tyrosine kinase inhibitorkaim.or.kr/pds/files/hmo/tyrosine kinase inhibitor.pdf · protein...

Tyrosine Kinase Inhibitory

June-Won CheongYonsei University College of MedicineYonsei University College of Medicine

Part IPart I

Protein KinasesProtein Kinases

Cellular communicationCellular communication• Signal transduction pathways• Signal transduction pathways• 3 stages of cell signalling

receptionreceptiontransductionresponseresponse

G-protein-linked

ProteinKinase

receptor receptor

Protein KinasesProtein KinasesTyrosine Kinases Serine/threonine Kinases

ABL Abelson PKC Protein kinase C

y

KITR c-Kit receptor CDK Cyclin-dep. kinase

PDGFR PLT-derived-GF receptor MKK1 Mitogen-act. PK kinase 1

EGFR Epidermal-GF receptor RAF Rapidly accelerated fibrosarcoma

ERB2R Erb2 receptor CHK1 Checkpoint kinase 1

VEGFR Vascular-endothelial GF receptor mTor Mammalian Target of rapamycin

FGFR Fibroblast-GF receptor ROCK RHO-dep. PK

NGFR Nerve-GF receptor p38/SAPK2a P38/Stress-act. PK2a

MLK Mixed-lineage PK

Protein Kinases as a TargetProtein Kinases as a Target• 200 300 PKs in a cell• 200-300 PKs in a cell • Upstream/downstream of relevant oncogenes ortumor suppressor genes

• Commonality & diversity among ATP-binding sitesCommonality & diversity among ATP binding sites of PKsP ibilit f t i t lid ti• Possibility of a step-wise concept validationat the biochemical, cellular & intact animal level ,as proof of concept in the clinic

Protein Kinases & CancerProtein Kinases & CancerOverexpression of GFRs

EGFR HER2 HER3 HER4 i b t l H&N d li bl t•EGFR,HER2,HER3,HER4 in breast, ovary, lung, H&N and glioblastoma•FGFR in lung, ovary and breast•PDGFR in glioblastoma•IGF-1R in solid tumors

Overexpression of GFs•TGF-α in carcinoma overexpressing the EGFR•PDGF-BB expression in glioblastoma•VEGF expression for neo-vascularization (angiogenesis and metastasis)p ( g g )

Altered PK levels and/or activities•Bcr-Abl in CML (95%), ALL (15%)•c-Met in renal carcinoma•c-Kit in gastric cancers (GIST)•Cancers with Onc Ras have deregulated PKC, Raf-kinase (bladder, colon, lung, breast)Cancers with Onc Ras have deregulated PKC, Raf kinase (bladder, colon, lung, breast)•Deregulation of cell cycle by CdKs

Protein KinaseProtein Kinase

Protein Kinase Inhibitor; PKIProtein Kinase Inhibitor; PKIIsoquinoline sulfonamides•From 1st PKI (Naphthalene sulfonamide)From 1 PKI (Naphthalene sulfonamide)

•cAMP- & cGMP-dept. PKI

Hidaka H et al. Biochemistry 1984;23:5036

Protein Kinase Inhibitor; PKIProtein Kinase Inhibitor; PKIStaurosporine•Antifungal agent (1977)•Antifungal agent (1977)

•From Streptomyces

•Indolocarbazole product

•Nanomolar inhibitor of PKC

K252 CEP-1347K252, CEP-1347,

UCN-01, PKC412, etc…Tamaoki T et al. Biochem Biophys Res Commun 1986;135:397

Kase H et al. J Antibiot 1986;39:1059

Protein Kinase Inhibitor; PKIProtein Kinase Inhibitor; PKI

Knighton DR et al. Science 1991;253:407/414

Part IIPart II

Tyrosine Kinases & TKITyrosine Kinases & TKI

Tyrosine KinasesTyrosine Kinases

www.uic.edu/.../mike/spring2003/lect07.htm

https://eapbiofield.wikispaces.com/file/view/11_07cRecTyrosineKinases-L.jpg

Important discoveries in TKImportant discoveries in TK

Hunter T. Curr Opin Cell Biol 2009;21:140

TKI discoveryTKI discoveryTarget TK Inhibitor Company

*Bcr-Abl, c-Kit, PDGFR STI 571 (Imatinib, GLIVEC) Novartis* CSF 1R EPHA4R AMN107 (Nil ti ib TASIGNA) N ti*, CSF-1R, EPHA4R AMN107 (Nilotinib, TASIGNA) Novartis

