HariP Amyloidosis.ppt...2/7/2011 1 Amyloidosis – Dealing with the forms Parameswaran Hari Assoc. Professor of Medicine Medical College of Wisconsin & CIBMTR CP1106207-15 The strange

2/7/2011

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Amyloidosis – Dealing with the forms

Parameswaran HariAssoc. Professor of Medicine

Medical College of Wisconsin & CIBMTR

CP1106207-15

The strange case of Mr. M75 yr old man – past history of DM, HTNIncidentally noted abnormal LFTs.

Alk Phos 421 (ULN 190)AST 54 , ALT normal. Bilirubin normal (Aug 2005)

Next month – AST normalized, Alk phos continued to be stably elevatedFollowed with LFTs q 2months8 months later:

Presented with Ascites Jaundice:Presented with Ascites, Jaundice:Alk Phos 1462, Bilirubin 8.5, AST 110, ALT normal

Investigated over the next 2 weeks:Alk phos - >1600, Bilirubin 23.1, AST 116, ALT 50, INR >3

Clinical and Imaging:No medication changes, Hepatomegaly, No GB problems, No varicesProfound hypoalbuminemia, Anasarca, Afib ……..LIVER BIOPSY

Mr. M (continued)

Infiltration and replacement of hepatic parenchyma by nodular accumulations of amyloid (pink).

Mr. M

Bone marrow biopsy:5% plasma cells

SPEP – no paraproteinUPEP – kappa light chains (800 mg/24hrs)mg/24hrs)Serum Free Light Chains (FLC):

Free Kappa chains 1520.0 (H) mg/L (3.30 - 19.40 mg/L) Free Lambda chains 34.5 (H) mg/L (5.71 - 26.30 mg/L) Kappa/Lambda ratio 44.06 (H)

Amyloidoses :Protein folding disorders

DysproteinemiaDisorders arising from failure of specific proteins to remain in native

• Extracellular deposition of insoluble fibrillar proteins in organs and tissues.

• Virchow in mid 19th century used the term amyloid(meaning starchy or cellulose related)remain in native

structureCystic fibrosisAmyloidoses & AlzheimersEarly onset Emphysema

related).• Cohen Fibrillar nature and

beta pleated sheet configuration described by electron microscopy in 1959.

NOT ALL AMYLOID IS AL AMYLOID

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AMYLOID FORMATIONAdequate precursor protein poolInitial Nucleation

AMYLOIDOGENESIS

Initial Nucleation EventAdditional depositionAmyloid Fibril growthTissue damage

Hereditary Amyloid – the precursor proteins circulate from early lifeAL Amyloid – Plasma Cell clone acquired during lifeLambda light chain more common (3:1 vs. Kappa)

Upto 24 proteins now recognized to be potentially Amyloidogenic

AL Amyloid is a Plasma Cell Disorder

PLASMA CELL DISORDERS:Multiple Myeloma – malignant , aggressive coursePlasma Cell LeukemiaBenign Monoclonal Gammopathies

Diseases which are consequential to Diseases which are consequential to having paraproteinemia

Amyloidosis (AL)CryoglobulinemiaLight Chain Deposition DiseaseScleromyxedemaPOEMSNeuropathies secondary to Gammopathy

Bad Luck !Physical properties of the protein secreted by the plasma cells leads to disease

Normal Plasma Cells arise from B cellscirculate all over

produce immune globulins

Memory B cellMemory B cell

“Activated B cell”

Plasma Cell

Malignant Plasma Cells

Grow , proliferate and infiltrate Secrete – Immunoglobulins or Light chainsDeposition of light chains / amyloid – Organ Impairment

DIFFERENCE f M lDIFFERENCE from MyelomaBurden of plasma cells lowerNo kidney failure/bone lesions/anemia/calcium increase (CRAB)

Pathological Diagnosis –identification of plasma cells

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Immunoglobulin

Plasma Cells produce the majority of the serum immunoglobulins immunoglobulins Life span of about a monthTerminally differentiated cells

Structure and Types of Antibodies (also called Immunoglobulins or Ig)

IgG κIgG λIgA κIgA λIgD κ

• IgG• IgA• IgM

• IgD• IgE

• Kappa• Lambda

gIgD λIgE κIgE λIgM κIgM λ

Whole Antibody and Free Light Chain Production by Plasma Cells

Whole intact antibody

Whole intact antibodies

Kappa Lambda

Plasma cellPlasma cell

Light chains

Light chains

Laboratory Tests Used to Detect Abnormal Antibodies Plasma Cell

Diseases

Serum protein electrophoresis (SPEP)Urine protein electrophoresis (UPEP)Immunofixation (IF)Quantitative immunoglobulinsSerum free light chain assay: newest of the diagnostic tools

Normal Monoclonal Protein in Myeloma

Serum Protein Electrophoresis

Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004

Immunofixation : Type of Monoclonal Protein & detect small amounts

Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004

IgG kappa M protein Lambda Light Chains

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Normal vs. Plasma Cell Malignancy

Lots of different types of whole antibodies

Normal

IgG κIgG LIgA κIgA LIgD κIgD LIgE κIgE LIgM κIgM L

IgG κIgG LIgA κIgA LIgD κIgD LIgE κIgE LIgM κIgM L

whole antibodies

Whole Ab and excess light chains – and too many of both!

