Risk-adapted stratification and treatment of childhood ALL · 2014. 4. 24. · 99 MRC-ALL 97/99 UKALL-R3 COALL-06-97 FRALLE 2000 EORTC-CLG 58951 NOPHO ALL-2000 (pre-)BMT ALL adult

Risk-adapted stratification and treatment of childhood ALL

Martin Schrappe

ALL-BFM Study Group

International BFM Study Group

Department of PediatricsUniversity Medical Center Schleswig-Holstein

Kiel – Germany

[email protected]

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Childhood ALL: The Treatment Dilemma

Treatment intensity (number of drugs combined, dose intensity)

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Status at the endof the 20th century

Current issues addressed in pediatric ALL

• To identify and to target the remaining 20% of patients who do not survive ALL

• To determine the essential elements of therapy

• To identify the patients at very low risk to relapse to prevent further intensification for them

• To adapt therapy to limit toxicity

• To eliminate treatment elements with potential long-term toxicity

Results of international clinical trials in ALL of children and adults

Pui CH et al. (2004) NEJM 350: 1535-48

Can differences be explained bydifferences in biology and aetiology?

Pui CH et al. (2004) NEJM 350: 1535-48


Pui CH et al. (2004) NEJM 350: 1535-48


Or is different treatment outcome dueto better ALL treatment protocols in Pediatric Hematology / Oncology?

Trials ALL-BFM 86, 90 and 95 (n = 4988)

Age distribution by immunologic subtypeCases per age group (year of diagnosis)

0

200

400

600

800

1.000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

T-ALL

pB-ALL

n

Age at dx (yrs)

age 1-17infants excl.

25%27%21%7%T-ALL

75%79%pB-ALL 73%93%

Trials ALL-BFM 86, 90 and 95 (n=1063)

Age distribution in pB-ALL by presence of TEL/AML1TEL/AML1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

n

0

50

100

150

200

TEL/AML1 positive

TEL/AML1 negative

Age (years)

9%27%TEL/AML1 pos. 12%27%

X² p<0.001

Trials ALL-BFM 86, 90 and 95 (n=2845)

Age distribution in pB-ALL by presence of BCR/ABL

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Age (years)

n

0

100

200

300

400

500

BCR/ABL positive

BCR/ABL negative

3.8%4.8%BCR/ABL pos. 5.5%1.4%

X² <6 vs >6 yrs: p<0.001

Trials ALL-BFM 86, 90 and 95 (n = 2654)

Age distribution in pB-ALL by presence of hyperdiploidyhyperdiploidy

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

n

DNA-Index >1.16

DNA-Index <1.16

Age (years)

16%24%DNA-Ind. >1.16 15%27%

0

100

200

300

400

500

X² p<0.001

1-5 years .83, SE=.01 (N=2732, 471 events)

6-9 years .75, SE=.02 (N=784, 195 events)

10-14 years .63, SE=.02 (N=539, 188 events)

>15 years .57, SE=.05 (N=147, 55 events)

years

Log-Rank p = <0.0001ag

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Trials ALL-BFM 86, 90 and 95

Treatment results of pB-ALL by agepEFS at 8 years (n=4356)

1-5 years .88, SE=.05 (N=180, 16 events)

6-9 years .93, SE=.07 (N=50, 3 events)

>10 years .95, SE=.13 (N=21, 1 event)

years

Log-Rank p = 0.67

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1 2 3 4 5 6 7 8 9 10 110

Trials ALL-BFM 86, 90 and 95Treatment results of TEL/AML1 pos pB-ALL by age

1-5 years .65, SE=.04 (N=193, 70 events)

6-9 years .74, SE=.03 (N=211, 55 events)

10-14 years .64, SE=.04 (N=203, 69 events)

>15 years .61, SE=.08 (N=50, 19 events)

years

Log-Rank p = 0.09

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ALL-BFM 86, 90 and 95, pEFS (at 8yrs)

Treatment results by ageT-ALL

Pui CH et al. (2004) NEJM 350: 1535-48

��

Comparison of geneticsubgroups in ALL of children and adults

Clinical challenge

• in childhood ALL, high risk (HR) subsets are small:

= data analysis per study group is limited, intergroup

metaanalysis may serve as substitute.

• most intermediate risk (IR, 5y-EFS ~80%) or low risk

(LR, 5y-EFS >90%) subsets are large:

– The contribution of any additional therapeutic element will only be proven if large patient numbers are available forsuch trial.

– The dilemma: any additional therapeutic intervention (if notclearly less toxic and replacing previously used elements) will be unnecessary for most patients as they are alreadycured with existing treatment.

