Amyloidosis Research and Treatment Center
IRCCS Policlinico San Matteo
Department of Molecular Medicine
University of Pavia, Italy
Giampaolo Merlini
AL amyloidosis:
an update
Giampaolo Merlini
• None
Disclosures
2018;132(14):1478-85
Merlini et al, Nat Rev Dis Primers. 2018
New developments in amyloidosis
• New epidemiology landscape → new diagnostic approach
• Novel drugs and therapeutic strategies
AL 70%
ATTRwt3%
ATTRm11%
ApoA18% AA
6%
Other2%
Patients referred to the Pavia Center for Amyloidosis
2240 patients (1998-2012) 2018
Wild-type TTR could be the most frequent form of cardiac amyloidosis, affecting mostly males
(>80%) in the late 70s. ~25% of patients have a monoclonal protein (Geller et al, Mayo Clin Proc. 2017)
34% of patients with ATTRwt have a monoclonal
component (s&uIFE + FLC)
Elderly patient with isolated cardiac involvement
• M-Ig present → cardiac biopsy and amyloid typing
• M-Ig absent (by serum + urine IF and FLC)
➢ Scintigraphy with DPD/HMDP/PYP → grade 2 or 3 → genetics for TTR
AL ATTR
Rapezzi et al, JACC Img 2011
Galat et al, Amyloid 2015Bokhari et al, Circ Cardiov Img 2013
Castano et al, JAMA Cardiol 2016
Symptomatic organ involvement portends a poor
outcome
AL amyloidosis should be searched before the onset of symptoms
Amyloidosis is often diagnosed late
32% of patients need to see ≥5 physicians to reach the diagnosis
Kyle, et al. Mayo Clinic Proc 2019
Lousada, et al. Adv Ther 2015
AL amyloidosis is a rare disease: 1.2 per 100,000 person-years (95% CI, 0.8-1.6)
EARLY DIAGNOSIS
Biomarkers Imaging
• sFLC
• NT-proBNP
• u. Albumin
• Echocardiography (SVI)
• CMR
• DPD/PYP scintigraphy
• 18F-florbetapir PET/CT
Diagnostic approach to systemic amyloidosis
2. Muchtar et al, Ann Med. 2017 – 3. Fernandez de Larrea et al, Blood 2015 – 4. Quarta et al, Eur Heart J 2017 – 5. Vrana et al, Blood 2009; 6. Lavatelli et al, Mol Cell Proteom. 2008; 7. Arbustini et al, Amyloid 2002; 8. Schonland et al, Blood 2012
Abdominal fat aspirate: (underutilised):2 sensitivity 81-84%3,4
Possible lip/minor salivary gland biopsy for Congo red
PositiveNegative
Cardiac MRI
Organ biopsy
Type amyloid deposits
- Proteomics-MS5,6
- Immuno-EM7
- Immunohistochemistry8
CR
FSBCR
Predicting outcomes in AL amyloidosis
Stage I (18%)
Stage II (44%)median 49 months
Stage IIIa (20%)median 14 months
Stage IIIb (18%)median 5 months
Staging is based on NT-proBNP (cutoff 332 ng/L) and troponin I (cutoff 0.1 ng/mL) Very high (>8500 ng/L) NT-proBNPidentifies patients with advanced cardiac dysfunction (Stage IIIb)
Mayo Clinic / European staging system Staging system incorporating BNP
Staging is based on BNP (cutoff 81 ng/L)and troponin I (cutoff 0.1 ng/mL) Very high (>700 ng/L)BNP identifies patients with advanced heart damage (Stage IIIb)
Renal staging system
Stage III (15%)dialysis 48% @ 2y
Stage II (42%)dialysis 12% @ 2y
Stage I (43%)dialysis 1% @ 2y
Staging is based on proteinuria(cutoff 5g/24h) and eGFR (cutoff 50 mL/min per 1.73 m2)
Palladini, et al. Blood 2014Lilleness et al, Blood 2019
Dispenzieri, et al. JCO 2004 - Wechalekar, et al.
