AL amyloidosis

Ashutosh Wechalekar
Senior Lecturer/Hon. Consultant Haematologist
National Amyloidosis Centre
UCL Medical School (Royal Free Campus), London, UK

Amyloidosis and amyloid fibrils

Disorder of protein folding
Structurally diverse
precursors adopt an
abnormal common fibrillar
conformation

New properties:
Bind Congo red and SAP
Unusual stability
Damage tissue structure and organ
function

AL

Classification of
amyloidosis

Monoclonal
Immunoglobulin

?AH

Acquired

AA

2M

Unclear
1%

Localised
Systemic
13%
Hereditary
12%

Amyloid

AA
14%

Senile TTR
Senile
3%

AL
Genetic variants of
Hereditary
57%

plasma proteins

Genuine

Usually AL due to
focal pc clones

Apparent

AL, hereditary or
senile

Localised

Clinical Features - Protean

Peripheral neuropathy

Visible tissue infiltration

Bruising - periorbital, general
Macroglossia
Muscle pseudohypertrophy

Cardiac

Carpal tunnel syndrome common

Symmetrical sensorimotor
neuropathy

Autonomic neuropathy

Renal
Proteinuria
Renal failure

Orthostatic
hypotension/arrhythmias

Gut motility/bladder emptying

Problem

Uncommon, non-specific presentation,

Gastrointestinal
often notWeight
considered
loss/anorexia/bloating

Restrictive cardiomyopathy
and
therefore
ECG - low
voltage,
pseudoinfarct

Liver

Blood loss
Delay in diagnosis

Hepatomegaly, high Alk Phos

Liver failure rarely

Constipation/diarrhoea

Adrenal axis

Hypoadrenalism

Lymphoreticular system

Strategy

Confirm amyloidosis

Determine the type

Demonstrate underlying
plasma cell dyscrasia
Amyloid
immunostaining
Determine
extent of organ involvement
by light chain sera
Management plan
Rule of hereditary
Definitive
amyloidosis

Supportive

100000.0

70% lambda

Lambda FLC mg/liter

10000.0

1000.0

Abnormal in
97% AL
cf 40% MGUS

100.0

10.0

28% kappa

1.0

0.1
0.1

1.0

10.0

100.0

1000.0

10000.0

100000.0

Kappa FLC mg/l

Lachmann et al BJH 2002

Determine the type

Clonal markers in AL analysis of 644 patients

100
90

Urine BJP - 61%

80

60

Serum PP or FLC - 69%

IF - 17%
IF-21%

50
40

79%

52%

30

Abnormal FLC ratio - 79%

40%

20
10

FL
C

U
rin

Se
ru
m

% patients

70

~3-5% of all patients have no detectable clonal dyscrasia

(sFLC assay + serum and urine immunoelectrophoresis)

Wassef et al; NAC; unpublished; 2009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 (<150mg/L) 63

months

Intermediate group (150-500

mg/L) 22 months
High FLC group (>500mg/L)
10 months
100%
80%
60%
40%

Alive
Dead

20%

Wechalekar et al EHA 2009

FL
C
H
ig

FL
C
In
t.

FL
C

0%

Lo
w

Percent patients alive or

dead at 2 years

Mayo Staging System - 2004

Unselected patients

Dispenzieri A, J Clin Oncol. 2004 Sep 15;22(18):3751-7.

HDM-ASCT patients

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- 10 months

ProBNP >332ng/L

Stage III

Both abnormal

3.5 months

Revised Mayo staging incorporation of dFLC

NT-ProBNP

1800 pg/ml

cTroponin-T

0.025 ng/ml

dFLC

18mg/dl

Stage

Median survival

Stage I

189

94 months

Stage II

206

40 months

Stage III

186

14 months

Stage IV

177

5.8 months

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

Plan management

Reduce supply of
amyloidogenic precursor
The clone

Stop Light chain

production
Chemotherapy
SCT

Native Monoclonal
protein

Light chain
removal

Inhibit or reverse
amyloidogenesis
Unfolding/Misfolding

Stop amyloid
formation GAG
inhibitors

Amyloid Deposits

Breakdown
the amyloid
fibrils antibodies

Treatment options in AL
Velcade (Bortezomib)

Thalidomide

Revlimid (Lenalidomide)

Dexamethasone

Cyclophosphamide

Melphalan

CTD, M-Dex, Vel-Dex, C/M-Vel-Dex, Len-Dex

Dex
MP
1990

ASCT

VAD
IDM

Thal

Pomalid.
CTD Velcade
Carfilzomib
M-Dex Revlimid
& comb. HSP
antibodies
2011

Impact of CR/VGPR on overall survival in AL

1.0
0.9

p=0.01

0.8

Proportion surviving

0.7

p<0.001

0.6
0.5

p<0.001

0.4
0.3

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)

