Management of AL amyloidosis in 2011
Giampaolo Merlini
gmerlini@unipv.it
Amyloid Research and Treatment Center
Fondazione IRCCS Policlinico San Matteo
University of Pavia, Italy
Disclosures
Honoraria:
Millennium, Novartis Diagnostics, Janssen
1
Systemic AL Amyloidosis: 8.9/million person-year
Small clone
heart (74%)
CHF 27%
kidney (65%)
Nephrotic s. 52%
Renal fail. 18%
Misfolded LC
liver (17%)
GI (8%)
PNS (19%)
ANS (16%)
soft tissues (12%)
Management of AL amyloidosis in 2011
o AL amyloidosis is characterized by progressive
damage of vital organs
o Patients are fragile and particularly sensitive to the
toxic effects of chemotherapy
o Survival is determined by cardiac dysfunction and
reduction of the FLC burden
2
Management of AL amyloidosis in 2011
Early diagnosis: anticipate irreversible
organ damage
DIAGNOSING AMYLOIDOSIS
Early red flags:
- increased levels of cardiac biomarkers (NT-proBNP)
(monitor NT-proBNP in patients with MGUS)
- urinary albumin > 300 mg/g creatinine
- hepatomegaly or alkaline phosphatase elevation
- progressive peripheral neuropathy
- orthostatic hypotension, autonomic neuropathy
(persistent diarrhea/constipation, impotence)
- profound fatigue and unexplained weight loss
Periorbital purpura 11%
Macroglossia 14%
3
Diagnosis of amyloidosis relies on tissue biopsy
IFix of serum and urine + serum FLC
Obtain fat and bone marrow specimens for Congo red staining
Sensitivity ~ 90%
Biopsy of the labial minor salivary
glands
Biopsy of the organ involved
(beware of the hemorrhagic risk)
The most common types of systemic amyloidoses
Type
Precursor
Organs involved
(abbreviation)
(site of synthesis)
Liver/
PNS/
Soft
Heart
Kidney
GI
ANS
Tissue
Immunoglobulin LC
Monoclonal LC
amyloidosis (AL)
(BM plasma cells)
X
X
X
X
X
Reactive
SAA1 (liver)
amyloidosis (AA)
(X)
X
X
XANS
Senile systemic
Transthyretin wild
amyloidosis (SSA)
type (liver >90%)
X
Transthyretin
Variant transthyretin,
amyloidosis (ATTR)
(liver >90%)
X
(X)
X
(X)
Fibrinogen
Variant fibrinogen
amyloidosis (AFib)
-chain (liver)
X
Apolipoprotein AI
Variant Apo A-1
amyloidosis
(liver, intestine)
X
X
X
(X)
(AApoA-1)
Clinically, it is difficult to distinguish between the various types of amyloidosis:
MGUS coincidental with hereditary and senile amyloidosis in the elderly
4
The most common types of systemic amyloidoses
Type
Precursor
Established Therapy
(abbreviation)
(site of synthesis)
Immunoglobulin LC
Monoclonal LC
Chemotherapy
amyloidosis (AL)
(BM plasma cells)
ASCT
novel agents
Reactive amyloidosis
SAA1 (liver)
Treat underlying diseases
(AA)
new drug
Senile systemic
Transthyretin wild type
amyloidosis (SSA)
(liver >90%)
Supportive
Typing of amyloidosis is essential for the choice of therapy
Transthyretin
Variant transthyretin,
Liver/heart transplantation
amyloidosis (ATTR)
>100 amyloidogenic
new drugs
mutations (liver >90%)
Fibrinogen
Variant fibrinogen
amyloidosis (AFib)
-chain (liver)
Organ transplantation
Apolipoprotein AI
Variant Apo A-1
Organ transplantation
amyloidosis (AApoA-1) (liver, intestine)
Supportive
Typing of amyloidosis
· Immunohistochemistry: unreliable in AL amyloidosis
· Electron microscopy + immunogold: reliable, limited by Ab
availability
· MS based proteomics will become (is, Rome Symposium on
Amyloidosis, 2010) the gold standard for classification of
amyloidosis
When compared to immunohistochemistry, MS is
- Objective-data driven
- More specific
- Reproducible
- Open to further analysis: increase in disease knowledge
