Refining Therapy for AL
AL Amyloidosis
Amyloidosis
Vaishali Sanchorawala, MD
12th
12 International Myeloma
Myeloma Workshop
Workshop
Washington DC
February 28, 2009
Faculty Disclosure Information
Consultant: No
Grant/Research Support:
pp
Celgene,
g
Johnson & Johnson
Speakers Bureau:
Bureau: Ortho Biotech
Biotech
Major Stock Shareholder: No
Treatment Targets
Tr
T eatment Target
Target
Tr
T eatment
Tr
T eatment Status
Approach
Precursor Protein Production
Chemotherapy
In use: AL
NSAID
In use: AA
Liver Transplant
In use: ATTR
Renal Tr
T ansplant In use: DRA
Fibril Formation
GAG mimetics
Human studies: AA
TTR stabilizers
Human studies: ATTR
Amyloid Deposits
GAG mimetics
Human studies: AA
IDOX
Human studies: AL
SAP depletion
Human studies:
studies: AL
Monitoring Therapeutic Effect
· Key elements
elements
Early diagnosis and correct typing
Fine balance of chosen treatment regimen and patient's
ability to bear toxicities
· Hematologic complete response
Absence of
of monoclonal
monoclonal gammopathy in serum and urine by
by
IFEs
Absence of clonal plasma cells in bone marrow biopsy
Normalization of
of free
free light chain ratio
ratio
· Organ/Clinical response
May take from 3-12 months after treatment
Gertz et al. Am J Hematol, 2005
Conventional Treatment
· Randomized clinical trials of oral cyclic
melphalan and prednisone
Boston1
1996
Mayo Clinic2
1997
· Median survival 16 -18 months
· Hematologic complete response rare
· Reversal of organ dysfunction rare
Skinner et al. Am J Med, 1996
Kyle et al. N Eng J Med, 1997
High-
High Dose Melphalan and Stem Cell
Transplantation (HDM/SCT)
· Development of this treatment approach
prompted by promising results of similar
regimens in myeloma.
· Objectives of early clinical trials:
Determine tolerability of this treatment approach in
patients with AL Amyloidosis.
Determine efficacy of this treatment in inducing
complete hematologic response
response.
Determine whether complete hematologic
response leads to reversal of amyloid-related
disease and increase survival.
Prolonged Survival with HDM/SCT
1994-2008
(n=497)
100
Median Survival 73 months
5 year Survival 55%
80
(%)
60
vival
40
Sur
20
0 02468
1
3
5
7
9
10 11
12
13 14
Time (years)
Pt
Pa iti t
en s, n: 497 378 309 256 212 183 151 116
11
83
60
43
24
17
6
3
Sanchorawala et al, ASH 2008
Long-
Long term Outcome after
after HDM/SCT
1994-1997
(n=80)
1.0
n
Md
Me i
dian > 10
0.8
10 yrs
0.6
CR
istributio
estimate
d
0.4
Median 4.1 yrs
p < 0.001
urvival
function 0.2
S
Non-CR
S
0 0
50
100
150
Months
Sanchorawala et al. Blood, 2007
Oral Cyclic Melphalan and
Dexamethasone
N
li ibl f
HDM/SCT
10
· Not eligible for HDM/SCT
1.0
· Hematologic response
0.8
67%, CR 33%
portion
g
· Clinical response 48%
0.6
pro
· Median time to response
0.4
survivin
4 5
. months
months (range 2 3
lativeu
.3-
0.2
10.1)
Cum
· Durable responses
0 0 12 3 47
5
6
· Overall median survival
Survival time, years
5.1 years
Overall survival of 46 AL amyloidosis patients treated
with M-Dex. The median survival is 5.1 years, and the
· TRM 4%
median follow-up of living patients is 5 years (range,
TRM 4%
3.5-6.7 years)
Palladini et al. Blood, 2004
Palladini et al. Blood, 2007
Randomized Study: IFM
100
90
80
al(%)
Melphalan plus dexamethasone
70
a
60
50
40
p = 0.04
llsurviv
30
High-dose melphalan plus stem-cell rescue
Overa
20
10
0 010
20
30
40
50
60
70
80
Months since randomization
Jaccard et al. NEJM, 2007
Comparison of results of HDM/SCT,
Jan 2000-2005 Multi-center vs. Single center
French
BUMC
Intergroup
Number of pts offered
offered SCT
SCT
50
172
Number of pts receiving
37 (74%)
152 (88%)
SCT
Treatment-related mortality
26%
9%
Md
Me i
dian
i
surv val
22.2 month
ths
Nt
Not
h
reac
d
e ,
6 yr survival
52%
Md
Me i
dian f l
o lllow-up
24 months
38 months
What is the Optimal Melphalan-Based
Chemotherapy?
