classification of systemic amyloidoses - uni-heidelberg.de · classification of systemic...
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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
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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
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Clinical manifestation
( )
Merlini, Blood 2007
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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
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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)
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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
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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
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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
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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
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Pathognomonic symptomsPathognomonic symptoms of AL amyloidosis
NEJM, 2005
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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
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Immunohistology
• Patient with kappa AL (Heart Biopsy)– Prof. C. Röcken, Kiel
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DISKUS 001
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DISKUS 002
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DISKUS 004
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DISKUS 006
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DISKUS 007
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DISKUS 010
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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
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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
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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
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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%
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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)
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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)
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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)
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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.
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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
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Thanks toThanks to
• Martha Skinner and her team
• Morie Gertz and his teamhis team
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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
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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