Ematologia 2018: Leucemie/Linfomi Anemie Disordini della ... · University of Milano Bicocca,...

University of Milano Bicocca, Monza, Italy

Ematologia 2018:

Leucemie/Linfomi Anemie

Disordini della coagulazione e delle piastrine

ESAME: 23 Aprile 2018


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


INSUFFICIENZA FUNZIONALE


LEUCEMIE


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 of Hematologic Malignancies

Type of Leukemia Incidence per 100,000*

Overall 10–14 CML 2–3 CLL 4–5 AML 3–4 ALL 1–2


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


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+


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)


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.


DIAGNOSI


CML: Peripheral Blood Smear

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


Epidemiology of CML

Median age range at presentation: 45 to 55 years

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

Male-to-female ratio—1.3:1


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


Clinical Course


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


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


TERAPIA

Therapy of CML: Response Criteria

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

Ph+=Philadelphia chromosome-positive.


IMATINIB

Tyrosine Kinase Inhibitor

for CML


Structure of imatinib

Class: Phenylaminopyrimidines, 589.7 mw

CH3SO3H

O

PATIENTS ENROLLED

3-10

28-46

128-151

384

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


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.

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: 1/100.000Incidence 2000: 1,5/100.000Incidence 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


ACUTE LEUKEMIAS


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

Symptoms

Fatigue, malaise, dyspnea Easy bruisability, weight loss

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

Signs Anemia 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)


AML


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