Slovenian specific issues and unmet needs in AL amyloidosis · /motorična (20%), in/ali avtonomna...
Transcript of Slovenian specific issues and unmet needs in AL amyloidosis · /motorična (20%), in/ali avtonomna...
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Slovenian specific issues and unmet needs in AL amyloidosis
Samo ZverClinical Department of Hematology
UCC Ljubljana
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With clinical examination we may discover:almost anything
Lab – laboratory, L – leukocytes, Hgb – hemoglobin, PLT – platelet, LDH – lactate dehydrogenase, CRP – C-reactive protein, BNP – beta natriuretic peptide, ISS – the International Scoring System, DS – the Durie-Salmon Staging System, FISH – fluorescence in situ hybridization, Ig –
immunoglobulin, Th – thoracic, L – lumbar
• cardiac involvement• kidney failure / renal involvement• GIT involvement / GIT failure
• Hepatosplenomegaly• Neurological imparements• Hemorrhagic diathesis• Bladder involvement
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Incidence approximatelly 10-15/1.000.000 inhabitants
Hematological dept., UCC Ljubljana 01/2000 – 10/2019
• 51 patients during this period• 2,5 pts/year
• median age at diagnosis 64 years• 5% younger than 40 years• male predominance 2:1
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• Female, born in 1975• 2004: Thrombocytosis over 700 x 109/L, BCR ABL neg., others mol. markers not in routine use• Budd Chiarri syndrome• 2005 visited my outpatient clinic , ET confirmed• 2007 liver biopsy not diagnostic• JAK-2 positive• 10/2018 liver transplant• 07/2019 spleen 20 cm i diameter• 10/2019 AL amyloidosis . Liver, Colon
• What to do now ? Treatment or maintanance or nothing ?
Two days ago ……..
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• What to do now ? Treatment or maintanance or nothing ?
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Diagnosis is like putting together mosaic picture
• anamnesis and clinical presentation• urin analysis• NT pro BNP // troponin• Kongo red cellular staining• Immunohistochenmistry
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Divide AL amyloidosis from other subtypes
• Svetlobnomikroskopska imunohistokemija s specialnimi protitelesi (95% senz. in specif.)
• Imunoelektronska mikroskopija s protitelesi (100% spec.)• Masna spektrometrija (100% specif. in senz.), samo specializirani
centri.• Analiza DNA za potrditev dedne oblike amiloidoze.
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SUBTYPES OF AMYLOIDIOSIS
tip proteini pridobljena/dedna
delež vseh oblik
prizadetost organov
AL monoklonske lahke verige imunoglobulinov
pridobljena 78% srce, ledvica, mehka tkiva, jetra, periferni in/ali avtonomni živčni sistem, GIT
ATTRm
ATTR wt
mutiran transtiretin
transtiretin(divji tip)
dedna
pridobljena
7%
6%
periferni in avtonomni živčni sistem, srce, oči, ledvica, leptomeninge
srce, ligamenti, sinovija
AA serumski amiloid A (SAA) pridobljena, reakcija na kronično vnetje
6% ledvica, jetra, srce, ščitnica, avtonomni živčni sistem, GIT
AApoAI apolipoprotein A-I dedna 3% jetra, ledvica, testisi, srce, periferni živčni sistem
ALECT2 povezava z levkocitnicelični kemotaksin -2
neznano 3% ledvica, jetra
Palladini G, Merlini G. Blood.2016;128:159-168
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Blood picture:
↑ SR↑ normocytic anemia↑ roloeaux in periphblood↑ proteins↑ urea, creatinine↑ Ca↑ uric acid
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Rolo formacije eritrocitov↑SR
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Diagnoza: OSNOVNI PRIMERI EF
normalno
monoklonski zobec
hipergamaglobulinemijapoliklonalnaoligoklonalne frakcije
pomanjkanje alfa-1-antitripsinahipogamaglobulinemija
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Proste lahke verige kappa in lambda v serumu
- proste lahke verige κ : 3,3 - 19,4 mg/L- proste lahke verige λ : 5,71 - 26,3 mg/L
- razmerje prostih lahkih verige κ/λ : 0,26 – 1,65
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MGUS
- prevalence 3,2/100 old 50 y (4,0 ♂ ; 2,7♀)- Prevalence in older than 85 y: 8,9% ♂ ; 7,0%♀- progress 1%/year
↓
Rajkumar et al. Blood 2018. vol 131(2): 163-70
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KLINIČNI ZNAKI
• Znaki AL amiloidoze
• Pozitivni biomarkerji pri bolniku z visokim tveganjem (MGUS): povišan NT-proBNP, albuminurija
HISTOLOŠKA DIAGNOSTIKA
• Biopsija podkožnega maščevja (žleza slinavka, rektalna sluznica, biopsija organa)
• Imunofiksacija seruma in urina, proste lahke verige v serumu
• Pregled kostnega mozga, FISH
• Opredelitev tip amiloida
• DNA analiza po potrebi
OCENA PRIZADETEGA
ORGANA
•SRCE (UZ srca, NT-proBNP, troponin, EKG, Holter EKG, MRI)
•LEDVICA (GFR, 24h proteinurija)
•JETRA (jetrni testi, UZ, CT, MRI)…
• NEVROLOŠKI PREGLAD; EMG, testiranje avtonomnega živčevja
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Blood 2018; 1132 (14)
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AL Amyloidosis - TREATMENT
Mediano preživetje 12-15 mesecev (srčno popuščanje: 6 mesecev)
Melfalan/prednizolon:- učinek v 20-30% (šele po 12 mesecih)
- podaljša preživetje če učinkovit (89 vs. 14 m.)
