Jacek WachowiakJacek Wachowiak
HEMOTOPOIETIC STEM CELL HEMOTOPOIETIC STEM CELL TRANSPLANTAION IN CHILDRENTRANSPLANTAION IN CHILDREN
2006/20072006/2007
ANNUAL NUMBERS OF BLOOD AND MARROW TRANSPLANTS WORLDWIDE
1970-2000
MDM01_21.ppt
NU
MB
ER
OF
TR
AN
SP
LA
NT
S
YEAR
1970 1975 1980 1985 1990 19950
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
Autologous
Allogeneic
2000
ALLOGENEIC STEM CELL SOURCES BY AGE1995-2000
% O
F T
RA
NS
PL
AN
TS
SUM02_27.ppt
100
0
20
40
60
80
1995-1997 1998-2000 1995-1997 1998-2000
Bone MarrowPeripheral BloodCord Blood
Age 20 yrs Age 20 yrs
AUTOLOGOUS STEM CELL SOURCES BY AGE1995-2000
SUM02_28.ppt
% O
F T
RA
NS
PL
AN
TS
100
0
20
40
60
80
1995-1997 1998-2000 1995-1997 1998-2000
Bone Marrow (BM)Peripheral Blood (PB)BM + PB
Age 20 yrs Age 20 yrs
2500
2000
1000
1500
500
70-74 79-82 83-86 87-90 91-94 95-98 99-0275-78
Sibling donor
Partially matched family donor
VUD
CB
6654
5000
35000
25000
20000
15000
10000
31713
18803
12910
70-72 76-78 79-81 82-84 85-87 88-90 91-93 94-96 97-9973-75
TOT Allo BMT
Cum Allo
Cum Auto
Cum BMT
00-02
30000
TOT Allo BMT
INDICATIONS FOR BLOOD AND MARROW TRANSPLANTATION
(IBMTR / ABMTR, 2002)
SUM02_45.ppt
TR
AN
SP
LA
NT
S
4,500
0
500
1,000
1,500
2,000
Non-HodgkinLymphoma
AML CMLHodgkinDisease
OvarianCancer
Allogeneic (Total N = 6,700)Autologous (Total N = 11,000)
2,500
3,000
4,000
3,500
Multiple Myeloma
BreastCancer
ALL MDS/OtherLeukemia
OtherCancer
Non-Malignant Disease
CLL
INDICATIONS FOR 552 ALLOGENEIC HSINDICATIONS FOR 552 ALLOGENEIC HSct IN POLISH CHILDRENct IN POLISH CHILDREN1989-20051989-2005
0
50
100
150
200
80%
20%
Malignant Non-malignant
Diagnosis Disease phase HLA matched alternativesibling donors 1
ALL I CR ( VHR ) 2 +
II CR + +
> II CR + + AML I CR ( HR ) 3 + +
II CR + + MDS + + CML chronic phase + +
accel. /blastic crisis + + NHL I CR 4 +
II CR + + + Hodgkin’s disease I CR 5 +
II CR 6 + SAA + + 7
Fanconi anemia + + Blackfana-Diamonda anemia + 8 + 8
Congenital immunodeficiences + + Inborn errors of metabolism + +
Allogeneic HSCT Autologous HSCT
INDICATIONS FOR HSCT IN CHILDREN WITH INDICATIONS FOR HSCT IN CHILDREN WITH HAEMATOLOGICAL HAEMATOLOGICAL MALIGNANCIESMALIGNANCIES AND NON-MALIGNANT DISEASE AND NON-MALIGNANT DISEASE
McCann SR, Lawler MMcCann SR, Lawler MMonitoring outcome: MRD, chimaerism and relapseMonitoring outcome: MRD, chimaerism and relapse
In : The EBMT Handbook 2004, Eds. J Apperley, E Carreras, E Gluckman, In : The EBMT Handbook 2004, Eds. J Apperley, E Carreras, E Gluckman, A Gratwohl, T MassziA Gratwohl, T Masszi
HLA-ID SIBHLA-ID SIB
Infection(17%)
Other(12%)
Organ toxicity(14%)
Relapse (34%)
IPn (8%)
GVHD (15%)
CAUSES OF DEATH AFTER
TRANSPLANTS DONE IN 1996-2000(ABMTR / IBMTR)
AUTOAUTO
Infection (5%)
Other (7%)
Organ toxicity(7%)
Relapse (78%)
IPn (3%)
UNRELATEDUNRELATED
Infection (21%)
Other(17%)
Organ toxicity15%)
Relapse (23%)
IPn (9%)
GVHD(15%)
HR3’
0
6-MP / MTX
10 12
HR1’
HR2’
