curs 6. leucemii acute
TRANSCRIPT
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LEUCEMIILE ACUTELEUCEMIILE ACUTE
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BOALA MALIGNA: definitieBOALA MALIGNA: definitie
Anomalie fenotipica
Monoclonalitate
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HEMATOPOIEZA NORMALAHEMATOPOIEZA NORMALA
Procesul de formare a elementelor celulare din sange
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Celula stem multipotenta: - autoreplicare - migrare in sange periferic - diferentiere ( angajare )
CFU = Unitati Formatoare de Colonii( CS angajate )
Linia mieloida Linia limfoida
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HEMATOPOIEZA NORMALAHEMATOPOIEZA NORMALA
lipocit
lipocit
megakariocit
sinus
Vena centrala
Celule endoteliale
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HEMATOPOIEZA NORMALAHEMATOPOIEZA NORMALA
Care este suportul genetic al procesului de diferentiere ?
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rearanjament genic => diferentiereCFU = Unitati Formatoare de
Colonii( CS angajate )
Linia mieloida Linia limfoida
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Studiul celulelor hematopoietice:Studiul celulelor hematopoietice:
Examen citologic si histologic
Imunofenotipare
Biologie moleculara
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Patologia maligna hematologica: Patologia maligna hematologica: clasificareclasificare
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SINDROAME LIMFOPROLIFERATIVE
SINDROAME MIELOPROLIFERATIVE
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SINDROAME LIMFOPROLIFERATIVE
SINDROAME MIELOPROLIFERATIVE
Acute:-LAM
Cronice - PV- TE-_LGC- MMM
Acute:-LAL
Cronice - LLC- HCL- LNH - BH - BW- MM
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Leucemii Acute : DefinitieLeucemii Acute : Definitie
Leucemiile acute ( LA) sunt un grup heterogen de boli maligne ale celulelor stem hematopoietice nediferentiate sau partial diferentiate.
Incidenta – 3-5 cazuri / 100 000 loc/ an
- pred. sex masculin
Varsta mediana: 62-65 ani pentru LAM
30-40 ani pentru LAL
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Factori de risc pentru aparitia Factori de risc pentru aparitia leucemiilor acuteleucemiilor acute
Radiatiile ionizanteRadiatiile ionizante Substante chimice si medicamente Hipoplazia medulara Factori genetici Agenti virali
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Radiatiile Ionizante:
Expunere accidentala Expunere profesionala Expunere terapeutica
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Factori de risc pentru aparitia Factori de risc pentru aparitia leucemiilor acuteleucemiilor acute
Radiatiile ionizante Substante chimice si medicamenteSubstante chimice si medicamente Hipoplazia medulara Factori genetici Agenti virali
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Substante chimice si medicamente:Substante chimice si medicamente:
Benzen Arsenic Fenilbutazona Cloramfenicol Agenti alchilanti Inhibitori de topoisomeraza II
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Factori de risc pentru aparitia Factori de risc pentru aparitia leucemiilor acuteleucemiilor acute
Radiatiile ionizante Substante chimice si medicamente Hipoplazia medularHipoplazia medulara Factori genetici Agenti virali
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Hipoplazia medulara
Anemia aplastica dobandita Anemia Fanconi Hemoglobinuria paroxistica nocturna
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Factori de risc pentru aparitia Factori de risc pentru aparitia leucemiilor acuteleucemiilor acute
Radiatiile ionizante Substante chimice si medicamente Hipoplazia medulara Factori geneticiFactori genetici Agenti virali
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Factori genetici:
Sindromul Down Sindromul Fanconi Sindromul Bloom Sindromul Klinefelter Telangiectazia ereditara ataxica
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Factori de risc pentru aparitia Factori de risc pentru aparitia leucemiilor acuteleucemiilor acute
Radiatiile ionizante Substante chimice si medicamente Hipoplazia medulara Factori genetici Agenti viraliAgenti virali
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Agenti virali
HTLV1( retrovirus )=> Limfomul / Leucemie cu celule T al adultului
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Patogeneza leucemiilor acute:Patogeneza leucemiilor acute:
Transformare maligna clonala Proliferarea unei populatii celulare imature si fara
functie fiziologica
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Hematopoieza leucemica:- monoclonala- blocare in maturatie / diferentiere- necontrolabila
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Mecanismul transformarii leucemice:1. ONCOGENE CELULARE
Factori de crestere extracelulari sis
Tirozin-kinaze membranare fms, kit, erb-B
Transductori de semnal intracelular:
a.) leaga GTP
b.)Serina / Treonina kinaza
c.) nuclear – factori de transcriptie
-receptori pt vit. / hormoni
- tirozin- kinaza
H-ras, K-ras, N-ras
raf, mos
jun, fos, myc, myb, ets,
erb-A, RARA-abl
2. GENE SUPRESOARE DE TUMORA p53, Rb
3. INHIBITORI DE APOPTOZA bcl-2
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Rezultatul expansiunii populatiei leucemice:
Infiltrare leucemica medulara=> insuficienta medulara
Infiltratie leucemica in tesuturi si organe
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LEUCEMII ACUTE: tablou clinicLEUCEMII ACUTE: tablou clinic
Sindrom anemic Sindrom infectios Sindrom hemoragipar: - cutanat - mucos - visceral Alte manifestari: - hipertrofie de organe - hipertrofie gingivala - neurologice - tumori mediastinale
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Hipertrofie gingivala – LAM 5
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
Criterii FAB:
1. Examen citologic ( SP / MO )
2. Examen citochimic standard
3. Citochimia ultrastructurala
4. Examenul markerilor de suprafata si intracitoplasmatici = citometrie in flux
5. Citogenetica si biologie moleculara
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB
1. Examen citologic :
- recunoasterea celulelor blastice
- numararea blastilor in MO .
