curs 10. sindroame mieloproliferative cronice
TRANSCRIPT
![Page 1: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/1.jpg)
LEUCEMIA MIELOIDA CRONICA
Conferenţiar Dr. COLIŢĂ ADRIANA
![Page 2: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/2.jpg)
![Page 3: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/3.jpg)
4 BMPC : LMC / LGC, PV, TE, MFI
![Page 4: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/4.jpg)
LMC LA PV TE MF
![Page 5: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/5.jpg)
1951: DameshekBMPC = PV, TE, MFI, LMC
2005: JAK2 V617F
PV, TE, MFI
Căi comune de semnalizare sunt uzilizate de JAK2 şi BCR/ABL
1960: cr Ph1985: BCR/ABL
Modificate după VAINCKENKER şi col., EHA 2007, Hemtology Education, 2007, 1(1), 239-246.
![Page 6: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/6.jpg)
BOLI MIELOPROLIFERATIVEBOLI MIELOPROLIFERATIVE
BCR-ABL JAK2 V617F Mutaţie necunoscută
LEUCEMIEMIELOIDĂCRONICĂ
Trombocitemie PolicitemieJAK2 poz. JAK2 poz.
Boală mieloproliferativăJAK2 neg.
Faza cronicăFaza cronică Faza cronică
Faza accelerată Faza accelerată Faza accelerată
Criza blastică Transformareleucemică
Transformareleucemică
MielofibrozăCitopeniiBlaşti
Leucocite
Clasificarea bolilor mieloproliferative pe baza caracteristicilor moleculare patogeniceCampbell PJ, Green AR – NEJM, 2006, 355, 2452.
![Page 7: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/7.jpg)
PV
TE
MFI
JAK2 V617F pozitiv sau negativ ?
![Page 8: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/8.jpg)
Clasificarea OMS a bolilor mieloproliferative cronice
Boli mieloproliferative croniceLeucemia mieloidă cronicăLeucemia neutrofilică cronicăLeucemia eozinofilică cronică şi sindromul hipereozinofilicPolicitemia veraMielofibroza idiopatică cronică (cu metaplazie mieloidă)Trombocitemie esenţialăMastocitozaBoli mieloproliferative cronice neclasificabile
Boli mixte mielodisplazice / mieloproliferativeLeucemia mielomonocitară cronicăLeucemia mieloidă cronică atipicăLeucemia mielomonocitară juvenilă
Boli mielodisplazice / mieloproliferative neclasificate
Wardiman JW, Harris NL, Brunning RD – The World Health Organization (WHO) Classification of the Myeloid Neoplasms, Blood 2002, 100, 2292-2302.
![Page 9: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/9.jpg)
CSHP
![Page 10: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/10.jpg)
![Page 11: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/11.jpg)
![Page 12: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/12.jpg)
![Page 13: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/13.jpg)
![Page 14: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/14.jpg)
![Page 15: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/15.jpg)
![Page 16: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/16.jpg)
![Page 17: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/17.jpg)
Doney K et al.: Treatment of chronic granulocytic leukemia by chemotherapy, total body irradiation and allogeneic bone marrow transplantation. Exp Hematol 6, 1978, 738-747.
Gratwohl A et al.: EBMT activity survey 2004 and changes in disease indication over the past 15 years. Bone Marrow Transplant 37, 2006, 1069-1085.
![Page 18: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/18.jpg)
…the findings suggest a causal relationship between the chromosome abnormality observed and chronic granulocytic leukemia…
A minute chromosome in human granulocytic leukemia. Science 132, 1960, 1497.
P.C. Nowell, D.A. Hungerford, University of Pennsylvania in Philadelphia
19196060
![Page 19: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/19.jpg)
![Page 20: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/20.jpg)
![Page 21: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/21.jpg)
![Page 22: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/22.jpg)
1985: Fusion protein BCR-ABL
• Shtivelman E et al.: Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 315, 1985, 550-554.