'
BM sampling
12 Gy*
* presymptomatic cranial irradiation# selected indications for allo-SCT in all strata of HR§ No randomization of AIEOP vs. BFM but choice by group according to previous
experience with one of the two high-risk strategies in trial 95
6-MP / MTXII
HR:PRED-PRIR,M3 d15
t(9;22)t(4;11)NR d33
6-MP / MTX
BFM
Allo-SCT#
III
12 Gy* only for T-ALL
III III 6-MP / MTXIII
III
II
MP/MTX4 wks
II 6-MP / MTXII
AIEOP
I/I‘ **
d15
104 W52
10 weeks interim maintenance with 6-MP / MTX
HR1'
HR2'
HR3'
MP/MTX4 wks
MP/MTX4 wks
d33
SR – R
IR – R
IT MTX (in maintenance)
** Protocol I‘ DNR 30mg/m2 x2 only for SR patients with BCP-ALL
dx
§
§
ALLIC BFM 2002 : TREATMENTVersion approved in Hannover on 23.02.2002
w12
6-MP / MTXII
$ for BCP-ALL: MTX 2g/m2/24h x4, for T-ALL: MTX 5g/m2/24h x4
12 Gy* only for T-ALL
mM/M$
12 Gy*
R 12 Gy*
TREATMENT OF ALL IN CHILDREN
INDICATIONS FORINDICATIONS FOR ALLO-HSCT IN CHILDREN ALLO-HSCT IN CHILDREN WITH HR-ALL W I CR WITH HR-ALL W I CR
((acc. toacc. to ALL SCT I-BMF 2006) ALL SCT I-BMF 2006)Criteria for allogeneic HSCT in CR1 Transplantation groups
MSD MD MMD
MRD (timepoint 2, day 77) >10-3 + + +
MRD (timepoint 2, day 77) =10-3 + + -
NRd33 + + +
PPR + t(9;22) + + +
PPR + t(4;11) # + + -
PPR + pro-B-ALL + (+)$ -
PPR + T-ALL (+)$ (+)$ -
PPR + M3-BM on day 15 * + (+)$ -
PPR + initial WBC 100.000/µL * + (+)$ -
PGR + t(9;22) + + -
PGR + t(4;11) # + - -
pEFS pEFS in children within children with VHR-ALL VHR-ALL treated according treated according to protocolto protocol BFM-95 BFM-95 MSD-BMT MSD-BMT
.41, SE=.05
Kein Spender (N=116, 65 Ereignisse)
.57, SE=.08
Spender (N= 40, 17 Ereignisse)Jahre
Log-Rank p = .20hrg
909
5.ta
b
18D
EC
02
P
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7
Kryteria kwalifikujące do allogenicznej HSCT Typ dawcy komórek krwiotwórczych
CR Grupa ryzyka
Lokalizacja wznowy i poziom MRD
(po bloku F2 lub przed Prot II-IDA lub R2)
Podgrupa MSD MD MMD
CR2 S2 BM MRD <10-3 A - - -
B/C + - -
Bez wyniku MRD A + - -
Bez wyniku MRD B/C + + -
MRD ≥10-3 A/B/C + + -
S2 IEM CNS, jedno jądro D - - -
Obustronne zajęcie jąder
D + + -
S3 + + +
S4 + + +
>CR2 + + +
S2 BMS2 BM S2 S2 z zajęciem szpiku kostnegoz zajęciem szpiku kostnegoS2 IEMS2 IEM S2 S2 z izolowaną wznową pozaszpikowąz izolowaną wznową pozaszpikową MRDMRD Minimal Residual DiseaseMinimal Residual Disease
INDICATIONS FOR ALLO-HSCT IN CHILDREN WITHINDICATIONS FOR ALLO-HSCT IN CHILDREN WITH ALL ALL CR2 CR2
((ACC.ACC. ALL SCT I-BMF 2006) ALL SCT I-BMF 2006)
pEFS in children with ALL in relapse type S3 or S4 pEFS in children with ALL in relapse type S3 or S4 according to according to treatment optiontreatment option (CHT vs CHT + HSCT) (BFM Study 95/96) (CHT vs CHT + HSCT) (BFM Study 95/96)
Jahre
86420
pEF
S
1,0
,8
,6
,4
,2
0,0
__ __ SCT: n = 73; CCR = 28; pEFS = .37 .06
______ no SCT: n = 33; CCR = 5; pEFS = .00 .00 p < 0.001
Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.
