Presentazione standard di PowerPointPavia, Italy l.obici@smatteo.pv.it
Il sottoscritto Laura Obici ai sensi dell’art. 3.3 sul Conflitto di Interessi, pag. 18,19 dell’Accordo Stato-Regione del 19 aprile 2012, per conto di Planning Congressi srl, dichiara che negli ultimi due anni NON ha avuto rapporti diretti di finanziamento con
soggetti portatori di interessi commerciali in campo sanitario che negli ultimi due anni ha avuto rapporti diretti di finanziamento con i
seguenti soggetti portatori di interessi commerciali in campo sanitario: - Pfizer - Novartis - Akcea - Alnylam
E che detti rapporti non sono tali da poter influenzare l'attività di docenza espletata nell'ambito dell'Evento nel senso di pregiudicare la finalità esclusiva di educazione/formazione dei professionisti della Sanità nell'attività formativa
Amyloidoses are protein misfolding diseases
Merlini G, Bellotti V. NEJM 2003; 349:583-96
AL 47%
AL 77% ATTR wt 5%
hATTR 7% Other
AL amyloidosis ++ ++ + + + +
hATTR amyloidosis ++ + - ++ ++ ++
ATTRwt amyloidosis ++ - - ± - -
AA amyloidosis ± ++ ++ - + +
AApoA-I amyloidosis + ++ ++ ± - -
When to suspect systemic amyloidosis
• Lethargy, fatigue
• Peripheral edema
• Heart failure
• Weight loss
Amyloid-related renal involvement
Heart involvement in amyloidosis
Echocardiography: wall thickness-GLS
Maceira et al, Circulation 2005 Banypersad et al, Circ Cardiovasc Img. 2013 Fontana et al, JACC Cardiovasc Img. 2017 Martinez-Naharro et al, ISA 2018 PA060 Cibeira et al, ISA 2018 PB095
Cardiac MRI: T1 mapping - LGE
ECG
Diagnostic pathway in systemic amyloidosis
1. Miyazaki et al, Int J Hematol, 2015 - 2.Coelho T, et al. EFNS abstract 2011 – Fernandez de Larrea et al, Blood 2015
Symptoms and signs Abnormal echo/MRI/bone scintigraphy
Abnormal NCS/GI/renal function
Identify the amyloid protein
Tissue of choice: - Abdominal fat aspirate - Labial minor salivary glands - Organ involved
Document amyloid deposits
Immunoelectron microscopy Proteomics
chains • Genetic analysis
NT-proBNP has 100% diagnostic sensitivity for cardiac involvement in AL amyloidosis
N T-
pr oB
N P
co nc
en tr
at io
n (n
g/ m
Palladini, et al. Circulation 2003
Screening with NT-proBNP and albuminuria of patients with MGUS and abnormal FLC ratio allows diagnosis at a pre-symptomatic stage Merlini & Palladini. Hematology 2012 Merlini, et al. Blood 2013 Palladini, et AL. ASH 2017 (poster #1760)
Prognostic factors in AL amyloidosis
Survival according to the revised Mayo Clinic staging system including FLC in the Pavia series
Revised staging system NT-proBNP >1800 ng/L, cTnI >0.07 ng/L, dFLC >180 mg/L
0 12 24 36 48 60
Time (months)
P ro
po rti
on s
ur vi
vi ng
Stage I (120 patients) Stage II (113 patients) Stage III (111 patients) Stage IV (124 patients)
P<0.001
P<0.001
P=0.002
Kumar, et al. JCO 2012; Kourelis, et al. JCO 2012; Bochtler, et al. JCO 2015
Survival according to BMPC infiltrate
High frequency of t(11;14) translocation (∼40- 60%): lower benefit from bortezomib, greater benefit from melphalan
Patients with higher tumor burden benefit most from induction therapy pre-ASCT
Hematologic and organ response are the ultimate goals of treatment in AL amyloidosis
AL amyloidosis
Cardiac damage
Reduced survival
Clonal, hematologic
Time (months)
P ro
po rti
on s
ur vi
vi ng
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<0.001
p<0.001
dFLC decrease ≥50%
Non-biopsy diagnosis of transthyretin amyloid cardiomyopathy
Gillmore et al. Circulation. 2016;133:2404-2412
Clinical presentation of 249 patients with ATTRwt amyloidosis
Variables N° (%) – median (IQR) Age, years 76 (55-80)
NT-proBNP, ng/L 2867 (1564-5243)
Creatinine, mg/dL 1.14 (0.93-1.35)
eGFR, mL/min 62 (51-78)
ALP, U/L 82 (62-119)
IVS, mm 17.7 (15.5-19.4)
mLVW, mm 16.5 (15-18.5)
Fat aspirate positive 5 (2)
Biopsy free diagnosis 165 (66)
MGUS No MGUS
MC and/or abnormal FLCR
160
hereditary ATTR amyloidosis
wt ATTR amyloidosis
• Non-hereditary, progressive disease
monomer
misfolding
Molecular mechanisms of TTR amyloid formation
1. Planté-Bordeneuve & Said. Lancet Neurol 2011 2. Benson MD et al. Muscle Nerve 2007
3. Bulawa et al. PNAS 2012 4. Marcoux et al. EMBO Mol Med 2015
Peripheral nerve bundle
Early onset Val30Met Late onset
Val30Met
Thr49Ala
Glu89Gln
Phe64Leu
Ile68Leu
Tyr78Phe
Male gender 185 (73)
Family history 66 (26%)
Concomitant CM 35 (14%)
Clinical presentation of 255 patients diagnosed in Pavia
0 5
C ou
nt
30 35 40 45 50 55 60 65 70 75 80 85
Age at Onset (± 2 y)
Male Female
0 20 40 60 80 100 120
Atrial Fibrillation PM implantation
Low GI Symptoms Upper GI Symptoms
Main Symptom at Onset
High penetrance Genetic anticipation possible