• …characterization of an 8-kilobase RNA specific to chronic myelogenous leukaemia shows it to be a fused transcript of the two genes. The fused protein that would be produced is probably involved in the malignant process…
![Page 23: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/23.jpg)
![Page 24: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/24.jpg)
![Page 25: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/25.jpg)
![Page 26: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/26.jpg)
![Page 27: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/27.jpg)
![Page 28: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/28.jpg)
![Page 29: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/29.jpg)
![Page 30: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/30.jpg)
![Page 31: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/31.jpg)
![Page 32: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/32.jpg)
20%
![Page 33: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/33.jpg)
![Page 34: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/34.jpg)
![Page 35: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/35.jpg)
![Page 36: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/36.jpg)
Diagnostic de Faza bl.:
1. Blaşti ≥ 20% în sânge în formula leucocitara sau din celulele nucleate
din MO
2. Proliferare blastică extramedulară
Faza bl. 70% blaşti de linie mieloidă
- blaşti de linie neutrofilică, eozinofilică, bazofilică, monocitică,
megacariocitică, eritriblaşti
- sau combinaţii
20-30% Limfoblaşti
Bl. în sp. – identificaţi morfologic; Bl. = “primitivi, heterogeni” citochimie, IFT
Acumulare Bl. în PBMO focale dar semnificative ocupa o regiune intertrabeculară susp. de Faza bl. chiar dacă restul biopsiei este de FC
IHC pentru CD34 sau TdT identificare focare de blaşti
Faza blastică (Faza bl.)WHO, 2008
![Page 37: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/37.jpg)
- Piele
- Ganglion
- Splină
- Os
- SNC
- “oriunde”
Bl: mielo sau limfo
Faza bl. cu determinări extramedulare
![Page 38: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/38.jpg)
Faza bl. mieloidă:
MPOMPO exprimată puternic, slab sau deloc dar exprimă
antigene asociate cu diferenţiere granulocitică, monocitică, MK şi/sau eritroidă
+/- coexpresie de unu sau mai multe antigene limfoide
Faza bl. limfoblastică – coexpresie de unu sau mai multe antigene mielo pe LBl
25% din cazurile de Faza bl. cu criterii de “mixed phenotype acute leukemia” (MFAL) (diferenţiata de MFAL de novo”)
Imunofenotipare în Faza bl.WHO, 2008
Perfectionare
![Page 39: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/39.jpg)
![Page 40: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/40.jpg)
![Page 41: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/41.jpg)
![Page 42: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/42.jpg)
![Page 43: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/43.jpg)
![Page 44: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/44.jpg)
![Page 45: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/45.jpg)
1996CGP 57148B = STI 571= imatinib
![Page 46: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/46.jpg)
1999: Clinical efficacy
• Druker BJ et al.: Clinical efficacy and safety of an Abl specific tyrosine kinase inhibitor as targeted therapy for chronic myelogenous leukemia. ASH 1999, abstract No 1639.
• …these data indicate that an Abl specific tyrosine kinase inhibitor has significant activity in CML…
• …this trial provides an example of successful drug development based on specific molecular abnormality present in a human malignancy…
![Page 47: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/47.jpg)
![Page 48: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/48.jpg)
![Page 49: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/49.jpg)
![Page 50: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/50.jpg)
![Page 51: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/51.jpg)
IMATINIB MESILAT (GLIVEC)STI 571
![Page 52: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/52.jpg)
Algoritmul de tratament pentru LMC-FC• O actualizare esenţială a recomandărilor ELN din 2009 este recunoaşterea
dasatinib şi nilotinib drept tratamente aprobate la pacienţii cu eşec terapeutic la imatinib
Allo-TCSHEşec terapeutic la dasatinib / nilotinib
Linia a treia
Continuarea dasatinib sau nilotinib, cu opţiunea allo-TCSH la pacienţii cu semne de avertizare*
sau scor de risc EBMT ≤2
Răspuns suboptim la dasatinib / nilotinib
Dasatinib sau nilotinib
Allo-TCSH la pacienţii care la care a apărut progresia la FA/FB sau la cei cu mutaţie T315I
Eşec terapeutic la imatinib
Continuarea imatinib în aceeaşi doză sau încercarea unei doze crescute de imatinib, încercarea dasatinib sau nilotinib
Răspuns suboptimal la imatinib
Dasatinib sau nilotinibIntolerant la imatinibLinia a doua
(după
imatinib))
Imatinib 400 mg zilnicToţi pacienţiiLinia întâi
Baccarani M, et al. JCO 2009: published online 2 November 2009, doi: 10.1200/JCO.2009.25.0779.Allo-TCSH=transplant alogen de celule stem hematopoietice; FA=faza accelerată; FB=faza blastică; EBMT=European Bone Marrow Transplant.