Woolfrey, A. E. et al. Blood 2002; 99: 2002-2008
Figure 1.
AIE1
SR
HR HAM AI haM HAE
AI1 haM1 HAE R Radioterapia
Leczenie podtrzymujące1 rokCytarabina ith 1, 2
Allogeniczne przeszczepienie komórek krwiotwórczych szpiku kostnego od zgodnego dawcy rodzinnego
Indukcja 1 Indukcja 2 Konsolidacja Intensyfikacja
▼ ▼ ▼ ▼ ▼ ▼ ▼Dzień 1 15 21-28 42-56 88 ~112 ~140 MRD MRD MRD MRD MRD MRDa MRDa
a – u pacjentów z obecnym markerem molekularnym1 – inne postępowanie dla dzieci z AML w zespole Downa i dla dzieci z AML M32 – jeden raz w tygodniu, przez 4 tygodnie od rozpoczęcia leczenia podtrzymującego
A: cytarabina HAE: wysokie dawki cytarabina/ etopozyd I: idarubicyna R: randomizacjaE: etopozyd SR: grupa standardowego ryzykaHA: cytarabina wysokodawkowana HR: grupa wysokiego ryzykaM: mitoksantron MRD: minimalna choroba resztkowa
TyPE OF DONOR
MSD MD MMD
De novo AML treated acc. to AML-BFM-2005 Interim - no CR after Induction 2 or - aplastic BM after 6 weeks from Induction 2
+ + +
CR2 - CR1 < 18 months + + +
CR2 - CR1 > 18 months + ++
or auto-HSCT
CR3 + ++
or auto-HSCT
TYPE OFTYPE OF HSCT I TYPE OF DONOR IN CHILDREN HSCT I TYPE OF DONOR IN CHILDRENWITH WITH DE NOVO DE NOVO AML RESISTANT TO TREATMENT AND IN AML RESISTANT TO TREATMENT AND IN
CHILDREN WITH AML IN CHILDREN WITH AML IN CR2CR2(WG AML SCT BFM-2005)(WG AML SCT BFM-2005)
PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING TRANSPLANTS FOR AML
BY REMISSION STATUS AND AGE, 1994-1999
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
0
YEARS
SUM02_5.ppt
P = 0.0001
CR2+, 20y (N = 184)
CR1, 20y (N = 839)
CR2+, 20y (N = 653)
CR1, 20y (N = 2,449)
1 2 3 4 65
PROBABILITY OF SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR AML
BY DONOR TYPE AND REMISSION STATUS, 1994-1999
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
0
YEARS
SUM02_4.ppt
P = 0.0001
HLA-identical sibling, CR1 (N = 3,298)
HLA-identical sibling, CR2+ (N = 837)
Unrelated, CR1 (N = 424)
Unrelated, CR2+ (N = 567)
1 2 3 4 65
PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR AML
AGE 20 YEARS, 1994-1999
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
0
YEARS
SUM02_8.ppt
P = 0.0001
1 2 3 4 65
CR1 (N = 209)
CR2+ (N = 64)
Not in remission (N = 29)
Checkpoint 1: not defined in chronic phase
increase imatinib to 400 mg/sqm
continue regular-dose imatinib Yes
Checkpoint 2:28 days after start of imatinib treatment
Checkpoint 3:2 months after start of imatinib treatment
Refractoriness !Stopp imatinib, check for bcr-abl gene mutations, start hydroxyurea+/- IFN-alpha, consider stem cell transplantation
No
No
reduction in white cell count by 50 % or better ?
