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