
dose dependent & acute
(17-28%)
• ECG
changes,myocardits/
pericarditis, cardiac
failure
Tichelli et al 2008 BJH
Tichelli et al 2008 BJH
BJH2008
Mucositis
• Due to conditioning regimen
and GVHD prophylaxis e.g.
MTX
• Risk– TBI, BMI>25,genetic
polymorphism
• Peak at 6-12 days after HSCT
• Prevention—oral
hygiene;rinses ;cryotherapy
• Palifermin(keratinocyte growth
factor)—increased thickness of
mucosal epithelium,stimulates
IL13 and ↓TNF
JNCCN vol 6 suppl 1
Haemorrhagic cystitis
• Early ( within 72 hours) and later (after 1
month)
• Early- due to chemotherapy drugs causing
mucosal damage
• Late– due to viral infections ( JC,BK and
adenovirus)
• Clinical– hematuria, dysuria
• Management– hyperhydration, mesna,
platelet support, bladder irrigation
CNS complication
• Incidence – 37%-91%
• Diagnosis maybe difficult due to difficulty
in obtaining biopsy (low platelets)
• Causes:
a) Regimen related toxicity
b) Infections
c) Cerebravascular events
d) Metabolic
Regimen related toxicity
Drug Toxicity
• Busulphan—seizures,
reversible
encephalopathy
• Ifosfamide- seizures,
hallucinations
• Intrathecal Methotrexate–
myeloradiculopathy
• Ara-C – polyneuropathy,
cerebellar syndrome
Procedures
• Lumbar Puncture–
intracranial hypotension
• BM harvest-- intracranial
hypotension
• Infusion of stem cells—
cerebral infarction,
transient global amnesia
(rare)
• Internal jugular vein
cannulation– Horners
syndrome, brachial
plexus injuries,CVA
infections
• Usually during the pancytopenia phase
• Non specific—altered mental status, headache,
fever, meningism, seizures
• Focal neurological signs
• Bacterial Infections– staphylococci, gram
negative
• Viral—adenovirus, coxsakie(usually from
donors); herpes, CMV
• Fungal – candida, aspergillus
• Investigations – LP, CT scan or MRI
Cerebral vascular events
• Subdural hemorrhage
• Intraparenchymal
hemorrhage
• Subarachnoid
hemorrhage
• Cerebral infarct from
septic emboli
Metabolic
• Corticosteroids—myopathy,mood
changes,insomnia,anxiety etc
• Cyclosporin/tacrolimus—tremor (40%),
subjective parathesis (11%),seizure (a/w ↓Mg),
reversible posterior leukoencephalopathy
syndrome (RPLS)
• Antibiotics (cefepime, imipenam) –
seizures,nonconvulsive seizures
• Antifungal (amphoB)- parkinsonism, tremor
RPLS
• Headache, confusion, visual
disturbances, seizures, motor
deficits
• MRI– white matter oedema
usually at parietal-occipital
regions
• Due to failure of cerebral
vascular regulation leading to
vasogenic oedema
• Can occur at normal drug level
• Usually resolve a few weeks
after discontinuation
Thrombosis
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Catheter related
Venous thromboembolism
Arterial thrombosis
Hepatic veno-occlusive disease
Transplantation associated micrangiopathy
Catheter thrombosis
• Occurs in 4-8%
• Allogeneic higher risk than autologous
• Risk of thrombus extension & pulmonary
embolism possible
• Treatment as per other VTE
Hepatic Veno-occlusive
disease/sinosoidal syndrome (VOD)
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10% in allogeneic
Risk factors
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Age
preexisting liver damage
myeloablative conditioning regimen (busulphan)
gender (female)
HLA mismatch
previous chemotherapy
Prior abdominal radiation
GVHD prophylaxis (MTX)
Previous gemtuzumab (mylotarg)
Reduced lung capacity (DLCO)
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Prognosis– mortality in 20-50%
Hepatic failure, renal failure, pulmonary failure (multiorgan failure)
Pathogenesis of VOD
• Toxic injury to sinusoidal endothelial cells and
hepatocytes due to chemotherapy
• Cell oedema leading to micro-occlusion, platelet
activation leads to release of transforming
growth factor beta (TGF-β) activating
endothelial cells releasing plasminogen
activation inhibitor 1(PAI-1) (an inhibitor of
endogenous fibrinolysis)
• Sinusoidal obstruction leading to more
hepatocytes damage and leading to multi-organ
failure
Diagnosis
Modified Seattle criteria
• High bilirubin (>2mg/dl)
and
• Hepatomegaly or right upper
quadrant pain of liver origin
• Sudden weight gain (>2%)
• ascites
At least 2 factors within 30 days of
transplantation
Baltimore criteria
• High bilirubin (>2mg/dl)
• Hepatomegaly
• right upper quadrant pain of
liver origin
• Sudden weight gain (>5%)
high bilirubin and at least 2 factors
within 100 days of transplantation
Biopsy- may not be feasible
Dupplex ultrasound of hepatic vein –needs experience
MRI liver-complementary to ultrasound
PAI-1 assay as a surrogate markers
Differential diagnosis– aGVHD of liver, sepsis
Management
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Prophylaxis
Ursodeoxycholic
Low dose LMW heparin
Defibrotide
Others
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Tissue plasminogen activator—high risk of bleeding; not recommended esp
