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University of Milano Bicocca, Monza, Italy Incidence of Incidence of Hematologic Hematologic Malignancies Malignancies Type of Leukemia Type of Leukemia Incidence per Incidence per 100,000* 100,000* Overall Overall 6 6 10 10 CML CML 1 1 2 2 CLL CLL 2 2 3 3 AML AML 2 2 3 3 ALL ALL 1 1 2 2

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Page 1: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

University of MilanoBicocca, Monza, Italy

Incidence of Incidence of HematologicHematologic MalignanciesMalignancies

Type of LeukemiaType of Leukemia Incidence per Incidence per 100,000*100,000*

Overall Overall 66––1010CMLCML 11––22CLLCLL 22––33AMLAML 22––33ALLALL 11––22

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Men 290,890

Women 272,810

26%26% Lung and bronchusLung and bronchus

15%15% BreastBreast

10%10% Colon and rectumColon and rectum

6%6% PancreasPancreas

6%6% OvaryOvary

4%4% LeukemiaLeukemia

3%3% NonNon--HodgkinHodgkin’’s lymphomas lymphoma

3%3% Uterine corpusUterine corpus

2%2% Brain/nervous systemBrain/nervous system

2%2% Multiple myelomaMultiple myeloma

22%22% All other sitesAll other sites

Lung and bronchus 33%

Prostate 10%

Colon and rectum 10%

Pancreas 5%

Leukemia 4%Non-Hodgkin’s lymphoma 4%

Esophagus 4%

Liver/intrahepatic bile duct 3%

Urinary bladder 3%

Kidney 3%

All other sites 21%

Leukemia Comprises a Vast Leukemia Comprises a Vast Proportion of Cancer Deaths in the Proportion of Cancer Deaths in the

United StatesUnited States

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Incidence and Mortality Associated With Incidence and Mortality Associated With Leukemias (United States, 2003)Leukemias (United States, 2003)

Incidence Mortality

OverallAMLCLLCMLALL

35,000

30,000

25,000

20,000

15,000

10,000

5000

0

35,000

30,000

25,000

20,000

15,000

10,000

5000

0

33,440

11,920

8,190

4,600 3,830

23,300

8,870

4,800

1,570 1,450

Page 4: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

University of MilanoBicocca, Monza, Italy

Page 5: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

University of MilanoBicocca, Monza, Italy

Courtesy of John K. Choi, MD, PhD, University of Pennsylvania.

Normal Chronic Phase CML

Comparative Peripheral Blood SmearComparative Peripheral Blood Smear

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University of MilanoBicocca, Monza, Italy

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Table 46.2-1 Diagnosis and Evaluation of Acute Leukemia-------------------------------------------------------------------

Symptoms

Fatigue, malaise, dyspneaEasy bruisability, weight loss

Bone pain or abdominal pain (less common)Neurologic symptoms (rare)

SignsAnemia and pallor

Thrombocytopenia, hemorrhage, ecchymoses, petechiae, fundal hemorrhage

Fever and infection (pneumonia, sepsis, perirectal abscess)Adenopathy, hepatosplenomegaly, mediastinal mass

Gum or skin infiltration (rare)Renal enlargement and insufficiency (rare)

Cranial neuropathy (rare)

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Clinical Presentation of CMLClinical Presentation of CML

Common SymptomsCommon Symptoms Common SignsCommon SignsFatigueFatigue Palpable Palpable splenomegalysplenomegalyWeight loss/anorexiaWeight loss/anorexiaAbdominal fullnessAbdominal fullness

Common Laboratory FindingsCommon Laboratory FindingsAbnormal differentialAbnormal differential AnemiaAnemiaLeukocytosisLeukocytosis BasophiliaBasophiliaThrombocytosisThrombocytosis

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LEUCEMIA MIELOIDE CRONICA

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University of MilanoBicocca, Monza, ItalySawyers. N Engl J Med. 1999;340:1330.

Faderl et al. Ann Intern Med. 1999;131:207.