No
complete hematological remission ?
occurrence of peripheral blood cytopenia ?
continue imatinib Yes
increase imatinib to 400 / 500 mg/sqm
Yes
continued next page
Chronic phase (CP)
TREATMENT OF CMLIN CPTREATMENT OF CMLIN CP(wg CML-paed II - 2006)(wg CML-paed II - 2006)
Checkpoint 4: 3 months after start of imatinib treatment
continue imatinib Yes
Checkpoint 5: 6 months after start of imatinib treatment
Checkpoint 6:9 months after start ofimatinib treatment
Refractoriness !Stopp imatinib, check for bcr-abl gene mutations, start hydroxyurea +/- IFN-alpha, consider stem cell transplantation
continued next page (3)
complete hematologicalremission ?
continue imatinib YesNo
complete hematologicalremission and either minor or minimal cytogentic response (35 – 94 % Ph+ metaphases) or better ?
Noalready treated with high-dose imatinib ?
Yes
major cytogenetic response (1 – 34 % Ph+ metaphases) or better ?
increase imatinib to 400 / 500 mg/sqm No
already treated with high-dose imatinib ?
No
Yes
continue imatinib Yes increase imatinib to 400/ 500 mg/sqm; schedule SCT with HLA-fully matched sibling donor within next 3 months
No
Chronic phase (CP) continued (2):
TREATMENT OF CML IN CPTREATMENT OF CML IN CP(wg CML-paed II - 2006)(wg CML-paed II - 2006)
Checkpoint 1:14 days after start of imatinib treatment
reduction in white cell count by 25 % ?
increase imatinib to 500 mg/sqm
continue high-dose imatinib Yes
Checkpoint 2:28 days after start of imatinib treatment
partial hematological remission ?
No
continue high-dose imatinib Yes
Checkpoint 3:2 months after start of imatinib treatment
chronic phase and/or complete or partial hematological remission ?
continue high-dose imatinib, plan fully HLA-matched or partially HLA-matched related or unrelated stem cell transplan-tation within 6 months after diagnosis Yes
check for bcr-abl gene mutations, stopp imatinib,give hydroxyurea, IFN-alpha +/- Ara-C
No
No
Accelerated phase (AP)
schedule forSCT from any donor
TREATMENT OF CML IN APTREATMENT OF CML IN AP(wg CML-paed II - 2006)(wg CML-paed II - 2006)
PROBABILITY OF SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR CML IN CHRONIC PHASE
BY DONOR TYPE AND DISEASE DURATION, 1994-1999
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
0
YEARS
1 2 3 4 6
SUM02_3.ppt
P = 0.0001
HLA-identical sibling, 1y (N = 2,876)
HLA-identical sibling, 1y (N = 1,391)
Unrelated, 1y (N = 613)
Unrelated, 1y (N = 936)
5
JMMLJMMLEvent-Free Survival by DonorEvent-Free Survival by Donor
YEARS AFTER TRANSPLANTATION
PR
OB
AB
ILIT
Y (
95%
CI)
MFD:MFD: N = 48; E = 21N = 48; E = 21UD:UD: N = 52; E = 26N = 52; E = 26
P = N.S.
MFD = 55% (41-70)MFD = 55% (41-70)
UD = 49% (35-63)UD = 49% (35-63)
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
Locatelli F et al. Blood 2005Locatelli F et al. Blood 2005
0 1 2 3 4 5
YEARS AFTER TRANSPLANTATION
0.0
0.2
0.4
0.6
0.8
1.0
MFD: 0.14, SE=0.08
UD: 0.17, SE=0.08
MFD:MFD: N = 23N = 23UD:UD: N = 24N = 24
CU
MU
LAT
IVE
INC
IDE
NC
E
Log Rank: p=n.s.
