leucemii
DESCRIPTION
leucemiiTRANSCRIPT
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BOLILE CELULEI STEM
• Proliferarea
• Diferentierea
• Autoreinnoirea
• Migrarea
Proprietati:
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CSH PLURIPOTENTA
CFU GEMMCFU-L
Protimocit
Pre-BBFU-E CFU-E
CFU-Meg
CFU-GM
CFU-Eo
CFU-Ba
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Leucemia mieloida cronica
Majoritatea leucemiilor acute
Policitemia vera
MMM
Trombocitoza primara
HPN
Majoritatea limfoamelor MMMulte neutropenii croniceAplazia eritroida pura Anemia Fanconi Anemia aplasticaNeutropenia ciclicaSindromul Shwachman -Diamond
BOLILE CELULEI STEM
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LEUCEMII
![Page 8: Leucemii](https://reader031.vdocuments.mx/reader031/viewer/2022013105/563db8bd550346aa9a96806c/html5/thumbnails/8.jpg)
DEFINITIE
Boli clonale ale celulei stem limfoide(LAL),respectiv
ale celulei stem mieloide sau progenitori(LAM),ce se
caracterizeaza prin acumularea de celule imature(blas-
tice) in MO si teritoriile extramedulare(sange si alte tesuturi).
![Page 9: Leucemii](https://reader031.vdocuments.mx/reader031/viewer/2022013105/563db8bd550346aa9a96806c/html5/thumbnails/9.jpg)
CLASIFICARE
• Leucemii acute
• Leucemii cronice
•Leucemii mieloide
•Leucemii limfoide
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INCIDENTA
• 3,6/100 000/AN
• M>F
• Creste cu varsta:1,7<65 ani;16,2>65 ani)
• Crestere semnificativa a incidentei
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ETIOLOGIE
1)Ereditatea:
incidenta familiala crescuta
incidenta bolii crescuta la gemenii univitelini
incidenta crescuta in aneuploidii
Down,Klinefelter,Patau
imunodeficientele cong.(s. Wiscott-Aldrich)
boli cu fragilitate cromozomiala
Fanconi,Bloom,ataxia-teleagiectazia
Kostmann
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ETIOLOGIE
2)Dobanditi
fizici-radiatiile
Japonia-incidenta maxima la 5-7 ani
radiatiile terapeutice cresc aditional AA
chimici -benzen,fumat
-pesticide,ierbicide,vopsea
-coloranti,petrol,oxid de etilen
medicamente
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ETIOLOGIE
Medicamente Anticanceroasele-cauza principala a LAM AA-4-6 ani de la tratament aberatii cromozomiale 5,7 Inhibitori de topoizomeraza II 1-3 ani de la tratament 11q 23 Cloramfenicol,fenilbutazona Clorochina,methoxipsoralen
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ETIOLOGIE
Boli ce preced LA:
SMD
HPN
SMPC
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Cresterea celulelor normale este controlata de un grup de gene numite protooncogene:
1.Factori de crestere sau receptori ai factorilor de crestere(G-CSF,GM-CSF,M-CSF)
2.Proteine implicate in conversia semnalului primit de receptorii membranari ai FC in reactii biochimice intracitoplasmatice si intranucleare care regleaza proliferarea celulara.
PATOGENIE
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CLONA LEUCEMICA
•AVANTAJ DE CRESTERE
•INSUFICIENTA MEDULARA
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PATOGENIE
Defectul genetic suprima capacitatea de diferentiere cu pastrarea capacitatii de proliferare .
