Classification of systemic amyloidosesAmyloidosis-Type Precursor Protein Clinical Association

Acquired

Classification of systemic amyloidoses

AcquiredAA SAA Rheumatoid arthritis, chronic-inflammatory bowel diseases,

bronchiektasia, tuberculosis, leprosis, lues, Mucoviscidosis

AL light chain Multiple Myeloma, monoclonal gammopathy,AL light chain Multiple Myeloma, monoclonal gammopathy, Waldenstrom´s Disease

Aβ2M β2-Mikroglobulin DialysisATTR Transthyretin Senile systemic amyloidosisATTR Transthyretin Senile systemic amyloidosis

Inherited

ATTR Transthyretin FAP: Familiar Amyloid-Polyneuropathy, FAC F ili C di thFAC: Familiar Cardiomyopathy

AFib Fibrinogen Apo A1/2 ApolipoproteinALys LysozymeALys LysozymeAGel Gelsolin

Adapted from Westermark, Amyloid 2002

Light chain (AL) amyloidosisLight chain (AL) amyloidosis

Stefan SchönlandStefan SchönlandMedical Department VDirector: Prof. A. D. Ho

Amyloidosis CenterUniversity Hospital Heidelbergy p g

Opening Symposium; Heidelberg, 02.05.09

Clinical manifestation

( )

Merlini, Blood 2007

Light chain amyloidosis (AL)

• Monoclonal plasma cell disorder lambda predominance– lambda predominance

• Multiple myeloma or Waldenstrom´s disease is the nderl ing diasease in abo t 10%is the underlying diasease in about 10%

• Incidence: 5-13 new diagnoses / 1 mio. / year (Falk, NEJM 1997)

• Median age at diagnosis about 65 yearsMedian age at diagnosis about 65 years• Predominance of males

Light chain amyloidosis (AL)

• Bad prognosis due to fast developing organ failurefailure

• Median Survival: 13 months after diagnosis– 13 months after diagnosis

– Cardiac failure present: 5 month (Kyle, Semin Hematol 1995)

Diagnostic algorhythmAmyloidosis suspected:

Biopsy / K R d t i i• Biopsy / Kongo-Red staining• Typing of amyloidosisyp g y

– Evaluation of gammopathy – Immunohistology– Immunohistology – Germ-line mutation analysis

• Organ involvement / Performance Status • Treatment recommendationTreatment recommendation

Amyloidosis suspected

• Myocardial hypertrophy without hypertension• Orthostatic dysregulation and dizziness without vascular y g

cause• Nephrotic syndrom• Chronic diarrhea • Hepatomegaly / AP elevation

S t ki bl di ith t ti l ti• Spontaneous skin bleedings without anticoagulation• Fast worsening polyneuropathy

PNP without diabetes positive family history• PNP without diabetes, positive family history• Carpaltunnel syndrome• Ongoing hoarseness• Ongoing hoarseness• Weight loss

T i f l id iTyping of amyloidosisGammopathyp y

• Serum electrophoresisf• Immunfixation

– Serum U i– Urine

• Presence of monoclonal light chain– Serum (free light chains)– Urine (24h collection)

B t l / bi• Bone marrow cytology / biopsy

• Sceletal X-ray / CT bone scan / MRI

Gammopathy in AL amyloidosisGammopathy in AL amyloidosisSensitivity of FLC

100%

80%

40%

60%Reihe1Reihe2

40%

20%

FLC test IFE serum IFE urine IFE serum +IFE urine

FLC test + IFE serum + IFE urine

FLC test Plasma cellcontent >5%

Bochtler, Haematologica 2008

urine

Pathognomonic symptomsPathognomonic symptoms of AL amyloidosis

NEJM, 2005

T i f l id iTyping of amyloidosisImmunhistology and mutation analysesgy y

• Amyloid typing on tissue biopsies • Presence of hereditary forms

– Genotyping (TTR, Apo A, Fib-alpha)Ge o yp g ( , po , b a p a)

• Cave misdiagnosis• Cave misdiagnosis– In older patients (senile TTR amyloidosis) – Concomitant presence of monoclonal

gammopathy and a hereditary amyloidosis

Immunohistology

• Patient with kappa AL (Heart Biopsy)– Prof. C. Röcken, Kiel

DISKUS 001

DISKUS 002

DISKUS 004

DISKUS 006

DISKUS 007

DISKUS 010

Therapeutic goal

• Reduction / Elimination of the plasma cell pclone

Sustain or improve function of involved organs– Sustain or improve function of involved organs– Avoid new organ involvement

