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Die Prognose der akuten lymphatischen Leukämie
Eine Analyse nach drei Jahrzehnten
Günter Henze
Otto-Heubner-Centrum für Kinder- und Jugendmedizin
Klinik für Pädiatrie m. S. Onkologie/Hämatologie
Charité, Universitätsmedizin Berlin, CVK
guenter.henze@charite.de
ALL-BFM (70)
Uniform Treatment
Maintenance
I
Weeks 0 8 12 18 22 30
Comparison of the Probability of CCR in 2 German ALL Trials
DAL 71/74 and BFM 70
Total Group
Cumulative Proportion in CCR
BFM 76/79 (N = 158; 0.72 ± 0.05)
BFM 70/76 (N = 119; 0.55 ± 0.05)
DAL 71/74 (N = 495; 0.33 ± 0.02)
Years
ALL-BFM (76)
Risk Adapted Treatment
Arm
Maintenance
A I
Standard
B1 I II
High
B2 I II
High
Weeks 0 8 12 18 22 30
Comparison of the Probability of CCR in 3 German ALL Trials
DAL 71/74, BFM 70 and 76
Cumulative Proportion in CCR
Total Groups
BFM 76/79 (N = 158; 0.72 ± 0.05)
BFM 70/76 (N = 119; 0.55 ± 0.05)
DAL 71/74 (N = 495; 0.33 ± 0.02)
Years
ALL-BFM
Front-Line
ALL-BFM 70/76 Einheitliche Therapie
ALL-BFM 70/76 Risiko-adaptierte Therapie (Prot. II)
ALL-BFM 79/81 Reinduktion Standard Risiko (Prot. III)
ALL-BFM 81/83 MHD-MTX (500mg/m²), B-NHL/ALL
ALL-REZ BFM 1983-2008
Ausgangslage
20-25% der Kinder mit ALL erleiden ein Rezidiv
ALL-Rezidiv ist eine häufige Diagnose
ALL immer noch Todesursache für 15% der Kinder
Multizentrische Therapieoptimierungsstudien
Etwa 100 Behandlungseinrichtungen in Deutschland,
Österreich, (Schweiz, Tschechien und Kanada)
Studien ALL-REZ BFM 83-90
Übersicht
ALL-REZ Gruppe Woche 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
BFM M24
A CV E R1 R2 R1 R2
R2 R1 R2 R1
R1 R2
M24
83 B CV R1 R2 R1 R2 R1 R2 R1
R1 R2
M12
C CV R1 R2 R1 R2
Gruppe Woche 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
R2 R1 R2 R1 R2 M24
A R CV F R1 R2 R1
85/87 B (R) CV R1 R2 R1 R2 R1 R2 R1 R2 M24
C (R) CV R1 R2 R1 R2 R1 R2 M12
Gruppe Woche 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
M24
A/B R CV R1 R2 R3 R1 R2 R3 R1 R2 R3
90
C R CV R1 R2 R3 R1 R2 R3 M24
R: Randomisierung MTX (12) vs 5 vs 1 g/m²
ALL-REZ BFM 83 - 96
Ereignisfreies Überleben (EFS) und Überleben (SRV)
1.0 1.0
.8 .8
.6 .6
pSRV
pEFS
.4 .4
.2 .2
0.0 0.0
0 5 10 15 20 Years 0 5 10 15 20
N = 1615; cens. = 568; pEFS = 0.32 ± 0.01 N = 1615; cens. = 680; pSRV = 0.39 ± 0.01
Spätestes Folgerezidiv nach 12.3 Jahren
Wahrscheinlichkeit für Ereignisfreies Überleben
Multivariate Cox-Regression
Parameter Risk ratio p
Zeitpunkt < 0.0001
Spät 1
Früh 3.74
Sehr früh 6.27
Immunphänotyp < 0.0001
non-T 1
T / prä-T 2.24
Lokalisation < 0.0001
Isoliert EM 1
Kombiniert KM 2.06
Isoliert KM 3.51
Neue Risiko-Stratifizierung seit Studie 95/96
EFS (ALL-REZ BFM 83-96) SZT zensiert
1,0
,8 S1: n = 51; pEFS = .75 ± .06
,6
pEFS
S2: n = 577; pEFS = .38 ± .02
,4
,2 S3: n = 153; pEFS = .02 ± .02
S4: n = 252; pEFS = .04 ± .02
0,0
0 2 4 6 8 10 years
p < 0.001
Design of Trial ALL-REZ BFM 95/96
week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