> 20 % = leucemie acuta
< 20 % = sindrom mielodisplazic
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Leucemie acuta M1
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Leucemie acuta limfoblastica
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB
2. Examen citochimic :
- PAS
- Negru Sudan
- Mieloperoxidaze
- Esteraza
- TDT
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Blasti PAS +
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Blasti MPOX +
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Blasti Esterazo +
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB
3. Citochimia ultrastructurala:
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB
4. Examenul markerilor de suprafata si intracitoplasmatici ( imunofenotipare )
foloseste Ac. Monoclonali
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Anticorpi Monoclonali
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Citometria in flux
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB 4. Examenul markerilor de suprafata si
intracitoplasmatici ( imunofenotipare ) foloseste Ac. Monoclonali - LAL B - CD 10; CD 19; CD 20; CD 22 - LAL T - CD 1; CD 2; CD 3: CD 4; CD5; CD 7 ; CD 8 - LAM - CD13; CD33
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB
5. Examenul citogenetic si biologie moleculara
- citogenetica clasica
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Examen citogenetic
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Examen citogenetic
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB
5. Examenul citogenetic si biologie moleculara
- citogenetica clasica in LA
t 8:14 (q24:q32) = LAL 3
t 15:17 (q22:q21) = LAM3
t 8:21 (q22:q22) =LAM 2
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB
5. Examenul citogenetic si biologie moleculara
- reactia de hibridizare fluorescenta in situ ( FISH )
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB
5. Examenul citogenetic si biologie moleculara
- PCR ( reactia in lant cu polimeraza )
- RT- PCR
- secventializarea ADN
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Examene de biologie moleculara = structura genei
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LEUCEMII ACUTE: diagnosticLEUCEMII ACUTE: diagnostic
criterii FABcriterii FAB
5. Examenul citogenetic si biologie moleculara
- PCR ( reactia in lant cu polimeraza )
- RT- PCR
- secventializarea ADN
Avantaje:
- identifica celulele nediferentiate
- demonstreaza caracterul clonal al proliferii
- studiul bolii minime reziduale
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CLASIFICAREA LEUCEMIILOR CLASIFICAREA LEUCEMIILOR ACUTE:ACUTE:
Leucemii acute limfoblastice (LAL )
Leucemii acute mieloide (LAM )
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CLASIFICAREA LEUCEMIILOR CLASIFICAREA LEUCEMIILOR ACUTE:ACUTE:
Leucemii acute limfoblastice (LAL )Citologic: L1 L2 L3Imunofenotipic: LAL comuna ( CALLA +) LAL B ( Burkitt like) LAL T LAL nullGenetic :
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CLASIFICAREA LEUCEMIILOR CLASIFICAREA LEUCEMIILOR ACUTE:ACUTE:
Leucemii acute mieloida ( LAM ):
- LA mieloida cu diferentire minima(LAM-M0 )
- LA mieloida fara maturatie (LAM-M1 )
- LA mieloida cu maturatie (LAM-M2 )
- LA promielocitara (LAM-M3 / LAP )
- LA mielo- monocitara (LAM-M4 )
- LA monocitara (LAM-M5 )
- Eritroleucemia (LAM-M6 )
- LA megacariocitara (LAM-M7 )
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Leucemia acuta promielocitara - particularitati: - citologice corpi AUER - biologice => CID - citogenetic => t 15:17 (q22:q21) => onc PML / RAR alfa
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TRATAMENTUL LEUCEMIILOR ACUTE:TRATAMENTUL LEUCEMIILOR ACUTE:
Principii:
Criterii de remisiune completa:
- < 5% blasti in MO
- sange periferic normal
- absenta altor determinari de boala
Remisiune moleculara
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TRATAMENTUL LEUCEMIILOR ACUTE:TRATAMENTUL LEUCEMIILOR ACUTE:
Tratamentul LA are 2 faze:
1. Faza de inductie: chimioterapie agresiva pentru obtinerea RC.
LAL: VCR, Cortizon, FRB, L-ASP, CFA, MTX, ARA-C
LAM: FRB, ARA-C
2. Faza de postinductie are 2 etape:
- intretinere
- intensificare ( consolidare )
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TRATAMENTUL LEUCEMIILOR ACUTE:TRATAMENTUL LEUCEMIILOR ACUTE:
Terapie speciala: Terapie ajutatoare: - terapia suportiva - substitutie – ME - MG - MT (afereza Tb) - terapia infectiilor - factori de crestere - reechilibrare H-E si metabolica - psihoterapia - izolare
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TRATAMENTUL LEUCEMIILOR ACUTE:TRATAMENTUL LEUCEMIILOR ACUTE: Transplantul de celule stem hematopoietice (CSH):
- in functie de sursa de CSH :
=> allotransplant
=> autotransplant
- in functie de modalitatea de recoltare a CSH:
=> CSH (CD 34 + ) din maduva osoasa
=> CSH (CD 34 + ) din sangele periferic
prin citafereza
=> CSH ( CD 34 + ) din cordonul ombilical
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TRATAMENTUL LEUCEMIILOR ACUTE:TRATAMENTUL LEUCEMIILOR ACUTE: Transplantul de celule stem hematopietice -
rezultate: Supravietuire libera de boala (Leukemia free survival) la 3 ani.
Transplant CSH Chimioterapie
LAL
prima RC 30-60 % 20-70 %
a doua RC 30-50 % 10 %
LAM
prima RC 40-60 % 10-50 %
a doua RC 30 % 10 %