Myeloma IgG κ

IgG κ

Intact Ig Myeloma

IgG κ

κ

IgG κ

κ

Light Chain Myeloma

Amyloidogenic Light Chains – Not excreted / destroyed but happen to accumulate and injure organs

κKidneySkin

Blood Vessel WallsLiver

Heart

Cellular source a single clone of the B-lymphocytic lineage, usually plasma cells.

Underlying clonal proliferative disorder could b i l

AL Amyloid in MM <20%.• Majority occurs in the setting of an

apparent “benign” monoclonal gammopathy.

• Low concentrations of monoclonal Ig’s in serum/urine + occult / low grade monoclonal plasma cell

AL Amyloidosis

be aggressive neoplasm (ie:multiple myeloma) or a low grade proliferation of monoclonal plasma cells.

grade monoclonal plasma cell proliferation in BM.

• Serum Free Light Chains

• Incidence roughly 8.9 per million person year.• M :60-65%• Median age at diagnosis approx 60 yrs with only 1%

being <40.

AL Amyloidosis: Amyloid Tissue Targeting

Reasons behind deposition in different tissuesOrgan tropismProperty of light chain Property of light chain itself?Tissue receptors or other proteins

AL Amyloidosis

Kidney (74%)IF anti λ

Can happen with Myeloma (MM with Amyloid)Or Amyloid alone - (AL Amyloid)

Heart (58%)

Liver (28%)

GI (8%)No of organs involved:  1 (31%) >1 (69%) 

Small Plasma Cell clone Synthesizing “amyloidogenic” light chains

Plasma Cells – Myeloma, MGUS B lymphocytes – NHL , CLLLymphoplasmacytes – Waldenstrom’s (IgM)

Adapted from N Engl J Med. 2003;349:583‐596.

Organ Involvement with AL Amyloid

7 major sites of organ involvement:RenalLiverHeartNerve

GILung

Soft Tissue – (multiple sites)

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Free light chains ( FLC Assay)

• Have been detected in urine for >50 years *

• Polyclonal antibody against free LC• Purified so no cross-reactivity and does

not bind to intact immunoglobulinnot bind to intact immunoglobulin• Bound to latex beads - detected by a

variety of techniques (turbidity)• FLC & Urine 24 h Electrophoresis are the

most sensitive tests to detect “Amyloidogenic Light chains”

* Korngold and Lapiri Cancer: (1956) 9:262-272

Abdominal Fat Pad Aspirate

PROGNOSIS

Serious disease with high mortality.Overall median survival after diagnosis is < 2years in most series.Patients with co-existent MM have a poorer prognosis.Survival time largely dependent upon the organ system predominantly involved.Cardiac involvement is major determinant of prognosis and most common cause of death –Median Survival Time from onset of heart failure is 7 months.

Natural History of AL Amyloidosis

Mayo Series …

Robert A. Kyle & Morie A. Gertz

CARDIAC

Rapid and progressive onset of CHF.Characteristically, features are predominantly of right sided CHF.ECG – low voltage and may have a pattern of MI in absence of CAD.ECHO – concentrically thickened ventricles with normal-small cavity and diastolic dysfunction.Clinical clue: marked worsening of failure when CCB used.

AMYLOIDOSIS- CARDIAC INVOLVEMENT PREDICTS MORTALITY

JCO September 2004 Vol 22

NT ProBNP and TroponinNone , 1 or both elevated define 3 subgroups

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Nephrotic syndrome in 30-50% at diagnosis.Nephrotic syndrome and renal failure

Hepatomegaly disproportionate to extent of liver enzyme abnormalities Alkaline phosphatase elevated.

• Presence of jaundice is an adverse prognostic factor.

RENAL & LIVER

and renal failure develop only rarely during course of the illness if not present at time of diagnosis.

• Median survival from onset of jaundice ~ 3 mo.

• OTHER ORGANS:• GI – upper ,lower or both• Nerves – Peripheral / Autonomic• Pleural spaces• Massive splenic deposition --functional

hyposplenism.

Definitive Treatment Goals

Stop Production of Amyloidogenic Light ChainsReduce Plasma Cell Burden

Removal of deposited light chains from

BurdenHematological Response

organsOrgan Response

Goals of Treatment of AL Amyloid

Landmark Analysis at 6moRemission defined Hematologic vs. OrganAchievement of CR/PRAchievement of CR/PR –superior  survival

Gertz et al, ASH 2006

Transplant Experience

Why do we transplant ?Who do we transplant?How do we do?

