/L)LC (mg/mbda FLrum LamSer

(1)

Advances in AL amyloidosis Advances in AL amyloidosis

Yonsei University College of Yonsei University College of

M di i M di i

Medicine Medicine

Jin Seok Kim

(2)

Amyloidosis

• Amyloidosis results from a sequence of changes in protein folding that leads to the deposition of insoluble amyloid fibrils, mainly in the extracellular spaces of

d ti

organs and tissues.

• Classified according to the identity of the fibril-forming protein.

– Acquired amyloidosis: 79% (AL 71%,q y % ( %, AA: 8%)%) – Hereditary amyloidosis: 21%

Rajkumar SV, Dispenzieri A, Kyle RA. Mayo Clin Proc 2006;81:693-703

(3)

Amyloidosis: protein misfolding disease

AL Amyloidosis

AL Amyloidosis N Engl J Med. 2003;349:583-96.

(4)

(5)

(6)

Clinical characteristics of AL Amyloidosis 10/ illi

; 10/million person-year

Peripheral nervous system Autonomic nervous system Autonomic nervous system

N Engl J Med. 2003;349:583-96.

(7)

Clinical manifestations of AL Amyloidosis Clinical manifestations of AL Amyloidosis

• Vague symptoms.

• Fatigue edema and weight loss

• Fatigue, edema, and weight loss

; generally not helpful in the formulation of an appropriate differential diagnosis.

the education program for the annual congress of the EHA | 2008; 2(1)

pp p g

(8)

70/M, 평소 어지러움으로 건강검진

과거력 상 특이 소견 없음

BP; 160/90 mmHg, PR; 100/min 12.1-5000-170K, BUN/Cr; 20.0/1.0

SPEP; Monoclonal gammopathy SPEP; Monoclonal gammopathy

IF; IgG & Lambda

가장 가능성이 높은 진단명은?

1) MGUS

2) AL amyloidosis 3) Multiple Myeloma ) p y

4) Waldenstrom’s macroglobulinemia 5) POEMS Syndrome

5) POEMS Syndrome

(9)

When should the diagnosis of AL be considered?

• Nephrotic-range proteinuria

• Unexplained nonischemic cardiomyopathy (Rt side Heart Failure)

(Rt. side Heart Failure)

• Peripheral neuropathy

• Unexplained hepatomegaly

• Orthostatic hypotension and other

manifestations of autonomic neuropathy (pseudo-obstruction etc)

(pseudo obstruction etc),

• Atypical multiple myeloma.

If a diagnosis is under consideration what is If a diagnosis is under consideration, what is

the appropriate diagnostic evaluation?

• Best non-invasive screens for AL;

immunofixation of serum and 24hrs urine and the free light chain assay

and the free light chain assay

• Positive finding can justify more invasive diagnostic studies to confirm the diagnosis.

• > 25% of patients do not have an intact immunoglobulin protein in the serum.

(10)

Free light chain assay Free light chain assay

Reference range

Kappa FLC; 3.3 – 19.4 mg/L Lambda FLC; 5 7 26 3 mg/L

Lambda FLC; 5.7 – 26.3 mg/L

/ ratio; Median = 0.6 (Range = 0.26 – 1.65)

(11)

AL amyloidosis- FLC y

100000

10000

/L)

Normal sera Kappa LCMM

1000

LC (mg/

Lambda LCMM AL amyloid

100

mbda FL

10

rum Lam

Ser 1

0.1

0.1 1 10 100 1000 10000 100000

S K FLC ( /L)

Lachmann H. et al. BJH 2003; 122 :78-84 Serum Kappa FLC (mg/L)

(12)

70세 남자, 피로, 체중감소, 부종으로 내원.

WBC 5400/L, Hb 7.6 g/dL, Platelet 117,000/L

117,000/L

골수생검 (Congo red stain) 및 편광현미경소견;

apple green birefringence apple green birefringence

Amyloid light chain amyloidosis (AL l id i )

(AL amyloidosis)

확진을 위하여 추가로 필요한 혈액검사 항목은?

1) Serum Protein electrophoresis (SPEP) 2) Serum Immunofixation

3) Serum Immunoglobulin Quantitation 3) Serum Immunoglobulin Quantitation 4) Serum Kappa/Lambda light chain level 5) Serum Amyloid A

5) Serum Amyloid A

(13)

If there is a strong suspicion, how is the

di i fi d?

diagnosis confirmed?

