LEUCEMIE

SONO TUMORI MALIGNI DEL SISTEMA

EMOLINFOPOIETICO.
ORIGINANO DA CELLULE PROGENITRICI/STAMINALI.
SONO DETERMINATE DA ALMENO UNA (SPESSO PIU
DI UNA) ALTERAZIONE GENICA CHE GENERA UN
CLONE DI CELLULE LEUCEMICHE.
PROLIFERAZIONE NON CONTROLLATA
MATURAZIONE DIFETTIVA
SI DISTINGUONO IN MIELOIDI E LINFATICHE E IN
- CRONICHE: QUANDO LA SOPRAVVIVENZA
SPONTANEA SI
MISURA IN ANNI
- ACUTE: QUANDO LA SOPRAVVIVENZA SPONTANEA
SI

LEUCEMIE ACUTE
SONO TUMORI MALIGNI DEL SISTEMA
EMOLINFOPOIETICO.
ORIGINANO DA CELLULE STAMINALI
RESIDENTI NEL MIDOLLO.
SONO PRODOTTE DA ALTERAZIONI GENICHE
SPESSO MULTIPLE CHE DETERMINANO UN
DIFETTO DI MATURAZIONE (PER CUI LE
CELLULE STAMINALI NON DANNO PIU
ORIGINE A CELLULE FUNZIONALMENTE
MATURE NON MATURANO) E DI
PROLIFERAZIONE (PER CUI LE CELLULE
LEUCEMICHE PROLIFERANO IN MODO
INCONTROLLATO).

LEUCEMIE ACUTE
ACCUMULO DI CELLULE IMMATURE (BLASTICHE)
NEL MIDOLLO E NEI TESSUTI
CELLULE BLASTICHE NEL SANGUE (LEUCEMIA,
SANGUE
BIANCO)
INSUFFICIENTE PRODUZIONE D CELLULE MATURE
(ERITROCITI, GRANULOCITI, PIASTRINE)
SINTOMI E SEGNI TUMORALI (DA
INFILTRAZIONE
ACCUMULO IN ORGANI / TESSUTI)
SINTOMI E SEGNI DI INSUFFICIENZA MIDOLLARE:
ANEMIA, INFEZIONI, EMORRAGIE

Leucemia
mieloide ACUTA:
sangue
periferico di una
donna di 22 anni
che mostra un
grosso aumento
del buffy coat
(Hb 6.1 g/dL; GB
532 x 109/L, Plt 6
x 109/L)

LEUCOCITOSI

Leucociti > 10 x 109 cellule /L

(10.000 cellule/L)

PSEUDOLEUCOCITOSI
LEUCOCITOSIFISIOLOGICA
LEUCOCITOSIPATOLOGICA

PSEUDOLEUCOCITOSI

CRIOGLOBULINE
AGGREGATI PIASTRINICI
MICROCOAGULI
ERITROBLASTI

Variazioni fisiologiche dei LEUCOCITI

Neonato e lattante
Fattori individuali
Attivit fisica
Stress, alterazioni emotive
Gravidanza, parto
Radiazioni solari, UV
Farmaci (cortisone, adrenalina,
anestetici)

Neutrofilie idiopatiche e familiari

Variazioni fisiologiche dei

LEUCOCITI
ETA

Alla nascita si osservano valori elevati

(12.000-26.000/L)
Brusca discesa dopo 24 ore
Lenta diminuzione nellinfanzia, fino a
raggiungere i valori propri delladulto verso il
10 anno
Riduzione nella vecchiaia

Variazioni fisiologiche dei

LEUCOCITI
FATTORI INDIVIDUALI

Diversi individui presentano delle variazioni

ritmiche giornaliere
Nella donna vi unoscillazione di 1.000 e
2.000 cellule/L, legata al ciclo mestruale con
modica riduzione dei leucociti nel premestruo
e tendenza allelevazione durante il ciclo e
nei giorni immediatamente successivi.

Variazioni fisiologiche dei

LEUCOCITI

ESERCIZIO FISICO
STRESS
Incrementi fino a 30.000/L, legati ad
iperincrezione di adrenalina
ASSUNZIONE DI FARMACI: Luso di
cortisonici comporta una dismissione dei
leucociti dal pool midollare.