in multiorgan failure
Antithrombin III and prostaglandin E
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• supportive
Defibrotide
• Mixture of single stranded oligonucleotide with
local antithrobotic,anti-ischemic and
antiinflammatory
• Binds to vascular endothelium via adenosine
receptor A1and A2 involved in endothelial
response to injury
• Modulates platelet activity (↑ prostaglandin) and
promotes fibrinolysis (↑ TFPI and tPA),reduces
thrombin generation and reduces PAI1
Ho et al BMT 2008
Transplant associated
microangiopathy
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Prevalence 4-6%
Closely linked to GVHD, maybe endothelial GVHD
Median time – D+ 27 -- +35
Risk factors– age, female, ABO mismatch, unrelated donor
Diagnosis
Schistocytes >4% in peripheral blood
New, prolonged and progressive thrombocytopenia (<50,000 or
>50% drop)
Sudden and persistent increase in LDH
Reduced Hb or increased red cell transfusion requirement
Reduced haptoglobulin
No specific treatment
Remove possible underlying cause e.g. sirolimus, CSA
Noninfectious Lung complications
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Pulmonary oedema/pleural effusion
Idiopathic pneumonia syndrome
Diffuse alveolar hemorrhage
Peri-engraftment respiratory distress
syndrome
Idiopathic pneumonia syndrome
(IPS)
• Widespread alveolar injury after HSCT in the
absence of infection of lower respiratory
tract/heart failure
• Usually within 100 days after HSCT
• Incidence 3-15% for allogeneic HSCT
• Risk- acute GVHD & older age
• Pathogenesis– injury from conditioning
regimen;immunologic cell mediated
injury;inflammatory cytokines
• Mortality about 70% - worse if need ventillation
Diagnosis of IPS
• Respiratory signs and symptoms
• Chest Xray/CT- multilobar infiltrates
• Absence of organisms (bacteria,fungi or
viral from BAL/biopsy)
• lack of improvement with antibiotics/
antifungal/antiviral
• Lung biopsies- diffuse alveolar damage,
interstitial lymphocyte infiltration
Management of IPS
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Supportive
Prevention and treatment of infection
High dose corticosteroid therapy
Mechanical ventillation
Complications–
pneumothorax,pneumonia,pulmonary
fibrosis
• Etanercept—anti-TNF
Diffuse Alveolar Damage (DAH)
• 5% in HSCT
• Risk factors—old age, TBI, myeloablative
and GVHD
• Possible due to lung injury, cytokines
release
• Mortality ranges from 50-100%
Diagnosis of DAH
• Cough, fever, dyspnea, hemoptysis, hypoxia
• Usually within the first 30 days
• CXR—alveolar/interstitial infiltrates involving
lower and middle lobes
• CT- bilateral ground glass
attenuation/consolidation changes
• BAL-- >20% hemosiderin ladden macrophages
without evidence of infection
• Biopsies-diffuse alveolar damage
Management
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Supportive
Ventillation
Corticosteroid therapy
Possible recombinant factor VIIa
Periengraftment respiratory
distress syndrome (PERDS)
• Engraftment syndrome—skin rash,
pneumonitis,fever, diarrhea and capillary
leak during the engraftment period
• Probably due to damage from conditioning
regimen and cytokines release from the
recovery of neutrophil and lymphocytes
• Mortality less than 30%
Diagnosis
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Fever ( >38.3˚C)
Hypoxia ( O2 sat <90%)
Pulmonary infiltrates
Absence of cardiac dysfunction and
infection
• Within 5 days of neutrophil engraftment
• Biopsy may be difficult due to low platelet
management
• Supportive
• Corticosteroids
• Usually does not require ventillation
Graft Failure
• Engraftment-presence of specified number of
donor cells characterised as hemopoietic cells
• Clinical definition—first day of achieving
sustained peripheral blood ANC>0.5
• Graft failure- inability to sustain donor
engraftment
• Secondary graft failure/rejection-substantial
diminution of donor cells after engraftment
• Incidence <5%
• Possible pathogenesis—immune mediated ( due
to residual host T cells & possible NK cells)
Risk factors
a)Type of transplant
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HLA mismatch (0.1% vs 5%)
Related vs unrelated (esp mismatch class 1)
Cord blood
T cell depleted
Non-myeloablative
ABO mismatch
b) Previous sensitisation
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Previous pregnancy
Previous blood transfusion
c) Cell dose
d) Infections
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CMV
HHV6
Parvovirus
e) Underlying disease
management
Prevention
Treatment
1. Intensified the
conditioning regimen
e.g. TBI
2. Addition of ATG in
aplastic anemia
3. Increased stem cell
dose (PBSC vs BM)
1. DLI – in cases of
decreasing T donor
chimerism
2. Addition of stem cell
dose
3. Growth factors (GCSF
or GMCSF)-esp in
partial donor chimerism
4. Infusion of autologous
stem cells
5. Second allogeneic SCT
Thank you