Leukemla

lsLory
W Means whlLe blood" ln Creek
W ulscovered by ur Alfred velpeau ln lrance
1827
W named by paLhologlsL 8udolf vlrchow ln
Cermany 1843
W s a mallgnanL hemaLologlc dlsorder
characLerlzed by prollferaLlon of abnormal
whlLe cells LhaL lnfllLraLe Lhe bone marrow
perlpheral blood and organs
Leukemla
W AcuLe Leukemlas
8lasL (precursor) cells
8apldly faLal lf noL LreaLed
W Chronlc Leukemlas
More maLure cells
Longer llfe expecLancy
ClasslflcaLlon of leukemlas
Acute Chronic
Myeloid
origin
Lymphoid
origin
Acute Myeloid
Leukemia (AML)
Acute Lymphoblastic
Leukemia (ALL)
Chronic Myeloid Leukemia
(CML)
Chronic Lymphocytic Leukemia
(CLL)
ematopoietic
stem cell
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloid
progenitor
Lymphoid
progenitor
BB- -lymphocytes lymphocytes
T-lymphocytes
Plasma
cells
3,M;0
ALL ALL
AML AML
Myelold maLuraLlon
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATION MATURATION
Adapted and modified from U Va website
9lcLures Cf 8lood
Normal human blood
White Cell Red Cell
Platelet
Blood with leukemia
Blasts Red Cell
Platelet
White Cell
Sources from Arginine.umdnj.edu
Sources from beyond2000.com
AcuLe LymphoblasLlc Leukemla
W 9rollferaLlon of lymphoblasLs
anemla LhrombocyLopenla lncreased W8C
lymphadenopaLhy/splenomegaly
W 8 or 1cell
flow cyLomeLry
W MosL common leukemla of chlldhood
AcuLe LymphoblasLlc Leukemla
AcuLe Myelogenous Leukemla
W 9rollferaLlon of myeloblasLs
anemla LhrombocyLopenla lncreased W8C
W Myelold monocyLlc 88C or
megakaryocyLlc
flow cyLomeLry
myeloperoxldase + 1d1
W Auer rods
W Cver age of 20
AcuLe Myelogenous Leukemla
Chronlc Myelogenous Leukemla
W Cne of myeloprollferaLlve dlseases (9v L1)
W 9rollferaLlon of more maLure granulocyLes
normal Lo lncreased plaLeleL counL
anemla
W Splenomegaly
W L(922) (bcrabl) (9hlladelphla chromosome)
Chronlc Myelogenous Leukemla
Chronlc LymphocyLlc Leukemla
W 9rollferaLlon of small maLure 8
lymphocyLes
flow cyLomeLry (monoclonal kappa or lambda)
W LymphadenopaLhy
relaLlonshlp Lo small lymphocyLlc lymphoma
W May have Ab producLlon
W 30 3year survlval
Chronlc LymphocyLlc Leukemla
uevelopmenL of Leukemla ln Lhe
8loodsLream
Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis
Stage 4- Worsening
Stage 5a- Anemia
Stage 5b- nfection
Legend
White Cell
Red Cell
Platelet
Blast
Germ
Sources from eukemia by D. Newton and D. Siegel
ACUTE MYELOID LEUKEMIA ACUTE MYELOID LEUKEMIA
(AML) (AML)
W Acute myeloid leukemia (AML) is one oI Iour types oI
leukemia.
W AML is cancer oI the blood-Iorming tissue (bone marrow).
W Normal bone marrow produces red cells, white cells, and
platelets.
W AML causes bone marrow to produce too many immature
white blood cells (blast cells).
W Suppresses normal blood cell production.