LEUCOCITOSI PATOLOGICA

Granulocitosi
Linfocitosi
Monocitosi

Infezioni virali e batteriche

Stati infiammatori acuti e cronici
Malattie mieloproliferative
Neoplasie

Leukemia Comprises a Vast Proportion of Cancer

Deaths in the United States

Lungandbronchus 33%
Prostate 10%
Colonandrectum 10%
Pancreas 5%
Leukemia
4%
NonHodgkinslymphoma
Esophagus 4%
Liver/intrahepaticbileduct
Urinarybladder
3%
Kidney 3%
Allothersites 21%

4%
3%

Me Wo
n men
29 272,
0,8 810

90

26%
15%
10%
6%
6%
4%
3%
3%
2%
2%
22%

Lungandbronchus
Breast
Colonandrectum
Pancreas
Ovary
Leukemia
NonHodgkinslymphoma
Uterinecorpus
Brain/nervoussystem
Multiplemyeloma
Allothersites

Jemaletal.CACancerJClin.2004;54:8.
AmericanCancerSociety.At:http://www.cancer.org/docroot/STT/stt_0.asp.AccessedNovember2004.

Incidence and Mortality Associated With

Leukemias (United States, 2003)
35,000

33,440

Incidence

30,000

30,000

25,000

25,000

20,000

20,000

15,000
10,000
5000
0

Mortality

35,000

Overall
AML
CLL
CML
ALL

23,300

15,000

11,920

10,000

8,190
4,600

3,830

5000

8,870
4,800

1,57
0

1,450

AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia;

CML = chronic myelogenous leukemia; ALL = acute lymphoblastic leukemia.
American Cancer Society. At: http://www.cancer.org/docroot/STT/stt_0.asp. Accessed November 2004.

LEUCEMIA ACUTA

Patologia clonale con blocco

maturativo dei precursori emopoietici
midollari (e immissione in circolo di
progenitori immaturi).

Dept. of Hematology - University of Florence

LEUCEMIA ACUTA : Clinica

Invasione midollare di blasti

Infiltrazione di organi e tessuti
Produzione di citochine

Dept. of Hematology - University of Florence

Invasione midollare :
ANEMIA= pallore affaticamento dispnea
PIASTRINOPENIA = sindrome emorragica
NEUTROPENIA = suscettibilita alle infezioni
Dept. of Hematology - University of Florence

Neutropenia :
Infezioni batteriche da germi non usualmente
patogeni o debolmente patogeni (Piocianeo,
Clostridium, Stafilococco),
infezioni fungine (Candida, Aspergillo)
e virali (linfopenia) (H.Zoster)
APPARATO RESPIRATORIO
APPARATO GENITOURINARIO
Dept. of Hematology - University of Florence

Invasione tessuti :
Splenomegalia
Epatomegalia
Linfoadenomegalia
Infiltrazione cute e derma (ipertrofia gengivale)
Infiltrazione SNC
Localizzazione testicolare

Dept. of Hematology - University of Florence

Produzione citochine :
TNFalfa

cachessia

IL-1beta

febbre

(GM-CSF)

CID

Dept. of Hematology - University of Florence

Neutropenia
Infezioni

LEUCOPENIANEUTROPENIA
= INFEZIONI

Leucemia mieloide
acuta: stato
isolato
Staphylococcus
aureus (a) da
un'infezione
dellorbita destra e
tessuto circostante
e (b) da un'ulcera
necrotica

Leucemia
mieloide
acuta: (a)
placche di
Candida
albicans della
bocca, con una
lesione da
herpes simplex
del labbro
superiore; (b)
placca da

LEUCOPENIANEUTROPENIA
= INFEZIONI
ASPERGILLOSI
Leucemia mieloide
acuta: questa donna di
32 anni ha ricevuto
ripetuta chemioterapia
per malattia refrattaria.
Sono visibili tre cavit
micotiche: (a)
radiografia; (b, c)
scansioni di tomografia
computerizzata (TC). [(b,
c)

MANIFESTAZIONI
EMORRAGICHE

INFILTRAZIONE
TESSUTI

LEUCEMIE ACUTE

LINFOBLASTICHE

Dept. of Hematology - University of Florence

MIELOIDI

LEUCEMIE ACUTE
CLASSIFICAZIONE
LE LA MIELOIDI (LAM) HANNO
ORIGINE DA CELLULE
STAMINALI COMMITTED
ALLEMOPOIESI
LE LA LINFATICHE (LAL)
HANNO ORIGINE DA CELLULE
STAMINALI COMMITTED ALLA

