Ashutosh Wechalekar Wild type ATTR is increasingly recognised S Ravichandran Lachmann H and Wechalekar AD N Engl J Med 202038215671568 23 of patients with wtATTR have underlying MGUS Typing cardiac amyloid remains of critical importance in older patients ID: 935859
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Slide1
Amyloidosis Update - 2021
Ashutosh Wechalekar
Slide2Wild type ATTR is increasingly recognised
S Ravichandran, Lachmann H and Wechalekar AD. N Engl J Med 2020;382:1567-1568.
23% of patients with
wtATTR
have underlying MGUS
Typing cardiac amyloid remains of critical importance in older patients
With isolated cardiac disease
Slide3Improvement in survival of patients with AL amyloidosis
1995-2008
2010-2016
Median survival – 65 months
Improvement in overall survival for patients with AL amyloidosis:
Until 2003 – 1.5-1.7
yrs
2004-2008- 2.2
yrs
2008-10 – 5.4
yrs
20010-18 – NR
Slide4Some things have not changed!
4
Early mortality has not improved for high-risk patients
Courtesy Dr Kastritis
EMN 23 study ASH 2020 abstract
Slide5What is new in amyloid imaging
18
F-Florbetaben – licenced of Alzheimer’s imaging –
18F-labelled p5+14 –
FDG labelled P5+14
Slide6New “functional” end points
Longitudinal Strain
6m walk test
Cohen O et al 2021 – manuscripts under review
Slide7Response assessment and Treatment
Definition of response:
new response category dFLC <10 mg/L
Composite organ + clonal response – multicentre Mayo led project – awaiting final analysisMRDMS-FLC based responses
Significantly greater cardiac and renal responses
Slide8Impact of Time to response on outcomes
Time to Response:
Early response and outcomes – ≥VGPR at 1 month better outcomes in all disease stages
Time to relapse and outcomes – TTNT < 24 months
Slide9Log-rank p<0.0001
dFLC<10mg/L:
Median TNT not reached
dFLC 10-40mg/L:
Median TNT 38 months
dFLC≥40mg/L:
Median TNT 13 months
CVD remains current front line with good outcomes
Analysis of
of
CyBorD treated patients from NAC shows improved outcomes and results for patients with deep long lasting responses
1
1
Manwani et al
Blood 2019
Main limitation of CyBorD
CR still <30% (ITT)
CR+VGPR ~60% (including 15% with added agents)
Slide10The debate continues: Transplant or no transplant
No significant difference between outcomes of a matched patient cohort – VCD vs. ASCT
Sharpley et al BJH 2020
Sharpley et al EJH 2021
Slide11Andromeda trial run in phase – new response classification are achievable
dFLC
, difference between involved and uninvolved free light chain; NR, no response; PR, partial response; VGPR, very good partial response; CR, complete response.
20/28 (71%) patients have an absolute
dFLC
level <10 mg/L
NR
VGPR
CR
PR
Lowest
dFLC
Achieved on Study (mg/L)
190
Slide adapted from EHA 2019 Oral presentation
Slide12Andromeda: Dara-VCD better than VCD
The CR rate at 6 months was consistent with overall CR rate
50% DARA-CyBorD vs 14% CyBorD
(odds ratio 6.1; P <0.0001)
Median time to CRa: DARA-CyBorD: 60 days
CyBorD: 85 days
Best Response of
Haematologic
CR
Odds ratio 5.1
(95% CI, 3.2-8.2);
P
<0.0001
53%
18%
n = 195
n = 193
% surviving without progression
0
2
4
6
8
10
12
14
22
20
18
16
Months
0
25
50
75
100
163
178
193
195
134
166
111
147
65
114
44
86
29
60
20
44
10
27
7
10
1
1
0
0
CyBorD
DARA SC +
CyBorD
No. at risk
CyBorD
DARA SC
+ CyBorD
MOD-PFS defined as haematologic progression (IRC assessed), end-stage cardiac or renal disease, or death
At a median follow-up of
11.4 months, MOD-PFS was
improved with DARA-CyBorD
a
DARA-
CyBorD
vs CyBorD
HR (95% CI)
0.58 (0.37-0.93)
P
value
0.0230
Slide: Courtesy Dr Kastritis
Slide13Stratification:
Cardiac risk stage
(1 vs 2 vs subgroup of 3)
Relapsed vs refractory disease
Prior PI exposure (naïve vs exposed)
Ixazomib in relapsed AL amyloidosis
TOURMALINE-AL1 phase 3 study design
Endpoints
Primary:
Hematologic ORR
2-year vital organ deterioration or death rate*
Key secondary:
OS
Hematologic CR rate
AL amyloidosis with cardiac and / or renal involvement
R/R after 1–2 prior therapies
N=168
Randomization
1:1
Until PD or toxicity
n=85
n=83
Ixa-Dex:
Ixazomib 4 mg on Days 1, 8, 15
Dexamethasone 20 mg
†
on Days 1, 8, 15, 22
Physician’s choice:
(prespecified choices)
28-day
cycles
*
Endpoint is not mature and was not intended to be analyzed at this data cut.
