1. health and fitness
2. disease

5/15/2013
What is a histiocytic disorder?
Langerhans Cell Histiocytosis
Sheila Weitzman MB
Histiocytic Disorders
Histiocytic disorders
(Disorders of dendritic cells
LCH
Histiocytoses: a group of disorders due to abnormal
accumulation of cells of the mononuclear-phagocytic
system
Juvenile Xanthogranuloma
( Disorders of monocyte/macrophage
Antigen presenting cells
Dendritic cells
Effector cells
Monocyte/macrophage
HLH
Sinus histiocytosis (Rosai-Dorfman )
( Malignant disorders
Langerhans Cells
Critical role in immune
surveillance
-
epidermis (1
(1-2%
2% of epidermal cells)
orobuccal mucosa
vaginal mucosa
respiratory epithelium
rectal mucosa (small numbers)
Langerin
keratinocyte
1
5/15/2013
Foreign
antigen
X
CCR6
CCL19/CCR7
Ð
cytokines
LCH skin CD1a x 40
2
5/15/2013
Do LCH cells arise from skin
LCs?
LCH skin Langerin x 40
• LCH cells likely arise from langerin
positive circulating precursor cell
Disorder due to accumulation of cells with immunohistochemical characteristics of Langerhans cells (LCs)
LCH cytokine storm
•
•
•
•
•
•
•
•
Clinical Langerhans Cell
Histiocytosis
Bone
Skin,
Lung
Li
Liver
and
d spleen
l
Hematopoetic
GI
Endocrine
CNS
Langerhans Cell Histiocytosis
↓
Single system
Clinical Langerhans Cell
Histiocytosis
↓
Multisystem
Letterer ‐Siwe High risk multisystem infant
Langerhans Cell Histiocytosis
↓
Single system
↓
unifocal
↓
multifocal
↓
Multisystem
↓
↓
low risk high risk
risk of death
3
5/15/2013
Clinical LCH
• Single system ---spontaneous regression or
good response to Rx
• Ch
Chronic
i llow grade
d di
disease –multiple
lti l
reactivations
high incidence of late effects
• Multisystem risk organ disease
life threatening
SS LCH
DAL-HX 83/90 studies n=170
Titgemeyer et al, 2001
unifocal
if
l bone
b
68%
multifocal bone
19%
isolated skin
11%
isolated lymph node 2%
4
5/15/2013
Bone LCH
• Can spontaneously regress
• Can reactivate –once
once to many times
• Can progress to involve pituitary stalk
(diabetes insipidus)
Bone LCH -natural history
Stuurman et al, 2004
Sickkids study
n=180 bone LCH
• Single bone –most disappear –healing is slow
12% reactivated, only 1 Diabetes Insipidus
• SS Multifocal bone –25% reactivated, some many
times
DI 12%
Bone LCH –teaching points
• Do all first bone lesions need biopsy?
Yes
---except if too risky
•
Vertebra plana without soft tissue mass ?
Observe carefully without biopsy
–risk outweighs benefit
• Vertebral body LCH with soft tissue mass?
• Bone as part of MS disease –50% reactivated
DI >25%
*Paraplegia from LCH does occur due to soft tissue
compression of cord -do MRI scan!
*Misdiagnosis of malignancy
Unifocal bone LCH
• No surgical excision!!
• Majority heal after curettage
5
5/15/2013
Bone -LCH
DEFINITION OF REACTIVATION
Why treat bone LCH?