ALL

DANNO GENETICO

ANLL o
AML

PER INQUADRARE LE
LEUCEMIE ACUTE
1.LA CLINICA
2.LEMOCROMO
3.LA CITOLOGIA / ISTOLOGIA DEL
MIDOLLO
4.IL FENOTIPO IMMUNOLOGICO
5.IL GENOTIPO (CITOGENETICA,
BIOLOGIA MOLECOLARE)

Classificazione leucemie acute :

FAB

WHO

(morfologica)

(Morfologica e

funzionale )

Dept. of Hematology - University of Florence

LEUCEMIE ACUTE

CRITERI CLASSIFICATIVI
1. MORFOLOGICI (IL FENOTIPO MORFOLOGICO SI
BASA SULLA MORFOLOGIA DELLE CELLULE
BLASTICHE COME SI VEDONO AL MICROSCOPIO
OTTICO, COLORATE COL MAY-GRUNWALDGIEMSA)
2. IMMUNOFENOTIPICI (FENOTIPO
IMMUNOLOGICO PERCHE SI BASA SUL
RICONOSCIMENTO DI PROTEINE CON ANTICORPI
MONOCLONALI)
3. CROMOSOMICI O CITOGENETICI (FENOTIPO
CROMOSOMICO, CHE SI BASA SULLA PRESENZA
DI ALTERAZIONI CROMOSOMICHE
MICROSCOPICAMENTE RILEVABILI)
4. GENOTIPICI (GENOTIPO) CHE SI BASA SU
ALTERAZIONI GENICHE SPECIFICHE (GENI DI

LEUCEMIE ACUTE
Fattori prognostici LA mieloidi
1)et(prognosisfavorevoleconetsuperioreai60anni)
1)et(prognosisfavorevoleconetsuperioreai60anni)
2)alterazionicitogenetichegruppiconsideratiaprognosifavorevole
2)alterazionicitogenetichegruppiconsideratiaprognosifavorevole
(t(8;21),inv(16),t(15;17))gruppiaprognosisfavorevole(t(6;9),11q23
(t(8;21),inv(16),t(15;17))gruppiaprognosisfavorevole(t(6;9),11q23
(geneMLL),monosomiedeicromosomi7(7)or5(5)eanomalie
(geneMLL),monosomiedeicromosomi7(7)or5(5)eanomalie
cariotipichecomplesse).
cariotipichecomplesse).
3)alterazionimolecolari:FLT3ITDprognosiomut.infausta
3)alterazionimolecolari:FLT3ITDprognosiomut.infausta
NPMprognosifavorevole.FLT3siassociadisolitoadunaltonumerodi
NPMprognosifavorevole.FLT3siassociadisolitoadunaltonumerodi
globulibianchi,formemonoblasticheerischiodirecidiveprecocimoltoalto.
globulibianchi,formemonoblasticheerischiodirecidiveprecocimoltoalto.
NPMsiassociainveceacariotipinormalieadunabuonaprognosiconalti
NPMsiassociainveceacariotipinormalieadunabuonaprognosiconalti
tassidirispostecompleteallachemioterapiadiinduzione.
tassidirispostecompleteallachemioterapiadiinduzione.
4)altonumerodiglobulibianchiallesordio:associatiariduzionedella
4)altonumerodiglobulibianchiallesordio:associatiariduzionedella
percentualedirispostecompleteallinduzioneeadaltafrequenzadirecidive.
percentualedirispostecompleteallinduzioneeadaltafrequenzadirecidive.
5)alcunisottotipiFABcomeM0,M6oM7,associatiaprognosipeggiore.
5)alcunisottotipiFABcomeM0,M6oM7,associatiaprognosipeggiore.
6)lapresenzadellaproteinaMDR1(multidrugresistance),associataa
6)lapresenzadellaproteinaMDR1(multidrugresistance),associataa
resistenzaaltrattamentoconalcunifarmacichemioterapici.
resistenzaaltrattamentoconalcunifarmacichemioterapici.
7)leformesecondarieamielodisplasie
7)leformesecondarieamielodisplasie
Dept. of Hematology - University of Florence