*) rezistenta hematologica anterioara la imatinib, mutatii
![Page 53: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/53.jpg)
Allo – TCSH recomandări
Baccarani M, et al. JCO 2009: published online 2 November 2009, doi: 10.1200/JCO.2009.25.0779.Allo-TCSH=transplant alogen de celule stem hematopoietice; FA=faza accelerată; FB=faza blastică; EBMT=European Bone Marrow Transplant.
![Page 54: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/54.jpg)
![Page 55: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/55.jpg)
![Page 56: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/56.jpg)
Definiţia răspunsului terapeutic hematologic, citogenetic şi molecular la pacienţii cu LMC-FC
Raportul dintre BCR-ABL şi ABL (sau alte gene constituţionale de tip housekeeping) ≤0,1% pe Scala InternaţionalăRMM
Transcript ARNm pentru BCR-ABL nedetectabil prin RQ-PCR şi/sau nested PCR în 2 probe de sânge consecutive de calitate corespunzătoare (sensibilitate >104)RMC
Mo
lecu
lar
Metafaze >95% Ph+Fără RCy
Metafaze Ph+ 66–95%RCy minimal
Metafaze Ph+ 36–65% RCyminor
Metafaze Ph+ 1–35%RCyP
Fără metafaze Ph+ RCyCCytogenetic
Splină nepalpabilă
Trombocite <450 x 109/l
Fără mielocite, promielocite, mieloblaşti în formula leucocitară
Bazofile <5%
Leucocite <10 x 109/l
RHC
Haem
atologic
Baccarani M, et al. JCO 2009: published online 2 November 2009, doi: 10.1200/JCO.2009.25.0779.RHC=răspuns hematologic complet; Ph+=cromozom Philadelphia pozitiv; RCyC=răspuns citogenetic complet; RCyP=răspuns citogenetic parţial; RCym=răspuns citogenetic minor; fără RCy=fără răspuns citogenetic; RMC=răspuns molecular complet; RQ=cantitativ în timp real; PCR=reacţia de amplificare genică (polymerase chain reaction); RMM=răspuns molecular majoş RCzC+RCyP=RCyMajor
• Nou: Definirea raspunsului molecular complet
Mo
lecu
lar
C
ito
gen
etic
Hem
ato
log
ic
RCyMAJOR
![Page 57: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/57.jpg)
Monitorizarea răspunsului la tratament la pacienţii cu LMC-FC care primesc terapie de linia întâi cu
imatinib1
• La diagnostic
• La fiecare 15 zile până la RHC
• Apoi cel puţin la fiecare 3 luni
Răspunsul hematologic
Răspunsul citogenetic
Răspunsul molecular Analiza mutaţională
• La diagnostic
• La 3 şi 6 luni
• La fiecare 6 luni până la RCyC
• Apoi la fiecare 12 luni dacă monitorizarea moleculară periodică nu poate fi realizată
• În caz de eşec terapeutic, răspuns suboptimal sau citopenie inexplicabilă
• La fiecare 3 luni, până la RMM
• Apoi cel puţin la fiecare 6 luni
• O creştere a nivelurilor de transcript justifică monitorizarea mai atentă
• În caz de răspuns suboptimal sau eşec terapeutic
• Întotdeauna înainte de trecerea la alţi TKI sau la alte terapii
1Baccarani M, et al. JCO 2009: published online 2 November 2009, doi: 10.1200/JCO.2009.25.0779; 2Baccarani M, et al. Blood 2006;108:1809–1820.CP=chronic phase; CHR=complete haematologic response; CCyR=complete cytogenetic response; MMR=major molecular response; ITK=tyrosine kinase inhibitor.