DNA analysis for hereditary amyloidosis
5
Classification of amyloidosis by laser microdissection and mass
spectrometrybased proteomic analysis in clinical biopsy
specimens
Vrana et al, Blood. 2009;114:4957-4959
Novel approach for proteomic analysis of whole subcutaneous
adipose tissue allows reliable typing of systemic amyloidoses
Brambilla, Lavatelli et al, 2011
IEM-
Case confirmed IgLCk* IgLC* TTR SAA
diagnosis
P6
13
212
6
6
P11
6
165
4
0
P2
0
130
0
0
- washing
P1
0
88
6
0
Congo
Congo
P9
13
61
9
0
red +
red -
- protein extraction P12
AL
8
50
0
0
P13
14
34
0
0
P8
7
33
0
0
- delipidation
P4
0
22
0
0
(centrifugation)
P3
0
21
0
0
P5
0
13
0
0
P10
0
6
0
0
P15
372
0
0
0
P14
176
0
0
0
Digestion of the
ALK
P25
44
0
0
0
protein mixture
P26
14
0
0
0
P19
4
0
1158
0
P20
0
0
185
0
P16
ATTR
4
0
145
0
P18
0
0
89
0
MudPIT
P7
4
0
16
0
P22
0
0
0
638
Multidimensional Protein
10-30 mg
P23
0
0
0
261
Identification Technology
P17
SAA
10
0
0
166
P24
0
0
0
93
P21
0
0
0
71
6
Monitoring amyloid load - SAP scan
Radiolabelled SAP scintigraphy: posterior images of a 52-year-old woman with systemic
AL kappa amyloidosis, before (left) and 1 year after (right) HDM chemotherapy. The serum
concentration of free kappa light chains had fallen from 551 mg/l to 52 mg/l.
Lachmann et al, Br. J. Haematol, 2003, 122:7884
Treatment of AL amyloidosis
Aim of therapy:
Clonal,
hematologic
o
prompt elimination of the
response
misfolded light chains
o
stabilization or reduction of
Organ
cardiac biomarkers
(cardiac)
response
o
minimization of treatment
toxicity
Improved
o
support of the function of
OS and
target organs
QOL
7
Chemotherapy for AL amyloidosis is highly
individualized and risk-adapted
Assessing the risk
Disease-related
Patient-related
Characteristics of the clone
Severity of heart involvement
· PC number, cyclin D1, miRNA, ploidy, · Cardiac biomarkers, imaging
karyotypic aberrations......
Characteristics of the LC
Other patient characteristics
· FLC burden, germline genes usage, · Age, renal function, other
instability, cytotoxicity...
biomarkers (uric acid, 2m...)
Overall survival according to the MFC immunophenotypic
evaluation of the BMPC compartment
% BMPC
% normal-PC/BMPC
100
100
90%
P = .02
P = .01
88%
80
80
)
)
(%
(%
al
60
al
60
iv
iv
44%
surv
surv
37%
40
40
eral
eral
Ov
Ov
20
20
0
0
0
20
40
60
80
100
120
0
20
40
60
80
100
120
Time from diagnosis (months)
Time from diagnosis (months)
1% BMPC (n=14) median OS: not reached
>5% N-PC/BMPC (n=17) median OS: not reached
>1% BMPC (n=21) median OS: 16 months
5% N-PC/BMPC (n=18) median OS: 15 months
Paiva et al. Blood 2011 117: 3613-3616
8
Serum immunoglobulin free light-chain measurement in primary
amyloidosis: prognostic value and correlations with clinical features
Kumar et al, Blood. 2010;116:5126-9
730 patients with newly diagnosed AL
> 294 mg/L
> 182 mg/L
In multivariate analysis, dFLC was independent of other prognostic factors
HEART INVOLVEMENT IN AL AND PROGNOSIS
85% of patients die a cardiac death
· ventricular thickening
· diastolic (systolic)
dysfunction
· pericardial effusion
· strain Doppler imaging
· low peripheral voltages
at ECG
Cardiac biomarkers:
Amyloid GAD kinetic on MRI
· Natriuretic peptide type B (NT-proBNP - BNP)
C. Rapezzi
· Troponins (cTnI or cTnT)
· High-sensitivity troponins
Staging system for AL amyloidosis
Dispenzieri et al, J Clin Oncol 2004; 22:3751-3757
9
The new high-sensitivity assay for cardiac troponin T (hs-cTnT) can
be used for cardiac staging in patients with AL amyloidosis.
