lezioni: · -linfoma di hodgkin -linfomi non hodgkin ad alto grado -leucemie acute -microcitoma...

University of Milano Bicocca, Monza, Italy

Lezioni : 7/3: Introduzione all’Oncologia Medica, neoplasie ematologiche (Carlo Gambacorti) 8/3: inquadramento diagnostico--terapeutico dei tumori polmonari (Paolo Bidoli) 14/3: Emergenze ematologiche (Matteo Parma)GIST, Ca. prostata (Carlo Gambacorti)/ 15/3: Inquadramento diagnostico--terapeutico del ca della mammella e del tratto gastroenterico (Paolo Bidoli)

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


ONCOLOGIA MEDICA - COSA E’ - COME SI POSIZIONA TRA LE PROFESSIONI MEDICHE - RAPPORTI CON L’EMATOLOGIA


Curare e guarire (to care and to cure)


Terapia (neo)adiuvante Terapia malattia avanzata


Tumori guaribili con terapia medica -Testicolo -Coriocarcinoma -Linfoma di Hodgkin -Linfomi non hodgkin ad alto grado -Leucemie acute -Microcitoma polmonare -Ca. tiroide -(Leucemia Mieloide Cronica)


NEOPLASIE EMATOLOGICHE


Leucemie acute. Induzione (3+7), consolidamento, BMT Tasso guarigione: 30-40% Estremi: APL - MDS


LEUCEMIA MIELOIDE CRONICA

Numbers of deaths compared to available rates in the italian population

MORTALITY

gender eligible OObserved 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 is not statistically different from that of the general population

Rates in the Italian population are referred to ISAT 2004


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

Sensitivity of dPCR

10-5

10-6

10-7

10-8

KG-1

Water (No template)

Procedure of dPCR

Cell to cell serial dilution (total 5 x 106 cells) BCR-ABL positive cell line: K562 BCR-ABL negative cell line: KG-1

RNA extraction

cDNA synthesis

Pre amplification (14cycles)

dPCR (40cycles)

0.00072%IS*

0.00010%IS*

*Conventional RQ-PCR (%IS) : CF=0.23

0%IS*

0%IS*

0%IS*

0%IS*

Amplification curves(left) and heat maps(right) generated from dPCR

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

48% 37%

15%

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%

Negative Predictive Value (NPV) is the probability that a subject negative with the test do not relapse

NPV(dPCR) = 47/82 = 64.6% NPV (Q-RT-PCR) = 55/107 = 51,4%

NPV(dPCR)/NPV(Q-RT-PCR) = 1.115 [95% CI: 1.013-1.227]

ISAV study

dPCR

dPCR RELAPSED NOT RELAPSED TOTAL

+ 17

(68%) 8

(32%)

25

- 35

(42.7%) 47

(57.3%) 82

TOTAL 52

55

107

ISAV study

Age and dPCR correlation


Maschio, 28 anni, figlio unico. In pieno benessere esegue emocromo per visita

di idoneita’ agonistica (scherma). WBC: 66.000/mmc, 4% blasti; PLT 540.000; Hb

12.1 g/dl. EO: splenomegalia, margine inf a 3 cm

dall’arcata costale. BMA: M/E 10/1; blasti 4%; 20/20 Ph+; PCR: 65% Sokal score 0.60


Prognosi e decisione terapeutica Sopravvivenza QoL Effetti a lungo termine Costo


HU: sopravvivenza 4-5 anni; costo basso; qualita’ di vita buona fino aprogressione.

AlloBMT: guarigione molecolare al 60%, aspettativa di vita -8/-15 anni; costo 50-150.000 E

Imatinib: guarigione molecolare al 10%, 80% CCyR a due anni con aspettativa di vita normale; costo 1.000.000 E.

Logistics of CML care

Dedicated CML Clinic


Linfomi ad alto grado di malignita’ CHOP, 6 cicli Rituximab: anti-CD20 Estremi: Burkitt – linfomi cerebrali


Anaplastic Large Cell Lymphoma


ALK: Anaplastic Lymphoma Kinase


Day 0 Day 28

Day 0

Pz di 26 anni, femmina; Comparsa in pieno benessere di febbre, sudorazioni notturne. EO: adenopatia inguinale sin di circa 4 cm. Esegue asporatazione linfonodo inguinale con EI: ALCL, ALK+ 6 cicli CHOP DHAP HD-VP16 1 fratello HLA identico


Day 0 Day 28

Patient

# Age

diagnosi

s

Stage

(Ann

Arbor)

ECO

G

BM

involveme

nt (%)&

Previous therapy

lines (n)

TTN

LDH

days

TTN

Fever

days

Previous

BMT

Response,

duration

(months)

1 26 ALCL IIIB 2 3-->0 3: CHOP, DHAP,

HD-VP16 29 2 no CR, 40+

2 19 ALCL IVB 3 8-->0 3: CHOP, DHAP,

BEAM 22 10 ABMT CR,2 †

3 22 DLBCL IVB 3 65-->0

4: BFM, HD-CTX,

HD-AraC,

Bortezomib

21 Na ABMT PR,2 †

4 22 ALCL IIB 1 0 3: CHOP, VAD,

H-CyVAD 30 30 no CR, 35+

5 39 DLBCL IVB 3 n.a. 4: BEP, CHOP, ICE,

H-CyVAD 19 Na no SD †

6 20 ALCL IIB 2 15-->0 3: CHOP, DHAP,

BEAM 30 10 ABMT CR,2

7 47 ALCL IIIBe 2 0 3: IEV, DHAP,

CHOP 30 14 no CR, 30+

8 28 ALCL IIIB 2 0 3: CHOP, DHAP,

mini-BEAM Na Na no CR 2

9 34 ALCL IVBe 2 0 2: CHOP, ESHAP Na 30 no * CR,10

10 38 ALCL IVB 4 0

3: CHOP,

DHAP,

VIM

28 15 allogeneic CR,8

11 55 ALCL IIIB 1 0 1: CHOP 30 30 no CR, 21+


Linfomi a basso grado Mieloma multiplo Sindromi mieloproliferative croniche LLC Sopravvivenza 4-8 anni


X


TUMOR HETEROGENEITY

SUBCLONAL EVOLUTION - METHYLCELLULOSE ASSAY

Methylcellulose Medium

TARGETED AMPLIFICATION MATCHED EXOME SEQUENCING

TARGETED RESEQUENCING

60-100 CLONES/PATIENT

Piazza R. et al., PLoS One. 2013 Oct 4;8(10):e74825 Itzykson R. et al., Blood. 2013 Mar 21;121(12):2186-98.

lezioni: · -linfoma di hodgkin -linfomi non hodgkin ad alto grado -leucemie acute -microcitoma...

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