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Referat

Terapi Target pada CML


Denny Indra Maulana
NIM. I4A012110
Pembimbing :
Dr. dr. M. Darwin Prenggono, Sp.PD KHOM, FINASIM

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).

CML merupakan keganasan


hematologi pertama yang
dihubungkan dengan lesi
genetik spesifik. Gen
spesifik yang terdapat pada
CML pertama kali diketahui
pada tahun 1845. Kemudian
pada tahun1960 oleh
Nowell dan Hungerford
dinamakan sebagai
kromosom Philadelphia
(Ph) (Frazer et al., 2007).

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

Typical Laboratory Parameters


by Phase of CML
Phase of CML
ParameterChronic

Accelerated

WBC count 20 x 109/L

Blasts 1%15%

15%

30%

20%

Basophils
Platelets

or normal

Blast Crisis

or

Bone marrow

Myeloid hyperplasia

Cytogenetics

Ph+

Bcr-Abl +

WBC = white blood cell; Ph+ = Ph chromosomepositive.

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

Phase I Studies With Imatinib Mesylate:


Results
Hematologic and Cytogenetic Responses
IFN-Resistant
Chronic Phase CML
300mg1000mg/day (n=55)

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%

Most adverse events were mild to moderate in severity (grades 12)


A maximal tolerated dose (MTD) was not reached
Higher frequency and severity of adverse events with doses 800mg

Imatinib Mesylate: Rapid Responses


Hematologic Response

100

Cytogenetic Response

80

% Ph+

10

60

40

20

1
0

WBC x 103

100

30

60

90

120

Days on Imatinib Mesylate

150

100

200

300

Days on Imatinib Mesylate

400

Imatinib Mesylate: Phase I Conclusions


Generally well tolerated with a mild side-effects
profile
In all phases of CML, imatinib mesylate
achieved
Hematologic responses
Cytogenetic responses

Time to response was rapid

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

Kantarjian H et al. N Engl J Med. 2002;346:645-653.


2002 Massachusetts Medical Society. All rights reserved.

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

Other Possible Mechanisms of


Resistance to Imatinib Mesylate

Mechanisms of resistance
Ph+ cell lines
Bcr-Abl overexpression
Gene amplification
Drug reflux mediated by P-glycoprotein
Other

In vivo murine model


Binding in the plasma of alpha 1-acid
glycoprotein to imatinib mesylate

TerapiPenggantiResistensiImatinib
ImatinibDosisTinggi
TransplantasiHSC
Dasatinib

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