·
HDM/SCT yields a high rate of complete, durable
hematologic responses, accompanied by clinical
responses
High risk of organ-related complications
Multidisciplinary patient evaluation and center experience
reduces treatment-related complications
·
Oral melphalan + dexamethasone also produces
ht
hemat l
o
i
og c
d
an clili i
n
l
ca responses
Toxicity due to chronic steroids and alkylating agents
Median time to response 4.5 months
·
Further phase III trials in tertiary referral centers are
required
MD vs risk adapted HDM/SCT
Consider addition of novel agents to the arms
Novel Therapies for AL
AL Amyloidosis
Amyloidosis
· Thalidomide
Thalidomide studied as single agent or in combination with
Dexamethasone
Single agent
gg
responses,
p
~25%
With Dexamethasone, ~50%
Thal/Dex combination
· Hematologic response 48%, CR 19%
· Clinical response 26%
Poorly tolerated
· 50% Gr 3/4 toxicity as single agent, 65% combined with
Dt
Dexame h
thasone
· Drug withdrawal in 25-50% patients
Seldin et al. Clin Lymphoma, 2003
Dispenzieri et al. Amyloid, 2003
Palladini et al. Blood, 2005
Novel Therapies for AL Amyloidosis
· Lenalidomide
Phase II trials at Mayo
y Clinic and Boston
University Medical Center
Lenalidomide +/- Dexamethasone
Pl
Pre ili i
m nary
l
resu ts i d
n i
dicate better l
to
b
era ili
bility
· Fatigue, rash, leukopenia, thromboses
Overall Hematologic
Hematologic Response Rate
Rate
· 56%, CR 27%
Median Time to Response
· 6 months (range 3-9)
50% responses durable even after stopping
treatment
Sanchorawala et al, Blood 2007; Dispenzieri et al, Blood
2007; Seldin et al, ASH 2007
Novel Therapies for AL Amyloidosis
py
· Bortezomib
International phase I/II trial opened 08/05, completed
accrual
Phase I dose-escalation study aimed to determine
MTD f
o once-weekly
d
an t i
w ce-weekl
kly schdl
hedule
d
an
preliminary hematologic response
31 patients with relapsed AL enrolled
DLT grade 3 CHF: 2 patients
MTD not defined, 1.6 mg/m2 (once-weekly) and 1.3
mg/m2
mg/m (twice weekly)
-
used
used for
for phase IIII evaluation
evaluation
Hematologic responses 50%, CR 20%
Median time to response 1.2 months
Kastritis et al. Haematologica, 2007; Wechalekar et al.
Haematologica, 2008; Reece et al. Blood 2009 (accepted)
Combination Therapies for AL
AL
Amyloidosis
· CTD: Cyclophosphamide, Thalidomide and
Dexamethasone
Hematologic response 74%, CR 21%
Md
Me i
dian overallll
i
surv
l
va 41
41 month
ths
TRM 4%
· MRD: Melphalan, Lenalidomide and Dexamethasone -
Boston
· CRD: Cyclophosphamide, Lenalidomide and
Dexamethasone Mayo Clinic
· VMD: Bortezomib, Melphalan
,p
and Dexamethasone Multi
center trial, poster by Zonder et al
· Vel-Mel transplant: Bortezomib and melphalan
conditioning for autoSCT, Boston
Wechalekar et al. Blood 2007
Treatment for amyloidosis is increasingly
based on an understanding of the
pathophysiology of the disease
Future Directions
· Clonal plasma cell expansion
Anti-plasma cell chemotherapy (current approach)
· Light chain synthesis and secretion
Anti-sense and siRNA strategies (Tennesse, Boston)
Light chain or oligome
gg
r-mediated cell toxicity
LCs or small oligomers may be taken up by cells and mediate acute
organ toxicity
Clinical observations
In vitro studies: Liao (heart), Trinkaus-Randall (fibroblasts),
Herrera (kidney)
Can drugs that block uptake or protect cells from damage be
fd
foun ?
d?
Aggregation and fibril formation
Very challenging since each LC protein sequence and structure is
different
www.bu.edu/amyloid
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