Complications of Stem Cell Transplant Or…. What to be worried about! Objectives To review a timeline regarding all complications of hematopoietic stem cell transplant Review.
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Transcript Complications of Stem Cell Transplant Or…. What to be worried about! Objectives To review a timeline regarding all complications of hematopoietic stem cell transplant Review.
Complications of
Stem Cell Transplant
Or….
What to be worried about!
Objectives
To review a timeline regarding all
complications of hematopoietic stem cell
transplant
Review the nurses role in achieving safe
outcomes for patients experiencing acute
complications
Objectives
To establish a framework for the assessing,
diagnosis, treatment and evaluation of chronic
complications of stem cell transplant
To compare and contrast features of acute and
chronic graft vs host disease in post stem cell
patients
To identify late infections in patients who are
greater than 100 days post transplant
Objectives
To discuss the need for a comprehensive
approach to the long term evaluation and
management of patients recovering from
HSCTX
Bone Marrow or Stem Cell
Tx
Replace and regenerate the bone
marrow with a new supply of stem cells
to repopulate and create a new and
improved immune system.
Historical Growth
180
160
140
Auto
120
Auto
100
Allo
80
Allo
60
40
20
0
CY
2003
2004
2005
2006
2007
2008
2009
Causes of Death
Post SCTx
2002-2007
Autologous
Relapse (73%)
Organ toxicity (5%)
IPn (1%)
Infection (6%)
Other (14%)
HLA-identical Sibling
Relapse (42%)
GVHD (1%)
Organ toxicity (9%)
IPn (2%)
Unrelated Donor
Infection
(16%)
Relapse (33%)
Organ toxicity (10%)
IPn (5%)
GVHD (12%)
Other (19%)
Infection (19%)
GVHD (13%)
Other (20%)
Slide 18
SUM09_19.ppt
GVH vs GVL
The immune therapy aspect of an
allogeneic transplant
Don’t want graft vs host disease
Do want graft vs disease (leukemia,
lymphoma, myeloma, etc)
What does having a SCTx
mean to the patients?
You say: You have cancer.
The patient thinks: OMG,
I’m falling out of an
airplane and I’m going to
die!
What does having a SCTx
mean to the patients?
You say: But there is a treatment we can
offer that could overcome the life
threatening illness.
The patient thinks: Thank goodness, I’m
going to land on that pile of soft hay and
live!
What does having a SCTx
mean to the patients?
You say: Unfortunately, you will develop
chronic illness that will have to be
managed and control for the rest of your
life.
Early or Acute Complications
of Stem Cell Transplant
Chemotherapy related toxicities
Infection
VOD
Renal failure
Pulmonary hemorrhage
Engraftment syndrome
Acute Graft Vs Host Disease
Late or Chronic
Complications of Stem Cell
Transplant
Chronic Graft vs Host disease
Late Infections
Bronchiolitis Obliterans
Cryptogenic Organizing Pneumonia
Sjogrens syndrome
Long Term Complications
of Stem Cell Transplant
Seizure disorders
Renal insufficiency or failure
Endocrine failure
Hypoadrenalism
Pituitary failure
Hypogonadism
transplant complications
Opportunistic infections
Infections
CGVHD
AGVHD
VOD, Engraftment syndrome
30
Conditioning and SCT
60
90
120
Days following SCT
150
180
Framework for evaluating
symptoms
GVH or
Infection or
Drug effect/reaction
VOD (Veno 0cclusive Dx)
Also known as SOS (Sinusoidal Occlusive
Syndrome)
Begins with injury to the hepatic venous
endothelium
Involves the deposition of fibrinogen and factor
VIII within the venular walls and liver sinusoids,
which then become congested by erythrocytes
Progressive venular occlusion occurs and
ultimately leads to widespread zonal liver
disruption and centrilobular hemorrhagic
necrosis
VOD (Veno 0cclusive Dx)
Serum total bilirubin concentration
greater than 2 mg/dL
Hepatomegaly or right upper quadrant
pain
Sudden weight gain due to fluid
accumulation (greater than 2 percent of
baseline body weight)
VOD
Monitor labs. Looking at trends in
bilirubin
Weights and I/O. Keep the patient dry
Ursodiol 250mg (or 300mg) TID
The mechanism of action of Ursodiol is
unclear
It is a hydrophilic bile acid which decreased
cholesterols and most likely replaces the
more toxic bile acids being produced
Engraftment Syndrome
Constellation of symptoms include fever,
erythrodermatous skin rash, and
noncardiogenic pulmonary edema
increased capillary permeability lead to a
capillary leak syndrome
cellular and cytokine interactions are believed
to be responsible for these clinical findings,
however a distinct cytokine profile has not
been defined
Engraftment Syndrome
Clinical picture overlaps with other
complications:
Fever r/t infection
Rash r/t GVH or drug reaction
Pulmonary compromise r/t volume overload,
renal failure
Engraftment Syndrome
What to do:
Close monitoring and ongoing assessment
Weights and I/O’s
Keep the patient dry
Rule out other causes
Steroids
GVH
Occurs when immuno competent cells
are introduced into an
immuno incompetent host.