1) Immunoglobulin light chain abnormality by immunofixation of serum and 24hrs urine d th f li ht h i

and the free light chain assay

2) Biopsy verification of the amyloid; apple green birefringence under polarized light after Congo red staining.

– Visceral biopsy is not usually necessary. (renal, cardiac, liver, or nerve biopsy) – BM biopsy; amyloid (+) in 50–60% of patients.

( di BM l ll 7%)

(median BM plasma cell 7%)

– Subcutaneous fat aspirate (? Bx);

amyloid (+) in 70–80% of patients amyloid ( ) in 70 80% of patients (Not thin preparation

(Not thin preparation  Classical method)Classical method)

– Biopsies of the minor salivary glands, gingiva, rectum, and skin.

3) Histologically confirm; the amyloid is the AL type

- immunohistochemical verification with kappa and lambda antisera.

immunoelectron microscopy mass spectrometry based methods DNA analysis - immunoelectron microscopy, mass spectrometry-based methods, DNA analysis.

- for rule out of MGUS & other form of amyloidosis

• Mutant transthyretin; Any African American > 70 years with cardiac amyloidosis should be screened for a mutant transthyretin (3.9% of African Americans).

Education program for the annual congress of the ASH 2004

(14)

Primary Amyloidosis

(Li ht Ch i A l id i AL A l id i ) (Light Chain Amyloidosis, AL Amyloidosis)

• The most common form of systemic amyloidosisy y

• Median age; 62

• < 20% of patients with AL amyloidosis have MM.

• About 15 to 20% of patients with MM have amyloidosis.About 15 to 20% of patients with MM have amyloidosis.

• Lambda chain class predominates over kappa in AL by a 2:1 ratio,

whereas in MM and normal immunoglobulin synthesis; the reverse is true.

• Diagnosis of systemic AL amyloidosis

(presence of all of the followings)

– Amyloid-related systemic syndrome (renal, liver, heart, G-I tract, or peripheral nerve involvement)

peripheral nerve involvement)

– Positive amyloid staining by Congo red in any tissue (fat aspirate, BM, or organ biopsy)

E id th t l id i li ht h i l t d t bli h d b di t – Evidence that amyloid is light chain related established by direct

examination of the amyloid (immunoperoxidase staining, direct sequencing) – Evidence of a monoclonal plasma cell proliferative disorder (serum or

urine M protein abnormal FLC ratio or clonal plasma cells in BM) urine M protein, abnormal FLC ratio, or clonal plasma cells in BM)

– Note: Approximately 2%-3% of patients with AL amyloidosis will not meet the requirement for evidence of a monoclonal plasma cell disorder; the diagnosis requirement for evidence of a monoclonal plasma cell disorder; the diagnosis of AL amyloidosis must be made with caution in these patients.

(15)

Under polarized light

to demonstrate the characteristic

l bi f i

Amyloid staining with Congo red.

apple green birefringence

(16)

(17)

Definition of Organ involvement Definition of Organ involvement

• Kidney: 24-hr urinary protein > 0.5 g/day, predominantly albumin

• Heart: Mean wall thickness > 12 mm on echocardiogram, no other cardiac disease responsible for the increase in wall thickness

• Liver: Total liver span >15 cm in the absence of heart failure, or alkaline phosphatase level >1.5 times upper limit of normal

• Nerve: Symmetric sensorimotor peripheral neuropathy in the legs and

autonomic neuropathy (gastric-emptying disorder, pseudo-obstruction, voiding dysfunction), not related to direct organ infiltration

• Gastrointestinal tract: Symptoms and verification by means of biopsy

• Lung: Symptoms and verification by means of biopsy, interstitial pattern

• Soft tissue:Soft tissue: Tongue enlargement, arthropathy, skin purpura, myopathyTongue enlargement, arthropathy, skin purpura, myopathy

(pseudohypertrophy or detected by means of biopsy), lymph node involvement, carpal tunnel syndromep y

Gertz MA, et al. Am J Hematol 2005;79:319-28.

(18)

M/70, AL amyloidosis

Kidney and cardiac involvement y

예후 예측을 위하여 중요한 검사 항목은?

