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