ACUTE MYELOBLASTIC LEUKEMIA (AML) –
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Transcript of ACUTE MYELOBLASTIC LEUKEMIA (AML) –
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ACUTE MYELOBLASTIC LEUKEMIA (AML) – classification and treatment
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Incidence of AML Adult 3/100 000 /year Rarely in children less than 15 year Median age 64 years Up 80 year 35/100 000
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Etiology Asociation with preexistic MDS Cytotoxic chemotherapy (alkylačing drugs and
epipodofphylotoxines) Ionizujúce žiarenie Benzen Chromozomal abnormalities (Down and Fanconi sy) Smoking Virus infection
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Diagnosis Investigation of PB and BM Over than 20% myeloblasts in BM Cytochemical investigation Imunophenotypic investigation Histological investigation Cytogenetic analysis Odlíšenie od iných podtypov AML
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Frekvencia jednotlivých typov leukémií podľa FAB klasifikácie
Type of leukamia
M0 M1 M2 M3 M4 M5 M6 M7
% zastúpenie
3% 15 -20%
25 -30%
6 -10%
25 - 30%
6% 3 - 5%
3%
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Dg criteria for AML M0 ( s minimal diferentiation) Bone marrow Imunophenotype> 20% blasts negativity or < 3% blasts + ( POX, SBB or A- EST)
> 20% blasts exprime one or more myeloid antigens: CD13,CD33,MPEX
Elektrón mirkoskopic can be positive on POX granuls in the endoplasmatic retikule(less than 50% blasts)
Lymfo- antigens on blasts are negativitiy, but can be positive for CD7, CD4 a TdT
POX – myeloperoxidase, SBB – sudan black, A-EST - naftolacetát esterase, TdT – terminál deoxynukleotidyl transferáase
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FAB clasification – acute myeloblastic leukemia ( AML )
blasty sú 20%buniek z ANC( s výnimkou M3a niektorých M6 )
3% blastov súMPEX pozitívne ( s výnimkou M0a niektorých M5A)
categorie FAB criteria for classification of subtype M0 s minimálnou diferenciáciou
< 3% buniek sú MPEX alebo SBBpozitívne, lymfoidné markery sú neg.je imunologický alebo ultraštrukturálny dôkaz myeloidnej diferenciácie.
M1 bez maturácie blasty sú 90% NECblasty sú 3% MPEX alebo SBB poz.vyzrievajúca monocytová línia < 10%vyzrievajúce granulocyty < 10%
M2 s maturácioublasty sú 20-89% NECvyzrievajúce granulocyty 10% NECmonocytová línia < 20% NEC a nie súiné kritériá M4
M3a M3v
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blasty sú 20%buniek z ANC( s výnimkou M3a niektorých M6 )
3% blastov súMPEX pozitívne ( s výnimkou M0a niektorých M5A)
kategória FAB kritéria pre klasifikáciu podtypov
M4 Akútna myelomonocytová leukénmiablasty sú 20% NECgranulocytová línia 20% NECmonocytová línia 20% NEC (KD,PK), monocytová línia 5.109/lalebo KD ako M2 alebo cytochémia potvrdzuje monocytovú líniu a je 5.109/l b.PK z monocytovej línie
M5a Akútna monoblastová leukémiablasty sú 20% NECmonocytová línia KD je 80% NECmonoblasty sú 80% monocytovej l.
M5b ako M5A, alebo monoblasty sú < 80%monocytovej línie v KD
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M6- acute erytroleukemia Myeloblasts with Auer s tyčkami + more than 50% bizarných multinuclearity
erytroblasts - frequently PAS positivity
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M7- acute megakaryoblastic leukemia Ťažko sa diagnostikuje morfologicky Suchá KD-fibróza Imunophenotypic investigation -
antibody to Tr Analysis og trombocyte peroxidase with
el.mikroscopy Very rarely in adult
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Cytochemické nálezy u akútnych myeloblastových leukémií ( AML )
FAB typ MPEX SBB
PAS CAE A-EST B-EST
TdT MGP Fe
M0 M1 M2 M3 M4 M5 M6A M6B M7
- + + + + +/- + - -
- + + + + +/- + - -
+/- +/- +/- +/- +/- +/- +/- +/- +
- -/+ +/- +/- +/- - +/- - -
-+/- (slabá)+/- (slabá)+/- (slabá)+ (NaF-S)+ (NaF-S)+/- (slabá)+/- (slabá)+ (NaF-S)
- - - - + + - - -
+/- -/+ -/+ -/+ -/+ -/+ -/+ - -
+/- +/- +/- +/- +/- +/- +/- + +/-
- - - - - -+/-+/- -
MPEX – myeloperoxidáza, SBB – sudanová čierna, PAS – Periodic Acid Schiff,CAE – chloracetát esteráza, A-EST - naftol acetát esteráza, B-EST naftyl butyrátesteráza, TdT – terminálna deoxynukleotidyl transferáza, MGP – metyl green pyronin,NaF-S - senzitívne na Natrium florid