![Page 58: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/58.jpg)
• Risc crescut• ACC / Ph+• (a fost şi del9q+ & ACA în celulele Ph+2)
•NA•NA•NAMomentul iniţial
• O creştere a nivelurilor de transcript
• ACC în celulele Ph–
•NA
•<RMM
•NA
•NA
Semne de avertizare
• Pierderea RHC / RCyC• Mutaţii†
• ACC în celulele Ph+
•Pierderea RMM•Mutaţii*• (a fost şi ACA în celulele Ph+2)
•RMM stabil sau care se îmbunătăţeşte
Oricând în timpul terapiei
•<RCyC•<RMM•RMM18 luni
•<RCyP(Ph+ >35%)
•RCyP(Ph+ 1–35%)
•RCyC12 luni
•Fără RCy
(Ph+ >95%) • (a fost şi <RHC2)
•<RCyP
(Ph+ >35%) •Cel puţin RCyP
• (Ph+ ≤35%)6 luni
•<RHC
(a fost fără RH2)•Fără RCy (Ph+ >95%)(a fost <RHC2)
•RHC & cel puţin RCy
minor • (Ph+ ≤65%)
3 luni
Eşecul terapeuticRăspunsul suboptimal
Răspunsul optimal(NOU2)
Definiţiile răspunsului optimal, suboptimal, a eşecului terapeutic şi a semnelor de avertizare la pacienţii cu LMC-FC timpurie netrataţi anterior care primesc terapie de linia
întâi cu imatinib1
*Mutaţii cu sensibilitate păstrată la imatinib; †mutaţii cu sensibilitate scăzută la imatinib.1Baccarani M, et al. JCO 2009: published online 2 November 2009, doi: 10.1200/JCO.2009.25.0779; 2Baccarani M, et al. Blood 2006;108:1809–1820.FC=faza cronică; RHC=răspuns hematologic complet; RCy=răspuns citogenetic; RCyP=Răspuns citogenetic parţial; RMM=răspuns molecular major; ACC=anomalii clonale cromozomiale; ACA=anomalii cromozomiale adiţionale; Ph+/–=cromozom Philadelphia-pozitiv/negativ; NA=nu se aplică.
Definiţia răspunsului suboptim:
• Pacientul poate încă avea un beneficiul substanţial pe termen lung prin continuarea unei terapii specifice, dar şansele unui rezultat optimal sunt reduse Pacienţii cu răspuns suboptimal pot fi eligibili pentru strategii alternative
• Condiţia răspunsului suboptimal este tranzitorie prin natura sa
Definiţia semnelor de avertizare:
• Caracteristicile bolii pot influenţa negativ răspunsul la terapia respectivă şi necesiă o monitorizare mai strictă şi mai atentă
Definiţia eşecului terapeutic:
• Un rezultat favorabil este puţin probabil
• Pacientul trebuie să primească un tratament diferit, dacă acesta este disponibil şi aplicabil
Definiţia răspunsului optim:
• Nu sunt indicaţii că o schimbare a terapiei poate creşte supravieţuirea care în prezent este proiectată la aproape 100% la 6-7 ani
![Page 59: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/59.jpg)
FACTORI DE PROGNOSTIC
![Page 60: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/60.jpg)
![Page 61: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/61.jpg)
![Page 62: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/62.jpg)
![Page 63: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/63.jpg)
![Page 64: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/64.jpg)
CML - 2009: Historical vs. Modern vs. Future Perspective
Parameter Historical Modern Future
Course Fatal Indolent Cured
Prognosis Poor Excelent Outstanding
Median survival (yrs) 3-6 25+ (est.) Norm. Life span
Frontline Rx Allo-SCT, IFN- Imatinib Better TKIs
Second line Rx Chemotherapy Allo-SCT
New TKIs; Allo-SCT Not Nedded
Helmann R, 2009, Barcelona
![Page 65: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/65.jpg)
BOLI MIELOPROLIFERATIVE BCR/ABL NEGATIVE
• POLICITEMIA VERA
• TROMBOCITEMIA ESENTIALA
• METAPLAZIA MIELOIDA CU MIELOFIBROZA / METAPLAZIA
MIELOIDA AGNOGENICA / MIELOFIBROZA IDIOPATICA PRIMARA
![Page 66: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/66.jpg)
POLICITEMIAVERA
Conferenţiar Dr. Adriana Coliţă
![Page 67: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/67.jpg)
PV
Clinic:
Hematologie: Ht, Hb, Nr. Er MET L ( > 12.000/mmc), Ba Trb ( > 400.000/mmc); MPV MO: hipercelulara; SE, SMK, SG Fe medular ( Mcf, Sbl): absent FAL ( >100 ) EPO
varsta: 50 – 60 ani, B/F = 1,2 / 1 eritroza splenomegalie prurit hemoragii / tromboze
Altele: Histamina ; Ac. uric ; SaO2 > 92%
Citogenetica: Ph1 absent
Colonii eritroide “ endogene”
![Page 68: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/68.jpg)
PV
Evolutie: faza asimptomatica faza eritroida activa faza de epuizare MMM post PV; LA
Complicatii: tromboembolii, hemoragii
DMS: 10 – 20 ani
Tratament: Flebotomii Mielosupresive : Hyo, BUS, 32P IFN CCNU, Melphalan, Anagrelide – pt. trombocitoza
![Page 69: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/69.jpg)
EPO: N POLICITEMIA VERA
EPO: - POLIGLOBULII SECUNDARE:
A. Hipoxie tisulara generalizata: - incarcare redusa cu O2 a eritrocitelor: hipoxia de altitudine pneumopatii cronice – BPOC boli congenitale de cord met-Hb.emie; sulf-Hb.emie - sunt A-V: cord, pulmon, vase mari - eliberarea redusa de O2 catre tesuturi: Hb.patii eritrogene scaderea ereditara a 2.3-DPG carboxiHb. B. Hipoxie renala localizata: - hidronefroza - chisturi - stenoza arterei renale - hipernefrom - transplant renal.