CLASSIFICAZIONE LEUCEMIE ACUTE MIELOIDI

MORFOLOGIAPREVALENTEDEIBLASTI(fab)
CITOCHIMICA
IMMUNOFENOTIPO
CITOGENETICA/BIOLOGIAMOLECOLARE

Dept. of Hematology - University of Florence

 acute myeloid leukaemia (AML) are acquired clonal

disorders of haemopoiesis
Until recently, they were classified purely on morphological
criteria using the French-American-British (FAB) system1-3

1. Bennett JM, Catovsky D, Daniel MT et al. Br J Haem 1976; 33: 451-8. 2. Bennett JM, Catovsky D,
Daniel MT et al. Br J Haem 1982; 51: 189-99. 3. Bennett JM, Catovsky D, Daniel MT et al. Ann Intern Med
1985; 103: 620-5.

 In 1999, a WHO Advisory Committee published a

new classification of AML
This takes into account cytogenetic
abnormalities, previous cytotoxic treatment,
myelodysplastic syndromes progressing to AML
and presence/absence of multilineage dysplasia1

1. Harris NL, Jaffe ES, Diebold J et al. J Clin Oncol 1999; 17: 3835-49

Diagnostic methods of importance

May Grunwald Giemsa stain morphology
Enumeration of blasts, maturing cells, recognition of
dysplasia
Cytochemistry
Myeloperoxidase, Sudan Black B, esterases to
determine involved lineages
Metaphase cytogenetics
Detects clonal chromosomal abnormalities, including
those of prognostic importance
Immunophenotyping
Defines blast cell lineage commitment as myeloid,
lymphoid or biphenotypic

Diagnostic methods of importance

RT-PCR
Detects known translocations by amplifying
fusion genes
Fluorescence In-Situ Hybridisation
Can detect ploidy changes, translocations
and deletions in metaphase or interphase
nuclei
Trephine biopsy histology and
immunohistochemistry
Useful in the presence of inaspirable marrow

Diagnostic methods of importance

Immunophenotyping
Flow cytometry
Dual, triple or quadruple-colour
analysis allows determination of
co-expressed antigens on blast
cells
Myeloid blasts express
combinations of CD34, CD13,
CD33, CD117, HLA-DR, CD14
and CD15
Dual colour flow cytometry CD34 v CD33
showing CD34-CD33+ and CD34+CD33+
populations of blasts in AML

Anti-glycophorin A and antiCD42b identify erythroid and

megakaryocytic blasts
respectively

Diagnostic methods of importance

Immunophenotyping

Immunohistochemistry/ immunofluorescence
APAAP or immunoperoxidase staining for
cytoplasmic MPO, CD3 and CD79b is required in all
cases of undifferentiated leukaemia
Immunofluorescent staining for nuclear PML protein
gives a characteristic pattern in all cases of acute
promyelocytic leukaemia

Diagnostic methods of importance

Clinical applications of immunophenotyping

Essential for separating morphologically

undifferentiated AML from acute lymphoblastic
leukaemia
Essential for identifying acute biphenotypic
leukaemias
Detects aberrant (promiscuous) antigen expression
Identifies patient specific unique blast cell
phenotypes
Can identify leukaemic contamination of remission
marrow harvests
Can identify early relapse

Diagnostic methods of importance

RT-PCR for t(8;21) fusion gene

AML/ETO
Positive control lane 2, Positive
patient sample lane 4.

PML nuclear protein

immunofluorescent stain.
One normal nucleus has four
large dots, four leukaemic
promyelocyte nuclei show the
scattered granular pattern
diagnostic of promyelocytic
leukaemia.

Interphase Fluorescence In-Situ

Hybridisation: Monoblastic
leukaemia. Alpha-satellite probe
for chromosome 8 showing
trisomy 8 (3 dots) in some nuclei
(arrows).

FAB morphological
classification

Acute Myeloid Leukaemia (AML)

Introduction
Acute myeloid leukaemia (AML) occurs at all ages, with
increasing incidence in the older age groups
Defined in WHO classification by presence of > 20% blast
cells in the marrow
Thus includes the FAB MDS category of Refractory
Anaemia with Excess Blasts in Transformation (RAEB-T)

Acute Myeloid Leukaemia (AML)

Introduction

AML usually occurs de novo

A minority of cases are secondary to
previous chemotherapy or radiotherapy
It may be a progression from MDS or
myeloproliferative disorders

Acute Myeloid Leukaemia (AML)