1) S M t i l l

1) Serum M protein level

2) 24hrs urine M protein level 3) Serum calcium level

4) Serum albumin level )

5) Serum free light chain concentration

(19)

Cardiotoxicity of amyloidogenic light chains Cardiotoxicity of amyloidogenic light chains

• Infusion of amyloidogenic light chains causes immediate diastolic y g g dysfunction in isolated mouse hearts; Liao et al Circulation

2001;104;1594-1597

P ifi i f li h h i f i i h di i l

• Purification of light chains from patients with severe cardiac involvement

• Cardiac involvement is causing the death of ~ 80% of AL patients

C di bi k N t i l f t i ti tid t B (NT

• Cardiac biomarkers: N-terminal of natriuretic peptide type B (NT-

proBNP - BNP) and troponins (cTnI or cTnT)

(20)

Systemic AL amyloidosis-Prognosis Systemic AL amyloidosis Prognosis

• The prognosis of AL amyloidosis has significantly improved in the last

significantly improved in the last decade, due to earlier diagnosis &

more effective specific and supportive

t t t

treatments.

• Of 868 AL amyloidosis 394 died

(median survival 3.8 yrs, Italy data)

( y , y )

• Die of cardiac complications, either congestive heart failure (50%) or sudden death (25%)

sudden death (25%).

• 2 significant independent prognostic factorsg p p g

; Response to therapy (protective) and cardiac involvement (p<0.001).

– Hematological response to CTx survived longer than other patients (median 108 vs.

21 months p<0 001) 21 months, p<0.001).

– Median survival of patients with heart involvement was significantly shorter than that of patients without cardiac amyloidosis (21 vs. 82 months, p<0.001),

• Serial concurrent quantification of the serum FLC and NT-proBNP is important.

the education program for the annual congress of the EHA | 2008; 2(1)

(21)

Evaluation of the cytogenetic aberration

- At least one CA using FISH in 89% of the AL Amyloidosis (n=75); German data - t(11;14) - the most frequent aberration in AL (47%) vs. 26% in MGUS (P = .03).

- t(11;14); associated with a lack of intact immunoglobulin in immunofixation.

- Low frequencies of t(4;14) & deletion of 17p13 (rapid progression markers)

- Gain of 1q21q - higher frequencies in MM I both with & without AL (50% and 53%)g q ( ) - suggest that the concept of gain of 1q21 as a progression marker

Blood. 2008;111:4700-4705

(22)

Translocation t(11;14) and OS- Mayo data Translocation t(11;14) and OS- Mayo data

• 56 AL Amyloidosis, cytoplasmic staining of specific Ig (cIg-FISH) 56 AL Amyloidosis, cytoplasmic staining of specific Ig (cIg FISH)

• IgH translocations [48%] – including t(11;14) [39%], and t(14;16) [2%]

• del13/del13q [30%]

• No t(4;14) or deletions of 17p (p53) were observed.

• Patients with t(11;14) had the lowest levels of clonal plasma cells, and those with del13 had the highest

those with del13 had the highest.

Bryce AH et al. Haematologica. 2009;94(3):380-6.

(23)

Serum-free light chain (FLC) – German data Serum free light chain (FLC) German data

• Higher FLC levels; associated with higher BM plasmocytosis, poorer Karnofsky index & heart involvement  reflected disease severity.

• Patients with cardiac involvement Patients with cardiac involvement had higher involved FLC

concentrations (p=0.002)

• Statistically significant effect on FLC concentrations for the

cardiac biomarkers cTNT (p=0.007) and NT-proBNP (p<0 001)

(p<0.001).

• FLC concentration also reflects the expansion of the aberrant

the expansion of the aberrant clone and, to some extent, the severity of organ involvement.

Haematologica. 2008;93(3):459-62.

severity of organ involvement.

(24)

Prognostic factors in AL amyloidosis

• Dominant organ involved (with cardiac amyloid having the worst outcome) – important role of echocardiography with Doppler

important role of echocardiography with Doppler

• Cardiac troponins and NT-proBNPp

• The number of affective major organs.

• Serum uric acid; Mayo Clin Proc. 2008;83:297 ; y ;

• Serum b2-microglobulin

• CA in FISH; t(11;14)

• Serum level of FLC

• Hematological response to CTx; A hematologic response to therapy correlates well with subsequent organ response

well with subsequent organ response.