C. Productie autonoma de EPO sau de substante EPO-like: - hepatom - feocromocitom - fibrom uterin - hemangiom cerebelos.
- POLIGLOBULII RELATIVE Sdr. Gaisböck
![Page 70: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/70.jpg)
♂♂ ♀♀Hb: 15+/- 2 g/dl 13+/- 1,5 g/dlHb: 15+/- 2 g/dl 13+/- 1,5 g/dl
Ht: 46+/- 6% 41+/- 5%Ht: 46+/- 6% 41+/- 5%
Er: 4,9+/- 0,7 mil/mmc 4,3+/- 0,6 mil/mmcEr: 4,9+/- 0,7 mil/mmc 4,3+/- 0,6 mil/mmc
Ht (♂ >52%♂ >52% ♀ ♀> 46%)> 46%)
MET EPO (Poliglobuliereala)
MET ( ml / kg ): ♂ ♂ 36 ; 36 ; ♀ ♀ 3232
MET = N ( Poliglobulie Vol. plasm. relativa )
N : PV Hipoxie
Generalizata
Localizata Sat. in O2
autonoma a EPO
Deshidratare
Poliglobulie “falsa” (Gaisböck)
![Page 71: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/71.jpg)
DIAGNOSTICUL PV
• Eritrocitoza ( Ht > 60% ♂; > 53% ♀ )
• Leucocitoza in absenta febrei / infectii (L > 12.000/mmc, N > 8.000/mmc) • Trombocitoza in absenta deficitului de fier, a inflamatiei sau neoplaziei ( Tr > 400.000/mmc )
1. Triada clinica:
2. Triada sanguina:
3. Triada medulara:
• Celularitate crescuta• Hiperplazie MgK• Lipsa rezervelor medulare de fier
• Prurit agnogenic• Tromboze si/sau hemoragii• Splenomegalie
![Page 72: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/72.jpg)
DIAGNOSTICUL PV
1. Cresterea MET ( > 36 ml/kg ♂; > 32 ml/kg ♀) sau Ht > 62%
2. Saturatia cu O2 a sangelui arterial > 92%
3. Splenomegalie
4. Nr. L > 12.000/mmc si Tr > 400.000/mmc
5. M.O.: hipercelularitate, Mgk crescute, Fier absent
6. EPO scazuta
7. Formarea coloniilor eritroide “endogene”
PV = patru criteriiPV = patru criterii
![Page 73: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/73.jpg)
Harta structurală a genei kinazei JAK2 Goldman, NEJM 2005; 353, 17.
![Page 74: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/74.jpg)
1951: DameshekBMPC = PV, TE, MFI, LMC
2005: JAK2 V617F
PV, TE, MFI
Căi comune de semnalizare sunt uzilizate de JAK2 şi BCR/ABL
1960: cr Ph1985: BCR/ABL
Modificate după VAINCKENKER şi col., EHA 2007, Hemtology Education, 2007, 1(1), 239-246.
![Page 75: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/75.jpg)
BOLI MIELOPROLIFERATIVEBOLI MIELOPROLIFERATIVE
BCR-ABL JAK2 V617F Mutaţie necunoscută
LEUCEMIEMIELOIDĂCRONICĂ
Trombocitemie PolicitemieJAK2 poz. JAK2 poz.
Boală mieloproliferativăJAK2 neg.
Faza cronicăFaza cronică Faza cronică
Faza accelerată Faza accelerată Faza accelerată
Criza blastică Transformareleucemică
Transformareleucemică
MielofibrozăCitopeniiBlaşti
Leucocite
Clasificarea bolilor mieloproliferative pe baza caracteristicilor moleculare patogeniceCampbell PJ, Green AR – NEJM, 2006, 355, 2452.