Introduction

In approximately 50% of cases a clonal

cytogenetic abnormality is detectable by
metaphase karyotyping
Specific abnormalities can now be detected
by molecular methods
Some cytogenetic abnormalities are related
to specific clinicopathological syndromes
and are of marked prognostic significance

Acute Myeloid Leukaemia (AML)

Classification of AML
The WHO classification recognises 4 main categories of AML
AML with recurrent translocations
t(8;21), t(15;17), inv/del/t(16p13), t(11;?)(q23;?)
AML with multilineage dysplasia
With prior MDS, without prior MDS
AML therapy related
Alkylating agent-related, Epipodophyllotoxin related
AML not otherwise categorised
FAB types M0 - M7, acute basophilic leukaemia

Acute Myeloid Leukaemia (AML)

AML with recurrent cytogenetic translocations

AML with t(8;21)(q22;q22), specific morphology

Fusion gene AML1/ETO detectable by RT-PCR
AML with t(15;17)(q22;q11-12), acute promyelocytic
leukaemia and variants, specific morphology
Fusion gene PML/RAR-alpha detectable by RT-PCR
Abnormal PML nuclear protein pattern detectable
by immunofluorescence

Acute Myeloid Leukaemia (AML)

AML with recurrent cytogenetic translocations

AML with inv(16)(p13q22) or t(16;16)(p13;q11), with

abnormal eosinobasophils and eosinophils,
specific morphology
Fusion gene CBF/MYH1 1X detectable by RT-PCR
AML with 11q23 abnormalities, no specific
morphology
MLL fusion genes detectable by RT-PCR
Systematic studies show that a significant number of these
translocations are missed by metaphase cytogenetics.1,2
1. Langabeer SE, Walker H, Gale RE et al. Br J Haem 1997; 96: 736-9
2. Langabeer SE, Walker H, Rogers JR et al. Br J Haem 1997; 99: 925-8

Acute Myeloid Leukaemia (AML)

AML with recurrent cytogenetic translocations

t(8;21): Marrow, MGG stain.

Mainly blast cells, minimal
maturation (FAB M1).
Note prominent Golgi region,
indented nuclei and long
slender Auer rod.

t(8;21): Marrow, MGG stain. M2

type. Blasts show prominent
Golgi regions. One long Auer
rod present. Note dysplastic
granulocytes and abnormal
eosinophils.

t(8;21): Marrow, Sudan Black B

stain. M2 type.
Note intense localised staining
in the blasts, heavy staining of
maturing cells and abnormal
eosinophil granules.

Acute Myeloid Leukaemia (AML)

AML with recurrent cytogenetic translocations

Acute promyelocytic leukaemia,

hypergranular type (M3): Bone
marrow MPO stain.
Characteristic heavy
cytoplasmic staining and
multiple Auer rods shown.

Acute promyelocytic leukaemia,

hypergranular variant (M3):
Bone marrow chloroacetate
esterase stain. Heavy staining
confirms maturation beyond the
blast stage. Note multiple Auer
rods.

Hypergranular acute
promyelocytic leukaemia (FAB
M3): Bone marrow MGG stain.
Two cells show multiple Auer
rods. Variable purple granules in
the other cells.

Acute Myeloid Leukaemia (AML)

AML with recurrent cytogenetic translocations

Acute promyelocytic leukaemia,

hypogranular variant (M3v):
Bone marrow MGG stain.
Characteristic bilobed nuclei
and basophilic agranular
cytoplasm.

Inv(16), (FAB M4EO). Bone

marrow MGG stain.
Myelomonocytic leukaemia with
abnormal eosinophils and
diagnostic cells with prominent
blue/black granules.

Acute Myeloid Leukaemia (AML)

AML with multilineage dysplasia

AML with multilineage

dysplasia: Marrow MGG stain.
Note small mononuclear
megakaryocyte (arrow) and
hypogranular poorly segmented
neutrophils.

AML with multilineage

dysplasia: Marrow MGG stain.
Dyserythropoiesis (arrow) and
hypogranular neutrophils.

Acute Myeloid Leukaemia (AML)

AML with multilineage dysplasia
Two subcategories: 1. With prior myelodysplasia. 2. Without prior myelodysplasia.