Epidemiology of CMLEpidemiology of CML

Median age range at presentation is Median age range at presentation is 4545--55 years55 yearsIncidence increases with ageIncidence increases with age-- Up to 30% of patients are aged >60 years Up to 30% of patients are aged >60 years

Slightly higher incidence in malesSlightly higher incidence in males-- MaleMale--toto--female ratiofemale ratio——1.3:11.3:1

At presentationAt presentation-- 50% diagnosed by routine laboratory tests50% diagnosed by routine laboratory tests-- 85% diagnosed during chronic phase85% diagnosed during chronic phase

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Courtesy of John K. Choi, MD, PhD, University of Pennsylvania.

Normal Chronic Phase CML

Comparative Peripheral Blood SmearComparative Peripheral Blood SmearAcute Leukemia

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PATOGENESI

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CytogeneticCytogenetic Abnormality of CML:Abnormality of CML: The Philadelphia ChromosomeThe Philadelphia Chromosome

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University of MilanoBicocca, Monza, Italy

The Philadelphia Chromosome: The Philadelphia Chromosome: t(9;22) Translocationt(9;22) Translocation

22

bcr

abl

Ph

bcr-abl

FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY

9 9+

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Chromosome Chromosome in in HematologicHematologic MalignanciesMalignancies

LeukemiaLeukemia % of Ph+ Patients% of Ph+ Patients

CMLCML 95 95

ALL (Adult)ALL (Adult) 1515––3030

ALL (Pediatric)ALL (Pediatric) 55

AMLAML 22Faderl S et al. Oncology (Huntingt). 1999;13:169-184.

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bcrbcr--ablabl Gene and Fusion Protein Gene and Fusion Protein Tyrosine Tyrosine KinasesKinases

Adapted from Melo JV. Blood. 1996;88:2375-2384.

p210 Bcr-Abl

p185 Bcr-Abl2-11

2-11

Chromosome 9c-bcr

Chromosome 22

c-abl

Exons

Introns

CML Breakpoints

ALL Breakpoints

1

2-11

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p210p210BcrBcr--AblAbl Fusion Protein Tyrosine Fusion Protein Tyrosine KinaseKinase

Faderl S. N Engl J Med. 1999;341:169.

Extracellular space

Y177

BAP-1 GRB2

Cytoplasm

SH3 SH2 SH1

CBL SHC CRKL

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BcrBcr--AblAbl Signal Transduction Signal Transduction PathwaysPathways

Adapted from Pasternak G et al. J Cancer Res Clin Oncol. 1998;124:643-660.

Bcr-Abl

BCL 2inhibition of apoptosis

MYC GRB2 CRKL CBL (p120CBL)

RAS

RAF-MEK-MAPK cascaderegulates cell cycle progression and differentiation

activates

JAK/STATs

upregulation of

Paxillin (Adhesion) PI-3 kinase

Actin (Adhesion)

Page 21: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

β-catenin is constitutively tyrosine (Y)-phosphorylated and associated to Bcr-Abl in human CML cells

nonpS/Tβ-cat

- + - + imatinib 2hCML m KU812IP:α β-cat

97 kDa

97 kDa β-cat

210 kDa Bcr-Abl

97 kDa p-Y-β-cat

imatinib prevents tyrosine (Y)-phosphorylation of β-catenin and accumulation of its transcriptional

competent pool which is serine/threonine (S/T)-nonphosphorylated

- + - + imatinib 210 kDa

97 kDa

Bcr-Abl

β-cat210 kDa p-Y-Bcr-Abl

IP:α Abl CML m KU812

97 kDa nonpS/Tβ-cat

97 kDa p-Y-β-cat

2h

Characteristics of CML Patient Samples

Pt. Age Type CML phase %blasts1 58 BM BC 30% 2 43 BM BC 73% 3 37 BM BC 37% 4 74 BM BC 54% 5 45 BM BC 96% 6 58 BM BC 58%

BM, bone-marrow mononuclear cells; BC, blast crisis

Ls174tKU812

CML 1CML 2

CML 3CML 4

CML 5CML 6

β-cat

Bcr-Abl210 kDa

97 kDa

97 kDa p-Y-β-cat

IP:α β-cat

Ls174t = human colorectal cancer cell line used as negative control for Bcr-AblKu812 = BC-CML-patient established cell lineCML 1 - 6 = fresh bone-marrow mononuclear cells from BC-CML-patients