![Page 76: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/76.jpg)
PV
TE
MFI
JAK2 V617F pozitiv sau negativ ?
![Page 77: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/77.jpg)
CRITERII PROPUSE PENTRU PV
(PJ Campbell, AR Green, 2005)
A1. Masa eritrocitara crescuta (> 25% fata de cea prezisa sau Ht >/= 60% la barbati si Ht >/= 56% la femei A2. Absenta cauzelor de eritrocitoza secundara (SaO2 normala; valori normale ale EPO)A3. Splenomegalie (palpare)A4. Prezenta mutatiei JAK2 V617F sau a altor anomalii citogenetice in celulele hematopoietice ( excluzand BCR-ABL)
B1. Trombocitoza ( Tr > 400.000/mmc)B2. Neutrofilie ( Neutrofile > 10 x 109/L; 12,5 x 109/L la fumatori)B3. Splenomegalie (investigatii imagistice)B4. Colonii eritroide endogene sau nivel al EPO scazut.
PV = A1 + A2 + PV = A1 + A2 + alt criteriu alt criteriu AA sau doua criterii sau doua criterii B B
![Page 78: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/78.jpg)
Principiile de tratament in PV
1. Asigurarea certitudinii diagnosticului de PV
2. Terapia individualizata
3. Reducerea initiala a volumului sanguin prin flebotomie,
cat mai repede posibil
4. Ht trebuie mentinut la 42 – 45%
5. Dozele excesive si chimioterapia prelungita = de evitat
6. Tratarea hiperuricemiei
7. Tratarea pruritului
8. Interventia chirurgicala mare si de mica chirurgie
(extractie dentara) trebuie temporizata pana cand masa
eritrocitara totala si nivelul trombocitelor se mentin la
normal timp de 2 luni. In situatiile de urgenta se apeleaza la
flebotomii si citafereza.
9. Pacientii cu viata sexuala activa si perioada de
procreatie vor fi tratati exclusiv cu flebotomii. In perioada
de sarcina, deseori tratamentul nu este necesar sau va fi
constituit exclusiv din flebotomii.
![Page 79: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/79.jpg)
TRATAMENTUL PV
Stratificare dupa factorii de risc pentru complicatii trombohemoragice (Gilbert, 2003)
Risc scazut
Risc crescut
Risc intermediar
*Obezitate, fumat, DZ, dislipidemii
AsimptomaticiAsimptomatici
Varsta < 40 aniVarsta < 40 ani
Tr. < 1.000.000/mmcTr. < 1.000.000/mmc
Fara comorbiditati*Fara comorbiditati*
Fara istoric de trombozeFara istoric de tromboze
Varsta >/= 60 aniVarsta >/= 60 ani
Toti pacientii simptomaticiToti pacientii simptomatici
Tr. >1.000.000/mmc Tr. >1.000.000/mmc (indiferent de (indiferent de
varsta)varsta)
ComorbiditatiComorbiditati
Istoric de trombozeIstoric de tromboze
Varsta 40-60 aniVarsta 40-60 ani
Tr. 600.000-1.000.000/mmcTr. 600.000-1.000.000/mmc
FLEBOTOMIE +ASPIRINA (DOZE
MICI)
FLEBOTOMIE +CITOREDUCTIE
IFNα, Hy, 32P*BUSULFAN
ANAGRELID + IFNαHy
FLEBOTOMII + ANAGRELIDFLEBOTOMII + ANAGRELID
EVIDENTA DE PROLIFERAREEVIDENTA DE PROLIFERARE
![Page 80: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/80.jpg)
TRATAMENTUL PACIENTILOR CU PV
1. Venesectii pentru a mentine Ht < 45%
2. Doze mici de Aspirina a
3. Tratamentul factorilor de risc trombotic reversibili (fumat, HTA,
hipercolesterolemie, obezitate)
4. Citoreductie daca:
- pacientul este intolerant la venesectii
- pacientul dezvolta trombocitoza
- splenomegalie simptomatica sau progresiva
5. Alegerea terapiei citoreductoare:
- < 40 ani - IFNα b
- > 40 ani - Hy b+c
a – Se evita Aspirina cand Tr > 1.500.000/mmcb – Anagrelid + venesectii la pacientii intoleranti sau rezistenti la IFN sau Hyc - 32P sau Busulfan intermitent, la varstnici
![Page 81: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/81.jpg)
![Page 82: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/82.jpg)
![Page 83: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/83.jpg)
![Page 84: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/84.jpg)
![Page 85: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/85.jpg)
TROMBOCITEMIAESENTIALA
Conferenţiar Dr. Adriana Coliţă
![Page 86: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/86.jpg)
TE
Clinic: -varsta: 50 – 70 ani, B/F = 1
- ~ 2/3 asimptomatici
- simptomatici:
- Tromboze:
a) manifestari vaso-oclusive ale microcirculatiei:
eritromelalgie
accidente ischemice cerebrale tranzitorii
b) tromboze arteriale – a. splenica – atrofie
c) tromboze venoase – v. splenica
- Hemoragii : a) trombopatie
b) tromboza + infarct hemoragic
c) CID
- sangerari cutaneo-mucoase, post-operatorii,
post-ingestie de Aspirina
- splina +/-
![Page 87: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/87.jpg)
TE
Evolutie: LA, MMM, PV
DMS: 10ani
Tratament: Trombocitofereza, Cariolysine Hyo, BUS, 32P IFN Anagrelide ! Aspirina !