FC(proprii,din micromediu)
clona leucemica
avantaj de crestere
insuficienta medulara
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CLASIFICARE
Criterii:
•morfologice
•citochimice
•imunologice
•citogenetice
•biologie moleculara
•clinice
LAL
LAM
BIFENOTIPICA
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CLASIFICARE FAB A LAM
M0 = citologie neindentificabila M1 = mieloblastica fara diferentiereM2 = mieloblastica cu diferentiere M3 = promielocitara M4 = mielomonoblastica(comp. monocitara > 20%)M5 = monoblastica (comp. monocitara >80%)M6 = eritroleucemia acuta (di Gugliemo) eritroblasti>50% M7 = megacarioblastica
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Corp Auer
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LAM-M3
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LAM 4
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MO asp M6
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CLASIFICARE FAB A LAL
Criterii morfologice:
L1-microlimfoblastica(copii)
L2-macrolimfoblastica
L3-celule Burkitt-like
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MO in
LAL 1
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MO asp L2
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MO asp L3
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LAL 3-linieT
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Bifenotipica
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CLASIFICARE IMUNOFENOTIPICA
Are semnificatie diagnostica si prognostica
LAM 0 -CD13,CD43
LAM 7- CD 41/CD 61
Pre-B- CD10,CD19, CD 20
Protimocit-CD2,CD 7,CD38, CD71
Timocit _CD1,CD2,CD 4,CD7, CD8, CD 38
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CD13
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CD43 imunofenotipare
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Fluorescenta PML-LAM3
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CLASIFICAREA CROMOZOMIALA
Cel mai important element prognostic
1) t(15;17) (q22;q12)-M3
2)inv (16) (p13q22)-M4Eo
t(8;21) (q22;q22)-M2
t(9;11) (p22;q23)-M5
11q23(translocatii)-M5
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CLASIFICAREA CROMOZOMIALA-
CARACTERISTICI CLINICE
t(8;21) si t(15;17) cu varsta tanara
del(5q) si del(7q) cu varsta avansata
t(8;21) (q22;q22)-sarcomul mieloid
t(15;17) –CID
monosomia 7 -diabet insipid,febra,infectii
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CLASIFICAREA CROMOZOMIALA
T(9;22) -cromozom Ph -LAL ale adultului
T(12;21) -25% LAL la copii
7si 14 in LAL de linie T(receptorul )
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CLASIFICAREA MOLECULARA
t(15;17) -Pml/Rar(fuziumea Rar cr 17-Pml cr 15)
Rar alfa -codifica receptori nucleari
Pml-Rar alfa-proteina de fuziune care suprima transcriptia genelor si blocheaza diferentierea celulelor-ATRA elibereaza blocul
inv(16)M4Eo subunitati ale fact. de transcriptie
t(8;21)M2 Cbf(core-binding factor)
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CLASIFICAREA MOLECULARA
Inv(16)-fuziunea CBFB(Pebp2) de pe q cu MYH 11
de pe bratul scurt
t(8;21)-CBFA(AML1) de pe cr. 21 se alatura cu ETO
pe cr.8 AML/Eto proteina care blocheaza
transcriptia CBFA-CBFB
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CLASIFICAREA MOLECULARA
Majoritatea translocatiilor intre 11q23 rearanjeaza MLL(leucemia de linie mieloida)
Gena are 2 regimuri care incorporeaza Zn fingers
anomalii ale MLL sunt relativ comune la pacienti care au anomalii citogenetice ale 11q23
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TABLOU CLINIC
•SINDROM ANEMIC
•SINDROM HEMORAGIPAR
•SINDROM INFECTIOS
•SIMPTOME NESPECIFICE
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Sindrom anemic
asteniepaloarepalpitatii
Sindrom hemoragipar
cutanat(petesii ,echimoze)mucos(epistaxis,gingivoragii)hemoragii (cerebrale,retiniene)
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Retina in LAM
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CID