Rajkumar SV, Dispenzieri A, Kyle RA. Mayo Clin Proc 2006;81:693-703

(25)

M/70, AL amyloidosis

Kidney and cardiac involvement

Kappa FLC; 10 mg/L pp ; g Lambda FLC; 200 mg/L

FLC

/ ratio; 0.05 (Range = 0.26 – 1.65)

FLC / ratio; 0.05 (Range 0.26 1.65)

NT-proBNP Elevation

24hrs urine protein; 1 500 mg/24hrs 24hrs urine protein; 1,500 mg/24hrs

• Most appropriate initial treatment for this patients

• Most appropriate initial treatment for this patients 1) M l h l P d i l

1) Melphalan Prednisolone 2) Melphalan-dexa

3) VAD chemotherapy

4) VAD chemotherapy followed by Autologous HSCT

5) Initial Autologous HSCT

(26)

Treatment of Systemic Amyloidosis Treatment of Systemic Amyloidosis

Rajkumar N Engl J Med 2007;356:2413

(27)

Colchicine Alone vs MP vs MP-Colchicine;

Mayo data

• 220 AL amyloidosisy

• Colchicine (0.6 mg twice daily)

• Melphalan (0.15 mg/kg) and PL (0.8 mg/kg) daily for 7 days once every 6 weeks

M l h l (0 15 /k ) d PL (0 8 /k ) d il f 7 d 6 k

• Melphalan (0.15 mg/kg) and PL (0.8 mg/kg) daily for 7 days once every 6 weeks plus colchicine (0.6 mg twice daily).

Survival from the Date of Randomization

N Engl J Med 1997;336:1202-7

(28)

High-Dose Dexamethasone; SWOG trial g ;

• 93 AL Amyloidosis

• Induction therapy (HD Dexa) followed by maintenance therapy (Dexa + α-INF)

• Induction therapy; Dexa, 40 mg/d po (d 1-4, 9-12, 17-20) every 35 d for 3 cycles.

• Maintenance therapy;y begin 5 weeks from day 1 of cycle 3 of induction therapy. g y y y oral Dexa 40 mg/d for 4 days every 4 weeks,

+ α-INF at 5 million units SQ 3 times/week for the first 2 years, followed by α-INF alone for the next 3 years.

• Dexa alone achieves a 53% HR (median time 3.4 mos) with 24% CR & 7% TRM

OS

Median OS; 31 Mo

PFS

Median PFS; 27 Mo

Median OS; 31 Mo Median PFS; 27 Mo

Blood. 2004 Dec 1;104(12):3520-6.

(29)

Melphalan & High-Dose Dexamethasone

• N=46, Italy data y

• Melphalan (0.22 mg/kg/day orally) on days 1-4

& HD dexa (40 mg/day orally) on the same 4 days

& HD dexa (40 mg/day orally) on the same 4 days.

• Repeated every 28 days for approximately 9 mos.

67% HR (h t l i ) ith 33% CR

• 67% HR (hematologic response) with 33% CR

Median survival; 5.1 years OS

Palladini G, Blood. 2007;110:787

(30)

Treatments for AL amyloidosis

education program for the annual congress of the ASH | 2004

(31)

Autologous stem cell transplant

• Mayo clinic; case control study (n=63)

• Boston data (n=312)

Median survival; 4.6 years; y

Dispenzieri et al, Blood. 2004;103:3960 Skinner et al, Ann Intern Med. 2004;140:85c

(32)

VAD Induction Tx + ASCT; phase II German data VAD Induction Tx ASCT; phase II German data

• N=28, 2 to 5 cycles of VAD, repeated every 28 d.

HD M l h l ASCT

• HD Melphalan ASCT

• VAD CTx; WHO grade III–IV toxicity (25%) and 7% TRM (2/28).

; did not interfere with stem cell mobilization

and HDM with ASCT was possible in 86% of patients.

• 13% (3/24) TRM after ASCT.

OS

• Additional VAD CTx did not increase the HR and clinical remission compared with HR and clinical remission compared with the results of HDM + ASCT without

induction CTx.

• Mortality and response rates

; seem to be comparable with previously reported data on HDM + ASCT without i d ti CT

Perez et al. Br J Haematol 2004;127:543–551 induction CTx.

(33)

Initial ASCT vs. 2th MP induction + ASCT

; prospective randomized Trial, Boston data

• Initial ASCT (Arm-1)Initial ASCT (Arm 1) vs.vs. 2 cycles of oral melphalan (0.2 mg/kg/d for 4 days) & 2 cycles of oral melphalan (0.2 mg/kg/d for 4 days) &

prednisone (1.0 mg/kg/d for 4 days) followed by ASCT (Arm-2)

• Median f/u; 45 mos (range 24–70), no different OS (P= 0.39).