Bu Cy Mel N = 37Bu Cy + other N = 4Bu Cy only N = 6
MFD: 0.86, SE=0.08
UD: 0.83, SE=0.08
SCT in RCSCT in RC
Bu Cy (Mel): EFS and TRM by DonorBu Cy (Mel): EFS and TRM by Donor
EWOG-MDS, Interim Analysis, August 2004EWOG-MDS, Interim Analysis, August 2004
0 1 2 3 4 5
YEARS FROM HSCT
0.0
0.2
0.4
0.6
0.8
1.0
PR
OB
AB
ILIT
Y (
95%
CI)
UD = 45% (31-58)UD = 45% (31-58)
MFD = 67% (53-81)MFD = 67% (53-81)
P = 0.02
MFD: N = 50; events = 15UD: N = 61; events = 31
H MDS 2 EFS High Grade MDS by DonorEFS High Grade MDS by Donor
4 / 2003
A comparison of allogeneic and autologous bone marrow A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphomatransplantation for lymphoblastic lymphoma
Levine JE, Harris RE, Loberiza FR Levine JE, Harris RE, Loberiza FR et alet al..on behalf ofon behalf of IBMTR i ABMTR IBMTR i ABMTR
Blood 2003; 101: 2476-2482Blood 2003; 101: 2476-2482
INDICATIONS FOR HSCT IN CHILDREN WITH ALCLINDICATIONS FOR HSCT IN CHILDREN WITH ALCL(wg EICNHL 2004)(wg EICNHL 2004)
Treatment plan of ALCL Relapse
progress during first line therapy
ICM
ICI
TBI/Thio/Eto allo-SCT
CD3 positive CD3 negative
CC
CC
CVA
BEAMauto-SCT
LeukapheresisMRD-RT-PCR
30.06.2004
progress after intensive phase of initial therapy
CC
CC
< 12 months or VBL in first line
> 12 months andno VBL in first line
24 months VBL Relapse
CVA
10/10 MUD no MSD and no 10/10 MUD
MSDany donor
Diagnosis Disease stage HLA matched alternativesibling donors
ALL I CR ( VHR ) +
II CR + + +
> II CR + + AML I CR ( HR ) + +
II CR + + + MDS + + CML CP I + +
AP / BP + + NHL I CR +
II CR + + + Choroba Hodgkina I CR +
II CR +
Neuroblastoma + CNS tumors + Ewinga’s tumor +
Soft tissue sarcoma + Nephroblastoma +
Allo Auto
INDICATIONS FOR HSCT IN INDICATIONS FOR HSCT IN SOLID TUMORSSOLID TUMORS IN CHILDREN IN CHILDREN
RESULTS OF AUTOLOGOUS HSCT IN CHILDREN WITH SOLID TUMORS
AUTHOR NUMBER
OF CHILDREN
DIAGNOSIS & DISEASE STAGE
pDFS (%)
Matthay, 1999 379
High risk neuroblastoma in I CR 43
Graham, 1997
Dunkel, 1998
Guruangan, 1999
23
49
20
CNS tumors <10 – 50%
Ladenstein, 1995 63 Ewing’s sarcoma 21%
Grupa Robocza ds.
Guzów Litych przy
EBMT
52 Soft tissue sarcoma 30
Kremens, 2002 25 Nephroblastoma 51
PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR NEUROBLASTOMA
1994-1999
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
0
YEARS
1 2 3 4 6
SUM02_26.ppt
P = NS
5
Remission (N = 412)
Not in remission (N = 327)
Diagnosis Disease phase HLA matched alternativesibling donors 1
ALL I CR ( VHR ) 2 +
II CR + +
> II CR + + AML I CR ( HR ) 3 + +
II CR + + MDS + + CML chronic phase + +
accel. /blastic crisis + + NHL I CR 4 +
II CR + + + Hodgkin’s disease I CR 5 +
II CR 6 + SAA + + 7
Fanconi anemia + + Blackfana-Diamonda anemia + 8 + 8
Congenital immunodeficiences + + Inborn errors of metabolism + +
Allogeneic HSCT Autologous HSCT
INDICATIONS FOR HSCT IN CHILDREN WITH HAEMATOLOGICAL INDICATIONS FOR HSCT IN CHILDREN WITH HAEMATOLOGICAL MALIGNANCIES AND MALIGNANCIES AND NON-MALIGNANT DISEASENON-MALIGNANT DISEASE
PROBABILITY OF SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR SEVERE APLASTIC ANEMIA
BY DONOR TYPE AND AGE, 1994-1999
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
0
YEARS
1 2 3 4 6
SUM02_14.ppt
P = 0.0001
5
HLA-identical sibling, 20y (N = 845)
HLA-identical sibling, 20y (N = 844)
Unrelated, 20y (N = 114)
Unrelated, 20y (N = 244)
PROBABILITY OF SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR FANCONI ANEMIA
BY DONOR TYPE AND AGE, 1994-1999
PR
OB
AB
ILIT
Y,
%
100
0
20
40
60
80
0
YEARS
1 2 3 4 6
SUM02_15.ppt
P = 0.0001
5
HLA-identical sibling, 10y (N = 109)
Unrelated, 10y (N = 36)
HLA-identical sibling, 10y (N = 100)
Unrelated, 10y (N = 58)
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