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ALTE MANIFESTARI CLINICE
•dureri osoase,articulare•semne de leucostaza•adenopatii,hepatosplenomegalie•semne ale infiltratiei leucemice infiltratie cutanata hipertrofie gingivala (M4-M5) sindrom meningeal paralizii de nervi cranieni renale sarcoame granulocitare -T(8,21)
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Hipertrofie gingivala in LAM4,LAM 5
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Infiltratie cutanata in LAM 5
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LAL
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TABLOU PARACLINIC
SANGE PERIFERIC
anemie-poate fi severa,normocroma,normocitara
trombocitopenie-100 000(25%<25 000)
NL variabil(40%<5000,20%>100 000)=15 000
L si T cu anomalii morfologice si functionale
prezenta de blasti
celule mature
!!blastii pot lipsi (forme aleucemice)
“hiatus”leucemic
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EVALUARE DIAGNOSTICA
•Anamnaza si examen fizic,status de performanta•HLTr si formula leucocitara•Aspirat si biopsie medulara (crioconservare)•Valori biochimie sangvina:electroliti,uree,creatinina•Ca,P,a.uric,TGO,TGP,Bi,LDH,amilaze,lipaza)•Profil de coagulare(TP,,PTT,Fibrinogen,D-dimeri)•Serologie virala(CMV,HSV-1,varicela zoster)•Rdg. Toracica(PA si L)•EKG,FE•Grup sangvin,determinare HLA,crioconservare celule•PL(simptomatici),RMN(dureri,parestezii,slabiciune )•Evaluare stomatologica
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DIAGNOSTIC PARACLINIC
Dimens.
Nucleoli 1 - 2 2- 5
Citoplasma redusa moderata
Corpi Auer absenti +/-(M2,M3 )
col. Sudan - +
peroxidaze - +
esteraze - +
PAS + +/-
Limfoblast Mieloblast
Morfologic C
itochim
ic
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Bifenotipica
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mieloperoxidaze
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Col. PAS in LAL
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PAS in LAM 6
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Esteraze nespecifice
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Coloratie Sudan in LAM
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Examen citochimic
mieloperoxidaza plachetara
alfa-naftil-esteraza
PAS-LAL
Imunofenotipare
markeri eritrocitari:glicoforina A,spectrina
markeri trombocitari:GlicoproteinaIb,GPIIbIIIa
CD61,fvW
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DIAGNOSTIC POZITIV
• Trei mari sindroame clinice
• Prezenta blastilor >/=20% in MO si/sau sangele periferic
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DIAGNOSTIC DIFERENTIAL
• Reactia leucemoida
• LA aleucemica-SMD
• Anemia aplastica
• LGC
• Mononucleoza infectioasa
• Metastazele medulare(rabdomiosarcom,sarcom Ewing,cancer bropnhopulmonar cu celule mici)
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EVOLUTIE,PROGNOSTIC,COMPLICATII
• Boli incurabile curabile
• Cele mai bune rezultate la copil(LAL)
• Rezultate bune si la adult dupa transplant
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FACTORI DE PROGNOSTIC
•Cel mai important remisiunea completa!!!!
•Gena 1-rezistenta multipla la tratament
•Varstnici-pompa de eflux mdr1
•t(8;21),inversiunea 16,t(15;17)-prognostic bun
•5q-;7q-;12p -prognostic f. prost
•inv(3)-rar RC
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FACTORI DE PROGNOSTIC
Varsta, statusul de performanta
Anomalii citogenetice
Citopenia sau afectiunile hematologice preexistente
citopenia>1 L
L, mieloblasti numerosi
LA dupa tratament citostatic si/sau iradiere
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TRATAMENT
Obiective-obtinerea RC
Mijloace-complex Polichimioterapie Iradierea Transplantul de M.O. Tratament adjuvant (antibiotic,substitutiv,simptomatic)
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TRATAMENT ADJUVANT
Hemoragiile severe-MT(20 000/mmc)
CID -doze mici de heparina:50 u/kg la 6 h
-MT,plasma,crioprecipitat(T>50 000;F>100mg)
-profilactic H la pacientii cu CID fara sangerare?