Hematologie: Tr > 600.000 – 1.200.000/mmc L ( moderat) < 30.000/mmc, FL Mc+/- Ba Er normocromie hipocromie (sangerari) (Er. in semn de “tras la tinta”, corpi Jolly, Ebl = atrofie spenica) MO: hipercelulara, Mgk (gramezi), Fe +
Altele: FAL: N ; Ac. uric
Citogenetica: Ph1 absent
Colonii Mgk / Eb de tip “ endogen”
![Page 88: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/88.jpg)
Tromboze sau hemoragii + -
Splenomegalie + -
IL6; Fbg; PCR - +
Fibroza reticulinica in MO + -
Mgk in gramezi + -
Hematopoieza clonala + -
Formare spontana de colonii + -
Anomalii citogenetice + -
TETrombocitoze
reactive
![Page 89: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/89.jpg)
Cauzele trombocitozelor secundare
Hemoragii acute
Status post-splenectomie
Hiposplenism
Boli maligne
Boli inflamatorii cronice
Infectii cronice
Anemii hemolitice
Anemia feripriva
Medicamente
Rebound dupa refacerea unei trombocitopenii
Efort fizic
![Page 90: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/90.jpg)
CRITERII DE DG. PROPUSE PENTRU TE (PJ Campbell, AR Green, 2005)
A1. Nr. de trombocite > 600.000/mmc ( cel putin doua luni)
A2. Mutatie JAK2 castigata
B1. Fara cauze de trombocitoza reactiva (probe inflamatorii normale)
B2. Fara evidenta de deficit de fier ( HSM in Mcf. prezenta si VEM = N )
B3. Fara evidenta de PV ( Ht < media nivelului normal sau
MEr = N cu rezerve de Fier = N )
B4. Fara evidenta de LMC ( fara cromozom Ph sau rearanjare bcr/abl )
B5. Fara evidenta de mielofibroza ( fara fibroza colagenica si
</= 2 fibroza reticulinica - scara 0-4 )
B6. Fara evidenta de SMD (fara displazie semnificativa,
fara anomalii citogenetice sugestive de
SMD)
TE = A1 + A2 + B3 – 6 ( TE V617F + )TE = A1 + A2 + B3 – 6 ( TE V617F + )
A1 + B1 – 6 ( TE V617F - )A1 + B1 – 6 ( TE V617F - )
![Page 91: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/91.jpg)
DIAGNOSTICUL TE
1. Nr. Tr. > 600.000/mmc la 2 determinari separate de 1 luna
2. Eliminarea cauzelor de trombocitoza secundara
3. MET normala (< 36 ml/kg ♂; < 32 ml/kg ♀)
4. Absenta fibrozei medulare
5. Absenta cromozomului Ph1
6. Splenomegalie moderata
7. MO: hipercelularitate + Mgk crescute ( “gramezi” )
8. Fier medular prezent
9. Hematopoieza clonala
10. Formare de colonii “endogene” de Ebl si/sau Mgk
11. Agregare anormala a Tr. la ADP si epinefrina
TE = 1 – 5 + >/= 3 TE = 1 – 5 + >/= 3 criterii dintre criterii dintre 6 - 116 - 11
![Page 92: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/92.jpg)
TRATAMENTUL PACIENTILOR CU TE
1. Pentru toti pacientii cu TE:
= tratamentul riguros al factorilor de risc reversibili: fumat,HTA,
hipercolesterolemie, obezitate
2. Pacientii cu risc crescut (tromboze anterioare sau varsta > 60 ani
sau Tr > 1.500.000/mmc):
= doze mici de Aspirina + Hy; Anagrelid sau IFNα – a doua linie
3. Pacientii cu risc intermediar ( 40 – 60 ani, fara elemente de high
risk):
= - doze mici de Aspirina
- citoreductie daca exista factori de risc cardio-vascular
4. Pacientii cu risc scazut ( < 40 ani si fara factori de high risk):
= doze mici de Aspirina.