• Hematologic response (32% vs. 30%) & organ improvements; no different.

• Fewer patients received ASCT in Arm-2 (43 vs. 32)

; Because of disease progression during MP CTx phase (mortality; 6/48, 13%),

→ ineligible for subsequent ASCT.

• The patients with cardiac involvement; early survival disadvantage in Arm-2.

• Newly diagnosed AL amyloidosis OS eligible for ASCT did not benefit

from initial treatment with oral MP.

I ti t h d t l

OS

N=52

• In patients who proceed to early

transplantation, there does not appear to be any need for induction

N=48

Sanchorawala V, BMT 2004;33:381 y

therapy.

(34)

HD Melphalan-ASCT vs. Melphalan + HD Dexa f AL A l id i

IFM & MAG d i d t i l

for AL Amyloidosis; IFM & MAG randomized trial

median OS 56.9 months

N=50

di OS 22 2 th

median OS 22.2 months N=50

• OS may not be superior with ASCT compared with melphalan + HD Dexa.

• Among high-risk disease; similar OS in the two groups

• Among high-risk disease; similar OS in the two groups.

• Among low-risk disease; non-significant difference in 3 yr OS

(58% in HD melphalan-ASCT vs. 80% in melphalan + HD Dexa; P = 0.13).

(58% in HD melphalan ASCT vs. 80% in melphalan HD Dexa; P 0.13).

• However, interpretation of this trial is confounded by very high TRM in ASCT arm (24%). (vs. 9% from Boston results)

N Engl J Med 2007;357:1083-93.

• Mayo Clinic-ongoing randomized phase 3 trial; ASCT vs. melphalan + HD Dexa.

(35)

New agents for AL Amyloidosis g y

• Thalidomide; poorly tolerated in AL amyloidosis patients

– Thal+dexa as 2nd-line Tx; 48% HR with 19% CR.

; > 60% developing > grade 3 toxicity. (Blood. 2005;105:2949)

– Cyclophosphamide, thalidomide, and dexa (CTD), (Blood. 2007;109:457)

; Thal 200 mg/day (starting dose 100 mg/d increased after 4 weeks if tolerated)

; Thal - 200 mg/day (starting dose, 100 mg/d, increased after 4 weeks if tolerated)

; 74% HR with 21% CR (15% IF(-) CR),

; Toxicity  grade 3 - 32%, 8% cessation of therapy, 4% TRM.

• Lenalidomide + dexa, (Blood. 2007;109:492-496)

– 34 patients (Boston data); 25 mg/d → reduced dose of 15 mg/d, 67% HR with 29% CR – Fatigue and myelosuppression were the most common (35%)Fatigue and myelosuppression were the most common (35%)

– Thromboembolic complications (9%) were the most serious.

• Proteasome inhibitor, bortezomib

• Phase I-II dose escalating trial

- 31 relapsed AL Amyloidosis, (Blood. 2009) - MTD was not defined - Maximum doses; 1.6 ;

mg/m² (weekly) & 1.3 mg/m² (twice weekly) - HR 15/30 (50%) with 6 (20%) CR, 30% PR.

- Median time to first response; 1.2 mos - 12 (39%) discontinuations

- 4 (13%) dose reductions for toxicity . - No TRM.

(36)

Bortezomib with or without Dexamethasone in AL Amyloidosis – multicenter retrospective

th

f

• 94 AL Amyloidosis, median 4

^th

cycles of Tx

• 19% first line, 81%  2

^nd

line (median 2) (69% refractory)

S t ti h t i l l t d NT BNP

• Symptomatic heart involve or elevated NT-proBNP

• 71% HR within median 52 days (25% CR)

47% CR in first line Tx – 47% CR in first line Tx

– Age  65 yrs & twice weekly use of bortezomib; associated with higher RR.

• 29% Cardiac response; sustained improvement 29% Cardiac response; sustained improvement

– HR; associated with cardiac response and NT-proBNP reduction

• 12 mo median F/U; 29% organ PD, 27% Hematologic PD g g

• Baseline NT-proBNP; independent prognostic factor for OS

•  30% NT-proBNP reduction & achieve HR; predictive factor for OS

• No TRM, ≥ Grade 3 toxicity; 29%.

• Toxicity was manageable and mostly consisted of neuropathy (grade 2;

30%), orthostasis, peripheral edema, and constipation or diarrhea.