Reappearance of disease activity after resolution of signs
and symptoms
y p
•
Treat acute problem
•
Prevent late effects
Reappearance
of old lesions
RISK AND TIMING OF FIRST
REACTIVATION
0.7
0.6
0.5
0.9
0.8
0.7
Probability
0.8
reactivation%
Permanent Consequences after
Reactivation
1
Multisystem LCH--According to Risk Organ
1
involvement at diagnosis
0.9
Appearance of
new lesions
0.6
0.5
0.4
03
0.3
0.4
0.3
0.2
p=0.356
0.2
0.1
0.1
0
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0
15
5
without RO
with RO
n=176
n=159
5-yrs. CI=0.45±0.04
0.49±0.05
median observation time
3 years (4mo-18y)
20
Grois et al, 2007
Permanent Consequences after Reactivation
124/134 evaluable Minkov et al, 2006- LCH data base
*±growth hormon deficiency **median time from first reactivation
15
n=18/68, 5-yrs. cumulative incidence=0.32±0.07
RO.......Risk organ involvement at diagnosis
no. at risk no affected
time**
DI
90
17 (19%)
1.2 y
Endocrinopathies
115
10 (9%)
3.8 y
Growth failure*
112
15 (13%)
2.8 y
CNS
114
7 (6%)
6.7 y
Liver fibrosis
120
1 ((1%))
1.9 y
Lung fibrosis
119
4 (3%)
2.3 y
Orthopedic PC
122
5 (4%)
1.5 y
Hearing impairment
119
2 (2%)
37d, 9mo
Teeth loss
119
1 (1%)
1.2 y
Associated malignances
124
1 (1%)
3.1 y
Ophthalmologic problems
122
3 (2%)
2.5 y
Other
121
0 (0%)
-
10
years since first reactivation
years since first NAD
How Common is DI in LCH?
Series
all pts DI in
(n)
all pts
Great Ormond St
(Nanduri, 20001)
Histiocyte Society 182
(Haupt, 20042)
24%
French LCH SG
589
(Donadieu, 20043)
24%
DAL & HS trials
(Grois, 20064)
1,741
1 Clin
12%
MS-LCH DI in
MSComments
(n)
MS--LCH
MS
144
34%
evaluated only MSMS-LCH
108
40%
1/3 had DI @ LCH dx;
Cum. risk 26% @ 14 yrs
1/3 had DI @ LCH dx
520
23%
½ had DI @ LCH dx;
20% risk @ 15 yrs
Endo 53:509; 2 PBC 42:438; 3 J Pediatr 144:344; 4 PBC 46:228
6
5/15/2013
CNS Mass Lesions in LCH
Hypothalamus
Pineal Gland
Meninges
Risk of neurodegenerative LCH among the 589 patients,
according to pituitary involvement.
Choroid plexus
Neurologic and Cognitive
Symptoms in LCH neurodegeneration Whitlock J, 2007
•
•
•
•
•
•
•
T2-weighted axial image demonstrating a hyperinten
of the dentate nucleus (black arrow) and the
surrounding white matter (white arrow).
Tremor
Headaches
Gait disturbances, ataxia
Dysarthria, dysmetria
Visual disturbances
Cognitive problems
Behavioral disturbances,
psychosis
Nanduri, JCO 21:2961, 2003 ; Haupt, PBC 42:438, 2004;
Donadieu, J Pediatr 144:344, 2004; Mittheisz, PBC 48:50, 2007
Bone LCH Can we prevent reactivations?
Are they an inevitable part of the natural history and nothing we can do will prevent them? LCH data base:
MS LCH ‐‐53% LCH and 61% LCH‐II (6 months)
DAL‐Hx studies‐‐12 mo and 5 drugs RR 27% If we decrease reactivations will that decrease late effects?
• Can we prevent progression to DI and CNS‐LCH?
Historically DI 25‐50% more recent 7‐20% ( Grois N, 2006)
DAL HX t di
DAL‐HX studies DI 10% when therapy promptly instituted DI 10% h th
tl i tit t d
LCH‐II MFB: local Rx MonoRX 2 drug DAL
React Rate 52% 45% 20% 10%
Historical comparisons ‐‐data from prospective trials are needed
LCH‐III LCH‐IV
LCH‐III Low risk MS 6 mo vs 12 mo
React Rate 44% 34%
LCH‐III high risk all 12 mo react rate 30% vs historical 50%
7
5/15/2013
LCH teaching points
Skin LCH
1/3 to 1/2 of patients with LCH
• Reactivations in risk bones need therapy
10% - skin is only affected site
• Recent onset of DI should be treated as a
reactivation
–path =active LCH
-warning sign of potentially disabling
late CNS effects
g nails
Anyy area of skin including
Scalp>skin flexures>other
Any age, newborn to 70 years
70% <17 years of age
• Chronic low toxicity therapy for chronic low
grade disease?
