Post on 05-Nov-2015
description
AL amyloidosis
Ashutosh Wechalekar Senior Lecturer/Hon. Consultant Haematologist
National Amyloidosis Centre
UCL Medical School (Royal Free Campus), London, UK
Amyloidosis and amyloid fibrils
New properties:
Bind Congo red and SAP
Unusual stability
Damage tissue structure and organ
function
Disorder of protein folding
Structurally diverse precursors adopt an
abnormal common fibrillar conformation
Apparent
Classification of
amyloidosis
AL
?AH
Amyloid
Systemic
Localised
Acquired
Hereditary
Monoclonal
Immunoglobulin
AA
2M
Senile
Genetic variants of
plasma proteins
Genuine Usually AL due to
focal pc clones
AL, hereditary or
senile
Monoclonal
Immunoglobulin
Localised
13%
AL
57%
Unclear
1%
Senile TTR
3%
AA
14%Hereditary
12%
Clinical Features - Protean
Visible tissue infiltration
Bruising - periorbital, general
Macroglossia
Muscle pseudohypertrophy
Renal
Proteinuria
Renal failure
Cardiac
Restrictive cardiomyopathy
ECG - low voltage, pseudoinfarct
Liver
Hepatomegaly, high Alk Phos
Liver failure rarely
Peripheral neuropathy
Carpal tunnel syndrome common
Symmetrical sensorimotor
neuropathy
Autonomic neuropathy
Orthostatic
hypotension/arrhythmias
Gut motility/bladder emptying
Gastrointestinal
Weight loss/anorexia/bloating
Blood loss
Constipation/diarrhoea
Adrenal axis
Hypoadrenalism
Lymphoreticular system
Problem
Uncommon, non-specific presentation, and therefore often not considered
Delay in diagnosis
Determine extent of organ involvement
Management plan Definitive
Supportive
Strategy
Demonstrate underlying
plasma cell dyscrasia
Amyloid immunostaining
by light chain sera
Rule of hereditary
amyloidosis
Confirm amyloidosis
Determine the type
Kappa FLC mg/l
0.1
1.0
10.0
100.0
1000.0
10000.0
100000.0
0.1 1.0 10.0 100.0 1000.0 10000.0 100000.0
La
mb
da
FL
C m
g/l
ite
r
Abnormal in
97% AL
cf 40% MGUS
70% lambda
28% kappa
Lachmann et al BJH 2002
Urine BJP - 61%
Serum PP or FLC - 69%
Abnormal FLC ratio - 79%
52%
IF - 17%
40%
IF-21%
79%
0
10
20
30
40
50
60
70
80
90
100
Ser
um
Urine
FLC
% p
ati
en
ts
~3-5% of all patients have no detectable clonal dyscrasia
(sFLC assay + serum and urine immunoelectrophoresis)
Determine the type Clonal markers in AL analysis of 644 patients
Wassef et al; NAC; unpublished; 2009
FLC and AL amyloidosis
The FLC ratio was abnormal in 507
(79%)
A lambda bias - 370 (57%) and
median 256mg/L
A kappa bias - 137 (21%) and
median 379 mg/L
Abnormal class of FLC > 100mg/L
425/644 (65%)
Wassef et al; NAC; unpublished; 2009
FLC a determinant of prognosis in AL amyloidosis
Median survival
Low FLC group (500mg/L)
10 months
0%
20%
40%
60%
80%
100%
Low
FLC
Int.
FLC
Hig
h FL
C
Alive
Dead
Perc
ent patients
alive o
r
dead a
t 2 y
ears
Wechalekar et al EHA 2009
Mayo Staging System - 2004
Dispenzieri A, J Clin Oncol. 2004 Sep 15;22(18):3751-7. Dispenzieri A, Blood. 2004 Sep 15;104(6):1881-7.
Stage I Normal Troponin and NT-ProBNP 26 months
Stage II Either Troponin-T >0.035ng/L or NT-ProBNP >332ng/L
10 months
Stage III Both abnormal 3.5 months
Unselected patients HDM-ASCT patients
Revised Mayo staging incorporation of dFLC
Stage N Median survival
Stage I 189 94 months
Stage II 206 40 months
Stage III 186 14 months
Stage IV 177 5.8 months
NT-ProBNP 1800 pg/ml
cTroponin-T 0.025 ng/ml
dFLC 18mg/dl
Kumar et al, JCO; 2012;10.1200/JCO.2011.38.5724
Confirm the diagnosis A biopsy is needed
Congo Red positivity is the only gold standard
apple green birefringence under high-intensity cross-polarised light
thick (6 micron) sections reduce false negatives
What it can and cant tell us
amyloid is there and where
. BUT its absence does not rule it out, esp if biopsy inadequate
amyloid type LM appearance
. EXCEPT AFib, pathognomonic renal biopsy appearance
I123 labelled SAP scintigraphy
Pathognomonic
of AL amyloidosis
Stop Light chain
production
Chemotherapy
SCT
Light chain
removal
Stop amyloid
formation GAG inhibitors
Breakdown
the amyloid
fibrils -
antibodies
The clone Native Monoclonal
protein Unfolding/Misfolding Amyloid Deposits
Reduce supply of
amyloidogenic precursor
Inhibit or reverse
amyloidogenesis
Plan management
Thalidomide Velcade (Bortezomib) Revlimid (Lenalidomide)
Dexamethasone
CTD, M-Dex, Vel-Dex, C/M-Vel-Dex, Len-Dex
Cyclophosphamide Melphalan
Treatment options in AL
MP ASCT
Dex VAD
IDM Thal CTD
M-Dex
Velcade
Revlimid
& comb.
Pomalid.