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Vzácne typy akútnych myeloblastových leukémií - AML
hypoplastic form of AML
acute eozinophil leukemia ( AEL )
acute basophil leuke ( ABL )
acute mastocelular leukemia
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Imunofenotypový nález u AML
AMLCD13, CD33, CDw65, cMPO, HLA-DR, CD45dim., najčastejšie aberatné antigény:CD7, CD4, CD19
Cytogenetické zmeny a ich prognostický význam u AML
typ zmeny výskyt podtyp AML prognózat(9;22)(q34;q11) 3% M1, M2 zlá
t(8;21)(q22;22) 18% M2 priaznivá
t(15;17)(q22;21) 95% M3 dobrá
inv(16), t(16;16) 10%95%
M4M4eo
dobrá
t(11q23) 10-20% M4, M5 nepriaznivá
inv(3)(q21;q26) 3 – 5% M2, M4, M7 nepriaznivá
t(6;9) 4% M2, M4 nepriaznivá
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WHO classification-correlation between:
MorphologyCytogenetic
Clinical
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WHO classification of AML AML AML with t(8;21)(q22;q22), AML1/ETO-AMacute promyelocytic leukemia with t(15;17)(q22;q11-12) and variants,
PML/RAR AML with abnormal eosinophils in BM inv(16)(p13q22) or
t(16;16)(p13;q11), CBFb/NYH11X) AML with abnormalities in 11q23 (MLL)
AML with multilíneal myelodysplasia s predchádzajúcim myelodysplastickým syndrómom bez predchádzajúceho myelodysplastického syndrómu
AML and myelodysplastic syndroms associated with treatment alkylating drugs/RAT epipodofylotoxíns(inhibítors topoizomeráse and other type
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WHO klasifikácia- AML inak nezaraditeľné
AML inak AML s minimál differentioation AML without maturity AML s maturity acute myelomonocytic leukemia acute monocytic leukemia acute erytroid leukemia, megakaryocytic leukemia acute bazophils leukemia acute panmyelosis with myelofibrosis (acute
myelofibrosis) Acute biphenotypic leukemia
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Klinický obraz AML Príznaky vyplývajúce z anémie a
defektnej hemostázy Infekcie pri postihnutí leukocytov
(bakteriálne,mykotické) Príznaky vyplývajúce z infiltrácie
extramedulárnych orgánov a tkanív Príznaky vyplývajúce z leukostázy
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Differential diagnosis Odlíšenie od leukemoidnej reakcie Odlíšenie klasickej AML od vzácnych typov AEozinophil leukemia AEbazophilic leukemia Acute mastocellular leukemia Promyelocytic leukemia with pravidelnými
nuclearaity Hypoplastic AML
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Cieľ liečby AML Iniciál goal:elimination of leukemic cells and the
achievement of CR CR - normalisation of PB (Hb up 100g/l,Ne up
1,5 and Tr more than 100 000) Poklesom blastov v KD pod 5% Leukemia is not detectal with morphologic
technics,but can be detection with molecular technics(PCR)
Achievement of CR is not cure
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Treatment phase Indukcion of remission-achievement of CR (1-2
cycles with combination of CHT) Consolidation of tretment ( s cieľom redukcie
zvyšných leukemických bb a redukcie rizika relapsu)-táto v sebe zahrňuje aj intenzifikačný cyklus s transplantáciou KB (aloSCT ev ASCT)
Maintance treatment( only in patients with nemôžu dostať ev.netolerovali intenzívnu konsolidáciu).
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Schematic ľad liečby AMLPočet leuk.
buniek
príznaky leukémiemorfologická diagnóza
kompletná remisia
minimálna zbytková choroba
INDUCTION RELAPS
RESISTANCE
POSTREMIS TREATAMENT
CURABILITY
102–
104–
106–
108–
1010–
1012–
Time
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EORTC – LCG/GIMEMA AML – 12 Trial –fáza III-schéma
Randomizácia I.
Randomi-zácia II.
Indukcia Konsolidácia Darca vhodný
IL-2 vs kontrola
Transp-lantation
M
HD Ara-C 3/8x VP 16- 50/5 DNR 50/3
ID Ara-C 500/12xDNR 50/3( + G-CSF and stem cell harvest )
all patient withsuitable familydonor or highrisk patient( < 40 years )with an unrelateddonor ( optional )
nie Alo -SCT nie
versus
SD A ra-C 100 /10 VP 16 50/5 DNR 50/3
all others áno Auto- SCT
IL-2ver-suskontc
HR: all patients with 3q, 5, t(6;9), t(9;22), 7, 11q23, coplex abnormalities and thoseneeded a second induction course to reach a CR, M – maintance
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Treatment scheme of EORTC – LCG/GINEMA AML – 12 Trial
Randomization I.