*, SRC, EPHR BMS 354825 (Dasatinib, SPRYCEL) BMS*, SRC SKI 606 (Bosutinib) Wyeth-AyerstEGFR ZD1839 (Gefitinib, IRRESA) AstraZenecaEGFR OSI 774(Erlotinib,TARCEVA) OSI Pharmaceuticals

EGFR, ERB2R PKI 166 NovartisEGFR, ERB2R CI 1033 (Canertinib) PfizerEGFR, ERB2R EKB 569 Wyeth-AyerstEGFR, ERB2R GW 572016 (Lapatinib, TYKERB) GlaxoSmithKline, ( p , )

VEGFR PTK 787 NovartisVEGFR ZK 222584 Schering-PloughVEGFR SU 5416 (TSU-16) Sugen/Pharmacia UpjohnVEGFR SU 5416 (TSU 16) Sugen/Pharmacia Upjohn

VEGFR, EGFR ZD 6474 (Vandetanib, ZACTIMA) AstraZenecaVEGFR, FGFR, PDGFR SU 11248(Sorafenib, SUTENT) PfizerVEGFR FGFR PDGFR SU 6668 (TSU 68) Pharmacia CorpVEGFR, FGFR, PDGFR SU 6668 (TSU-68) Pharmacia Corp.

bFGFR PD 173074 PfizerNGFR CEP 2583 Cephalon

Tyrosine Kinase Inhibitor; TKITyrosine Kinase Inhibitor; TKIInvestigation of catalytic mechanism of EGFRInvestigation of catalytic mechanism of EGFR•Structure-based searching & discovery of a potent inhibitorC t lli ti•Crystallization process

Ward WH et al. Biochem Pharmacol 1994;48:659

PD153035PD153035•EGFR inhibitor

Fry DW et al. Science 1994;265:1093

AG1478•EGF-dept. activation of Src-family TK inhibitor

Osherov N et al. Eur J Biochem 1994;225:1047

Tyrosine Kinase Inhibitor; TKITyrosine Kinase Inhibitor; TKI4-(Phenylamino)pyrrolopyrimidines4-(Phenylamino)pyrrolopyrimidines •By pharmacophore model of ATP binding siteEGFR TKI•EGFR TKI Traxler P et al. J Med Chem 1996;39:2285

PKI166 66•By optiminization process•EGFR/erbB-2 TKIEGFR/erbB 2 TKITraxler P et al. Clin Cancer Res 1999;5:3750s

Tyrosine Kinase Inhibitor; TKITyrosine Kinase Inhibitor; TKI

Folia Pharmacol Jpn. 2003;122:482

Part IIIPart III

Individual TKIsIndividual TKIs

Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS study

ImatinibRA

y

Crossover

ANDO

n = 553

IFN-α+

OMIZ +

Ara-C Crossover for:• Lack of response

ZE

553 p• Loss of response• Intolerance of treatment• Reluctance to continue IFN

n = 553

• Reluctance to continue IFN

O’Brien SG et al. N Engl J Med 2003;348:994

Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS studyy


Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS studyy

MCyR PFS


Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS study – 7 yrs after

All randomized to imatinib(n= 553; 100%)

y y

(n 553; 100%)

Still receiving study imatinib(n = 332; 60%)

Discontinued study imatinib*(n = 221; 40%)( ; )

In CCR (n = 317;

No CCR (n = 15;

(n 221; 40%)

(n 317; 57%)

(n 15; 3%) Safety

(n = 43; 8%)

Efficacy (n = 82;

15%)

Other (n = 96;

17%)

Alive Dead Alive Dead Alive Dead(n = 17;

40%)(n = 26;

60%)(n = 52;

63%)(n = 30;

37%)(n = 81;

84%)(n = 15;

16%)

O’Brien SG et al. Blood 2008;112: Abstract 186.

Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS study – 7 yrs aftery y

90

100

t

80

90

Estimated OS at 7 years is 86% (94% considering only CML-related deaths)ut

Eve

nt

60

70

( g y )

% W

itho

40

50

Survival: deaths associated with CMLOverall Survival

%

20

30

Overall Survival

0

10

0 1 2 3 4 5 6 7 8 year after random.

O’Brien SG et al. Blood 2008;112: Abstract 186.

Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; IRIS study – 7 yrs after

90

100

s

y y

BCR-ABL% (IS)

≤0.1%≤0.01%

70

80

90

e Sa

mpl

es

≤0.01%

50

60

Avai

labl

e

20

30

40

% o

f A

0

10

20

Sample Analysis Time Points (months)0 3 6 9 12 15 18 21 24 30 36 42 48 54 60 66 72 78 84

Hughes et al. Blood 2008;112: Abstract 334.

Imatinib GlivecImatinib, GlivecStandard Frontline Tx for CML ; Failure / Suboptimal Response

Time Failure Suboptimal Response Warnings

Dx

•High risk •Del9q+ •Additional ch’somal abNLs in Ph+ cellsPh cells

3 m No HR < CHR

6 m No CHR or CyR < PCyR

12 m < PCyR PCyR < < CCyR Any MR < MMRy y y y

18 m < CCyR < MMR

Any•Loss of CHR •Loss of CCyR

•Additional ch’somal abNLs in Ph+ cells •Increase in BCR-Any

time•Loss of CCyR •Mutation with high insensitivity to Glivec

abNLs in Ph+ cells •Loss of MMR •Mutation with low insensitivity to Glivec

ABL level •Other ch’somal abNLs in Ph-cells

Baccarani M et al. Blood 2006;108:1809.


(n=81)s 8090

100

( )

(n=19)6 m

onth

s

607080

Suboptimal

(n=16)

CC

yR >

6

304050

Failure

(n=16)

% C

102030 Failure

0

Months since randomization0 3 6 9 12 15 18 21 24 27 30 33

Druker et al. Blood 2003; 102: Abstract 634

CyR at 6 months (Ph+) 1-35% 36-65%66-95% >95%

Months since randomization


86%95%

P = 0.0190100

86%

62%vent 70

80

62%58%

thou

t Ev

5060

BCR ABL % (IS) at 18 months

% W

it

203040

≤0.1% (n = 164)>0.1-1% (n = 47)

BCR-ABL % (IS) at 18 months

01020

( )>1-10% (n = 25)>10% (n = 13)

Hughes et al. Blood 2008;112: Abstract 334.

00 12 24 36 48 60 72 84


Standard Frontline Tx for CML ; AP and BC patients

Overall CyR 48% Overall CyR 17%

PFS

Palandri F et al. Haematologica 2009;94:205 Palandri F et al. Haematologica 2008;93:1792



Standard Frontline Tx for CML ; Bcr/Abl mutations20%

Data from the GIMEMA CML WP on 655 imatinib-resistant patients15%

10%

Data from the GIMEMA CML WP on 655 imatinib-resistant patients

5%

P-loop Catalytic domain

Activation loop

M351T L387M/F

H396R/PL248V

M343TV289A

D276GT277A

E281A/K L364I

oop domain loop

G250E

Q252R/HY253F/H

E255K/VT315I

F317L

E355G/DF359V/I

V379I

F311L/I

F382L S417Y/F

E459K/QF486S

T277A

A380T

E279KE292V

L384M

E453G/K



Standard Frontline Tx for CML ; Bcr/Abl mutations....

2nd generation TKIsNilotinibNilotinib

Dasatinib

Bosutinib

Imatinib

Nilotinib Dasatinib BosutinibNilotinib Dasatinib Bosutinib

Potency & Selectivity of TKIsPotency & Selectivity of TKIs

Imatinib: PDGFR > Kit > BcrAbl > Src(Phos IC ) 72 nM 99 nM 192 nM >1000 nM(Phos IC50) 72 nM 99 nM 192 nM >1000 nM

Dasatinib: Src > BcrAbl > PDGFR > KitDasatinib: Src > BcrAbl > PDGFR > Kit(Phos IC50) 0.1 nM 1.8 nM 2.9 nM 18 nM

Nilotinib: BcrAbl > PDGFR > Kit > Src(Phos IC ) 19 nM 75 nM 209 nM >1000 nM(Phos IC50) 19 nM 75 nM 209 nM >1000 nM

Mestan J et al. Blood. 2004;104: Abstract 1978. Weisberg E et al. Cancer Cell 2005;7:129.