Kastritis J Clin Oncol 2010;28:1031-1037

(37)

HD Melphalan-ASCT + Adjuvant Thal/dexa p j

• MSKCC data, n=45, Newly diagnosed AL involving  2 organ systems

• Risk adapted ASCT;p ; MEL 100/140/200 mg/mg ² based on age, renal Fx, cardiac g , , involve.

• 9 mo adjuvant thal/dex from 3 mo after ASCT (dex if DVT + or neuropathy +).

Th lid id t t t 50 /d & tit t d 2 k t 200 /d t l t d – Thalidomide; start at 50 mg/d & titrated every 2 wks up to 200 mg/d as tolerated.

– Dexamethasone; given at 20 mg/m²/d for a 4-d pulse, with up to 3 pulses/Mo

• 31 patients began adjuvant therapy, with 16/31 (52%) completing 9 cycles p g j py, ( ) p g y

• 71% Overall HR (36% CR), with 44% organ responses.

• 4.4% TRM. 31 mo Median f/u - 84% 2-year OS.

• Risk-adapted ASCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients.

Br J Haematol 2007;139:224

(38)

Allogeneic stem cell transplant g p

• EBMT Data (N=19, 7 patients treated with HD Melphalan-ASCT)

• Allogeneic (allo; n = 15) or syngeneic (syn; n = 4) HSCT Allogeneic (allo; n = 15) or syngeneic (syn; n = 4) HSCT

• 7 Full-intensity conditioning and 8 RIST.

• 40% Death of TRM.

• 8 CR after HSCT and 2 PR, 8 Organ response.

• 7/10 patients in remission are long-term survivors.

• In 5/7 evaluable patients in CR, chronic GvHD

- Main clinical problem; cardiac failure

1 Yr OS; 60%

in patients with poor performance status due to amyloidosis or in combination with

; severe infections.

- Patients could be eligible for allo-HSCT 1 Yr PFS; 53% if they have not achieved a CR 6 mos

after HD Mel-ASCT, are still in a good

PS d h HLA t h d d

Blood. 2005;107:2578-2584 PS, and have an HLA-matched donor.

(39)

Prognostic markers in AL amyloidosis undergoing ASCT

undergoing ASCT

• Cardiac involvement

Bl d 2006 107 3378 83 A I t M d 2004 140 85

• Higher level of baseline FLC

Blood. 2006;107:3378-83.

Ann Intern Med. 2004;140:85

• Cardiac troponins and NT-proBNP

• Excessive fluid accumulation during PBSCH (>2% weight gain)

; predictive of a higher mortality rate with ASCT.

A hi t f ft ASCT H t l i CR

• Achievement of response after ASCT; Hematologic CR

hematologic CR. - Boston data; 57 Mo median OS (4.75 yr).

- Durable remissions and prolonged survival who achieve a hematologic CR.

; Median survival exceeds 10 yrs

Blood. 2007;110:3561-3563

; Median survival exceeds 10 yrs

(40)

ASCT after heart transplant for AL amyloid cardiomyopathy.

• Heart transplantation followed by ASCT is feasible in selected patients with cardiac AL amyloidosis and may confer substantial survival benefit.

- In patients presenting with end-stage organ failure, sequential solid organ (kidney heart liver) transplant followed by ASCT has been successfully

J Heart Lung Transplant. 2008;27(8):823-9.

(kidney, heart, liver) transplant followed by ASCT has been successfully applied.

(41)

Treatment and Monitoring therapeutic effects Treatment and Monitoring therapeutic effects

• Key elements y

– Early diagnosis and correct typing

– Fine balance of chosen treatment regimen and patient’s ability to bear toxicities

• Aim of therapy

obtain durable improvement of AL amyloidosis-related organ function → extend survival

• Monitoring response to therapy

– Chemotherapy guided by frequent assessment of FLC and cardiac biomarkers (every 2 cycles)( y y )

– Hematologic response – Organ response:

• NT-proBNP, troponins, rapid

• Kidney markers (proteinuria, s. creatinine) may be delayed by > 3 mos p to 1 r

mos up to 1 yr

(42)

Organ Response & Hematologic response Organ Response & Hematologic response

(43)

Role of the FLC assay in response assessment Role of the FLC assay in response assessment

• The consensus opinion from the 10

^th

International

• The consensus opinion from the 10 International Symposium on Amyloid and Amyloidosis

• FLC response 50% reduction in involved FLC (iFLC) in

• FLC response - 50% reduction in involved FLC (iFLC) in AL amyloidosis patients with iFLC > 100 mg/L

P i 50% i i iFLC

• Progression - 50% increase in iFLC.