Blood 2013 - Palladini, et al. Haematologica 2014 -
Sharpley et al. EHA PF553
Muchtar et al, ASH 2018
• GDF-15 is a strong predictor for renal outcomes
• GDF-15 reduction after therapy is associated with better
outcome Kastritis et al, Blood 2018
TherapySuppressing the synthesis of the amyloid protein provides the highest degreeof therapeutic efficacy
• AIM: 1. Rapid and profound decrease of the amyloid precursor
2. Removal of fibrils
• GOAL: Organ (cardiac) function improvement→ survival extension
• CHALLENGE: Frail patients in need of rapid and deep responses → risk stratification
o Patient characteristics (severity of cardiac damage)
o Clone biology (burden of FLC)1
1. Kumar et al, J Clin Oncol 2012
Dexamethasone
Alkylators
Targeting the clone to improve organ dysfunction and prolong
survival
ASCTIMiDs
Anti-plasma cell treatment
Proteasome inhibitors
Immunotherapy
Hematologic response FLC
Improve organ dysfunction
Organ response NT-proBNP, proteinuria, ALP
Prolong survival
Patients surviving 5 years (%)data from1065 patients at Pavia ARTC
Patients with organ response (%)
CR, VGPR, and PR data from 1065 patients at Pavia ARTC
?MRD data by NGF on 69
patients at Pavia ARTC
Organ response strictly depends on the quality of hematologic
response
• 1,536 patients at 134 centers from1995 to 2012
• HR/CR 61/33%, TRM 4% (2007-2012)
• Renal response 30%
D’Souza et al, J Clin Oncol 2015
Fit patients: ~20%
age < 70 years, ECOG PS≤2, BP >90 mmHg,
cTnT < 0.06 ng/mL, Creatinine clear. >30 mL/min,
NYHA I or II, ≤ 2 organs involved
ASCT in AL amyloidosis
1. Tandon et al, BMT 2017 - 2. Sidiqi et al, JCO 2018
• CyBorD induction3,4,5
• Consolidation with BDex if < CR6
ASCT with MEL 2001,2
CRPR
VGPR
NRNA
3. Hwa et al, Am J Hematol, 2016 - 4. Scharman et al, ASH 2017 Abstr .4552 – 5. Afrough, et al.
Biol Blood Marrow Transplant 2018 - 6. Landau et al, Leukemia 2017
1,2
Choice of upfront treatment in transplant ineligible patients
• CyBorD – stem cell sparing, is preferred in patients with renal failure, in
patients with t(11;14)(~50% of patients) is associated with lower response
rate
• BMDex – overcomes the effects of both gain 1q21 and t(11;14)
• MDex – preferred in patients with neuropathy or fibrotic lung disease
High risk patients (stage IIIb, NYHA class III or IV) – Low dose combination
regimens or standard regimens with intensive care support
Merlini, et al. Nat Rev Dis Primers. 2018
Stage IIIb: NT-proBNP> 8500 ng/L (~20%)
Bortezomib-based regimens
Palladini et al, Blood 2015 – Le Bras et al, Eur J Cancer 2017
Heart transplantation • age < 65 yrs,
• no significant extra-cardiac amyloidosis
• ASCT after HTx very effective1-4
• outcomes comparable to non-amyloid5
1. Lacy et al, J Heart Lung Transplant. 2008 – 2. Dey et al, Transplantation 2010 –
3. Sattianayagam et al, Am J Transplant. 2010 - 4. Gray Gilstrap, et al, J Heart Lung
Transpl 2014 – 5. Kristen et al, J Heart Lung Transplant. 2018
Rapid and deep responses improve outcome of patients with
advanced heart involvement
Manwani et al, Haematologica 2018
Interfering with cardiac toxicity in AL amyloidosis
Wechalekaret al, Blood Cancer J 2017
30 patients treated with doxycycline (100 mg bid) + CT
73 matched controls CT
P=0.001
Survival of patients treated with an
upfront bortezomib-based regime
Doxycycline
Controls
P=0.012
An international Phase III trial is ongoing
D'Souza et al, ASH 2018
When and how to re-treat ?