†
Dex could be increased up to 40 mg after 4 weeks if no grade >2 drug-related toxicities (also applies to Dex in physician’s choice).
‡
Mdex patients were treated to best response plus 2 additional cycles (max. 18 months or 600 mg total melphalan dose).
dexamethasone (Dex)
melphalan-dexamethasone (Mdex)
‡
cyclophosphamide-dexamethasone (CyD)
thalidomide-dexamethasone (Td)
lenalidomide-dexamethasone (Rd)
First IA for hematologic ORR planned when ~176 patients had completed 6 cycles/discontinued before receiving 6 cycles, for 90% power at a 2-sided alpha of 0.04 to test for a difference in hematologic ORR of 40% with physician’s choice and 65% with Ixa-Dex
Slide14Ixazomib in relapsed AL amyloidosis
Odds ratio > 1 favors Ixa-Dex
Hematologic response*
Patients (%)
Median duration of hematologic response
†
Physician’s choice regimens were Rd (n=47),
Mdex
(n=24),
CyD
(n=10), and Td (n=2)
Odds ratio (95% CI):
1.10 (0.60, 2.01), p=0.7623
Odds ratio (95% CI):
1.58 (0.76, 3.32), p=0.2234
HR (95% CI):
0.55 (0.26, 1.18), p=0.1176
HR < 1 favors Ixa-Dex
First interim analysis: All patients had completed 6 cycles of treatment or discontinued beforehand
Slide15Towards targeted treatment: Venetoclax in AL
Premkumar et al Blood Cancer Journal volume 11, Article number: 10 (2021)
All patients
(n=43)
No t(11;14)
t(11;14)
Slide16Anti-fibril antibody Cael-101 – phase I data shows early cardiac function by strain
http://www.caelumbio.com/wp-content/uploads/2017/02
Bhutani, D. et al. 60th Annual American Society of
Hematology; 2018. Abstract 958.
Slide17VITAL study update: Mayo (2012) stage IV patients
Gertz et al Abstract ASH 2019
mITT
analyses Mayo Stage IV disease (n=77):
Median OS: Placebo: 8.3 months vs not reached (>12 months) in the NEOD001
NEOD001 + SOC group - deaths occurred within the first 9 months
Placebo + SOC group - deaths occurred within first 3 months
(HR [95% CI]: 0.413 [0.191, 0.895];
P
=0.0251)
Slide18British Journal of
Haematology
, First published: 18 February 2020, DOI: (10.1111/bjh.16436)
Monoclonal antibodies in the treatment of AL amyloidosis: targeting the plasma cell clone and amyloid deposits
Anti SAP
Peptide p5+14
NEOD001
CAEL101
Proclara
CAR macrophage
Daratumumab
Belantamab
Slide19Planned trials
About to open
Newly diagnosed AL: CAEL101
CyBorD +/- CAEL101 or placebo – two studies IIIa and IIIbAwaiting contracts all stage III patients with eGFR >15ml/min eligible
Relapsed ALMelflufen-Dex in relapsed AL Phase 1/2 study was due to open but delayed by COVID
In planning for Q2 2021
NEO001 in Mayo stage IV patients
Belantamab
Mafoditin
awaiting ethics submission