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Wassef et al; NAC; unpublished; 2009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