Carfilzomib
HSP
antibodies
1990 2011
Impact of CR/VGPR on overall survival in AL
0 12 24 36 48
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0P
roport
ion s
urv
ivin
g
CR (97 patients, 3.6 deaths/100 py)
VGPR (233 patients, 9.6 deaths/100 py)
PR (140 patients, 23.7 deaths/100 py)
NR (179 patients, 47.2 deaths/100 py)
p=0.01
p
Regression Stable Progression
0
25
50
75
100
125
150
200
300
400
500P
erc
enta
ge F
LC
rem
ain
ing p
ost t
reatm
ent
Perc
enta
ge F
LC
rem
ain
ing p
ost
chem
oth
era
py
Clonal response and amyloid regression
CTD and Mdex the current standard
Oral Melphalan-Dex
Overall responses 64%
Median PFS 2.5 yrs
OS 5.5yrs
Palladini et al Blood 2007
0 10 20 30 40 50 60
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
port
ion s
urv
ivin
g
Ovearll survival (median not reached) Progression free survival (median 2.5 years)
Cyclo-Thal-Dex
>300 patients in UK
2732
4327
30
41
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1st Line Relapsed
CR
PR
NR
0 20 40 60 80 1000
20
40
60
80
100
>90% dFLC response
51-90% dFLC response
0-50% dFLC response
p
Increased proteasomal
workload (caused by
misfolded light chains) -
higher apoptotic sensitivity
of plasma cells to
proteasome inhibitor
Proteosome inhibitors in AL a special relationship
Dimopoulos M A , Kastritis E Blood 2011;118:827-828 2011 by American Society of Hematology
Survival of patients according to (A) hematologic and (B) proBNP response.
2010 by American Society of Clinical Oncology
Bortezomib in AL amyloidosis
Well tolerated
Overall responses 71%
Median PFS ~ 2 years
Very rapid responses 0
20
40
60
80
100
120
140
160
180
15 J
une
2000
29 M
arch
200
1
08 N
ovem
ber 2
001
13 J
une
2002
15 A
ugus
t 200
2
23 O
ctobe
r 200
2
19 N
ovem
ber 2
002
12 D
ecem
ber 2
002
14 J
anua
ry 2
003
07 F
ebru
ary
2003
13 M
arch
200
3
09 A
pril 2
003
27 M
ay 2
003
05 J
une
2003
08 J
uly 2
003
11 A
ugus
t 200
3
05 S
epte
mbe
r 200
3
06 O
ctobe
r 200
3
27 N
ovem
ber 2
003
30 J
anua
ry 2
004
25 M
arch
200
4
29 A
pril 2
004
14 J
une
2004
19 J
uly 2
004
31 A
ugus
t 200
4
07 S
epte
mbe
r 200
4
15 N
ovem
ber 2
004
14 F
ebru
ary
2005
05 M
ay 2
005
25 J
uly 2
005
16 S
epte
mbe
r 200
5
24 N
ovem
ber 2
005
09 J
anua
ry 2
006
01 F
ebru
ary
2006
22 F
ebru
ary
2006
16 M
arch
200
6
18 A
pril 2
006
16 M
ay 2
006
14 J
une
2006
12 J
uly 2
006
17 A
ugus
t 200
6
11 S
epte
mbe
r 200
6
16 N
ovem
ber 2
006
Lam
bda
FLC
(m
g/L
) FLC
SCT ABCM Thalidomide CTD Bortezomib
Study Regimen Hematologic
Response (%)
Kastritis et al (2007) Bortezomib 94%
Wechalekar et al (2008) Bortezomib 80%
Kastritis et al (2010) Bortezomib 74%
Cyclo-Vel-Dex UK experience
Venner et al ASH 2011
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
NR
OR
R
CR
CR
OR
R
PR
PR
VG
PR
P
R
N=37 (Upfront 14;
Relapsed 23)
Stage III 46%
Cyclo-Vel-Dex UK experience
Organ response 46% including cardiac 11%
Long term outcomes after ASCT
Cibeira et al. Blood; 2011; 118 (16);4646-52
Organ response - 78%
Organ response - 39%
Stop Light chain
production
Chemotherapy
SCT
Light chain
removal
Stop amyloid
formation GAG inhibitors
Breakdown
the amyloid
fibrils -
antibodies
The clone Native Monoclonal
protein Unfolding/Misfolding Amyloid Deposits
Reduce supply of
amyloidogenic precursor
Inhibit or reverse
amyloidogenesis
Targeting the deposits
Towards a cure?
SAP is universal in amyloid deposits
SAP in amyloid deposits is not degraded
SAP binding stabilises amyloid fibrils in the test tube
SAP promotes amyloid formation in the test tube
Genetically engineered mice without SAP develop amyloid less
SAP & amyloid formation
Concept
Deplete plasma of SAP using CPHPC
Some SAP still remains on amyloid deposits
Give anti-SAP antibody to target amyloid deposits
Acknowledgements
National Amyloidosis Centre
Prof. Philip Hawkins
Prof. Mark Pepys
Dr Julian Gillmore
Dr Helen Lachmann
Dr Carol Whelan
Dr Simon Gibbs
Dr Jenny Pinney
Dr Chris Venner
Dr Prayman Sattiayanagam
Ms.Thirusha Lane
Mr. Darren Foard
Ms. Lisa Rannigan
Rest of the NAC Team
Heart Hospital
Dr James Moon
Dr Sanjay Banyprasad
University Of Pavia
Prof. Giampaolo Merlini
Dr Giovanni Palladini
St Georges Hospital
Dr Lisa Anderson
Dr Jason Dungu
Royal Brompton Hospital
Dr Sanjay Prasad
Prof. Dudley Pennel
Dr. Agata Grasso