Palladini G...Schönland S, 13th IMW Paris 2011, P-439
Survival of 221 patients with AL amyloidosis according to hs-cTnT and NT-
proBNP concentrations
1.0
0.9
0.8
p=0.005
0.7
0.6
viving
sur 0.5
tion
p<0.001
0.4
oporPr 0.3
median survival 8.6 months
0.2
Stage I-hs , hs-cTnT <77 ng/L and NT-proBNP<332 ng/L (45 patients)
0.1
Stage II-hs , hs-cTnT >77 ng/L or NT-proBNP >332 ng/L (126 patients),HR 3.1
Stage III-hs , hs-cTnT >77 ng/L and NT-proBNP >332 ng/L (50 patients),HR 9.9
0.0
0
12
2436
486072
84
Time (months)
Recent improvements in survival in primary systemic amyloidosis
and the importance of an early mortality risk score
Kumar et al, Mayo Clin Proc. 2011;86:12-8 used with Permission
313 patients seen during 2006-2009
Risk factors:
· cardiac troponin T >0.01 g/L
· NT-proBNP >4200 ng/L
· s.uric acid >8.0 mg/dL
10
Management of AL amyloidosis in 2011
Survival determinants:
cardiac involvement and response to therapy
Validation of the criteria of response to treatment in AL amyloidosis
Palladini G, Dispenzieri A, Gertz MA, Wechalekar A, Hawkins PN, Schönland S, Hegenbart U,
Comenzo R, Kastritis E, Dimopoulos MA, Jaccard A, Klersy C, Merlini G
XII Intl. Symposium on Amyloidosis, Rome 18-21 April, 2010
ASH 2010 Abstr. # 1364
816 patients from 7 centers (enrolled between 1995-2010)
649 (80%) with response data at 6 months.
1.0
1.0
0.9
0.9
p=0.016
p=0.01
0.8
0.8
p=0.007
0.7
p<0.001
0.7
0.6
0.6
p=0.041
surviving
surviving
0.5
p<0.001
0.5
0.4
0.4
Proportion
Proportion
0.3
0.3
CR (97 patients, 3.6 deaths/100 py)
CR (37 patients, 1.0 deaths/100 py)
0.2
VGPR (233 patients, 9.6 deaths/100 py)
0.2
VGPR (122 patients, 7.4 deaths/100 py)
PR (140 patients, 23.7 deaths/100 py)
PR (47 patients, 19.9 deaths/100 py)
0.1
0.1
NR (179 patients, 47.2 deaths/100 py)
NR (94 patients, 32.9 deaths/100 py)
0.0
0.0
0
12
243648
012
24
36
48
Time (months)
Time (months)
Survival of 649 patients based
Survival of 300 patients based
on hematologic response at 6 months
on hematologic response at 3 months
11
Validation of the criteria of response to treatment in AL amyloidosis
Palladini G, Dispenzieri A, Gertz MA, Wechalekar A, Hawkins PN, Schönland S, Hegenbart U,
Comenzo R, Kastritis E, Dimopoulos MA, Jaccard A, Klersy C, Merlini G
XII Intl. Symposium on Amyloidosis, Rome 18-21 April, 2010
ASH 2010 Abstr. # 1364
New Response Criteria
negative serum and urine IFE
aCR
normal / ratio
VGPR
dFLC <40 mg/L
PR
dFLC decrease 50%
NR
other
The use of dFLC (involved FLC-uninvolved) FLC compensates for
altered FLC metabolism in patients with renal failure
Pinney et al, JCO 2011; 29:674-681
See also Poster 431 by Gibbs et al
Validation of the criteria of response to treatment in AL amyloidosis
Palladini G, Dispenzieri A, Gertz MA, Wechalekar A, Hawkins PN, Schönland S, Hegenbart U,
Comenzo R, Kastritis E, Dimopoulos MA, Jaccard A, Klersy C, Merlini G
