lezioni: · 2018. 4. 5. · pancreas 5% leukemia 4% non-hodgkin’s lymphoma 4% esophagus 4%...

University of Milano Bicocca, Monza, Italy

LEZIONI: http://www.ilte-cml.org/listing/Medicina/


Esercitazioni

http://services.ilte-cml.org/esercizi/


LEUCEMIE


Incidence of Hematologic Malignancies

Type of Leukemia Incidence per 100,000*

Overall 8–13 CML 1–2 CLL 2–3 AML 4–6 ALL 1–2


Men

290,890

Women

272,810

26% Lung and bronchus

15% Breast

10% Colon and rectum

6% Pancreas

6% Ovary

4% Leukemia

3% Non-Hodgkin’s lymphoma

3% Uterine corpus

2% Brain/nervous system

2% Multiple myeloma

22% All 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 Proportion of Cancer Deaths in the

United States


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

Incidence Mortality

Overall AML CLL CML ALL

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


LEUCEMIA MIELOIDE CRONICA


Sawyers. N Engl J Med. 1999;340:1330. Faderl et al. Ann Intern Med. 1999;131:207.

Epidemiology of CML

Median age range at presentation is 45-55 years

Incidence increases with age - Up to 30% of patients are aged >60 years

Slightly higher incidence in males - Male-to-female ratio—1.3:1

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


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

Normal Chronic Phase CML

Comparative Peripheral Blood Smear Acute Leukemia


PATOGENESI


Cytogenetic Abnormality of CML: The Philadelphia Chromosome


The Philadelphia Chromosome: t(9;22) Translocation

22

bcr

abl

Ph

bcr-abl

FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY

9 9+


Chromosome

in Hematologic Malignancies

Leukemia % of Ph+ Patients

CML 95

ALL (Adult) 15–30

ALL (Pediatric) 5

AML 2

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


bcr-abl Gene and Fusion Protein Tyrosine Kinases

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

p210 Bcr-Abl

p185 Bcr-Abl 2-11

2-11

Chromosome 9

c-bcr

Chromosome 22

c-abl

Exons

Introns

CML Breakpoints

ALL Breakpoints

1

2-11


p210Bcr-Abl Fusion Protein Tyrosine Kinase

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

Extracellular space

Y177

BAP-1 GRB2

Cytoplasm

SH3 SH2 SH1

CBL SHC CRKL


Bcr-Abl Signal Transduction Pathways

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

Bcr-Abl

BCL 2 inhibition of apoptosis

MYC GRB2 CRKL CBL (p120CBL)

RAS

RAF-MEK-MAPK cascade regulates cell cycle progression and differentiation

activates

JAK/STATs

upregulation of

Paxillin (Adhesion) PI-3 kinase

Actin (Adhesion)


DIAGNOSI


Clinical Presentation of CML

At presentation:

50% diagnosed by routine laboratory tests 85% diagnosed during chronic phase


Clinical Presentation of CML

Common Symptoms Common Signs Fatigue Palpable splenomegaly Weight loss/anorexia Abdominal fullness Common Laboratory Findings Abnormal differential Anemia Leukocytosis Basophilia Thrombocytosis


Typical Laboratory Parameters by Phase of CML

Parameter Chronic Accelerated Blastic WBC count >20 x 109/L — — Blasts 3%–10% >15% >30% Basophils >20% — Platelets or normal ↓ or ↓ Bone marrow Myeloid hyperplasia Cytogenetics Ph+ Bcr-Abl + + +


Nucleo Ph+

Nucleo normale

Metafase Ph+


M

692 bp 501 bp

Patie

nt E

.L.

BaF

3-T/

P

C Neg

ativ

e Pa

tient

TM HLH TKD

308 bp

533 bp

B.

C.