Requires the presence of :

Dyserythropoiesis
Multinuclear cells, nuclear rosetting, defective
haemoglobinisation, PAS positivity, sideroblastic change
Dysgranulopoiesis
Hypogranular cytoplasm, pseudo-Pelger-Huet nuclei,
binucleation, pseudo-Chediak-Higashi granules
Dysmegakaryopoiesis
Hyper- or hypo-lobated nuclei, nuclear lobe separation,
small mononuclear megakaryocytes,
micromegakaryocytes, megakaryoblasts

Acute Myeloid Leukaemia (AML)

AML not otherwise categorised*
* This group of cases is
classified by morphology and
cytochemistry only, and
corresponds to the FAB
subtypes M0, M1, M2, M4, M5,
M6, and M7 with the addition
of the new category acute
basophilic leukaemia.

Acute Myeloid Leukaemia (AML)

AML therapy-related

AML, alkylating agent-related: Peripheral blood MGG stain.

Dysplastic neutrophils, large undifferentiated blast cell.

Acute Myeloid Leukaemia (AML)

AML not otherwise categorised

AML minimally differentiated

(FAB M0): Bone marrow MGG
stain.
Small undifferentiated blasts.
Cytochemistry negative.
CD34+, CD13+, CD33+.

AML, without maturation (FAB

M1). Bone marrow MGG stain.
The marrow is replaced by
agranular blast cells. Fine Auer
rods are present.

AML without maturation (FAB

M1): Bone marrow
Myeloperoxidase stain. Majority
of blasts positive, frequent Auer
rods present.

Acute Myeloid Leukaemia (AML)

AML not otherwise categorised

AML with maturation (FAB M2):

Bone marrow MGG stain.
Note abnormal promyelocytes
and dysplastic metamyelocyte
and neutrophil.

AML with maturation (FAB M2):

Bone marrow combined
esterase stain. The blue
(chloroacetate esterase)
staining confirms maturing
granulocytes.

AML, myelomonocytic (FAB M4):

Bone marrow, MGG stain.
Note variation in blast size and
nuclear/cytoplasmic ratio.

Acute Myeloid Leukaemia (AML)

AML not otherwise categorised

AML, Myelomonocytic,
combined esterase stain.
Granulocyte component blue
(chloroacetate esterase),
monocyte component brown
(non-specific esterase).

AML, monocytic (FAB M5): Bone

marrow MGG stain.
Monoblasts are large with
rounded central nuclei and
abundant cytoplasm.

AML, monocytic (FAB M5): Bone

marrow combined esterase
stain. Monoblasts staining
brown (non-specific esterase).
One neutrophil is blue
(chloroacetate).

Acute Myeloid Leukaemia (AML)

AML not otherwise categorised

AML, erythroid (FAB M6): Bone

marrow MGG stain.
Majority of cells are abnormal
erythroid precursors.

AML, erythroid (FAB M6): Bone

marrow PAS stain.
All the erythroid precursors
contain glycogen (red), which is
never present in normal red cell
precursors.

AML, megakaryoblastic (FAB

M7): Bone marrow MGG stain.
Shows blasts with dense
chromatin and reticulated
cytoplasm. Blasts CD61 positive.

Common leukemogenesis mechanism:

the PML/RARalpha, PLZF/RARalpha
paradigm

REPRESSIONEdellaTRASCRIZIONEGENICA
(Modulazionedeacetilazioneacetilazione)

PossibilemeccanismopatogeneticoLAM
Possibiletailoringterapeutico
t(8,21)

NCoR/SMRT
ETO

Sin3
HDAC

AML1
RHD
genibersaglio
TGTGGT

TranscriptionalderegulationinAML
NCoRSMRT
R
X
R

R
A
R

mSin3A

PML

HDAC1
Targetgenes

RARE

PMLRARalpha

NCoRSMRT
R
X
R

R
A
R

mSin3A
PLZF

HDAC1
Targetgenes

RARE

PLZFRARalpha

NCoRSMRT
ETO
AML1

rhd

mSin3A
HDAC1
Targetgenes

AML1ETO

Acute Myeloid Leukaemia (AML)

AML therapy-related
Subcategories
Alkylating agent-related
Epipodophyllotoxin-related
Other types

Usually show granulocyte dysplasia, multilineage

dysplasia common
May have a preceding phase of myelodysplasia
Frequently show myelodysplasia-related karyotype
abnormalities
Bone marrow may be normocellular or hypocellular
Respond poorly to intensive chemotherapy

Acute Myeloid Leukaemia (AML)

AML not otherwise categorised

AML megakaryoblastic: Bone

marrow trephine H&E stain.
Atypical small megakaryocytes,
fibrosis and megakaryoblasts
with dense nuclei.