group
S1 C F1 F2 R1 R2 R1 R2 R1 R2 M12
d 36
S2 R C F1 G? F2 G? R1 G? R2 R1 R2 R1 R2 R1 R2 M24
S3 R C F1 G? F2 G? R1 G? R2 Stem cell transplantation
S4 I G S G S G S G Stem cell transplantation
R: G-CSF randomization in groups S2/S3
ALL-REZ BFM 95/96
Group S2: MRD after F2 (d 36)
Event-free survival Overall survival
1,0 1,0
,8 ,8
,6 ,6
pEFS
pOS
,4 ,4
,2 ,2
0,0 0,0
0 2 4 6 8 10 0 2 4 6 8 10
Years Years
_____ MRD <10-3 n= 46; cens.= 36; pEFS(6y)= .78 .06 cens.= 42; pOS(6y) = .91 .04
____ MRD =>10-3 n= 34; cens.= 7; pEFS(6y)= .21 .07 cens.= 12; pOS(6y) = .35 .08
p<0.001 p<0.001
Update 03 2007
Eckert C, et al. Lancet 2001
Protocol ALL-REZ BFM 95/96 vs P02/2002
EFS by MRD post Induction
1,0 95/96 1,0 P02/2002
,8 ,8
,6 ,6
pEFS
pEFS
P < .001
,4 ,4
,2 ,2 P = . 719
years
0,0 0,0
0 2 4 6 8 10 0 2 4 6 8 10
MRD
<10-3: n = 46; cens. = 35; pEFS = .76 ± .06 N = 92;cens. = 70; pEFS = .67 ± .06
≥10-3: n = 34; cens. = 6; pEFS = .18 ± .07 N = 92;cens. = 67; pEFS = .63 ± .05
ALL-REZ BFM 01/09
MRD in Stem Cell
Transplantation
MRD prior to SCT in relapsed ALL
MRD groups prior to allogeneic SCT in ALL CR2 and 3:
EFS / CI relapse; Cut-off 10-4
1.0
1.0
EFS CI
Event-free Survival Probability
0.8 0.8
Cumulative Incidence
MRD < 10-4
0.6 0.6 MRD ≥ 10-4
0.4 0.4
MRD ≥ 10-4
0.2 0.2
MRD < 10-4
0.0 0.0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Years after SCT Years after SCT
MRD
< 10-4: n = 46; cens.= 29; pEFS = .60 .08 CI (relapse) = .13 .06
≥ 10-4: n = 45; cens.= 14; pEFS = .27 .07 CI (relapse) = .57 .08
p = .036 p < .001
ALL-REZ BFM Bader et al., JCO 2009
“Isolated” Extramedullary Relapse
(In the Era of MRD)
Childhood relapsed ALL – isolated extramedullary relapse
Event-free Survival of Children With Extramedullary Relapse
by the extent of leukemic BM metaplasia (SCT censored): ALL-REZ BFM 83 - 95
1.0
.8
.6
pEFS
.4
.2
0.0
0 2 4 6 8 10
years
_____ M1 (< 5%): n = 162; cens. = 86; pEFS = 0.48 0.04
_ _ _ M2 ( 5 and <25 %): n = 44; cens. = 21; pEFS = 0.45 0.08
--------- M3 ( 25%): n = 166; cens. = 84; pEFS = 0.37 0.06
11./13.10.2007
Childhood relapsed ALL – Sub-microscopic BM involvement at relapse diagnosis
Results
Frequency of sub-microscopic bone marrow involvement at relapse diagnosis
patients
28%
n=18 (28%) 22%
n=14 (22%) 34%
n=22 (34%) 16%
n=10 (16%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64
1.00E+00
sub-microscopic BM involvement
1.00E-01
1.00E-02
1.00E-03
1.00E-04
1.00E-05 10-2
10-4 -- <10 -3
10
10-3 - <10 -2
10 -
10-2
<10 -4 -4 -3 -3 -2
<10-4 <10 <10
- CNS relapses have higher involvement than testicular relapses
cut-off: 10-3 () 62% vs 29% p=0.029
cut-off: 10-4 () 80% vs 57% p=0.08
Hagedorn et al., Blood 2007
Childhood relapsed ALL – Sub-microscopic BM involvement at relapse diagnosis
SITE OF RELAPSE
Cumulative incidence of subsequent relapse
CNS relapses (n=39) testicular relapses (n=21)
1.0 1.0
cumulative incidence of subs. rel.