XII Intl. Symposium on Amyloidosis, Rome 18-21 April, 2010
ASH 2010 Abstr. # 1364
1.0
1.0
0.9
0.9
0.8
0.8
p=0.021
p<0.001
0.7
0.7
ngvi 0.6
0.6
survi
surviving
p=0.005
0.5
p<0.001
ion
0.5
0.4
Proport
Proportion 0.4
0.3
0.3
0.2
NT-proBNP progression (169 patients)
NT-proBNP progression (58 patients)
NT-proBNP progression (at least 300 ng/L and 30% increase), 169 patients
NT-proBNP stable (108 patients)
0.1
NT-proBNP stable, 108 patients
0.2
NT-proBNP stable (91 patients)
NT
NT-proB
-pr N
o P res
BN pons
P r e
e (at least 300
sponse ng/
(1 L and
00 30%
pati dec
e reas
nts)e), 100 patients
NT-proBNP response (53 patients)
0.0
0.1
012
24
36
48
0
122436
48
Time (months)
Time (months)
Survival of 377 patients with
Survival of 202 patients with baseline
baseline NT-proBNP 650 ng/L according
NT-proBNP 650 ng/L according to
to NT-proBNP response and progression
NT-proBNP response and progression
at 6 months
at 3 months
Caution using NT-proBNP in patients treated with IMiDs
Tapan et al, Blood 2010; 116: 5071-2
Dispenzieri et al, Am. J. Hematol 2010; 85:7579
12
Management of AL amyloidosis in 2011
Chemotherapy guided by frequent assessment of FLC
and cardiac biomarkers
Early intervention with rapidly-acting agents is necessary
to achieve optimal response
Available treatments for AL amyloidosis (ITT)
Melphalan and Dexamethasone
Patient/
Organ
TRM%
HR/CR %
Author
prev.tx
Resp %
(SAE%)
Melph-predn-colch
50
NR
20
NR (8)
Skinner 1996
Melph-prednisone
148
28
18
NR (5)
Kyle 1997
Dexamethasone
44/19
40-53/10-16
12-16
5-8 (NR) Gertz 1999
Dexa+maint. IFN
87/14
33/15
45
7 (67)
Dhodapkar 2004
HDM/SCT (single center)
312
58/23
26
13 (NR)
Skinner 2004
HDM/SCT (single center)
171
68/NR
NR
12 (NR)
Gertz 2004
HDM/SCT (multicenter)
37
67/41
45
24 (NR)
Jaccard 2007
Melphalan-Dex
46
67/33
48
4 (11)
Palladini 2004
43
68/32
39
2 (16)
Jaccard 2007
13
Trends in day 100 and 2-year survival after auto-SCT for AL amyloidosis:
outcomes before and after 2006
Gertz et al, Bone Marrow Transplant. 2010 Oct 11.
265 patients pre Jan 2006 - 157 patients post Jan 2006
Survival through d 100 in patients with AL who
Survival through 24 mo. in patients with AL who
underwent SCT before and after 2006 (P=.09)
underwent SCT before and after 2006 (P=.09)
On multivariate survival analysis, higher levels of serum troponin T and NT-
proBNP were the only predictors of early mortality after SCT.
Short-term mortality reduced more than 40% after 2005.
Outcome of AL amyloidosis after high-dose melphalan and
autologous stem cell transplantation: long-term results in a
series of 421 patients
Cibeira et al, 13th IMW Paris, 2011 P-434
ITT Analysis (N=421)
100%
Median EFS: 2.6 years (CI95% 2.0-3.4)
TRM: 11.4% overall, decreased to
Median OS: 6.3 years (CI95% 5.4-7.4)
80%
5.6% in the last 5 years
,% 60%
vival
340 (80%) evaluable at 1 year:
Sur
43% CR and 78% organ resp.