Based on initial clinical and diagnostic parameters:

– age

– WBC

– extramedullary involvement

– immunphenotype

– cyto- and molecular genetics

ALL: Stratification (1)

Based on initial clinical and diagnostic parameters:– age– WBC– extramedullary involvement (e.g. CNS-3, TLP+)– immunphenotype– cyto- and molecular genetics:

• relevant high risk (HR) subsets: – t(9;22) (BCR-ABL)– t(4;11) (MLL-AF4)– hypodiploidy (<46 [<44] chromosomes)– [other MLL rearrangements]

• relevant low risk (LR) subsets: – t(12;21) (TEL-AML1)– hyperdiploidy– [t(1;19) (E2A-PBX1)]

Stratification (2)

Individual Treatment Responseas additional tool for risk assessment

ALL-BFM 90, 95 and AIEOP-BFM ALL 2000: Induction and induction-consolidation ("Protocol I-A/B")

Day 1 8 15 22 29 36 43 50

PRED p.o. 60mg/m2/d

VCR i.v. 1.5mg/m2

CPM p.i. (1h) 1000mg/m2

DNR p.i. (1h) 30mg/m2

L-ASP(E.coli) p.i. (1h) 5,000 U/m2 *

ARA-Ci.v. 75mg/m2/d

6-MP p.o. (28 d) 60mg/m2/d

57 64

MTX i.t. Dose is age adapted

BMResponse

PB

Prednisone Prephase

* In previous ALL-BFM trials dose and product was different

0.82, SE=0.01

Pred Good-Resp (N=1963, 362 events)

0.55, SE=0.04

Pred Poor-Resp (N=184, 82 events)

years

Log-Rank p = <.0001

al9

5_e

nd

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28

FE

B07

P

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0.1

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1.0

0 1 2 3 4 5 6 7 8 9 10 11 12

ALL-BFM 95 EFS (6 years)Prednisone Response (PB d8)

ALL-BFM 95

Prognostic Impact of BM Response on Day 15pB-ALL

BM d15 M1: 6y-pEFS 87%, SE=1% (N=741, 97 events)



years

all p(log-rank) <0.0001

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0 1 2 3 4 5 6 7 8 9 10 11

0.55, SE=0.08

PRED Good Response (N= 37, 16 events)

0.10, SE=0.07

PRED Poor Response (N= 20, 18 events)

years

Log-Rank p = 0.0001

P

0.0

0.1

0.2

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0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10

EFS in Ph+ ALL according to Prednisone ResponseResults from BFM and AIEOP (1986-95)

Schrappe M, Arico M, Harbott J, et al. BLOOD 92 (1998): 2730

Improve risk group definition

through detection of MRD

I-BFM-SG MRD Study (1991-95)

BFM-G, BFM-A, DCOG, AIEOP

JJM van Dongen et al., Lancet 352 (1998): 1731

I-BFM-SG MRD Study (1991-95): Monitoring of minimal

residual disease (MRD) in the course of treatment

220

I

M

104Weeks

M R G (61 %)P R E D- G R and R F>0.8

S R G (28 %)P R E D- G R andR F<0.8 and Non-T and C N S neg.

52

H R G (11 %)PR E D-P R, orN R d33, orPh+ ALL

10 3012 20 28

IIRM-A

MI II

156

IAHR1

HR2

HR3

HR1

HR2

HR3

12 Gy*

HR1

HR2

HR3

12 Gy*

Bone marrow puncture

* preventive cranial radiotherapy

1 2 3 4 5 6 7 8 9

Risk groups

No. Timepoints of BM sampling for MRD

Tp 1+2 neg.: RFS .98, SE=.02; n= 55 (43%), 1 relapse ( 3%)

Tp 2 < 10-3: RFS .76, SE=.06; n= 55 (43%), 13 relapses (43%)

Tp 2 >=10-3: RFS .16, SE=.08; n= 19 (14%), 16 relapses (54%)

years

MR

D0599h

.tab

23M

AY

99

P

3

Pat. at risk

274453543223642434854222456100.0

0.1

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0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8

54

I-BFM-SG MRD-Study: Relapse free survival *

Risk groups by MRD at 5 weeks (Tp 1) and 12 weeks (Tp 2)

* Update 2002, see JJM van Dongen et al., Lancet 352 (1998): 1731

MRD-based low risk group

MRD-based intermediate risk group

MRD-based high risk group

Distributionof relapses

Use of a MRD based risk group

definition for stratification to improve

risk-adapted therapy

AIEOP-BFM ALL 2000

Trial Steering Committee:

M. Schrappe, Kiel

G. Masera, Monza

H. Gadner, Wien

1407N. pts

61N. events

92.8%(1)5 yrs EFS

SR 20002660

N. pts

364

N. events

80.1%(1.1)

5 yrs EFS

MR 2000663

N. pts

198

N. events

63.1%(2.3)