cumulative incidence of subs. rel.
10-4
0.8 0.8
0.6 0.6
0.4 0.4
10-4
0.2 <10-4 0.2 <10-4
0.0 0.0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
years years
____sub-micros.BMinv. <10-4 n= 8; cum.inc.(6y) = 0.13 0.00 n= 9; cum.inc.(6y) = 0.24 0.03
_ _ _sub-micros.BMinv. 10-4 n= 31; cum.inc.(6y) = 0.82 0.02 n= 13; cum.inc.(6y) = 0.31 0.02
p=0.0059 p=0.059
Hagedorn et al., Blood 2007
Childhood relapsed ALL – Sub-microscopic BM involvement at relapse diagnosis
TIME POINT OF RELAPSE
Probability of event-free survival
Very early / early (n=44) Late (n=20)
____sub-micros.BMinv. <10-4 n=12; cens.=8; pEFS(5y) = 0.67 0.14 n= 6; cens.= 3; pEFS(5y) = 0.42 0.22
_ _ _sub-micros.BMinv. 10-4 n=32; cens.=8; pEFS(5y) = 0.11 0.89 n=14; cens.=10; pEFS(5y) = 0.70 0.13
p=0.016 p=0.21
Hagedorn et al., Blood 2007
Protocol ALL-REZ BFM Pilot 02/2002 vs 95/96 and 83-90
N = 2085
1,0 Event-free Survival 1,0 Overall Survival
,8 ,8
,6 ,6
pOS
pEFS
,4 ,4
,2 ,2
p < 0.001 p < 0.001
years
0,0 0,0
0 2 4 6 8 10 0 2 4 6 8 10
P02/2002: n = 471; cens. = 265; pEFS(6y) = .47 ± .03 cens. = 311; pOS(6y) = .55 ± .03
95 / 96: n = 581; cens. = 220; pEFS(6y) = .39 ± .02 cens. = 266; pOS(6y) = .48 ± .02
83 - 90: n = 1033; cens. = 299; pEFS(6y) = .29 ± .01 cens. = 356; pOS(6y) = .36 ± .02
ALL-REZ BFM 01/2009
ALL – Studien in Deutschland 1970-95
Überleben
1.0
ALL-BFM 90 (N=2178): .82 ± .01
0.8
ALL-BFM 86 (N= 998): .78 ± .01
ALL-BFM 83 (N= 653): .71 ± .02
0.6
P ALL-BFM 70 (N= 119): .62 ± .04
0.4
DAL 70-74 (N= 495): .33 .02
0.2
0.0
0 1 2 3 4 5 6 7 8 9 10 Jahre
ALL- Therapie in Russland
Ergebnisse der MB-Gruppe seit 1991
Wahrscheinlichkeit
Überleben: N = 3192; 0.73 0.01
Ereignisfreies Überleben: N = 3192; 0.67 0.01
Jahre
ALL-MB 2000 – Ongoing Study
Participating Centres
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