Nilotinib as a Second Tx for CP pts

100

Nilotinib, as a Second Tx for CP pts

95%

78%80

90

100

44%

56%59%65%

51%50

60

70

% 41%44%

30

40

50

Pat

ient

s, %

32120 321 226 2260

10

20

MCyR CCyRCHR

95321207 321 226 22695nOverall No BL

CHROverall Imatinib-

ResistantImatinib-Intolerant

Overall Imatinib-Resistant

Imatinib-Intolerant

321

y

Kantarjian HM, et al. J Clin Oncol. 2009;27(15S): Abstract 7029.

Patients with a minimum follow-up of 24 months

Nilotinib as a Second Tx for CP ptsNilotinib, as a Second Tx for CP pts

PFS

90

10089% 84% 78%

70

80

90

Dea

th

40

50

60

gres

sion

or D

20

30

40

With

out P

rog

Number of patients = 189Number failed = 35

0

10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

% W Number failed = 35

= Censored observations

Months Since MCyR

Kantarjian HM, et al. Blood. 2008;112: Abstract 3238.

Nilotinib as a Second Tx for CP pts

95%

Nilotinib, as a Second Tx for CP pts

OS

90

100

95% 87%

Aliv

e

60

70

80

% A

30

40

50

Number of patients = 321Number failed = 44

= censored observations10

20

30

00

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Months Since Start of Treatment

36

Kantarjian HM, et al. J Clin Oncol. 2009;27(15S): Abstract 7029.

• 87% of patients were estimated to be alive on nilotinib at 24 months

Dasatinib as a Second Tx for CP ptsDasatinib, as a Second Tx for CP ptsFor imatinib-resistant or –intolerant CML-CP pts.Prior imatinib 400 600 mg (48%) ≥600 mg (52%)Prior imatinib 400-600 mg (48%), ≥600 mg (52%)

Non-Hema SE(G3,4): ≤3% MCyRNon Hema SE(G3,4): 3%Hema SE(G3,4): 22-49%

MCyR

PFS

Hochhaus A et al. Blood 2007;109:2303

Dasatinib as a Second Tx for CP ptsDasatinib, as a Second Tx for CP pts

100 CHR100

80

9288 87

92 MCyRCCyR

80

60

63 61 63 61

5054

50 50

%

60

40

50 50 50

20

100 mg O D il

70 mg BID

140 mg O D il

50 mgBID

0Once Daily BID Once Daily BID

Shah NP, et al. Blood. 2008;112: Abstract 3225.

Dasatinib as a Second Tx for CP ptsDasatinib, as a Second Tx for CP pts

100

80R

88%

80

60s of

MC

yR

24-month response rates

CCyRMCyR

60

40

hout

Los

s

53%

CCyR

62%

MCyR20%

With

00 3 6 9 12 15 18 21 24 27 30

369 of 387 patients evaluable for molecular response


Months since MCyR

Dasatinib as a Second Tx for CP pts

94%97%

Dasatinib, as a Second Tx for CP pts

OS100

80

94%97%

91%

OS

80

60

80%91%

PFS60

40

%

20

00 3 6 9 12 15 18 21 24 27 30 33

Months


Nilotinib/Dasatinib AEsNilotinib/Dasatinib, AEs

Dasatinib Nilotinib

Dasatinib 70 mg BID, Nilotinib 400 mg BID

Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4

Myelotoxicity - 49-50 - 28-30

(Thrombocytopenia & Neutropenia)49 50 28 30

Pleural Effusion (Peripheral Edema) 26 (29) 9 (1) 1 (6) 1 (0)

Bleeding 16 4 6 2

Hyperglycemia - - - 13

Lipase elevation - - - 15

Stone RM, et al. Blood. 2007;110: Abstract 734 / Kantarjian HM, et al. Blood. 2007;110: Abstract 735.