5 yrs EFS

HR 2000

AIEOP-BFM 2000by risk group

4730 patients

no Ph+CORS/Hannover - Apr 2007

EF

S

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1.0

YEARS FROM DIAGNOSIS

0 1 2 3 4 5

Interim result

Risk adapted stratification: Combination of

upfront and response derived criteria

• Based on initial parameters:

– age

– WBC

– extramedullary involvement

– immunphenotype

– cyto- and molecular genetics

• Based on early response:

– prednisone response: blast count d8 in PB

– BM response: blast count at d15

– BM response: blast count at d33 (end of induction)

– MRD response:

Organization of Treatment

• well-controlled clinical trials comprising

– registry and follow-up,

– diagnostics and sample banking,

– prospective treatment questions.

European Study Group on MRD detection in ALLQuality control and further refinement

(ESG-MRD-ALL; 30 labs in 15 countries)

Rotterdam

Amsterdam

Heidelberg

Vienna

Monza

Paris

Salamanca

Stockholm

London

Copenhague

Kiel

BerlinHannover

Glasgow

Leeds

Sheffield

Bristol

Brussel Prague

Hamburg

Zurich

Padova

LilleFrankfurt

PetachTikwa

Singapore

Sydney

Europe Israel Singapore

Australia

ESGMRDALL

BFM-AIEOP

ALL-2000

R elap s ed

AL LALL- R EZ

B F M2 002

DCLSGALL9

Interfant99

MRC-ALL 97/99UKALL-R3

COALL-06-97

FRALLE2000

EORTC-CLG 58951

NOPHOALL-2000

(pre-)BMTALL

adultALL

GMALL06/99

adult ALLLALA 2000

adult ALLUKALL XII

adult ALLPETHEMA/

GETH

by courtesy of J.J.M. van Dongen

Organization of Treatment

• well-controlled clinical trials comprising

– registry and follow-up,

– diagnostics and sample banking,

– prospective treatment questions

• population-based patient entry

• internal and external data and safety monitoring

• funding through public research grants orfoundations

Pediatric ALL: Coverage through clinical

trials in Europe

Country Study Patients Population

Group (est., p.a.) based

A BFM-A 50 yes

B/F/P EORTC-CLG 200 (yes)

CH BFM, others 50 n.k.

D BFM-G; COALL 550 yes

F FRALLE 370 (yes)

I AIEOP 340 yes

Scand. NOPHO 180 yes

U.K. CCG-LWP 350 yes

Treatment

Prot. M Prot. II

Weeks

INDUCTION/CONSOLIDATION

EXTRACOMPART-MENT THERAPY

REINDUCTION MAINTENANCE

Prot. I

0 1043010 21 28

12 Gy*

5

• no prophylactic cranial radiotherapy (pCRT) if age <1y; • since ALL-BFM 95, pCRT only in T-ALL and HR-group• CNS positive: 0 Gy <1y, 18 Gy >=1y

ALL-BFM “Backbone“: Platform for prospectiveevaluation of treatment variants

Studies on: PDN MD/HD-MTX ASP DEX/VCR pulsesDEX ASPASP ARA-C

CPM pCRTallo SCT DDI

Relevant treatment componentsApproaches and open questions

• Induction/consolidation

– Corticosteroid: DEX (dose?) replacing PRED?

– Asparaginase: Timing, type, dose?

– role of anthracyclines?

• Extracompartment therapy: HD-MTX, IT therapy?

• Preventive cranial radiotherapy (for which pts?)

• Delayed intensification (x1, or x2?)

• Allogeneic hematopoetic stem cell transplantation?

• Maintenance therapy: components?

Example of a large subset of ALL in which

the result of a prospective clinical trial may

allow to avoid treatment burden in the

future

RandomizedRandomized casescases: n=2618: n=2618

IR pts treated between 1995 and 2001 from:

Argentina (GATLA), Austria (BFM-A), Chile (PINDA), CzechRepublic (CPH), Belgium/France (EORTC-CLG), Germany (BFM-G), Hungary (HPOG), Italy (AIEOP)

I-BFM-SG study on pulses in maintenance

IR-ALL: Impact of DEX/VCR during Maintenance Therapy(I-BFM-SG)

IR-ALL: Impact of DEX/VCR during M.T. (I-BFM-SG)

Examples for small and unfavorable

subsets of ALL(published)

• CNS involvement: BFM (2003, 2007)

• intergroup analysis for

– Ph+ ALL (2000)

– 11q23 rearrangements (2002)

– Hypodiploidy (2007)

• inadequate early response: I-BFM study on HR ALL (2006)

CNS1: .80, SE=.01 (N=1605, 250 events)CNS2: .80, SE=.04 (N= 103, 18 events)

CNS3: .50, SE=.08 (N= 58, 26 events)TLP+: .73, SE=.04 (N= 135, 33 events)