Therapy of AL Amyloidosis2003

Therapy of AL Amyloidosis

19942006

Allogeneic

Thalidomid 2004

Bortezomib2005

19751994

HDM + ASCTAllogeneic

SCT2005

LenalidomideMelphalan / Prednison

1970 1980 1990 2000

19801972 19981990 1995 2001DMSOColchicin VADINFa

Vit EDexa MDex

High-dose melphalan / autologous stem cell transplantation (HDM)stem cell transplantation (HDM)

P ti t l ti ( t H id lb )Patient selction (at Heidelberg)• Age < 70 years• NYHA Stage < III • WHO PS < 3WHO PS < 3 • Systolic RR > 90 mm Hg

t ti ff i• no symptomatic effusions

High-dose melphalan

Age at Tx, years 57 (35-69) M l / F l 56 / 44Males / Females 56 / 44

ResultsComplete remissions 42 / 95 44%Complete remissions 42 / 95 44%Partial remissions 32 / 95 34%Organ response 40 / 92 43%Organ response 40 / 92 43%

Mortality 3 / 100 3%

Hi h d M l h lHigh-dose MelphalanOverall survival, N=100

100

80

60bilit

y (%

)

60

40

val p

roba

b

20Sur

viv Median follow-up 31 Mo

0 20 40 60 80 100 120 1400

Time (mo)Time (mo)

Hi h d l h lHigh-dose melphalanImportance of CR achievementImportance of CR achievement

Overall Survival (N=95)

100

80

y (%

)

CR

60

prob

abili

ty

PR40

20

Surv

ival

p PRNR

0 20 40 60 80 100 120 1400

S

P<0,0001

( )Time (mo)

Hi h d l h lHigh-dose melphalanImportance of CR achievementImportance of CR achievement

Event-free-Survival

100

80(%)

E t d f60

roba

bilit

y

CREvent def.:• Death• Organ progression• Haem progression40

20

Sur

viva

l p PR

NR

• Haem. progression• Second chemotherapy

0 20 40 60 80 100 1200

S P<0,0001

Time (mo)

SSummary

• Diagnostic tools have improved. • Chemotherapeutic spectrum has importantly• Chemotherapeutic spectrum has importantly

widened in the last 10 years.

• HDM ist currently treatment of choice for eligible patients in experienced centres.

• Solid organ transplantation is possible in selected patientspatients.

P tiPerspective

• Conventional chemotherapy in combination with new drugs is currently being tested in clinical trials

(L-MD, B-MD)

• Development of new Anti Amyloid Treatment• Development of new Anti-Amyloid-Treatment

Thanks toThanks to

• Martha Skinner and her team

• Morie Gertz and his teamhis team

Danke anDanke anAmyloidoseAmbulanz

WissenschaftAmbulanz

• U. Hegenbart • A. Jauch

• M. HansbergA M tt• T. Bochtler

A B d

• A. Mangatter• M. Moos

• S. Dietrich• A. Bondong• K. Zerfass• M Kaden

• M. Hundemer• H. Tran

• D. HoseM. Kaden

Medizinische Klinik V

• H. Goldschmidt

Medizinische Klinik VDirektor A.D. Ho

Alle Ärzte und Pflegekräfte die Amyloidose Patienten seit 1998 versorgenAlle Ärzte und Pflegekräfte, die Amyloidose-Patienten seit 1998 versorgen

Alle Kolleg/innen, die uns Patienten überwiesen haben

Amyloidose-Zentrum am Universitäts-Klinikum HeidelbergAmyloidose-Zentrum am Universitäts-Klinikum Heidelberg

Biostatistik DKFZ Heidelberg:Hämatologie:

S Schönland gA. Benner / C. Heiß / M. Zucknick

Institut für Humangenetik:

S. SchönlandU. HegenbartT. BochtlerS. Dietrich

A. Jauch, J. Dikow, K. Hinderhofer

Institut für Pathologie:Ph Schnabel C Andrulis

H. GoldschmidtA.D. Ho

Rheumatologie: Ph. Schnabel, C. AndrulisRadiol. Klinik

W. Hosch

N. BlankChirurgie:

R. Singer, F-U Sack, P. Schemmer

Institut für Pathologie, KielC. Röcken

Nephrologie:J. Beimler / M. Zeier

Neurologie: E Hund C. Röcken

Klinische Chemie - Großhadern Universität München

P. Lohse

E. HundKardiologie:

A. Kristen / S. Buss Gastroenterologie:

MDC, Berlin – NeuroproteomicsE. Wanker, J. Bieschke

Gastroenterologie:T. Ganten, K.-H Weiss