0.2
0.1
0.0
0

12

24

36

48

Time (months)
Courtesy: Dr Giovanni Palladini

Percentage FLC remaining post

chemotherapy

Percentage FLC remaining post treatment

Clonal response and amyloid regression

500
400
300
200
150
125
100
75
50
25
0
Regression

Stable

Progression

CTD and Mdex the current standard

Cyclo-Thal-Dex

Oral Melphalan-Dex

>300 patients in UK

Overall responses 64%

100%

Median PFS 2.5 yrs

90%
30

NR

80%

41

70%

OS 5.5yrs

60%
50%

43

27

PR

40%
30%
20%

1.0

CR

0%

1st Line

0.8

Relapsed

100

0.7
0.6
0.5

Percent survival

Proportion surviving

32

27

10%

0.9

0.4
0.3
0.2

Ovearll survival (median not reached)

Progression free survival (median 2.5 years)

0.1
0.0
0

10

20

30

40

50

60

Time (months)

80
60

p <0.0001

40
p = 0.13
>90% dFLC response
51-90% dFLC response
0-50% dFLC response

20
0
0

20

40

60

80

100

Months from diagnosis

Palladini et al Blood 2007

1 Wechalekar et

al Blood. 2007 Jan 15;109(2):457-64

al Blood (Abstracts), Nov 2008; 112: 1733
3 Gillmore at al Blood (Abstracts), Nov 2009; 114: 2869.
2 Gibbs et

Proteosome inhibitors in AL a special relationship

Increased proteasomal
workload (caused by
misfolded light chains) -

higher apoptotic sensitivity

of plasma cells to
proteasome inhibitor

2011 by American Society of Hematology

Dimopoulos M A , Kastritis E Blood 2011;118:827-828

 Overall responses 71%

Median PFS ~ 2 years

Very rapid responses

Study

2010 by American Society of Clinical Oncology

Lambda FLC (mg/L) FLC

Well tolerated

15
J
29 un
08 M e 2
N arc 0 00
ov h
em 20
b 0
13 er 1
2
15 Ju 00
n
A e 1
23 ugu 20 0
O s 2
19 ct t 2
N o b 002
o e
12 ve r 2
D mb 00
ec e 2
e r
14 m 20
b 0
Ja er 2
07 nu 20
Fe ary 0 2
br 2
u 0
13 ar 03
M y2
ar 00
09 ch 3
A 200
p
3
27 ri l 2
M 00
05 ay 3
Ju 20
n 0
08 e 2 3
11 Ju 0 0
05 A ly 2 3
u
S gu 00
ep s 3
te t 2
06 m 00
be 3
27 Oc r 2
t
N ob 00
ov er 3
e
30 m 200
b
Ja er 3
nu 20
25 ar 0 3
M y2
ar 00
29 ch 4
A 200
14 pri l 4
Ju 2 0
n 04
19 e 2
31 Ju 0 0
07 A ly 2 4
S ugu 00
e
s 4
15 pte t 2
N mb 004
ov e
r
14 em 20
Fe be 04
br r 2
ua 00
r
05 y 2 4
M 00
16 25 ay 5
2
S Ju 00
ep ly 5
24 te
2
N mb 005
ov e
r
09 em 20
Ja ber 05
01 nu 20
Fe ary 0 5
22 bru 20
Fe ary 06
br 2
u 0
16 ar 06
M y2
ar 00
18 ch 6
A 200
p
6
16 ri l 2
M 00
14 ay 6
2
Ju 0
n 0
12 e 2 6
17 Ju 0 0
11 A ly 2 6
ug 0
S
e us 06
16 pte t 2
N mb 006
ov e
em r 2
0
be 06
r2
00
6

Survival of patients according to (A) hematologic and (B) proBNP response.

Bortezomib in AL amyloidosis
180

160

140

SCT
ABCM
Thalidomide
CTD
Bortezomib

120

100

80

60

40

20

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

NR
PR
VGPR

CR

ORR

PR

PR
CR

Stage III 46%

ORR

N=37 (Upfront 14;

Relapsed 23)

100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%

Venner et al ASH 2011

Cyclo-Vel-Dex UK experience

Organ response 46% including cardiac 11%

Long term outcomes after ASCT

Organ response - 78%

Organ response - 39%

Cibeira et al. Blood; 2011; 118 (16);4646-52

Targeting the deposits

Reduce supply of
amyloidogenic precursor
The clone

Stop Light chain

production
Chemotherapy
SCT

Native Monoclonal
protein

Light chain
removal

Inhibit or reverse
amyloidogenesis
Unfolding/Misfolding

Stop amyloid
formation GAG
inhibitors

Amyloid Deposits

Breakdown
the amyloid
fibrils antibodies

Towards a cure?
SAP & amyloid formation

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

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
St Georges Hospital
Dr Lisa Anderson
Dr Jason Dungu

Royal Brompton Hospital

Dr Sanjay Prasad
Prof. Dudley Pennel
Dr. Agata Grasso
University Of Pavia
Prof. Giampaolo Merlini
Dr Giovanni Palladini