can be optimized - siematologia · hds 2/1 d1 d4 d1 d4 bm dg bm d28 northern italy leukemia group...
TRANSCRIPT
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R Bassan
UOC Ematologia, Ospedaledell’Angelo eOspedale SS. Giovanni e Paolo,Mestre‐Venezia
SIE Regionale Triveneta, Udine 18 maggio 2012
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CAN BE OPTIMIZEDCAN BE OPTIMIZED
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StudyStudy typetype AgeAgegroupsgroups
StudyStudy parametersparameters
ageage cytogencytogen geneticsgenetics otherother
MRC (1999) Re/val C, A, E ‐ + ‐ CR cycle 1
NILG (2000) Pro A ‐ + FLT3 CR cycle 1 WBC,MDS/sec
AMLSG(2008)
Re A ‐ + (NK) FLT3, NPM1,CEBPA
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AMLCG(2010)
Re/val(CR)
E + + ‐ FLT3, NPM1 Temperature, sec, Hb, PLT,LDH, fibrinogen‐
ELN (2010) Cons ‐ ‐ + FLT3, NPM1,CEBPA
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AMLSG‐ELN(2011)
Re A, E ‐ + FLT3, NPM1,CEBPA
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SAL (2012) Re/val A + + FLT3 MDS/sec, CD34
ECOG (2012) Re/val A ‐ + FLT3, NPM1,CEBPA, IDH,MLL, ASXL1,PHF6, TET2,DNMT3A
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Re =retrospecticeRe/val = retrospective with validation cohortPro = prospectiveCons = consensusC, A, E = children, adult, elderly AML
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incidence
survival
Age
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NorthernNorthern ItalyItaly LeukemiaLeukemia GroupGroup
ClinicalTrials.gov Identifier: NCT00495287
Days from diagnosis
N 1235 (1351 – 116 APL)Median age (range): 62 (17‐90)N 573 to Random 1 (46.4%)
N 792 >55 yy (64.1%)
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Score 1With cytogenetics/geneticsNPM1/FLT3
Probability of CR: from 12 to 91%Risk of ED : from 6 to 69%
Score 2Without cytogenetics/genetics
(only clinical data: temperature, age, sec. AML, Hb, PLT, fibrinogen, LDH)
Probability of CR : from 21 to 80%Risk of ED: from 7 to 63%
In HR cytogenetic/genetic group, 25% of patients still have
>40% CR probability
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0.00
0.25
0.50
0.75
1.00
0 2 4 6 8 10 12years
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(n=401) 0.43
NILG AML 01/00
HOVON JPN
MRC 15Australia
EORTC/GIMEMA
Italy
Res
t of th
e world
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5‐year survivalRisk category Definition* age 15‐34 age 35+
GOOD APL , CBF 70% 64%STANDARD intermediate, normal 52% 39%
CR c1POOR adverse cytogenetics, 19% 8%
no CR c1
*two parameters:‐cytogenetics‐CR after course 1 (c1)
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Study cohort
Validation cohort
TherapyTherapy
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Schlenk et al, NEJM 2008
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Rollig et al, JCO 2011
Dohner et al, Blood 2010
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Allo‐SCT
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favourablefavourable1)1)t(8;21t(8;21))2)2)invinv(16(16), t(16;16), del(16q)), t(16;16), del(16q)
intermediateintermediate1)1)NORMALNORMAL2)2)OTHER OTHER non‐HIGHnon‐HIGH33) ) UnknownUnknown
unfavourableunfavourable‐‐5/del(5q), ‐7, t(11q23), t(9;22),5/del(5q), ‐7, t(11q23), t(9;22),abnabn 3q, 9q, 11q, 20q, 21q,3q, 9q, 11q, 20q, 21q,17p17p, , isoiso(17q), t(3;5), t(6;9), (17q), t(3;5), t(6;9), t(9;22t(9;22), complex (), complex (>>3)3)
CYTOGENETICSCYTOGENETICS
WBC >50x109/l sec/MDS CR cycle 2 FLT‐3, MLL FAB M0,6,7
none
any
HHRR
SRSR
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HHRR
SSRR
ClinicalTrials.gov Identifier: NCT00400673
ICE (c1)IC (c2)
A8HD (c2)
CR
res
A20
alloSCT
x3 (monthly)
CD34+ harvest/reinfusion (1‐2 x106/kg)
A8/20 with total Ara‐C 8/20 g/m2
Risk definition risk‐oriented therapy
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0.00
0.25
0.50
0.75
1.00
Cum
ulat
ive s
urviv
al
0 2 4 6 8 10 12years
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5-year probability
SR c1 (n 136) 0.65
SRHR c2 (n 12) 0.49
HR c1 (n 164) 0.43HR c2 (n 24) 0.21
ED/NR
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Reference data («3+7») CR after cycle 1ECOG (NEJM 2009)
DNR 45 mg/m2 x3135 121/293 (41.3%) standard arm ↓ DNR 90 mg/m2 x3270 170/289 (58.8%)
JALSG (Blood 2011) DNR 50 mg/m2 x5250 321/525 (61.1%) IDR 12 mg/m2 x336 341/532 (64.1%) IDR = HD DNR
Personal data («ICE»)NILG 01 (unpublished)
IDR 12 mg/m2 x336 300/401 (74.8%)NILG 02 (unpublished)
IDR 12 mg/m2 x336 192/272 (70.5%) ext. age (>70) Exp. arm (HD) 220/269 (81.7)
RR
RR
RR
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CR timing No.of cycles▪ Anthracycline type/dose, HD Ara‐C
Remission and relapse kinetics Blast cell clearance▪ PB, BM▪ Timing
MRD▪ Remission▪ Relapse
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…….