Leukemia. 2009 Feb;23(2):215-24.

(44)

NCCN Guideline

(45)

Treatment of AL Amyloidosis

– Mayo clinic protocol

(46)

Criteria for eligibility for ASCT

in UK amyloidosis treatment trial (UKATT)

• Age  65 years

• ECOG performance status  1

 NYHA l I II h t f il

•  NYHA class I or II heart failure

•  2 organs involved by amyloid by consensus guideline

(Gertz, 2005)

Creatinine clearance  0 8 ml/s (50 ml/min)

• Creatinine clearance  0.8 ml/s (50 ml/min)

• Bilirubin  1.5 times and ALP  2  upper limit of normal

• Inter ventricular and LV posterior wall thicknesses of  15 mm by Echo

• Inter ventricular and LV posterior wall thicknesses of  15 mm by Echo.

• Absence of clinically important amyloid related autonomic neuropathy

• Absence of clinically important amyloid related GI hemorrhage

Patients must satisfy all the above criteria to be eligible for a stem cell transplant

• Patients must satisfy all the above criteria to be eligible for a stem cell transplant.

• When analysed retrospectively, patients satisfying all the criteria had no TRM (Goodman et al, 2006).

( )

(47)

Proposed criteria for patient selection and dose adaptation for high-dose melphalan.

Comenzo RL Gertz MA Comenzo RL, Gertz MA.

Blood. 2002;99:4276.

Skinner M, Ann Intern Med.

2004;140:85-93.

Education program for the annual congress of the ASH 2004

(48)

Supportive care for AL Amyloidosis pp y

• Supportive therapy is importance; sustaining the function of the target organs.

• Best supportive therapy; collaboration with nephrologists, cardiologists

• Amyloid cardiomyopathy; Diuretics with frequent monitoring, Salt restriction, permanent pacemaker implantation (for recurrent syncope)

• Orthostatic hypotension; fluoricortisone, midodrine.

• Renal amyloidosis; control of the edema by diuretics.

ACE inhibitors, treatment of hypercholesterolemia, treatment of renal vein thrombosis, dialysis.

Eff i /A it P t i /Th t i

• Effusion/Ascites; Paracentesis/Thoracentesis

• Diarrhea (common and incapacitating problem); Octreotide

Ch i i t ti l d b t ti ll f t t t t t

• Chronic intestinal pseudo-obstruction; usually refractory to treatment.

• Neuropathic pain; difficult to control, Gabapentin

• Bleeding; frequent and multifactorial Factor X deficiency dramatically

• Bleeding; frequent and multifactorial. Factor X deficiency dramatically

improves following effective chemotherapy

(49)

Current clinical trials Current clinical trials

• Mayo clinic phase 3; Low-Dose Melphalan + Dexa vs. High-Dose Melphalan followed by ASCT

• Boston Medical Center; Bortezomib + Dexa followed by ASCT, Phase 2

• Memorial Sloan-Kettering Cancer Center ; HD melphalan + ASCT followed by bortezomib + dexa, Phase 2

• Mayo clinic; Bortezomib, Cyclophosphamide, and Dexa y ; , y p p ,

• ECOG phase 3; Melphalan + Dexa With or Without Bortezomib

• Italy Giovanni Palladini; CLD (Lenalidomide)

• German-University Clinic Heidelberg & Boston Medical Center;

Lenalidomide Melphalan Dexa

Lenalidomide-Melphalan-Dexa

(50)

Summary Summary

• Diagnosis of AL amyloidosis Diagnosis of AL amyloidosis

– Clear evidence of a plasma cell dyscrasia (IF, FLC)

– Light chain derived amyloid deposit by direct examinationLight chain derived amyloid deposit by direct examination

• Prognosis of AL amyloidosis

– Response to therapy and cardiac involvement p py

– Serial evaluation of the serum FLC and NT-proBNP is important.

• Treatment of AL amyloidosis y

– No therapy is uniformly effective in the treatment of AL amyloidosis.

– ASCT is widely used but is applicable only to a minority.

– Melphalan + high-dose dexamethasone; appropriate initial regimen in the AL amyloidosis who are not eligible for ASCT

– Novel agents (eg, thalidomide, lenalidomide, and bortezomib) also have a significant role for treatment of AL amyloidosis