Anemia, leucopenia, thrombocytopenia
ACU1L MLLCID LLUkLMIA (AML)
C||n|ca| Overview
ClasslflcaLlon of AML
APL, PML
W atigue
W Shortness oI breath on exertion
W Easy bruising
W Petechiae
W Bleeding in the nose or Irom the gums
W Prolonged bleeding Irom minor cuts
W Recurrent minor inIections or poor healing oI minor cuts
W Loss oI appetite or weight loss
W Mild Iever
$igns and $25942s
CausaLlon
W CeneLlc changes ln AML
W Chromosomal changes lead Lo acLlvaLlon of
oncogenes
W 1ranslocaLlon beLween chromosomes 8 and 12
W 1ranslocaLlon beLween chromosomes 13 and 17
W ueleLlon of a segmenL of chromosome 3 or 7
W CeneLlc facLors LhaL predlspose an
lndlvldual Lo AML
W lanconl's anemla
W uown syndrome
W 8loom's syndrome
CausaLlon
W LnvlronmenLal facLors
W Lxposure Lo lonlzlng radlaLlon
W Lxposure Lo benzene
W 1reaLmenL wlLh alkylaLlng agenLs or procarbazlne
W 1reaLmenL wlLh oLher drugs
W vlral oncogenesls (speculaLlve)
W Age
W AdulLs are more llkely Lo develop AML
W Smoklng
W 20 of AML cases are llnked Lo smoklng
W uoubles Lhe rlsk of dlsease ln people older Lhan 60
t(15;17) transIocation in AML
Cllncal manlfesLaLlons
W sympLoms due Lo
marrow fallure
Llssue lnfllLraLlon
leukosLasls
consLlLuLlonal sympLoms
oLher (uC)
W usually shorL duraLlon of sympLoms
Marrow fallure
W neuLropenla lnfecLlons sepsls
W anemla faLlgue pallor
W LhrombocyLopenla bleedlng
nfllLraLlon of Llssues/organs
W enlargemenL of llver spleen lymph nodes
W gum hyperLrophy
W bone paln
W oLher organs CnS skln LesLls any organ
Cum hyperLrophy

Chloromas
NEJM 1998
LaboraLory feaLures
W W8C usually elevaLed buL can be normal or
low
W blasLs ln perlpheral blood
W normocyLlc anemla
W LhrombocyLopenla
W neuLropenla
W uC
Auer rods ln AML
W ChemoLherapy
9ase Cne 8emlsslon lnducLlon Lherapy
9ase 1wo 8emlsslon conLlnuaLlon Lherapy
W 8adlaLlon Lherapy for cerLaln cases
W 8one marrow LransplanLaLlon
1reatments for AML
W ChemoLherapy
W nducLlon Lherapy
W nlLlal sLage of Lherapy Lo eradlcaLe sysLemlc and
marrowlocallzed leukemlc cells leadlng Lo
remlsslon
W ComblnaLlon of an anLhrocycllne anLlbloLlc and a
cyLarablne
W 8oLh prevenL unA synLhesls Lhus sLopplng growLh and
leadlng Lo Lhelr deaLh
W f remlsslon ls noL achleved wlLh Lhe flrsL round of
lnducLlon Lherapy anoLher round ls begun
1reaLmenLs
W 9osLremlsslon Lherapy
W ConsolldaLlon Lherapy
W Coal ls Lo desLroy any undeLecLable leukemlc cells
W Many dlfferenL approaches all of whlch lnvolve
shorL doses of lnLenslve Lherapy
W MalnLenance Lherapy
W monLhs Lo years of less lnLenslve Lherapy Lo prevenL
furLher recurrence
1reaLmenLs
W 8one marrow LransplanL
W used as a lasL resorL lf 3 rounds of lnducLlon
Lherapy have been unsuccessful
W used as or along wlLh posLremlsslon Lherapy
W 1wo Lypes of LransplanLs are used
W AuLologous
W Allogenelc
1reaLmenLs
W 8adlaLlon Lherapy