40%
OS
CR patients: median EFS 8.3 yrs and
20%
EFS
OS 13.2 yrs
0%
02
4
6
8
10 12 14
16
Time from SCT (years)
14
An Italian prospective study of outcomes in AL amyloidosis
Treatment of intermediate-risk patients with MDex
· 131 patients, median age 64y
· Mayo Stage I 29%, Mayo Stage II 71%
· Deaths at 3 months 2%, SAE 19%
1.0
· Hematologic Response (ITT): 0.9
CR:
26%
0.8
VGPR: 24%
0.7
64%
ving
PR:
14%
0.6
survi
NR:
36%
0.5
on
0.4
Proporti 0.3
· Organ response
median survival 77 months
0.2
heart:
33%
0.1
kidney: 34%
0.0
0
1224
3648607284
Time (months)
Autologous stem cell transplantation (ASCT) versus oral melphalan and
high-dose dexamethasone in patients with AL (primary) amyloidosis: long
term follow-up of the French multicentric randomized trial
Jaccard et al, N Engl J Med. 2007;357:1083-93
Jaccard et al, ASH 2010, Abstr. # 1344
Survival according to treatment
Event-free survival according to treatment
group in the landmark analysis
15
Available treatments for AL amyloidosis (ITT)
Novel agents
Patient/
Organ
TRM%
HR/CR %
Author
prev.tx
Resp %
(SAE%)
Thalidomide-Dex
31/31
48/19
26
0 (65)
Palladini 2005
Cycl-Thal-Dex
75/44
74/21
27
4 (32%) Wechalekar 2007
Lenalidomide±Dex
22/13
41/NR
23
18 (86)
Dispenzieri 2007
34/31
47/21
21
3 (35)
Sanchorawala 2007
Lenalidomide-MDex
26/0
58/23-4215mg
50
0 (81)
Moreau 2010
Pomalidomide-Dex
32/32
41/9VGPR
H 11, K 17
NR (65) Dispenzieri 2010abs
Bortezomib
54/54
67/29
28
0 (50-79) Reece 2011
Bortezomib-Dex
94/76
71/25
30
0 (29)
Kastritis 2010
Bortezomib-MDex
33/19
84/29
H 14, K 27
NR (60) Gasparetto 2010abs
Cycl-Bortez-Dex
15/7
93/73
K 40
NR
Mikhael 2010abs
Adjuvant bortezomib and dexamethasone following risk-adapted melphalan
and stem cell transplant in systemic light-chain amyloidosis (AL): A phase II
study
Landau et al, ASH 2010 Abstr. #2391
ORR 55%
ORR 95%
CR 24%
CR 62%
ORR 82%
CR 53%
(n=28)
(n=21)
(n=17)
Months post-SCT
16
A European collaborative study of treatment outcomes in 428
patients with systemic AL amyloidosis
Wechalekar AD, Kastritis E, Merlini G, Hawkins PN, Dimopoulos MA, Gillmore J, Gibbs S,
Palladini G.
ASH 2010, Abstr. #988
· Bortezomib is associated 80% haematological responses with 50%
achieving at least dFLC-VGPR
· It is rapidly acting (hematologic responses in 4-6 weeks)
· Translates in high organ response rates even in advanced risk patients
European collaborative study of 242 patients with systemic AL amyloidosis
with Mayo Stage III disease Wechalekar AD, Schoenland S, Kastritis E, Merlini G,
Hawkins PN, Dimopoulos MA, Russo P, Lane T, Foli A, Foard D, Milani P, Rannigan L,
Hegenbart U, Gillmore JD, Palladini G.
13th IMW Paris, 2011 P-438
dFLC
Response
response
CR/dFLC-VGPR
50 (21%)
PR
34 (14%)
NR
29 (12%)
ECOG performance status
1
112 (47%)
Response (ITT)
84 (34%)
2
71 (29%)
3
59 (24%)
NYHA status
1
41 (17%)
median OS: 8 months
2
57 (23%)
3
114 (54%)
37% of patients completed the
planned treatment
17
An Italian prospective study of outcomes in AL amyloidosis
Survival of 531 patients with AL amyloidosis
1.0
0.9
16% died at 3 months
0.8
0.7
0.6
surviving 0.5
0.4
median survival 42 months
Proportion
median follow-up of living patients 34 months
0.3
0.2
0.1
0.0 0
12
2436
486072
Time (months)
An Italian prospective study of outcomes in AL amyloidosis
Survival of 464 patients with AL amyloidosis according to
the Mayo Clinic staging system
1.0
0.9
18%
0.8
p<0.001
0.7
ing
median survival 49 months
iv
urv 0.6
s
43%
ion
p<0.001
0.5
Proport 0.4
median survival 6 months
0.3
39%
Stage I (82 patients)
0.2
Stage II (202 patients)
Stage III (180 patients)
0.1
0
1224
3648
60