Randomi-zation II.
Induction Consoli- dation
Donor availability
IL-2 vs control
Transp-lantation
M
High doseAra-C +etoposide+daunorubicin
Intermediatedose Ara-C+daunorubin( + G-CSF and stem cell harvest )
all patient withsuitable familydonor or highrisk patient( < 40 years )with an unrelateddonor ( optional )
no Allogeneic SCT
no
versus
standard doseAra-c+etoposide+daunorubicin
all others yes Autolo-gous SCTif possible
IL-2ver-suscontrol
HR: all patients with 3q, 5, t(6;9), t(9;22), 7, 11q23, complex abnormalities and thoseneeded a second induction course to reach a CR, M – maintance
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Odporúčané indikácie alogénnej transplantácie kmeňových krvotvorných buniekpri malígnych hematologických chorobách. Darcom je buď HLA – identický súrodenec alebo nepríbuzný darca identický molekulovo - geneticky
ochorenie Vek (r) Stav ochorenia
Darca HLA – identický
súrodenec
nepríbuzný
AML
£ 16£ 55
KR1KR1KR2/KR3
S S S
I V V
Odporúčané indikácie autotransplantácie kmeňových krvotvorných buniek pri malígnych hematologických chorobáchochorenie Vek Stav
ochorenia indikácia
AML£ 55r KR1
KR2/KR3relaps
S S N
S- rutinne indikovaná, I – indikovaná v rámci klinickej štúdie, V- klinický výskum,N- neindikovaná, KR- kompletná remisia,
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Prognostic factors Najvýznamnejšie prognostické ff predpovedajúce
dosiahnutie CR: Age (pod 50 years- good prognosis) Leukocytosis (pod 25-priaznivá,nad 100-nepriaznivá) Anamnesis MDS or leukemogenic treatment Prítomnosť špecifických cytogenetických zmien FAB subtype (M3,M4Eo-priaznivá.,M0,M5a,M5b,M6,M7
nepriaznivá) Nedosiahnutie CR po 1.cykle indukčnej terapie predpovedá
relaps AML
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Treatment of relaps AML Najviac relapsov sa vyskytuje v prvých 2-3
rokoch Mladší pts a dlhšie trvanie prvej CR majú
dobrú prognózu pre dosiahnutie 2.CR Asi 50 % pts dosiahne 2.CR po ďalšej
terapii 10% prežíva viac ako 3 roky bez SCT
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Supportive treatment Princips of regimen of reversal isolation (JIHS) RBC and Tr transfusion Neutropenic regimen (profylaxis sepsa) Hydratation (prevention of cytotoxicity and urats
nephropathy)-100ml/hour Antiemetic treatment CVK Psychoterapy
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New drugs in AML treatment New combinations of
cytostatics with different mechanisms activity
New formulations of drugs(liposomal AC)
Inhibitors of TOPO(Topotecan)
HD AraC in induction phase
MoAb treatment
Liečba namierená na cesty transdukčných signálov včítane RAS(inhibítorsa FTI)
Inhibitors of angiogenesis Nucleosis
analogs(Troxacitabin,Clofarabin,Decitabin)
ATRA (As2O3)
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Problémy v liečbe AML starší chorí ( de novo, MDS, MDR 1 – PGP,LRP,MRP )
rezistentné leukémie
relabujúce leukémie ( použitie DLI )
využitie hemopoetických rastových faktorov(G CSF,GM CSF)
postihnutie CNS
dlhodobé následky liečby
toxicita
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Target treatmentMonoclonal antibody Farnesyltransferase inhibitors Inhibitors of RASGene therapy (ASO)
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HematopoesisCD33+
Myeloidstemcell
T-lymphocytes
MyeloidprogenitorCFU-GEMM
Progenitors
CD33-
CD33+ CD33+Pluripotent stem cell
Earlystemcell
CFU-GEMM = colony-forming unit–granulocyte-erythrocyte-macrophage-megakaryocyte.
Thrombocytes
GranulocytesMacrophagesEosinophilsBasophilsMast cells
ErythrocytesCommitted stem cells
B-lymphocytes
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Mylotarg (gemtuzumab ozogamycin; CMA-676)
Mylotarg+ Mo pl
CALICHAEMICINanti-CD33 humanizovaná monoklonová protilátka
(Wyeth Laboratories, Philadelphia, PA)
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Mechanizmus účinku mylotargu
Mblasty
MCD33 CD33
DNAnormálne progenitory
pHhydrolázy
MMylotarg
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Mechanizmus účinku Mylotarg
špecifický nešpecifický
fagocytárna aktivitaCD33
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