Febra si granulocitopenie
Insuficienta renala,hipervascozitate
ME pentru Hb>80g/L(filtrat,iradiat,neg CMV)
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TRATAMENT ADJUVANT
Tratament preventive Z1 de Chi in absenta febrei, infectiilor manifeste:
•Ciprofloxacin 2X500 mg la 12h
•Fluconazol 200 mg la 12h po
•+/- dezinfectie tub digestive 3 zile (Normix,
Metronidazol)
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TRATAMENT ANTIBIOTIC
Carbapenemi (Imipenem, Meropenem)
Piperacilin-aminoglicozid
Cefalosporine gen. III ceftazidim,cefapim
Combinatii dublu lactam
piperacilina-ceftazidim
Aztreonam-AG/chinolona
Vancomicina (neutropenie si febra>3Z)
Amfotericina din ziua 7 daca persista febra
Voriconazol, Caspofungin
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TRATAMENT ADJUVANT
Factori de crestere
Nu cresc rata RC
supravietuirea
Recomandati la:
varstnici
scheme agresive, LAL
infectii necontrolate L<1000
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Cateter multilumen AD prin tunel cutanat
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TRATAMENT-POLICHIMIOTERAPIE
Prednison
Vincristina-microtubulii fusului mitotic
L-asparaginaza- asparagina celulara scazuta
Metotrexat-inhiba dihidrofolat reductaza
Daunorubicina-intercalare baze azotate
Citozin-arabinozid-analog pirimidinic
Tioguanina-analog purinic
Mercaptopurina-analog purinic
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CRITERII DE REMISIUNE COMPLETA
Sange periferic normal(N>1500;T>100.000)
Absenta altor determinari
<5% blasti in maduva,celularitate>20%,C.Auer -
12 citoreductie 6
10 celule tumorale <10 cel. tumorale
(b.manifesta clinic) (boala reziduala)
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BOALA MINIMA REZIDUALA
RT-PCR-anomalii moleculare
FISH-aberatii citogenetice
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FISH
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TRATAMENTUL LAL
I INDUCEREA REMISIUNII
adult daunorubicina
L asparaginaza
vincristin
prednison
II PROFILAXIA RECADERII SNC
metotrexat intratecal
radioterapie craniana
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TRATAMENTUL LAL
III.MENTINEREA REMISIUNII 6 mercaptopurina metotrexatIV.CONSOLIDARE vincristin prednison metotrexat ciclofosfamida
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TRATAMENTUL LAL
• Rata remisiunii:85% copii,50% adulti
• Durata remisiunii 10-12 L
• Transplantul de MO:
a doua remisiune la copil
prima remisiune la adult
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TRATAMENTUL LAM
I INDUCEREA REMISIUNII
Citozin-arabinozid pev continua 100-200mg/mp/ zi 7 zile
Antraciclina
Daunorubicina 45mg-60/mp /zi, zilele 1,2,3. Idarubicina 12-13mg/mp pe zi,zilele 1,2,3
+/-Etopozide(imbunatateste durata RC)
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TRATAMENT LAM
Remisiunea completa se obtine de obicei in 4S la 75%
O treime necesita doua cicluri de tratament:C5-A2
Administrarea de G-CSF uman recombinat dupa 12h
Allotransplant daca nu se obtine remisiunea
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TERAPIA POSTREMISIUNE
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TRANSPLANT MEDULAR
Allotransplant(singenic)AutotransplantGrefa cu celule stem periferice TMO CHI R1 30-60% 20-70%LAL R2 30-60% 10%
R1 40-60% 10-50%LAM R2 30% 10%
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CELULE STEM
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TRATAMENTUL LAM3
ATRA 45mg/mp/zi po + CT(7si3)
10% Sdr. de acid retinoic
10%cei cu CT mor cu DIC
Mentinere RC :ATRA /CT
Arsenic trioxid -formele refractare la ATRA
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LEUCEMIA LIMFATICA CRONICA
• Def.-boala clonala caracterizata prin proliferarea de limfocite cu aspect morfologic adult cu evolutie relativ lunga.
