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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:
University of Milano Bicocca, Monza, Italy
ONCOLOGIA MEDICA - COSA E’ - COME SI POSIZIONA TRA LE PROFESSIONI MEDICHE - RAPPORTI CON L’EMATOLOGIA
University of Milano Bicocca, Monza, Italy
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)
University of Milano Bicocca, Monza, Italy
Leucemie acute. Induzione (3+7), consolidamento, BMT Tasso guarigione: 30-40% Estremi: APL - MDS
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
University of Milano Bicocca, Monza, Italy
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
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
University of Milano Bicocca, Monza, Italy
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
University of Milano Bicocca, Monza, Italy
Prognosi e decisione terapeutica Sopravvivenza QoL Effetti a lungo termine Costo
University of Milano Bicocca, Monza, Italy
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.
University of Milano Bicocca, Monza, Italy
Linfomi ad alto grado di malignita’ CHOP, 6 cicli Rituximab: anti-CD20 Estremi: Burkitt – linfomi cerebrali
University of Milano Bicocca, Monza, Italy
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
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+
University of Milano Bicocca, Monza, Italy
Linfomi a basso grado Mieloma multiplo Sindromi mieloproliferative croniche LLC Sopravvivenza 4-8 anni
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.