These cells recognize the recipient’s
tissue antigens as foreign and mount an
inflammatory, apoptotic response (mainly
T-cell mediated)
Incidence of GVH
70%
60%
50%
40%
30%
20%
10%
0%
matched related
mismatched
related
matched
unrelated
Acute GVH Clinical
Features
Clinical syndrome resulting from allo reactivity
of donor T cells to host tissues
Presents as a maculopapular rash commonly
of the neck, ears, palmar & plantar surfaces
Considered a complication occurring from 6
weeks to 3 months after transplant
Must differentiate it from other causes such as
chemo related toxicities, infection
Acute GVH
Acute GVH Clinical
Features
Associated with onset of WBC
engraftment
Can be minimal ie erythroderma and
pruritis
Can be severe ie with formation of
bullous lesions c/w toxic epidermal
necrolysis
Acute GVH Histological
Features
Changes in the dermal and epidermal
layers of skin (interface dermatitis)
Perivascular lymphocytic infiltration
Lichenoid dermatitis
Individual cell death (apoptosis)
Acute GVH Histology
Acute GVH Histology
Acute GVH Histological
Features
GVH of liver:
Apoptosis of hepatocytes
Decreased interlobular ducts or ductopenia
Cytoplasmic vacuolization of epithelial cells
Reactive Kupffer cells (macrophages)
GVH of gut
Focal apoptotic necrosis
Chronic GVH
Not entirely known
Obviously related to allo-reactive T-cells
similar to acute GVH
Pathogenic donor T cells expand in
response to alloantigens or autoantigens
Pathologic T cells attack target tissue
through cytolytic attack with cytokines
responsible for inflammation and fibrosis
Chronic GVH
The role of auto-reactive, post thymic
T-cells not clear, but thought to contribute
to the clinical manifestations which mimic
autoimmune diseases
Promotion of B cell activation and
autoantibody production
Chronic GVH:
Clinical Features
Occurs in 20%-70% of people surviving >
100 days
50% of affected pts have 3 or more
involved organs
Treatment requires immunosuppression
for median of 1-3 yrs
Major cause of late death despite
association with lower relapse rates
Chronic GVH:
Clinical Features
Secondary malignancies more common
in people with chronic GVH
Functional consequences of chronic GVH
are major determinants of health and
QOL of survivors
Chronic GVH:
Risk Assessment
Prior acute GVH is the most important predictor
of chronic GVH
Type of GVH prophylaxis used influences risk
Risk increases with:
Age of recipient
Degree of mismatch of non HLA identical stem cells
Chronic GVH
Histological Features
Chronic GVH of the skin
Schlerosis of dermal layers
Apoptotic keratoinocytes
Schlerodermoid changes
Chronic GVH
Chronic GVH
Chronic GVH changes of
the mouth
Chronic GVH changes of
the mouth
Chronic vs Acute
Definition of chronic GVH no longer
based on onset of greater than 100 days
post tx
Recent definitions are based on clinical
manifestations rather than time of onset
Although acute GVH is the strongest
predictor for chronic GVH, 25%-35% of
cases occur de novo and 20%-30% of
pts with acute GVH will not develop
Chronic GVH:
NIH Consensus Criteria
Classic chronic GVH is without features
of acute GVH
Overlap syndrome in which features of
chronic GVH and acute GVH appear
together
Must exclude other possible diagnoses
No time limit is set for diagnosis of
chronic GVHD
Chronic GVH:
Limited disease
Characterized by localized skin
involvement &/or hepatic dysfunction
Limited GVH does not require treatment
Chronic GVH:
Extensive disease
Presents with generalized skin
involvement, or as limited disease, plus
one of the following:
Eye involvement
Involvement of salivary glands or oral
mucosa
Involvement of other target organ
Extensive disease requires treatment
Chronic GVH Staging
Multivariate analysis of 151 pts over
20yrs done through Johns Hopkins
Medical Center
Predictors of survival related to Chronic
GVHD
Extensive skin involvement (>50% BSA)
Thrombocytopenia (<100K)
Progressive onset of GVH at diagnosis
KPS <50%
Staging
Prognostic Factor Scores (PFS)
0 = no factors
0-2 = extensive skin or low platelets,
progressive onset, or both
2-3.5 = extensive skin and low platelets or
progressive onset
>3.5 = all three factors
Staging
PFS of:
0 assoc with 82% survival at 10yrs
0-2 assoc with 68% survival at 10 yrs
2-3.5 assoc with 34% survival at 10 yrs
>3.5 assoc with survival of 3 yrs
Case Study: TJ
25 yo man with CML
s/p unrelated allo tx, 1999
Multiple pulmonary infections 2001 &
2002
Chronic pulmonary changes r/t
BOOP/COG
PFT’s in pt with BOOP
Date
FVC
FEV1
DLCO
4/20/00
83%
92%