501 bp 692 bp

M 10-1 10-2 10-3 10-4 10-5 10-6 C U


Clinical 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


TERAPIA


Bcr-Abl as a Therapeutic Target for CML

Bcr-Abl is detected in 95% of patients with CML

Bcr-Abl is the causative abnormality of CML

Bcr-Abl tyrosine kinase is constitutively activated intracellularly - Tyrosine kinase activity is required for CML

cell function

Therapy of CML: Response Criteria

Disappearance of splenomegaly Normal 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+ cells Platelets <450 x 109/L Minor: 35%–

95% Ph+ cells No immature cells Molecular Response: log reduction by Q-PCR (-3 = MMR)

Ph+=Philadelphia chromosome-positive.


IMATINIB

Tyrosine Kinase Inhibitor

for CML


Structure of imatinib

Class: Phenylaminopyrimidines, 589.7 mw

CH3SO3H

O


Bcr-Abl–Positive and –Negative 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


LAMA84 Control

LAMA84 24h 1uM

LAMA84 44h 1 uM


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.


0

20

40

60

80

100

120

140

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

% c

pm


bcr/abl

bcr/abl

anti-phosphotyrosine

anti-abl

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


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.


0102030405060708090

100

0 10 20 30 40 50days

tumor free survival

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


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

= Censored observations

% w

ithou

t los

s of

MCy

R

0102030405060708090

100

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


Annual Event Rates in Patients on First-line Imatinib Year after achieving CCyR All events* AP/BC 1st 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 including progression to AP/BC

Carlo Gambacorti-Passerini Lo studio ILTE (Imatinib Long Term Effects)

PATIENTS ENROLLED

3-10

28-46

128-151

384

REL - CML, 15/04/2010, MILANO

z

Numbers of deaths compared to available rates in the italian population

MORTALITY

gender eligible O=Observed E=Expected SIR 95% CI - inf

95% CI - sup p-value

M 487 24.0 33.7 0.71 0.46 1.06 0.14

F 345 17.0 14.3 1.19 0.69 1.90 0.54

TOTAL 832 41.0 48.0 0.85 0.61 1.16 0.42

Only 10 out of 41 observed death (24.4 %) were caused by progression of CML

Survival at 8 years was 95.2% (95%CI=92.5% to 98.1%)

Survival is not statistically different from that of the general population

Rates in the Italian population are referred to ISAT 2004


Clinical 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


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.

Ambulatorio dedicato per pazienti con LMC


0

50000

100000

150000

200000

250000

300000

350000

400000

2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

Prev

alen

ce

Year

Incidence 2000: 1/100.000

Incidence 2000: 1,5/100.000

Incidence 2000: 2/100.000

Projection of CML Prevalence Up to 2050 Assumptions: Population: 500 Mill., mortality: 2% per year, Incidence increasing by about 0.01/100.000 per year

20%-25% increase per year in projected prevalence


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 ?

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

2.0

ISAV study

ISAV STUDY

DAY 1 M12 M24 M36 M48 M60

STOP IMATINIB

>18 months

dPCR

FOLLOW-UP

ISAV study

dPCR

QRTPCR 1/MONTH QRTPCR EVERY 2 MONTH QRTPCR EVERY 6 MONTH

STUDY DESIGN

ISAV study

PATIENTS DISPOSITION

All enrolled patients (N=112)

N % Total enrolled 112 100.00 Eligible 111 99.1 Evaluable 108 96.4 Drop-out: - Screen failure - Death - Consent withdrawn - Investigator’s decision

10 1

1 4 4

9.0 0.9

0.9 3.6 3.6

Remain on study as of Nov. 3 2014

102 91.1

ISAV study

52% 40%

16%

Time to relapse

Time from first PCR + to relapse

3 GROUPS OF PATIENTS

ISAV study

Age Total Patients

(N=108) Not Relapsed

(N=56) Relapsed

(N=52) p-value

n n % n %

Age (years) < 45 20 1 5 19 95

<0.0001 45 -< 65 48 28 58.0 20 42.0 >= 65 40 27 68.0 13 32.0

95% 42% 32%

ISAV study

Age and dPCR correlation


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


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)


Tas(22q11)

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

0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Months

n No. progressed Median

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

lezioni: · 2018. 4. 5. · pancreas 5% leukemia 4% non-hodgkin’s lymphoma 4% esophagus 4%...

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