W Cnly used ln rare cases where leukemlc cells
are cenLrallzed ln one parL of Lhe body
oa| of treatment kem|ss|on
W 8lood cell counLs reLurn Lo normal
W Leukemlc cells can no longer be found ln blood
or marrow
W f aL any Llme afLer remlsslon ls achleved a relapse
occurs Lhe lnlLlal LreaLmenL may be repeaLed
usually wlLh mlnor changes ln proLocol
W f afLer flve years of remlsslon Lhere have been no
new ouLbreaks of leukemlc cells Lhe paLlenL ls
consldered cured
After rem|ss|on
differentiation
block
enhanced
proliferation
Acute
Leukemia
+
Gain of function mutations of
tyrosine kinases
eg. FLT3 c-KT mutations
N- and K-RAS mutations
BCR-ABL
TEL-PDGF.R
Loss of function of
transcription factors
needed for differentiation
eg. AML1-ETO
CBF.-SMMC
PML-RAR-
1wohlL model of leukemogenesls
LOOD STEM CELL
NormaI progenitor
ceII
Leukemic
progenitor ceII
Leukemic
mutation
1% of
Ieukemic ceIIs
99% of
Ieukemic ceIIs
LEUKEMIA
Brian J. P. untly & D. Gary Gilliland
Leukem|a stem ce||s cou|d be targeted w|t cemo
d|fferent from tat k||||ng |eukem|c ce||
True Tumor
invoIution
Disease
remission
Disease recurrence
ConventionaI
Chemotherapy
Stem ceII kiIIing +
ConventionaI Chemotherapy
Stem ceII kiIIing
Brian J. P. untly & D. Gary Gilliland
1o understand te d|fference between |eukem|c ce||
and norma| b|ood ce|| we sa|| |ook |nto
d|fferent|at|on re|ated patways
hematopoietic
stem cells
UpreguIation PU.1
DownreguIation PU.1
common |ympo|d
progen|tor (CL9)
CCAAT/enhancer
binding protein-
(C/EP) o
upreguIation
Factor
interpIay
fork
Lymphoid
ceIIs
MyeIoid
ceIIs
Erythroid
ceIIs
common myeIoid
progenitor (CMP)
1ranscrlpLlon facLors lnvolved ln normal
hemaLopolesls
(C/EP)o
(C/EP)
(C/EP)r
AML1
GATA1
PU.1
1. SignaIing event changes the ratio of PU.1 and GATA proteins in a stem
ceII.
2. GATA protein inhibit PU.1 bIocking its interaction with c-JUN
3. PU.1 inhibitions GATA function
through inhibition of GATA DNA binding.
4.
GM-CSF
and EPO
faciIitate
differentiation
aIong either
the myeIoid
or erythroid
pathways
Nature Cancer Review
UpreguIation PU.1
DownreguIation PU.1
Lymphoid
ceIIs
MyeIoid
ceIIs
Erythroid
ceIIs
+ PU.1
- GATA = MyeIoid
- PU.1
+ GATA =Erythroid
9U1 factor
DUAL ROLE OF PU.1 factor
deveIopment of a
Iymphoid
precursor
deveIopment of
monocytes/
macrophages
PU.1 reguIates aImost every myeIoid gene, incIuding GM-CSF
receptor, macrophage M-CSF, granuIocyte G-CSF
asaI
transcription
factors
C-Jun positive
% C/EBP
negative
Degradation
http://images.medscape.com/pi/editorial/cmecircle/2002/1023/nimer_intro/slide03.gif
The Fu9ure
W linical trials
W New drug treatments
W Vaccines
W Immunotherapy
W Leukemia type-speciIic therapy
W Gene therapy
4. en.4ding ins9ru.9i4ns 41 an 4n.4gene
Targe9 9he 4n.45r49ein
W Blood and marrow stem cell transplantation
4ne 2arr4w 9rans5an9a9i4n 5r4vides 4ng-9er2 disease-1ree
surviva a24ng 5a9ien9s in re2issi4n