Nilotinib/Dasatinib as a Second Tx for CP2 yr % Nilotinib Dasatinib

Nilotinib/Dasatinib, as a Second Tx for CP2 yr % Nilotinib DasatinibCHR 95 92

MCyR 59 63CCyR 44 54

D MCyR 78 88D.MCyR 78 88PFS 80PFS 80OS 87 94

Nilotinib/Dasatinib AP2 yr % Nilotinib Dasatinib

Nilotinib/Dasatinib, as a Second Tx for AP2 yr % Nilotinib DasatinibCHR 31 53

MCyR 32 43CCyR 21 35

D MC R 66 75D.MCyR 66 (after MCyR) 75 (after MCyR)

PFS 55PFS 55OS 66

le Coutre PD, et al. J Clin Oncol. 2009;27(15S): Abstract 7057 / Kantarjian HM, et al. Blood. 15 April 2009. Epub ahead of print.

Dasatinib as a Second Tx for BC ptsDasatinib, as a Second Tx for BC pts116 imatinib-resistant or –intolerant CML-BC pts.Non Hema SE(G3 4): 0 24%Non-Hema SE(G3,4): 0-24%Hema SE(G3,4): 12-14%

MHR

PFS

Cortes J et al. Blood 2007;109:3207

Dasatinib for nilotinib-resistant PtsDasatinib for nilotinib-resistant PtsFor imatinib & nilotinib-resistant Ph(+) leukemiaN= 13 (CP 1 AP 9 BC 3)N= 13 (CP 1, AP 9, BC 3)Bcr-Abl mutation 100%140 mg/d (twice daily)140 mg/d (twice daily)Median Tx duration: 4 months (1-10)

OR: 57%CHR: 43%CHR: 43%CyR: 30%

Quintas-Cardama A et al. Blood 2006;109:497

Nilotinib for Dasatinib-resistant PtsNilotinib for Dasatinib-resistant Pts100

80

79%90

60

70

40

50 43%

20

3024%

0

10

20

Giles F et al. Blood 2008;112:1110

0CHR MCyR CCyR

Mutations recovered after TKI therapypy

*20ImatinibDasatinibNilotinib*

*

10

15

%

Nilotinib

* **

5

10

* *

0

5

* * * *

* T315I & F359V recovered after treatment with bosutinib

0G250E Y253F/H E255G/K V299L F311I/L T315I F317L/V M351T E355G/A F359C/V H396P/R

BCR/ABL Mutation

T315I & F359V recovered after treatment with bosutinib

Jabbour E, et al. Blood. 2006;108: Abstract 750.

2nd generation TKIs2 generation TKIsRandomized Trials for Frontline TxRandomized Trials for Frontline Tx

Study Imatinib 2nd TKI No. of Pts Year started

USA-SWOG 400/800 Dasatinib 518 2005

Novartis 400 Nilotinib 845 2005

Wyeth 400 Bosutinib 2007

Nilotinib as a frontline TxNilotinib, as a frontline Tx

50% 80% 90% 83% 98% 97% CCyR

90%100%

y

< CCyR

60%70%80%

40%50%60%

10%20%30%

High Risk (n=10)Months

Non-High Risk (n=63)

0%3 6 12 3 6 12

High Risk (n=10) Non High Risk (n=63)

Rosti G, et al, Presented at: 14th Congress of the EHA; 2009: Berlin, Germany. Abstract 1090.

Nilotinib as a frontline Tx

3% 21% 52% 66% 73% 85%

Nilotinib, as a frontline Tx

100%MMR

80%

90%100% < MMR

NE

60%70%

80%

40%

50%

10%

20%

30%

Months0%

10%

1 2 3 6 9 12

Rosti G, et al, Presented at: 14th Congress of the EHA; 2009: Berlin, Germany. Abstract 1090.

Dasatinib as a frontline Tx

N 48 N 43 N 37 N 32 N 25 N 15

Dasatinib, as a frontline Tx

N = 48 N = 43 N = 37 N = 32 N = 25 N = 15

34

65

1790

100

nse CCyR

PC R417

70

80

Res

pon PCyR

93848895937940

50

60

ge w

ith

20

30

40

erce

nta

0

10

20

3 6 12 18 24 30

Pe

Cortes J, et al. Blood. 2008;112: Abstract 446.

