University of Milano Bicocca, Monza, Italy - ilte-cml.org · University of Milano Bicocca, Monza,...

University of MilanoBicocca, Monza, Italy


ONCOLOGIA:

LEUCEMIE E TUMORI SOLIDI


Monoclonalita’ dei tumori:

Studio della Glucosio 6PDeidrogenasi (G6PD) in pazientifemmine


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


Incidenza = nuovi casi/10E5 anno

Prevalenza = incidenza x sopravvivenza media


Leucemia Mieloide Cronica


DIAGNOSI


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 ++ ++ ++


CML: Peripheral Blood SmearCML: Peripheral Blood Smear

CMLHoffbrand AV, Pettit JE, eds. In: Color Atlas of Clinical Hematology. 2nd ed. Mosby-Wolfe; 1994:198.


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


Epidemiology of CMLEpidemiology of CML

Median age range at presentation: 45 to Median age range at presentation: 45 to 55 years55 years

Incidence increases with ageIncidence increases with age-- 12%12%––30% of patients are >60 years old30% of patients are >60 years old

MaleMale--toto--female ratiofemale ratio——1.3:11.3:1


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


PATOGENESI


1960


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+


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


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)


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


TERAPIA


IMATINIB IMATINIB

Tyrosine Tyrosine KinaseKinase InhibitorInhibitorfor CMLfor CML


Structure Structure of imatinibof imatinib

Class: Class: PhenylaminopyrimidinesPhenylaminopyrimidines, 589.7 mw, 589.7 mw

CH3 SO3 H

O


Effect of STI571 on Growth ofEffect of STI571 on Growth of BcrBcr--AblAbl––Positive and Positive and ––Negative Cell LinesNegative Cell Lines

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


0102030405060708090

100

0 10 20 30 40 50days

tumor free survival

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


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


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


Annual Event Rates in Patients After Achievement Annual Event Rates in Patients After Achievement of CCyR on Firstof CCyR on First--line Imatinibline Imatinib

Year afterachieving CCyR All events* AP/BC

1st 5.5% 2.1%2nd 2.3% 0.8%3rd 1.1% 0.3%4th 0.4% 0%

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


Without CML-related deathsOverall Survival

% a

live

0102030405060708090

100

Months since randomization0 6 12 18 24 30 36 42 48 54 60 66

Overall Survival on FirstOverall Survival on First--line Imatinib (ITT line Imatinib (ITT principle) principle)

10.6%4.6% (2-7)

(8-14)

Estimated rate at 60 months (with 95%CI)CMLCML--related deaths related deaths All deathsAll deaths

95.4%89.4%

Survival without CMLSurvival without CML--related deaths related deaths


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


Lung cancer


Colo Rectal Cancer (CRC)


GIST. Clinical presentationGIST. Clinical presentation


Shc

Ras

Raf

MEK

ERK

Jak

Stat

PI3K

Akt

SCF SCF

Cell membraneKIT KIT

Apoptosis inhibition Proliferation

SHP2Grb2 SOS

NF1

pp90 rsk

Src

Mast Cell Neoplasms

GISTs

816

502-503 550-586 642 822

NH2 COOH

TM JM TK-I KI TK-IIEC

Human Kit

820

Germ cell tumors

820

816557 820 822


EXPRESSION

EXPRESSION

CAUSAL RELATIONSHIP TO TRANSFORMATION

RELEVANT TARGET FOR THERAPY

HIGHER INTEGRATION BETWEEN LABORATORY AND CLINICAL ACTIVITY NEEDED


TYPE MOLECULAR PATHOGENESIS KNOWN

TARGETABLE ABNORMALITIES

AVAILABILITY OF SPECIFIC DRUGS

EXAMPLES

I

II

III

IV

YES

YES

YES

NO

YES

YES

NO

?

YES

NO

NO

NO

CML, GIST

Medullary Thyroid Carcinoma

Ewing’s Sarcoma

Melanoma, many Epithelial Cancers

Basic Research

Translational Research


Indica la definizione NON corretta:a. IPERGLICEMIA: aumento del glucosio nel sangue oltre i valori normali

b. POLIDIPSIA: aumento della sete c. POLIFAGIA: aumento della fame d. GLICOSURIA: presenza di glucosio nel sangue e. POLIURIA: aumento del volume delle urine

Indica la definizione corretta:a. Somatostatina: ormone che stimola la produzione di insulina e glucagone

b. Glucagone: ormone prodotto dalle cellule Delta c. Insulina: ormone prodotto dalle cellule Beta d. Pancreas: ghiandola esocrina e. Glicemia: quantità di glucosio presente nelle urine

La maturazione dell’insulina avviene in diversi compartimenti cellulari e secondo un dato ordine. Indica la sequenza corretta:

a. Pre-proinsulina nel Golgi, Proinsulina nel RER, insulina nel citosol;b. proinsulina nel RER, Pre-Proinsulina nel RER, insulina nel citosol;c. X Pre-proinsulina nel RER, Proinsulina nel Golgi, insulina nelle vescicole di

secrezione;d. Pre-proinsulina nel RER, Proinsulina nel citosol, insulina nelle vescicole di

secrezione;

University of Milano Bicocca, Monza, Italy - ilte-cml.org · University of Milano Bicocca, Monza,...

Documents

Transcript of University of Milano Bicocca, Monza, Italy - ilte-cml.org · University of Milano Bicocca, Monza,...