Palladini, et al. Blood 2018
Organ progression at second line therapy predicated inferior survivalHwa et al, Blood 2017
Tandon et al, Am J Hematol 2017
Treatment of relapsing/refractory patients
HR 68%, ≥VGPR 29% Responders 36 mos
NR 19 mos
P=0.001
IMiDs are effective rescue agents (increase in NT-proBNP, Len potential nephrotoxicity)
Pomalidomide produces rapid and profound responses(Dispenzieri et al, Blood 2012, Sanchorawala et al., Blood 2016 – Palladini et al, Blood 2017)
Daratumumab in AL amyloidosis
Phase III international study of CyBorD vs CyBorD+Dara upfront (ANDROMEDA) - Safety run-in results: Merlini et al, EHA23 PS1318
Kaufman et al, Blood 2017 & Kaufman et al, EHA23 PS1305
40 patients
CR 5%
VGPR 43%
PR 10%
58%
-200
-150
-100
-50
0
50
100
Jaccard et al, EHA23 S851No 44
Prior lines of therapy, n (range) 3 (1–8)
ORR n (%) 25 (83)
CR n (%) 5 (17)
VGPR n (%) 19 (63)
PR n (%) 1 (3)
Time to 1st/ best response, 2.2 months
Abeykoon et al, Leukemia 2018Sanchorawala et al, ASH 2018See also: Lee et al, ASH 2018 - Rahman et al, ASH 2018 - Milani et al, ASH 2018 – Kastritis et al ASH 2018
Anti-SAP antibodies
1. CPHPC to deplete circulating SAP
2. monoclonal IgG1 anti-SAP antibody
Most patients receiving >
200 mg of anti-SAP
antibody had manageable
infusion reaction
Phase 2: patients with cardiac amyloidosis NCT03044353
Fibril-reactive antibody 11-1F4
Phase 1a 8 patients
Single IV infusion 0.5 to 500 mg/m2 Week 1
Phase 1b 19 patients
Weekly IV infusion for 4 weeks
Wall et al, Blood 2010
Edwards et al, Amyloid 2017 and ASH 2017 Abstr.509
Bhutani et al, ASH 2018
SAE ≥3 in 5 patients
(diarrhea, pain, pruritus,
pleural/pericardial effusion)Richards et al, NEJM 2015;373:1106-14
Richards et al, Sci Transl Med. 2018;10(422).
Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain
AL amyloidosis patient
Swuec et al, Nat Commun. 2019
Inhibition by small-molecule ligands
of formation of amyloid fibrils of an
LC variable domain
Sulfasalazine
Brumshtein et al. eLife 2015
Stabilization of amyloidogenic
immunoglobulin light chains by small
molecules
Morgan et al. PNAS 2019
Anti-clone
therapies
LC stabilizers
Anti-SAP
MoAb
Anti-LC
fibrils
MoAb
Doxy, EGCG
Merlini et al, Nat Rev Dis Primers. 2018
Conclusions
• Early diagnosis, novel agents, biomarker-guided treatment strategy
are improving the outcome of patients with amyloidosis
• Advanced cardiac AL amyloidosis remains an unmet need: improve
the understanding of the mechanisms of cardiac damage
• In the near future the treatment of systemic amyloidosis will include
the combination of agents increasing efficacy, but raising concerns
about sustainability and access to drugs
Acknowledgements
Giovanni PalladiniLaura Obici Andrea Foli Paolo Milani Mario NuvoloneFrancesca Lavatelli Roberta Mussinelli
Marco BassetCarlos Fernandez de LarreaStefano PerliniGiuseppina PalladiniMargherita MassaPaola Rognoni Tasaki Masayoshi
Giovanni Ferraro Pasquale Cascino Margherita BozzolaClaudia Cagnoni Simona CasariniJessica RipepiAlice Nevone
Caludia SforziniElona Luka Eleonora Di BuduoAlberto BoveraArianna PasiAnna Carnevale Baraglia