Time (months)
18
An Italian prospective study of outcomes in AL amyloidosis
Survival of 180 patients with Mayo Clinic stage III AL amyloidosis according to
NYHA class, NT-proBNP and dFLC
Risk factors
· NT-proBNP >10,000 ng/L
1.0
· dFLC >500 mg/L
0.9
Group 1, no risk factors (40 patients)· NYHA class 3 or 4
0.8
Group 2, 1 risk factor (53 patients)
i
Group 3, 2 or 3 risk factors (87 patients)
0.7
vivent
0.6
median survival not reached
Soprava
Consider heart
0.5
mulatu
p=0.02
transplantation upfront
C 0.4
median survival 9 months
ione
0.3
p=0.003
Proporz
0.2
0.1
median survival 3 months
0.0
0
1224364860
Tempo
Management of AL amyloidosis in 2011
Transplanting the irreversibly damaged organs
Orthotopic heart transplantation (+ASCT)
in selected patients:
· younger
· at high cardiac risk
· without significant extra-cardiac amyloidosis
Best tolerated treatment should start immediately at diagnosis and after
OHT while waiting for possible ASCT
Criteria for eligibility remain to be defined
International prospective studies needed to establish guidelines
Dey et al, Transplantation 2010; 90:905-11
Sattianayagam et al, Am J Transplant 2010;10:2124-31
Kristen et al, Eur J Heart Fail 2009; 11:1014-20
Lacy et al, J Heart Lung Transplant 2008; 27:823
Mignot et al. Arch Cardiovasc Dis. 2008;101:523-32.
19
Management of AL amyloidosis in 2011
Cardiac stage 1 & 2
Cardiac stage 3
ASCT eligible
MDex
(15-25%)
(BMDex)
Low dose regimens
OHT
Novel therapies
CyBorD
CR or
CTD
PR
PR+OR
CR or
PR
BDex
Follow up or
PR+HR
CTD
maintenance ?
LenDex
LenBDex
Follow
PomDex
ASCT
up
Patients should be treated within
consolidation
controlled clinical trials
BDex, LenDex,
TDex
Conclusions
· Early and correct diagnosis is vital
· Use cardiac biomarkers for risk assessment
· Prompt therapy and frequent monitoring with FLC
and cardiac biomarkers
· Novel therapeutic approaches needed for patients
with advanced cardiac involvement
· Phase III trials necessary to define optimal therapy:
international collaboration needed
20
· AL amyloidosis is a rare disease. In order to make progress
national and international collaborations are needed
Italian Amyloidosis Network
European Network for Phase III trial
comparing MDex vs BortezMDex
A common diagnostic and
therapeutic protocol is periodically
discussed and updated: in Brescia
on April 2, 2011
Survival of 1131 patients with AL amyloidosis according to the year of diagnosis
followed at the Pavia Amyloid Research and Treatment Center
1.0
0.9
0.8
0.7
0.6
surviving 0.5
0.4
Proportion
0.3
p=0.016
0.2
1984-1994 (153 patients)
1995-1999 (208 patients)
0.1
2000-2004 (418 patients)
2005-2008 (352 patients)
0.0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
Time (months)
21
Perspectives in the treatment of AL amyloidosis
Proteasome Inhibitors
siRNA
MoAb
mRNA
CPHPC
GAG mimetics
GAGs
Amyloidogenic
AntiSAP moAb
plasma cell
111F4 Ab
Misfolded LC
Chemotherapy (bendamustine,
HDAC inhib.......)
Amyloid
Inhibitors of
deposits
Novel therapeutic approches
proteotoxicity
for new drug targets will be
integrated with chemotherapy
in the future
University of Pavia and Fondazione IRCCS Policlinico San Matteo
Amyloidosis Research and Treatment Center
Vittorio Bellotti
Paolo Milani
Giovanni Palladini
Gabriele Sarais
Simona Casarini
Francesco Musca
Margherita Pasotti
Monica Stoppini
Simona Donadei
Vittorio Necchi
Vittorio Perfetti
Veronica Valentini
Andrea Foli
Mario Nuvolone
Stefano Perlini
Laura Verga
Sofia Giorgetti
Laura Obici
Paola Rognoni
Francesca Lavatelli
Paola Russo
Francesco Salinaro
Fondazione
IRCCS Policlinico
San Matteo
Pavia
22