Page 22: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

Proposed mechanism:

Page 23: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

University of MilanoBicocca, Monza, Italy

Page 24: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

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Page 25: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

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Page 26: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

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Page 27: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

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DIAGNOSI

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Clinical Presentation of CMLClinical Presentation of CML

At presentation:At presentation:

50% diagnosed by routine 50% diagnosed by routine laboratory testslaboratory tests

85% diagnosed during chronic 85% diagnosed during chronic phasephase

Page 29: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

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Clinical Presentation of CMLClinical Presentation of CML

Common SymptomsCommon Symptoms Common SignsCommon SignsFatigueFatigue Palpable Palpable splenomegalysplenomegalyWeight loss/anorexiaWeight loss/anorexiaAbdominal fullnessAbdominal fullness

Common Laboratory FindingsCommon Laboratory FindingsAbnormal differentialAbnormal differential AnemiaAnemiaLeukocytosisLeukocytosis BasophiliaBasophiliaThrombocytosisThrombocytosis

Page 30: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

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Common laboratory findingsCommon laboratory findings-- Abnormal differentialAbnormal differential-- LeukocytosisLeukocytosis-- ThrombocytosisThrombocytosis-- AnemiaAnemia-- BasophiliaBasophilia

Faderl et al. Ann Intern Med. 1999;131:207.Goldman. Curr Opin Hematol. 1997;4:277.

Clinical Presentation of Clinical Presentation of Chronic Phase CMLChronic Phase CML

Asymptomatic in ~50% of casesAsymptomatic in ~50% of casesCommon symptomsCommon symptoms-- FatigueFatigue-- Weight loss/anorexiaWeight loss/anorexia-- Abdominal fullnessAbdominal fullness

Common signsCommon signs-- Palpable splenomegalyPalpable splenomegaly

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Typical Laboratory Parameters Typical Laboratory Parameters by Phase of CMLby Phase of CML

ParameterParameter ChronicChronic AcceleratedAccelerated BlasticBlasticWBC countWBC count >>20 x 1020 x 1099/L/L —— ——BlastsBlasts 3%3%––10%10% >>15% 15% >>30%30%

BasophilsBasophils ↑↑ >>20% 20% ——PlateletsPlatelets ↑↑or normalor normal ↓↓ or or ↑↑ ↓↓

Bone marrowBone marrow Myeloid hyperplasia Myeloid hyperplasia CytogeneticsCytogenetics Ph+Ph+BcrBcr--AblAbl ++ ++ ++

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Clinical Course: Phases of CMLClinical Course: Phases of CML

Chronic phase

Median 4–6 years stabilization

Accelerated phase

Median duration up to 1 year

Blastic phase (blast crisis)

Median survival 3–6 months

Terminal phase

Advanced phases

Page 33: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

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Nucleo Ph+

Nucleo normale

Metafase Ph+

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University of MilanoBicocca, Monza, Italy

M

692 bp501 bp

Patie

nt E

.L.

BaF

3-T/

P

CNeg

ativ

e Pa

tient

TMHLH TKD

308 bp

533 bp

B.

C.

501 bp692 bp

M 10-1 10-2 10-3 10-4 10-5 10-6 CU

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TERAPIA

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The Ideal Target for Molecular The Ideal Target for Molecular Therapy Therapy

Present in the majority of patients with a Present in the majority of patients with a specific diseasespecific disease

Determined to be the causative Determined to be the causative abnormalityabnormality

Has unique activity that isHas unique activity that is

-- Required for disease inductionRequired for disease induction

-- Dispensable for normal cellular functionDispensable for normal cellular function

Courtesy of BJ Druker, MD.

