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Definisi
Chronic myeloid leukemia
(CML) adalah penyakit
gangguan
myeloproliferasi yang
ditandai oleh peningkatan
proliferasi dari sel-sel
myeloid pada semua
tahap maturasi (Faderl et
al., 1999; Forrest et al.,
2008).
Epidemiologi
Median age range at presentation: 45 to 55 years
Incidence increases with age
12%30% of patients are >60 years old
Male-to-female ratio1.3:1
At presentation
50% diagnosed by routine laboratory tests
85% diagnosed during chronic phase
FaseFaseCML
Chronic phase
Median 56 years
stabilization
Advanced phases
Accelerated phase
Blast crisis
Median duration
69 months
Median survival
36 months
Manifestasi Klinis
Gejala Umum
Tanda umum
Lemah
Splenomegaly
Penurunan BB
Abdominal discomfort
Temuan Laboratorium
Abnormal differential Anemia
Leukocytosis Basophilia
Thrombocytosis
Accelerated
Blasts 1%15%
15%
30%
20%
Basophils
Platelets
or normal
Blast Crisis
or
Bone marrow
Myeloid hyperplasia
Cytogenetics
Ph+
Bcr-Abl +
PilihanTerapi
Allogeneicstemcelltransplantation(SCT)
IFNbasedtreatments
Chemotherapywithhydroxyurea,busulfan
Imatinibmesylate
GoalTherapy
Hematologic Response Cytogenetic Response
Complete: Major:
Normal peripheral blood count Complete: 0% Ph+ cells
WBC <10 x 109/L Partial:
1%35% Ph+ cells
Platelets <450 x 109/L Minor:36%95% Ph+ cells
No immature cells
Disappearance of splenomegaly
Normal physical examination
Philadelphia Chromosome
Sitogenetik Ph Chromosome
1
13
14
19
20
15
21
10
16
22
11
17
12
18
Terapi Target
Studi Fase 1
atologic response
Complete
Cytogenetic response
Major
Complete
98%
98%
49%
31%
Blast Crisis
Myeloid
Phenotype
(n=39)
Blast Crisis
Lymphoid
Phenotype
(n=20)
54%
13%
70%
20%
14%
4%
40%
20%
100
Cytogenetic Response
80
% Ph+
10
60
40
20
1
0
WBC x 103
100
30
60
90
120
150
100
200
300
400
Studi Fase 2
ResultsinChronicPhaseCMLPatients
Total
Hematologic
Failures
Resistant
Cytogenetic
Failures
Relapsed
Resistant
IFN-
Intolerant
Relapsed
Cytogenetic Response
Major
60
41
57
55
83
66
Complete
41
25
41
31
76
47
Partial
19
16
16
24
19
11
16
16
11
95
89
99
97
98
93
Minor
Minimal
Hematologic Response
Complete
Studi Fase 3
OverviewofClinicalResultswithImatinib
EfekSamping
Hematologi
NonHematologi
EdemadanRetensicairan
SkinRash
GangguanGIT
Atralgia,MyalgiadanNyeriTulang
Resistensi
ResistancetoImatinibMesylate
Studiesofpatientsresistanttoimatinibmesylate(mostoftheminblast
crisis)indicatedthatforsomepatients,pointmutationsintheATPbinding
domainofthekinasewereinvolvedintheresistancetoimatinibmesylate
Study
Gorreetal
2
Kreiletal
No.ofpatients
resistantto imatinib
mesylate
11
40
No.ofpatientswith
amutation
6
6
Mutations(numberof
patients)
T315I(6)
T315I(2);Y253F(1);
E255K(2);E255V(1)
3
Branfordetal
12
9
T315I(1);G250E(2);
Y253H(1);E255k(3);
F317L(1);M351T(1)
4
Shahetal
31
26
T315I(9);Q252H(6);
E255K(5);M351T(4)
G250E(2)
5
van Bubnoffetal
8
7
T315I(1);others
1.GorreMEetal.Science.2001;293:876.2.KreilSetal.Blood.2001;98:435a.3.BranfordSetal.Blood.2001;98:769a.4.
ShahNetal.Blood.2001;98:770a.5.vanBubnoffNetal.Blood.2001;98:771a.
ResistancetoImatinibMesylate
Othermechanismsofresistancearepredictedtoexist:
Amplificationofthebcrablgene
Unknown
Resultsobtainedsofarindicatethat,inblastcrisisCML,
wherethecancerismorecomplexthaninearlierphases,
itstillremainsdependentonactivationofBcrAbl
Mechanisms of resistance
Ph+ cell lines
Bcr-Abl overexpression
Gene amplification
Drug reflux mediated by P-glycoprotein
Other
TerapiPenggantiResistensiImatinib
ImatinibDosisTinggi
TransplantasiHSC
Dasatinib
Terima Kasih