• Epidemiologie -cea mai frecventa forma de leucemie(30%) -incidenta 30/100 000 -M:F=2:1,varsta>60 ani
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LEUCEMIA LIMFATICA CRONICA
• 75% de linie B`
• Trisomia 12 factor de prognostic negativ
• T(14;15)(q32;q13)
ETIOPATOGENIE-necunoscuta
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Tablou clinic
• Debut:descoperire intamplatoare
oboseala,astenie,fatigabilitate
infectii frecvente
adenopatie
hepatomegalie,splenomegalie
HAI,PTI
aplazie pe seria rosie
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Tablou clinic
• Examen obiectiv:
adenopatie
hepatomegalie,splenomegalie
manifestari hemoragipare cutaneo-muc
paloare
infiltrarea tegumentelor,ggl. salivare
infiltrarea tubului digestiv
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EVALUAREA PACIENTULUI CU LLC
• HLG cu formula leucocitara
• Biochimie-afectare organica
• Electroforeza
• BMO
• Ecografie,CT pentru adenopatii,H,S
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Diagnostic paraclinic
Sange periferic :limfocitoza(umbre Gumprecht) anemie trombocitopeniePunctie sternala:infiltrarea cu acelasi tip de celule confirma diagnosticul la Ly 4000Biopsia ganglionaraAnomalii cromozomiale:Trisomia 12,cromozom 13Investigatii imunologice: hipogamaglobulinemie,marker CD5 tulburari ale imunitatii celulare(Ts/Th)
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CLASIFICAREA RAI
O.Risc scazut Limfocitoza >10ani Infiltrat medularI.Risc intermediar Limfocitoza+ 7 ani adenomegalie II.Risc intermediar Limfocitoza+ 7 ani
splenomegalie+/- hepatomegalieIII.Risc inalt Limfocitoza+ 1,5 ani anemieIV.Risc inalt Limfocitoza+ 1,5 ani trombocitopenie
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BINET (5 arii limfatice:cervicali,axilari,
inghinali,F,S)
A. Fara anemie,trombocitopenie >10
Mai putin de trei arii ganglionare
B. Fara anemie,trombocitopenie 7 Mai mult de trei arii ganglionare
C. Hb</=10g/dl si/sau 2 Tr <100 000/mmc
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Citogenetic
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Complicatii,prognostic
• Linie B: AHAI TI hipogamaglobulinemie sindromul Richter infectiile sunt principala cauza de mortalitate,morbiditate sangararile secundare trombocitopeniei• Prognostic : IPI pentru limfomul non-Hodgkin secventa imunoglobulinelor si CD38 (prognostic mai bun) infiltrat medular difuz limfocitoza peste 100 000
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Sindrom Richter
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TRATAMENT
Stadiile I si II:
organomegalii
AHAI
hiperslenism
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Stadiile III si IV (indicatii absolute de tratament)
• Momochimioterapia:
clorambucil p.o
fludarabina i.v.
asocieri rituximab,alemtuzimab
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RADIOTERAPIA adenopatii compresive
organomegalii inmportante
IMUNOGLOBULINELE IV
o data pe luna de obicei in std.avansatt
SPLENECTOMIE :AHAI,TI refractare
TRATAMENT ADJUVANT hidratare,allopurinol
tratamentul infectiilor,anabolizante
TRANSPLANTUL DE MO allogenic la tineri
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LEUCEMIA CU CELULE PAROASE
• Barbati>40 ani• Pancitopenie• Splenomegalie importanta• Fibroza medulara• Manifestari de vasculita• Prezenta celulelor cu aspect “paros”tipic• 10-15 microni,citoplasma albastru-gri• Prelungiri,nucleu excentric,cromatina laxa• Fosfataza acida rezistenta la tartrat• Markeri de limfocit B
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TRATAMENT
• INTERFERON ALFA
• PENTOSTATIN
• CLADRIBINE-RC cu supravietuire indelungata
• Linia a doua Rituximab