3 6 12 18 24 30Months on Therapy

Dasatinib as a frontline Tx

100

Dasatinib, as a frontline Tx

80

100% MMR % CMR

60 644

60

espo

nse

41

7

82

40

e w

ith R

e

20 24 27

2

220

erce

ntag

MonthsN 46 45 42 37 31 25 14

20

3 6 9 12 18 24 30

Pe

Cortes et al. Blood 2008;112: Abstract 182.

Nilotinib/Dasatinib as a Frontline Tx for CP1 yr % Nilotinib Dasatinib

Nilotinib/Dasatinib, as a Frontline Tx for CP1 yr % Nilotinib DasatinibCCyR* 96 95y≥MMR 85 95

* Imatinib: 74%

• 2nd generation TKIs can improve outcome of pts with early CP-CML

• Responses with nilotinib/dasatinib are better & faster than imatinib

• Nilotinib is better tolerated and more selective than dasatinib

More approved TKIsMore approved TKIs….ATP-Binding

T315I-Active Nonkinase InhibitionBcr-Abl Abl & Src

Imatinib Dasatinib MK-0457 17-AAG

Nilotinib Bosutinib KW-2449 HDAC

INNO-406 XL228 DAC

AT9283 HHT

PHA-739358

CASE 168/F, CML-CP in Jan 2004.Frontline Tx: Imatinib 400 mg/d. At 12 months of Tx: CCyRAfter 2 month, WBC 25,000/ul & 15 % basophils, BM: Blast 16%.What step would you take next?

Continue imatinib at 400 mg/dayIncrease the dose of imatinib to 800 mg/daySwitch therapy to a 2nd generation TKIRecommend immediate alloHSCT


Time Failure Suboptimal Response Warnings

Dx

•High risk •Del9q+ •Additional ch’somal abNLs in Ph+ cellsPh cells

3 m No HR < CHR

6 m No CHR or CyR < PCyR

12 m < PCyR PCyR < < CCyR Any MR < MMRy y y y

18 m < CCyR < MMR

Any•Loss of CHR •Loss of CCyR

•Additional ch’somal abNLs in Ph+ cells •Increase in BCR-Any

time•Loss of CCyR •Mutation with high insensitivity to Glivec

abNLs in Ph+ cells •Loss of MMR •Mutation with low insensitivity to Glivec

ABL level •Other ch’somal abNLs in Ph-cells

Baccarani M et al. Blood 2006;108:1809.

CASE 168/F, CML-CP in Jan 2004.Frontline Tx: Imatinib 400 mg/d. At 12 months of Tx: CCyRAfter 2 month, WBC 25,000/ul & 15 % basophils, BM: Blast 16%.What step would you take next?

Continue imatinib at 400 mg/dayIncrease the dose of imatinib to 800 mg/daySwitch therapy to a 2nd generation TKIRecommend immediate alloHSCT

Pt shows imatinib failure after optimal responsethan

CASE 244/F, CML-CP, with sibling HLA matched donorFrontline Tx: Imatinib 400 mg/d. Grade 2 fluid retentionsPh(+) metaphases in BM: 30% at 6 months 50% at 12 monthsImatinib plasma level: adequate & No mutationsWhat step would you take next?

Increase the dose of imatinib to 800 mg/dayIncrease the dose of imatinib to 800 mg/daySwitch therapy to nilotinib 400 mg twice dailySwitch therapy to dasatinib 100 mg dailySwitch therapy to dasatinib 100 mg dailyRecommend immediate alloHSCT

CASE 244/F, CML-CP, with sibling HLA matched donorFrontline Tx: Imatinib 400 mg/d. Grade 2 fluid retentionsPh(+) metaphases in BM: 30% at 6 months 50% at 12 monthsImatinib plasma level: adequate & No mutationsWhat step would you take next?

Increase the dose of imatinib to 800 mg/dayIncrease the dose of imatinib to 800 mg/daySwitch therapy to nilotinib 400 mg twice dailySwitch therapy to dasatinib 100 mg dailySwitch therapy to dasatinib 100 mg dailyRecommend immediate alloHSCT

Pt shows imatinib failure after optimal responsethan or

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