Regimen ORR %(PR+CR)

CR % TRM %

Survivalyrs

Ref(PR+CR) % yrs

HDM + TXIDM + TX

7653

3318

12‐13

7.8 Skinner (Annals Int. Med 04)Gertz  (BMT 04)

Mel‐Dex 67 33 4 5.1 Palladini (Blood 04)

High dose DEX

53 24 7 2.6 Dhodapkar (Blood 04)

Thal ‐Dex 48 19 0 >3 Palladini (Blood 05)

Mel ‐ P 28 0? 0? 1.5 Kyle (NEJM 97)

Established therapies for AL Amyloidosis

Transplant Trials in for AL Amyloid

TRM – Transplant Related Mortality

Organ response after Auto-transplant

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RANDOMIZED FRENCH STUDY TRANSPLANT vs. NO TRANSPLANT

Survival According to Hematologic Responses and Treatment

Jaccard A et al. N Engl J Med 2007;357:1083-1093

ELECTRON MICROSCOPY OF FAT PAD ASPIRATE

TISSUE CONFIRMATION OF AMYLOID:Marrow Biopsy – 10% Plasma Cells

Kappa Light Chains restrictedKappa Light Chains restrictedFat Pad Aspirate - Positive

AL AMYLOIDOSIS:SUSPECT

Presence of Amyloid Related Syndrome SCREEN

Monoclonal plasma cell disorder PROVE

Positive Tissue Biopsy (Fat pad, Marrow, Organ) AL by typing – IHC, sequencing etc  

• Plasma Cell Disorders are a spectrum of illnesses:– Myeloma (MM) – AL Amyloidosis– Light Chain Deposition Disease

THE PLASMA CELL DISORDERS

Light Chain Deposition Disease– POEMS syndrome– MGUS (Monoclonal Gammopathy of Unknown

Significance)– Smoldering MM– Plasmacytoma– Plasma Cell Leukemia

The Forms:Is there a paraprotein?

Serum and Urine Paraprotein

e.g. : IgG Kappa

IgG – heavy chain andKappa – light chain

Organs Involved at diagnosis

RENAL INVOLVEMENT:

24 hr urine protein electrophoresis

In amyloid – albuminuria is common.E.g. 24 hr total protein loss – 8 grams /24hUPEP – 23% Lambda light chains.Lambda – 24% x 8 – 1.9 g/24hRemainder is albumin

LIVER INVOLVEMENT

LIVER INVOLVEMENT:

Liver span – clinical or imaging

Alkaline phosphatase elevation is classic

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CARDIAC INVOLVEMENT

Heart Involvement:

DIASTOLIC Heart failure is classic

Ejection fraction variable –Echo/MUGA/MRI/ /

Interventricular Septum

Cardiac Biopsy

Cardiac BiomarkersNT ProBNPTroponin

BNP vs. NT ProBNPTroponin I or Troponin T

MRI Heart

septum

Other organs involved – GI, Nerves OTHER ORGANS

AUTONOMIC NEUROPATHY:

Hypotension –Orthostasis –Clinical Evidence –

Heart rate changesGI symptoms –

FAT PAD results –

Other organs –Joints, Lung , Soft tissue masses

Amyloidosis Lab Markers to follow

Biochemical Markers:

Monoclonal Spike

Free Light Chains

Involved Light Chain

Uninvolved Light Chain

Urinary Light chain excretion

Chemotherapy Prior to Transplant

COMMON DRUGS:

Bortezomib

Melphalan

D th /P d iDexamethasone/Prednisone

Lenalidomide

Thalidomide

Cyclophosphamide

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RESPONSE MEASUREMENT in AMYLOID

Gertz et al Am Journal Hematology 2005

Hematological Response –Very Similar to MM

Usually the only response seen at 100 days.

Measurable disease is low:Serum M spike 0.5g/dlUrine 24h M spike 100mg/dlInvolved FLC >10 mg/dl

REMISSION BASED ON:SPEPSerum IFEUPEP 24 hrsUrine IFEMarrow&Free Light Chains: 50% decline

Marrow not part of PR or Progression

ORGAN RESPONSE MEASUREMENT

ORGAN RESPONSE lags behind Hematological Response

CARDIAC RESPONSE

GI and Liver Autonomic Response

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BEST HEMATOLOGIC RESPONSE ORGAN RESPONSE - KIDNEY

PLANNED MAINTENANCE

MAINTENANCE:Treatment given after transplant – BUT not for Progressive diseasePlanned vs. Unplanned ???? Difficult

CURRENT DISEASE STATUS

Organ Disease Progression ORGAN RESPONSE and PROGRESSIONFrequent source of angst!!

NOT Commonly seen At 100 days!Kidney: common to see decline in proteinuriaHeart : EF increase , IVS thickness decrease.

Functional Improvement commonNerve : Rare improvement in EMG NCVLiver : Reduction in Alk Phos common

Liver Span reduction

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Specific Form Related Questions on AMY

Pre TED form :Plasma Cell Disorders (Amyloid not separated out)

Disease Status question reflects MMi.e sCR, CR, PR … etcNOT appropriate / complete since it only measures hematological remission in AMYOK to report hematological status

M t ti t ill b NE/U kMost patients will be NE/UnkIF no prior treatment -- NE

When to report organ response?Unlikely to have substantial organ response assessed at D100Most of the response at d100 - functionalIF your center looked for organ response , please report

e.g U24hr with decline in proteinuria – OK to report