74%
7/9/03
69%
73%
72%
1/23/08
58%
62%
61%
Basic approach to
treatment
Immunosuppression
Prednisone 1mg/kg daily
Treat to maximum response and maintain for 3
months
Wean over equivalent time frame of 3 months
Calcinueron inhibitor, CyA or Tacrolimus weight
based
Steroid sparing immunesuppression such as
Mycophenolate
Evaluation of response
Difficult at best
Changes to underlying schlerodermatous
disease resolves slowly if at all
No erythroderma and no new sclerosis
Range of motion should be evaluated
Case Study: KS
58 yo female with MDS
s/p non myeloablative allo related tx,
1/24/06
Chronic GVH of skin, extensive treated
with multiple immunesuppressive
regimens
h/o autoimmune hemolytic anemia
Chronic GVH:
Underlying Principles
Stephanie Lee, 2005
Not a continuation of Acute GVH
Improved outcomes related to acute GVH
have not affected incidence of chronic GVH
Although there is overlap of organ
involvement, the distribution of affected
organs is broader in chronic GVH
Chronic GVH is an inflammatory and fibrotic
process, acute GVH reflects apoptosis and
necrosis
Other treatments
Pentastatin
Etanercept
Photophoresis
Rituxan
Photophoresis
•A decrease in T cell proliferation, and natural killer
(NK) cell activity
•A modulation of alloreactive cytotoxic T-cell precursors
•Activation of suppressor pathways by ultraviolet
resistant antigen presenting cells
•Alteration of cytokine production, such as IL-1 and IL-2
Extracorporeal
Photophoresis
Extracorporeal
Photophoresis
Late Infections
Occuring after Day +100
Viral
CMV
HSV
EBV
BK
Fungal
Infection: Risk factors
Highest risk factor is cytopenias
Infection was primary or secondary
cause of death in 60% of transplant
recipients.
CMV: Risk factors
Significant increase in pts who are
seropositive to CMV
Concomittant acute GVH
Receipt of T-cell depleted product
CMV: Treatment
Gancyclovir 5mg/kg IV till negative
Valcyte 900mg po BID till negative
Then maintenance
Case Study: MR
48 yo female, h/o ALL
s/p conventional related allo, from her
HLA matched brother, 12/26/06
h/o pulmonary symptomatology and
multiple infectious problems
Invasive Fungal Infections
Yeasts such as Candida and
Cryptococcus
Moulds such as Aspergillus, Fusarium,
Scedosporium and Zygomycetes
Invasive Fungal Infections
Disseminated Candidiasis is assoc with
mortality in excess of 25%
Non Albicans Candida are highly virulent
and assoc with treatment failure due to
reduced susceptibility to antifungal
agents
Decreased incidence of Candidiasis
related to prophylaxis with azoles
Invasive Fungal Infections
Aspergillus are most common invasive
molds
Invasive aspergillosis reported at 13%
overall in allo and auto transplants
Invasive Fungal Infections
Symptoms vary and can be
asymptomatic in 30%
CT scan followed by bronchoscopy and
VATS if needed
CT findings: multiple nodules, halo sign
(central necrosis)
Platelia assay (galactomannan) has
helped in early detection
Case History: RN
9yo boy with h/o aplastic anemia, s/p
related allo transplant from HLA matched
brother
Recovered but developed interosseous
infection which proved to be
Scedosporium
Underwent below the knee amputation to
prevent further spread of infection
Invasive Fungal Infections
Zygomycetes (bread mold) has increased
in incidence accounting for 18%
Associated with higher mortality (62% vs
54%) than Aspergillus
Prophylaxis & Treatment
Amphoterecin B
Azoles
Echinocandins
Case History: JC
66 yo man, h/o Mantle Cell NHL
s/p non myeloablative related allo from
his HLA matched sister, 2/16/05
h/o extensive chronic GVH of skin and
eyes, mouth, lungs
Multiple infectious complications
Case History: MR
53 yo female with h/o MDS
s/p non myeloablative related allo from
her HLA matched sister, 12/19/07
Doing well till approx day +100 when she
developed acute onset of GVH of liver
Symptomatic
Case History: MR
T Bili
30
25
20
15
T Bili
10
5
0
1
2
3
4
5
6
7
Case History: MR
800
700
600
500
ALT
400
AST
Alk phos
300
200
100
0
1
7
14
21
28
35
42
Pt outcomes: NP
29 yo female h/o CML
s/p conventional unrelated allo 1997
h/o extensive chronic GVH of gut and
skin
Doing well, NED, 11 years out
Pt outcomes: KK
33 yo male, h/o CML
s/p conventional related allo 10/21/99
h/o chronic GVH, eyes and mouth; very
debilitating
Doing well, NED, 8 years out
Long Term Follow Up
As patients live longer there is a need for
a systematic approach to long term follow
up
To identify chronic complications for early
intervention
To help maintain performance status and
improve quality of life
The End