Avtologna PKMC
Bortezomib/CY/dexamethasonRevlimid/CY/dexamethason
Daratumomab combinationsIxazomib (carfilzomib ??)
Mainatanance ? LEN; CY/dmt
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AL amiloidoza (+ DP) in avtoPKMC
- absolutna kontraindikacija (TRM 14-39%)!!!
- funkcionalna sposobnost srčne mišice
- KLO na HD; autonomna polin.; GIT sym./krvavitve
- brez primarne kemoterapije pred PKMC
- stimulacija CD34+: samo G- CSF
- avtologna PKMC: MEL100-200
Mediano preživetje: 42 mesecev5 oz. 10 – letno preživetje: 36% oz. 15%
(ohranjena funkcija srca, ledvic in jeter)
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HSCT eligibillity
• age < 65-70 years,• Troponin T< 0,06ng/mL,• NT-proBNP < 5000 ng/L,• Systolic blood pressure >90mmHg,• GFR > 30ml/min,• ECOG < 2,• NYHA I ali II,• Involvement of 2 organs max• No pleural effusions• No need for oxygen treatment
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Autologous HSCT in AL Amyloidosis 2009/19
• 23 pts.
• 6/23 died (3+, 5+, 2+, 1+, 2+, at HSCT)
• 42 - 69 years
• ME 200 21x ; MEL 140 2x
• further analysis required (BNP, troponin, organ involvement/kidney, liver, …, HSCT related toxicity; effectiveness - PFS, OS; …….)
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Klinična slika sistemske AL amiloidoze
• Odvisna od prizadetosti organa – generalizirana (izjema CŽS).
• Klinično zelo heterogena.
• Splošni znaki: utrujenost, hujšanje.
• Prizadetost ledvic (70%): asimptomatska proteinurija, klinično nefrotski sindrom v 50%.
• Prizadetost srca (60%): restriktivna kardiomiopatija, nenadna srčna smrt, motnje ritma, ishemična bolezen srca.
• Prizadetost perifernega živčevja: periferna nevropatija, mešana senzorno /motorična (20%), in/ali avtonomna nevropatija (15%), sindrom karpalnegakanala.
• Prizadetost prebavnega sistema(70%): hepatomegalija z/brez splenomegalije, patološki jetrni testi, GIT krvavitve, gastropareza, zaprtje, malabsorbcija, psevdoobstrukcija zaradi motnje motilitete, diareje.
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Klinična slika sistemske AL amiloidoze
• Odvisna od prizadetosti organa – generalizirana (izjema CŽS).
• Klinično zelo heterogena.
• Splošni znaki: utrujenost, hujšanje.
• Prizadetost ledvic (70%): asimptomatska proteinurija, klinično nefrotski sindrom v 50%.
• Prizadetost srca (60%): restriktivna kardiomiopatija, nenadna srčna smrt, motnje ritma, ishemična bolezen srca.
• Prizadetost perifernega živčevja: periferna nevropatija, mešana senzorno /motorična (20%), in/ali avtonomna nevropatija (15%), sindrom karpalnegakanala.
• Prizadetost prebavnega sistema(70%): hepatomegalija z/brez splenomegalije, patološki jetrni testi, GIT krvavitve, gastropareza, zaprtje, malabsorbcija, psevdoobstrukcija zaradi motnje motilitete, diareje.
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AMILOIDNA PURPURA – pomanjkanje FX