Induction consolidation / SCT FUP
MRD threshold (
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Early prediction of response to standard induction in a“clinically relevant time”
NRNR
CRCR
1012
108
109
1010
1011
Neo
pla
stic
cell
s
Bone Marrowat diagnosis
Bone Marrowat recovery (Day 28)
Induction Aplasia
Peripheralblood
Bone Marrowat day 14
courtesy G Gianfaldoni, F Mannelli (FI)
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0 1 2 3 4 5 6 76
54
32
10
day
Log
Red
uctio
nNCRCR
Overall
0 1 2 3 4 5 6 7
65
43
21
0
day
Log
Red
uctio
n Low Risk
0 1 2 3 4 5 6 7
65
43
21
0
day
Log
Red
uctio
n Intermediate Risk
0 1 2 3 4 5 6 76
54
32
10
day
Log
Red
uctio
n High Risk
RESULTS: PILOT STUDY
In some pts (mainly CR), peripheral blasts not detectable at days 6-8Analysis restricted to days 1-5
BJH, 2006
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PBC: predictive value on CR
DAY 5: CUT-OFF = 2 LOG
< 2 LOG: CR 1/20 (5%)
> 2 LOG: CR 31/41 (76%)
NCR CR RankSumDay Median (95% CI) Median (95% CI) W P
2 0.18 (0.04, 0.17) 0.46 (0.46, 0.54) 149.5 .0123 0.58 (0.17, 0.58) 1.19 (0.95, 1.80) 132.5 .0044 1.19 (0.32, 1.26) 2.26 (1.90, 3.07) 93 .0005 1.70 (0.61, 1.86) 2.93 (2.79, 3.69) 75 .000
Specificity 67%
Sensibility 97%
Blood, 2008
Predictive value of PBC independent of baseline PB burden
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R1
ICE
HDS 2/1
D1 D4
D1 D4
BM DG
BM D28
Northern Italy Northern Italy LeukemiaLeukemia Group (NILG) Group (NILG)AML 02-06 protocolAML 02-06 protocol
Endpoints: To confirm results on a larger cohort adjusting cut-off
To verify the feasibility in a multicenter setting
To study PBC along with 2 induction regimens
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0.00
0.25
0.50
0.75
1.00
Cum
ulat
ive s
urviv
al
0 2 4 6 8 10 12years
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SR
ED/NR
for allo-SCTSR, late CRHR HR, late CR
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CR
Noconsolidation(early relapse/death,toxicity)
Allo‐SCT Chemotherapy
314 58 (18.4%) 112 (35.6%) 144 (46%)
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0.00
0.25
0.50
0.75
1.00
0 2 4 6 8 10 12analysis time
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CHT (n 144) 0.37
SCT (n 112) 0.55
P
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RD SCT (n 69) CR‐SCT interval (mos.) 3.5 (0.7‐10)
URD SCT (n 40) CR‐SCT interval (mos.) 5.9 (0.6‐13)
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0.00
0.25
0.50
0.75
1.00
0 5 10 15 20months
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Incidence of relapse in HR AML(n=202)25% at 5 mos.50% at 10 mos.
Incidence of SCT in HR AML(n=109)
0.00
0.25
0.50
0.75
1.00
0 5 10 15 20months
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Incidence of relapse(n=202)
Incidence ofRD SCT URD SC(n=69) (n=40)
25% after ~40 % relapse incidence50% after >25% relapse incidence
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CenterCenter No. No. PtsPts.. MedianMedian((mosmos.).)
Max. (Max. (mosmos.).)
11 99 3.73.7 5.95.9
22 99 8.28.2 1313
33 88 55 1313
44 44 44 9.29.2
55 33 6.56.5 6.76.7
66 33 1111 1111
77 22 6.96.9 77
88 22 7.97.9 8.78.7
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Many markers and models, few universalAGE, CYTOGENETICS, GENETICSflt3, npm1, cebpa
Therapy‐related issues CR time, frequency (drug/regimen) MRD how/when/why SCT actual v planned
Marker‐therapy relationship: of interest FLT3+ (midostaurin, lestaurtinib…) C‐kit (dasatinib) NPM1 (ATRA) NK/CBF (mylotarg, demethylating, hystone deacetylase inhib.)
«it is plausible that regulatory agencies will approve XXX or YYY foruse in AML.
While I would have no problem with such approval,I think it would be unfortunate if these drugs were regarded as the‘standard of care’ for such patients if this phrase meant nota standard of comparison for future trials, but a mandate to use thesedrugs as initial therapy, rather than placing a patienton a clinical trial, such as one using these drugs as ‘epigenetic priming’»
Estey, LEUKEMIA 2012