HariP Amyloidosis.ppt · 2/7/2011 1 Amyloidosis – Dealing with the forms Parameswaran Hari Assoc....
Transcript of HariP Amyloidosis.ppt · 2/7/2011 1 Amyloidosis – Dealing with the forms Parameswaran Hari Assoc....
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