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University of MilanoBicocca, Monza, Italy

BcrBcr--AblAbl as a Therapeutic Target for CMLas a Therapeutic Target for CML

BcrBcr--AblAbl is detected in 95% of patients is detected in 95% of patients with CMLwith CML

BcrBcr--AblAbl is the causative abnormality of is the causative abnormality of CMLCML

BcrBcr--AblAbl tyrosine tyrosine kinasekinase is constitutively is constitutively activated activated intracellularlyintracellularly-- Tyrosine Tyrosine kinasekinase activity is required for CML activity is required for CML

cell functioncell function

Page 41: Incidence of Hematologic Hematologic Malignancies Type · PDF fileIncidence of Hematologic Hematologic Malignancies Type of Leukemia ... CML 1 - 6 = fresh bone ... Normal physical

Therapy of CML: Response Criteria

Disappearance of splenomegalyNormal physical exam

Hematologic Response Cytogenetic Response

Complete: Major:Normal peripheral blood count Complete: 0% Ph+ cells

WBC <10 x 109/L Partial: 1%–34% Ph+ cellsPlatelets <450 x 109/L Minor: 35%–95% Ph+ cellsNo immature cells

Ph+=Philadelphia chromosome-positive.

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IMATINIB IMATINIB

Tyrosine Tyrosine KinaseKinase InhibitorInhibitorfor CMLfor CML

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University of MilanoBicocca, Monza, Italy

Structure Structure of imatinibof imatinib

Class: Class: PhenylaminopyrimidinesPhenylaminopyrimidines, 589.7 mw, 589.7 mw

CH3 SO3 H

O

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BcrBcr--AblAbl––Positive and Positive and ––Negative Cell Negative Cell LinesLines

Adapted from Gambacorti-Passerini C et al. Blood Cells Mol Dis. 1997;23:380.

*Bcr-Abl-negative cell lines†Bcr-Abl-positive cell lines

U937*KG1*KCL22*K562†

KU812†

SU DHL1†

STI571 Concentration (μM)

% Control CPM

0 0.1 0.3 1 3 10

0

20

40

60

80

100

120

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LAMA84 Control

LAMA84 24h 1uM

LAMA84 44h 1 uM

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University of MilanoBicocca, Monza, Italy

0

1

2

3

4

5

6

7

8

9

0 10 20 30 40

days

tumor weight mg x 1000 ctrl

2x50 mg/kg i.p.

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University of MilanoBicocca, Monza, Italy

0

20

40

60

80

100

120

140

ctrl 6h 7h 20h 21h 30h 30htime of drug exposure

% c

pm

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University of MilanoBicocca, Monza, Italy

bcr/abl

bcr/abl

anti-phosphotyrosine

anti-abl

i.p. 2h p.o. i.p. 5h p.o. i.p. 9h p.o.

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University of MilanoBicocca, Monza, Italy

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

0 5 10 15 20

days

tumor weight mg x 1000

ctrl3x160 mg/kp p.o.

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0102030405060708090

100

0 10 20 30 40 50days

tumor free survival

ctrl3x50 mg/kg i.p.3x160 mg/kg p.o.

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University of MilanoBicocca, Monza, Italy

Chronic Phase patients

30.00

20.00 23.08

45.16

32.0028.57

44.83

30.00

96.77

76.9280.00

70.0073,68

54.84 55.17

71.43 68.00

3.230.00

20.00

40.00

60.00

80.00

100.00

0 3 6 9 12 15 18 21 24

Therapy, month

% p

atie

nts

% pt without response % pt with major or complete response

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MCyR within <=3 mthsMCyR within >3-6 mthsMCyR within >6-12 mthsMCyR later than 12 mths

= Censored observations

% w

ithou

t los

s of

MC

yR

0102030405060708090

100

Months since MCyR0 6 12 18 24 30 36 42 48 54 60 66

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Annual Event Rates in Patients Annual Event Rates in Patients onon FirstFirst--line Imatinibline ImatinibYear after

achieving CCyR All events* AP/BC1st 3.3% 1.5%

2nd 7.5% 2.8%3rd 4.8% 1.6%4th 1.5% 0.9%5th 0.9% 0.6%

* All deaths or loss of response* All deaths or loss of response includingincluding progression to AP/BCprogression to AP/BC

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Decreasing residual leukemia

Num

ber of leukemia cells (log

10 )

0

1

2

3

4

5

6

7

8

9

10

11

12

13

0

6.0

5.0

4.0

3.0

1.0

0

Log

redu

ctio

n fr

om b

asel

ine Leukocytosis

RQ-PCR positive

RQ-PCR negative

Ph-chromosome pos

Ph-negative but…

Cure ?