AML, basophilic: Bone marrow

MGG stain.
Abnormal basophils are
agranular with bizarre nuclei
showing overlapping nuclear
segments.

Acute basophilic leukaemia:

Bone marrow toluidine blue
stain.
Three abnormal basophils show
bright red metachromatic
granules.

Acute Myeloid Leukaemia (AML)

Prognostic factors in AML1,2

Age
Above the age of 50 years the complete remission rate
falls progressively

Cytogenetics
Three risk groups defined
Good risk: patients with t(8;21), t(15;17) and inv/t(16)
Intermediate risk: Normal, +8, +21, +22, 7q-, 9q-,
abnormal 11q23, all other
Poor risk: patients with -7, -5, 5q-, abnormal 3q and
complex karyotypes

1.
2.

Wheatley K, Burnett AK, Goldstone AH et al. Br J Haem 1999; 107: 69-79

Grimwade D, Walker H, Oliver F et al. Blood 1998; 92: 2322-33

Acute Myeloid Leukaemia (AML)

Prognostic factors in AML1,2
Treatment response
Patients with >20% blasts in the marrow after first course
of treatment have short remissions (if achieved) and poor
overall survival

Secondary AML
Patients with AML following chemotherapy or
myelodysplasia respond poorly

Trilineage myelodysplasia
Patients with trilineage myelodysplasia have a lower
remission rate

1.
2.

Wheatley K, Burnett AK, Goldstone AH et al. Br J Haem 1999; 107: 69-79

Grimwade D, Walker H, Oliver F et al. Blood 1998; 92: 2322-33

Acute Myeloid Leukaemia (AML)

Treatment and prognosis of AML1,2
Intensive chemotherapy
Patients < 55 years old: 80% remissions
Patients > 55 years old: progressive reduction in remission
rate

Stem cell transplants

Autologous and allogeneic transplants reduce the relapse rate

Importance of cytogenetics for prognosis in children and

adults < 55 years old
Good risk cytogenetic group
91% remissions, 65% five year survival

1.
2.

Wheatley K, Burnett AK, Goldstone AH et al. Br J Haem 1999;107: 69-79

Grimwade D, Walker H, Oliver F et al. Blood 1998; 92: 2322-33

Leucemia Acuta Linfoblastica

Disordine clonale neoplastico originante da progenitori linfoidi nel

midollo, nel timo e nei linfonodi.
Fenotipo B in circa l80 % , fenotipo T nel 20 %
Classificazione FAB: LLA-1, LLA-2, LLA-3
WBC con presenza di blasti
Anemia frequente
Piastrinopenia < 25.000/ mmc nel 30 % dei casi
Midollo osseo infiltrato da blasti per il 50-90%
Iperuricemia
Ipercalcemia (rara)

ALL-1

ALL-2

ALL-3

LEUCEMIE LINFOBLASTICHE ACUTE

PATOLOGIE CLONALI CARATTERIZZATE DA

BLOCCO DIFFERENZIATIVO E
PROLIFERAZIONE DEI PROGENITORI
LINFOIDI DEL TIMO, LINFONODI, MIDOLLO
OSSEO
Incidenza:
80% LINFOCITI B
20% LINFOCITI T

LEUCEMIE LINFOBLASTICHE ACUTE

CLASSIFICAZIONE FAB BASATA SULLA

MORFOLOGIA DEI BLASTI MIDOLLARI
L1
L2
L3

LEUCEMIA LINFOBLASTICA ACUTA

L1

BLASTI PICCOLI, A MORFOLOGIA

OMOGENEA, CON SCARSO CITOPLASMA E
NUCLEO A CROMATINA MODERATAMENTE
LASSA, CON RARI NUCLEOLI
(VARIETA PIU FREQUENTE NEI BAMBINI)
Fenotipo pro-B, B calla pos , pre-B, tutti gli stadi maturativi T
Presenza t(12;21)
t(1;19)

LEUCEMIA LINFOBLASTICA ACUTA

L2

BLASTI DI MEDIE DIMENSIONI, A

MORFOLOGIA E DIAMETRO DISOMOGENEI,
CON CITOPLASMA IRREGOLARE E NUCLEO
CON NUCLEOLI EVIDENTI E CERCINATI
Fenotipo pro-B, B comune e tutti gli stadi maturativi T