Langerhans Cell Histiocytosis skin
Langerhans Cell Histiocytosis
Skin
Skin LCH –teaching points
• Seborrheic dermatitis that does not
respond or keeps recurring
• Diaper dermatitis that does not respond
or keeps recurring
Think LCH
8
5/15/2013
Natural history skin-only
LCH
Skin-only LCH in the young child may:
• Spontaneously disappear
• Progress to multisystem even fatal
disease
Lau et al, 2006
Sickkids study n=13 infants <12mo
Skin -only LCH-teaching point
All patients with skin-only LCH need careful
observation
Some will come and go and then spontaneously
disappear
Some will progress in weeks to months to life
lifethreatening disease
Some, usually <2 years old will die from disease
Self Healing LC Histiocytosis should only be
diagnosed after a few years of observation
9
5/15/2013
Multisystem LCH
Skin, Bone, Lymph nodes
Lung
Liver*, spleen*
Hematopoetic*
GI
CNS
Endocrine
May be associated with secondary HLH which
may need to be treated separately
Survival (RO+)
Gadner H, 2008
CH--IIIA:n=102, 0.85±
CH
0.85±0.04
H-IIIB: n=104,0.82± 0.04
LCH--IIB: n=74, 0.76 ±0.05
LCH
LCH--IB: n=42, 0.70
LCH
0.70±
±0.07
LCH--IIA:n=64, 0.68±
LCH
0.68±0.05
LCH--IA:n=45,0.59±
LCH
IA:n=45,0.59±0.07
LCH-I
20% LCH III
LCH-III
-Arm A
---Arm B
MS-LCH—better survival
Reduction of mortality in MS
40% LCH I
LCH-II
•
Early introduction of salvage therapy for poor
responders
• Better salvage therapy
Possible reasons:
2-CdA/Ara-C combination
► second course initial tx
► earlier + effective salvage tx
► better supportive care
Clofarabine
LCH-S-2005
Rodriguez-Galindo 2011
10
5/15/2013
Risk of Treatment-related Mortality
by day +100
after Myeloablative Preparative
Regimen
50
LCH-salvage
• If fail salvage protocol –mortality is very
high
45
40
% Riskk
35
• Only survivors In LCH-S-98 study
underwent allogeneic SCT
30
25
20
15
10
5
0
Auto
2. Reduced intensity conditioning (RIC) regimen
will allow SCT in heavily pretreated patients
with acceptable transplant related mortality
URD
HLH
LCH
Non-myeloablative/Reduced Intensity
Conditioning Transplant
in LCH
Hypotheses for LCH-SCT
1. Allogeneic hematopoietic stem cell
transplant (SCT) can salvage high risk LCH
patients refractory to available
chemotherapy
h
th
approaches
h
Allo Sib
• Nine patients
• 2/9 (22%) treatment-related mortality by day +100
• 7/9 (78%) alive without LCH
– One patient with recipient cells
Steiner M, et al. Bone Marrow Transpl 36:215-225, 2005
Conclusions: Single system
LCH
Conclusions: “Risk” LCH
• --prolong
induction therapy for partial
responders
• Single system unifocal disease should not be
overtreated
• Multifocal bone and low risk MS LCH--treat
LCH treat to try to
prevent late effects
• 12 months therapy reduces reactivations by 10% but
still >30% reactivate --? 24 months will be better?
• -early switch of poor responders to salvage
Rx
• -then treat to try to prevent late effects ( 12 or
24 months?)
-
11
5/15/2013
References LCH I , LCH II,
DAL-HX
•
Gadner H, Grois N, Arico M, Broadbent V, Ceci A, Jakobson A, et al. A
randomized trial of treatment for multisystem Langerhans' cell
histiocytosis. J Pediatr 2001;138(5):728-34.
•
Gadner H, Grois N, Potschger U, Minkov M, Arico M, Braier J, et al.
Improved outcome in multisystem Langerhans cell histiocytosis is
associated with therapy intensification. Blood 2008;111(5):2556-62.
•
Gadner H, Heitger A, Grois N, Gatterer-Menz I, Ladisch S. Treatment
strategy for
f disseminated
di
i
d Langerhans
L
h
cell
ll histiocytosis.
hi i
i DAL HX-83
HX 83 Study
S d
Group. Med Pediatr Oncol 1994;23(2):72-80.
•
Minkov M, Grois N, Heitger A, Potschger U, Westermeier T, Gadner H.
Treatment of multisystem Langerhans cell histiocytosis. Results of the
DAL-HX 83 and DAL-HX 90 studies. DAL-HX Study Group. Klin Padiatr
2000;212(4):139-44.
•
LCH-III -in press
• We have learned a lot
• We have a lot more to learn !!
12