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)