LEUCEMIA LINFOBLASTICA ACUTA

L3

BLASTI DI GRANDI DIMENSIONI, A

MORFOLOGIA MODERATAMENTE
DISOMOGENEA, CON NUMEROSI VACUOLI
SIA CITOPLASMATICI CHE NUCLEARI.
CITOPLASMA ABBONDANTE E FORTEMENTE
BASOFILO
Fenotipo B maturo, presenza t(8;14)

LEUCEMIE LINFOBLASTICHE ACUTE

ANOMALIE CROMOSOMICHE PRESENTI NEL
90% DEI CASI
ANOMALIE NUMERICHE

(DIVERSA FREQUENZA TRA

ADULTI E BAMBINI, NUMERO NORMALE 20% DEI CASI)

ANOMALIE STRUTTURALI
(TRASLOCAZIONI , SPESSO COINVOLTI GENI TCR E Ig)

LEUCEMIE LINFOBLASTICHE ACUTE

ANOMALIE CROMOSOMICHE PIU FREQUENTI
t (9;22)
t ( 1;19)
t (4;11)
t (8;14)
t(12;21)

25% adulti 5% bambini bcr-abl

***

5% adulti 6% bambini pbx1-e2a

6% adulti

3% bambini af4-all1 ***

8% adulti 2% bambini c-myc-IgH

2% adulti

25% bambini tel-aml1

Varie traslocazioni coinvolgenti geni TCR o Ig sono rare

singolarmente, ma frequenti come gruppo

LEUCEMIE LINFOBLASTICHE ACUTE

Localizzazioni EXTRA MIDOLLARI di malattia
SNC :

MENINGI (MENINGOSI LEUCEMICA)

TESSUTO CEREBRALE (NODULARE O DIFFUSO)

17% BAMBINI , ADULTO 10% FORME B MATURE, 8% FORME T

MEDIASTINO

: SINDROME MEDIASTINICA 50% FORME T

LINFOADENOPATIE-EPATOSPLENOMEGALIA:
TESTICOLO:

FREQUENTE NELLE RICADUTE

50% CASI

IMMUNOFENOTIPO IN LEUCEMIE
LINFOBLASTICHE ACUTE

FATTORI PROGNOSTICI NEGATIVI IN

LEUCEMIE LINFOBLASTICHE ACUTE

ALTERAZIONI MOLECOLARI IN LEUCEMIE

LINFOBLASTICHE ACUTE

INFILTRAZIONE
LEUCEMICA
LINFADENOPATIA
Leucemia acuta,
sottotipo a cellule
T: radiografie del
torace di un
bambino di 4 anni
che mostrano (a)
slargamento
mediastinico
causato da
ingrossamento
timico;

LEUCEMIE ACUTE

CONCETTI GENERALI DI TERAPIA

1. PROTEZIONE DALLE INFEZIONI E DALLE EMORRAGIE
E CORREZIONE DELLANEMIA (AMBIENTI PROTETTI E
TERAPIA DI SUPPORTO: TRASFUSIONI, ANTIBIOTICI,
ECC).
2. TERAPIA ANTILEUCEMICA DI INDUZIONE
- CITOTOSSICA (CHEMIOTERAPIA)
- MIRATA (LA Ph POS / INIBITORI TK, LAPRO / ACIDO,
RETINOICO)
PER RIDURRE LA MASSA LEUCEMICA
3. TERAPIA ANTILEUCEMICA DI CONSOLIDAMENTO /
MANTENIMENTO PER RIDURRE ULTERIORMENTE LA
MASSA DELLA LEUCEMIA, CONTENERLA E SE
POSSIBILE ERADICARLA.
4. TRAPIANTI DI CELLULE STAMINALI
EMOLINFOPOIETICHE (ALLO / AUTO).

PERCHE LA PROGNOSI DI TUTTE

LE LEUCEMIE ACUTE PEGGIORA
CON LETA ?
PERCHE IL PAZIENTE DIVENTA
PIU FRAGILE
PERCHE IL GENOTIPO DELLE
LEUCEMIE DIVENTA PIU
COMPLESSO ( = PIU
RESISTENTE, PIU DIFFICILE DA
ELIMINARE)