BCRBCR--ABL transcript numbers expressed as ABL transcript numbers expressed as log reduction in patients responding to treatmentlog reduction in patients responding to treatment

2.0

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Clinical Course: Phases of CMLClinical Course: Phases of CML

Chronic phase

Median 4–6 years stabilization

Accelerated phase

Median duration up to 1 year

Blastic phase (blast crisis)

Median survival 3–6 months

Terminal phase

Advanced phases

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Degree of Degree of BCRBCR--ABLABL log reduction in 124 log reduction in 124 CCyRCCyR pts at 1 and 4 yearspts at 1 and 4 years (in percent)(in percent)

39

12

31

39

41

8

22

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Year 1 Year 4

>= 4 log reduction

3 - < 4 log reduction

2 - < 3 log reduction

< 2 log reduction

8

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Carlo Gambacorti-Passerini

Lo studio ILTE

(Imatinib Long Term Effects)

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z

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REL - CML, 15/04/2010, MILANO

z

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HR

MUD ALLO

LR

NR R

α -IFN

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BMT activity for CML in Eurolandia

0

200

400

600

800

1000

1200

1400

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

total

V.U.D.

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RESISTENZA

Recidiva ematologica, citogenetica (>10%) o aumento confermato di >5 volte in PCR.

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Cytogenetic and hematological response of patient 506

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12Therapy, month

% of Ph+ cells WBC (* 1000) % of blasts PLT(*1000)

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ASH 2007

Duration of major cytogenetic response

Dasatinib in blast phase CML

Progression was defined as loss of major or minor HR, or no decrease in blasts (PB or BM) from baseline within 4 weeks of maximum dasatinib dose; patients who underwent SCT were censored

Prop

ortio

n no

t pro

gres

sed

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Months

n No. progressedMedian

(months)Myeloid blast 36 15 16.8Lymphoid blast 25 18 4.1

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IIIIII Amplification of BCR/ABLAmplification of BCR/ABL

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0

20

40

60

80

100

120

0 0,1 0,3 1 3 10

STI571 (µM)

% C

ontr

ol

LAMA84

LAMA84R

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LAMA84 LAMA84RSTI571(µM) - 1 3 10 - 1 3

bcr/ablAnti-phospho

Tyrosine

Anti-actin Actin

1010

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Pt 010/12_01Pt 010/12_01

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Tas(22q11)

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Tas(22q11)

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IVIV Mutations of BCR/ABLMutations of BCR/ABL

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„„onon““ state (active)state (active)„off“ state (inactive)

IRK3P

IRK

F1007

Y1162

R1155

Abl:STI571

Y253

Y393

R386

Y1162

F1007

Hck:PP1

F278

R409Y416

Abl:PD173955

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T315I

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Abl w.t.: prospettiva 2

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Abl T315I: prospettiva 2 (la freccia indica il residuo di Ile315)

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D276

E279

K274

R386

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CONFORMATION

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Molecular structures and Molecular structures and biological databiological data

N

NON

NH

NC O

O

ClClDasatinibBosutinib

DasatinibDasatinib SKISKI--606606

rr--AblAbl 0.3 0.3 nMnM 2.6 nM2.6 nM

Table below shows the IC50 values of these two kinase inhibitors.

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Bosutinib: A Dual Inhibitor of Srcand Abl Kinases

Boschelli et al. J Med Chem. 2005;48:3891-3902.Golas et al. Cancer Res. 2003;63:375-381.Golas et al. Cancer Res. 2005;65:5358-5364.

N

C N

H N

C l C l

O

O

ON

N

Src Enzyme (Elisa) IC50 = 1.2 nMSrc Enzyme (Lance) IC50 = 3.8 nMAbl Enzyme IC50 = 1.4 nM

K562 Cell IC50 = 20 nM KU812 Cell IC50 = 4.3 nM

Puttini et al. Cancer Res 2006; 66: 11314-22Courtesy of L Scapozza and A Shaheen, University of

Geneva, Switzerland

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Published Ahead of Print on December 15, 2008 as 10.1200/JCO.2008.19.8853The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2008.19.8853

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