![Page 93: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/93.jpg)
TRATAMENTUL TE Stratificare dupa factorii de risc pentru complicatii trombohemoragice (Barbui, 2003)
Risc scazut
Risc crescut
Risc intermediar
*Obezitate, fumat, DZ, dislipidemii
Varsta < 60 aniVarsta < 60 ani
Tr. < 1.500.000/mmcTr. < 1.500.000/mmc
Fara comorbiditati*Fara comorbiditati*
Fara istoric de trombozeFara istoric de tromboze
Varsta >/= 60 aniVarsta >/= 60 ani
Tr. >1.500.000/mmc Tr. >1.500.000/mmc
Istoric de trombozeIstoric de tromboze
ANAGRELIDUL NU SE ASOCIAZA CU ASPIRINAANAGRELIDUL NU SE ASOCIAZA CU ASPIRINA
IFNαAnagrelid
Hy
Aspirina (doza mica)
Fara tratament
TinerisimptomaticiTr > 1.000.000/mmc
> 60 anicomplicatii: tromboze, hemoragii, comorbiditatiTr > 1.000.000/mmc
eritromelalgieaccidente ischemice tranzitorii
TineriasimptomaticiTr < 1.000.000/mmc
ASPIRINA – doza mica ?
![Page 94: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/94.jpg)
![Page 95: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/95.jpg)
![Page 96: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/96.jpg)
![Page 97: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/97.jpg)
METAPLAZIE MIELOIDACU MIELOFIBROZA
Conferenţiar Dr. ADRIANA COLIŢĂ
![Page 98: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/98.jpg)
![Page 99: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/99.jpg)
![Page 100: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/100.jpg)
![Page 101: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/101.jpg)
![Page 102: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/102.jpg)
![Page 103: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/103.jpg)
![Page 104: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/104.jpg)
![Page 105: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/105.jpg)
![Page 106: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/106.jpg)
![Page 107: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/107.jpg)
![Page 108: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/108.jpg)
![Page 109: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/109.jpg)
![Page 110: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/110.jpg)
![Page 111: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/111.jpg)
![Page 112: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/112.jpg)
![Page 113: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/113.jpg)
![Page 114: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/114.jpg)
![Page 115: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/115.jpg)
![Page 116: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/116.jpg)
![Page 117: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/117.jpg)
![Page 118: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/118.jpg)
![Page 119: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/119.jpg)
1951: DameshekBMPC = PV, TE, MFI, LMC
2005: JAK2 V617F
PV, TE, MFI
Căi comune de semnalizare sunt uzilizate de JAK2 şi BCR/ABL
1960: cr Ph1985: BCR/ABL
Modificate după VAINCKENKER şi col., EHA 2007, Hemtology Education, 2007, 1(1), 239-246.
![Page 120: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/120.jpg)
BOLI MIELOPROLIFERATIVEBOLI MIELOPROLIFERATIVE
BCR-ABL JAK2 V617F Mutaţie necunoscută
LEUCEMIEMIELOIDĂCRONICĂ
Trombocitemie PolicitemieJAK2 poz. JAK2 poz.
Boală mieloproliferativăJAK2 neg.
Faza cronicăFaza cronică Faza cronică
Faza accelerată Faza accelerată Faza accelerată
Criza blastică Transformareleucemică
Transformareleucemică
MielofibrozăCitopeniiBlaşti
Leucocite
Clasificarea bolilor mieloproliferative pe baza caracteristicilor moleculare patogeniceCampbell PJ, Green AR – NEJM, 2006, 355, 2452.
![Page 121: Curs 10. Sindroame Mieloproliferative Cronice](https://reader033.vdocuments.pub/reader033/viewer/2022061403/5571f3e449795947648ebabe/html5/thumbnails/121.jpg)
PV
TE
MFI
JAK2 V617F pozitiv sau negativ ?