Andrade Brain 1952 Planté-Bordeneuve & Said. Lancet Neurol 2011 Conceição et al. J Peripher Nerv Syst 2016
A relentlessly progressive sensory-motor polyneuropathy
• Symptoms are limited to feet and legs with impaired pain and temperature sensation2
• Sensation of touch is maintained2
• Unassisted walking2
• Patient is bedridden or in a wheelchair with generalised weakness, malnutrition, cachexia and incontinence2,3
• Pain and temperature sensation is lacking apart from in the head/neck2
• Motor dysfunction in the lower limbs and loss of touch sensation2
• Mobility is maintained but crutches or a stick are needed for walking2,3
D is
ea se
p ro
g re
ss io
Time Worsening disease over an average of 10 years
1. Hou X et al. FEBS J 2007 2. Coutinho P. In: Glenner GG et al, eds. Amyloid and amyloidosis 1980 3. Benson MD et al. Amyloid 1996
Non-invasive tests for amyloid support the
diagnosis
sensitive
Suppression of the synthesis • Liver transplantation • Gene silencing (RNAi, ASO) • Second generation RNAi
Amyloid fibril degradation/reabsorption • Anti-TTR misfolded • Doxycycline + TUDCA
Misfolded monomer Folded full length
monomer
misfolding
Blocking ribosomes or other factors “steric block”
Recruiting protein factors (e.g. RNase H)
Modulating splicing
mismatched)
m7G
AAAAn
• Duplex associates with RISC • Passenger strand is removed • Guide strand leads RISC to target
siRNA, small Interfering RNA; RISC, RNA-induced silencing complex–responsible for the silencing phenomenon known as RNA interference Watts & Corey. J Pathol 2012;226:365–79
Innovative Disease-Modifying Therapeutics: TTR-lowering Agents
Suppression of hepatic production of wild-type and mutant TTR
Adams et al, NEJM 2018
Cardiac subpopulation1,2
• Prespecified exploratory cardiac endpoints were assessed in the prespecified cardiac subpopulation (baseline LV wall thickness ≥13 mm and no history of hypertension or aortic valve disease)
Adams et al, NEJM 2018
Reduction in serum TTR Levels was rapid and sustained over 18 Months
Mean reduction of serum TTR level after 18 months’ patisiran treatment was 84 %
Patisiran Improved the Primary Endpoint mNIS+7 from baseline to Month 18
Adams et al, NEJM 2018
Approved by FDA and EMA for hereditary ATTR polyneuropathy FAP stages I and II
Improvement in mNIS+7 score at 18 months was consistent across all subgroups, significantly favoring patisiran
All secondary endpoints were significantly improved with patisiran compared with placebo
Adams et al, NEJM 2018
Patisiran global open-label extension study
Polydefkis et al, PNS 2019
Benson et al, NEJM 2018
Patient Population (n~195)
polyneuropathy: any TTR mutation, hATTR amyloidosis Stage I or II
• Amyloid deposit by biopsy
2: 1
Ra nd
om iza
tio n
Inotersen 300 mg SC (Day 1, Day 3, Day 5)
then qw
Placebo SC (Day 1, Day 3, Day 5) then qw
Double- blind
Primary endpoints • Change in
mNIS+7Ionis from baseline
Other endpoints: • Individual
mNIS+7Ionis components
assessments • SF-36
*Patients who complete the study may be eligible for inotersen treatment on Phase 3 OLE study (NCT02175004)
Benson et al, NEJM 2018
Primary efficacy end points: change in mNIS+7 and Norfolk QOL-DN from baseline at week 66
Approved by FDA and EMA for hereditary ATTR polyneuropathy
FAP stages I and II
Patients with ≤ 0-point change from baseline at week 66
Safety and tolerability
Enhanced safety monitoring implemented for thrombocytopenia and renal parameters, no additional issues
Patients receiving inotersen should take oral supplementation of vitamin A per day to reduce potential risk of ocular toxicity
TEAEs more common with inotersen vs placebo: low platelet count, nausea, chills, fever, vomiting, anemia, thrombocytopenia
Hereditary lysozyme amyloidosis
ALys amyloidosis experience at Pavia Amyloid Centre
Presenting features Median (range)
Age at symptoms onset (y) 40 (15-64)
0 10 20 30 40 50 60 70 80 90
Dyspepsia
Giampaolo Merlini Giovanni Palladini Andrea Foli Paolo Milani Mario Nuvolone Francesca Lavatelli Roberta Mussinelli
Marco Basset Stefano Perlini Paola Rognoni Tasaki Masayoshi Giovanni Ferraro Margherita Bozzola Simona Casarini
Jessica Ripepi Anna Carnevale Baraglia Claudia Sforzini Elona Luka Eleonora Di Buduo Alberto Bovera Arianna Pasi
Pavia Amyloidosis Research and Treatment Center
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Amyloid-related renal involvement
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ATTR in Italy: a typical non-endemic area
Clinical presentation of 255 patients diagnosed in Pavia
Clinical presentation in 255 patients
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Hereditary lysozyme amyloidosis
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