TLP-: .83, SE=.04 (N= 111, 18 events)

5y-pEFS according to CNS statusTrial ALL-BFM 95 (-6/99); n=2012, 295 events

years

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

Log-rank: p = 0.003 TLP+ vs. CNS1

p = 0.001 TLP+ vs. CNS3

TLP+: RR: 1.5, CI 1.0 - 2.2, p = 0.04

CNS3: RR: 2.3, CI 1.4 - 3.6, p = 0.0005

Bürger, B. et al. J Clin Oncol, 21: 184-188, 2003

all brain tumors .034, SE=.016 Events/N 15/1394

years

P

Cumul. incidence of secondary brain tumors (CI at 16 years)HR and MR patients without initial CNS involvement (pB and T-ALL):

Preventive CRT performed with 12 Gy(Data from trial ALL-BFM 90)

0.00

0.05

0.10

0.15

0.20

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

CNS Disease in Childhood ALL

Problems:

• Comprehensive characterization of CNS status at diagnosis is

difficult.

• Adequate adaptation of CNS-directed therapy is still missing

Hypothesis:

• Leukemic cells migrating into the CNS display specific

biological characteristics that can be uncovered by

genome-wide gene expression profiling.

Characteristics of 43 childhood ALL patients from trial ALL-BFM 2000 analyzed by gene expression profiling of initial BM samples:

Results of frequency matchingNumber of subjects and prevalence (%)

0.1512 (11.8)-TEL/AML1 positive

---MLL/AF4 positive

---BCR/ABL positive

0.2808 (47.1)8 (30.8)T-ALLtype

9 (52.9)18 (69.2)B-precursorImmunopheno-

0.9468 (47.1)10 (38.5)> 100,000

2 (11.8)3 (11.5)50,000 - < 100,000

4 (23.5)7 (26.9)10,000 - < 50,000 WBC count/µl

3 (17.6)6 (23.1)< 10,000 Presenting

0.9255 (29.4)8 (30.8)female

12 (70.6)18 (69.2)maleSex

0.7576 (35.3)8 (30.8)> 10

11 (64.7)18 (69.2)1 - < 10 Age (years)

PCNS3CNS1

Methods

Spotted cDNA Arrays > 42,000 spots (~30,000 genes)(Stanford Functional Genomics Facility)

Analysis

1. Unsupervised Clustering Analysis

2. Analysis of differentially expressed genes using SAM (Significance Analysis of Microarrays, PNAS, 2001)

SAM identified 18 candidate genes differentiallyexpressed in initial BM samples (with >70 % blasts)

comparing CNS-positive and -negative ALL

(SAM: 1000 permutations, FC > 2, FDR 61%)

Can this result adversely be influenced through contaminating normal cells ?




Analysis of the expression of candidate genes after purification of blasts in four B-pc-ALL samples

[Purification: Cell sorter: FACSVantage BD, anti-CD19/anti-CD10 antibody]

NAME CNS-neg_B-Z5_s CNS-neg_B-Z10_s CNS-pos_B-Z25_s CNS-pos_B-Z29_s FC pos/neg

IL15 || Interleukin 15 -2.07 -0.65 2.05 2.12 10.89

PDE4A || Phosphodiesterase 4A -1.3 -0.51 -1.49 -2.14 0.53

PFKFB2 || 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 -2.88 -0.52 1.75 2.81 15.78

CD9 || CD9 antigen 2.01 2.99 3.5 1.36 0.95

ARHGEF10 || Rho guanine nucleotide exchange factor (GEF) 10 NA 2.37 2.59 1.19 0.72

TGFB1I4 || TSC22 domain family, member 1 0.18 NA 0.37 -0.02 1.00

GLDC || Glycine dehydrogenase -2.62 -1.1 -1.01 -3.39 0.79

CLTC || Clathrin, heavy polypeptide (Hc) -2.66 -1.84 -2.32 -2.56 0.88

IRX2 || Iroquois homeobox protein 2 NA -1.31 -0.96 -2.9 0.65

HDHD1A || Haloacid dehalogenase-like hydrolase domain

containing 1A -0.06 0.24 1.36 -0.86 1.12

ZNF300 || Zinc finger protein 300 -3.97 -2.82 -1.08 -2.87 2.68

PTPRS || Protein tyrosine phosphatase, receptor type, S -4.62 -2.82 -3.25 -5.86 0.56

PHYH || Phytanoyl-CoA hydroxylase (Refsum disease) -0.22 -0.61 0.77 0.51 2.08

AKAP12 || A kinase (PRKA) anchor protein (gravin) 12 -1.25 -4.49 -0.19 -5.24 1.11

SGCB || Sarcoglycan, beta -0.51 1.08 -0.63 -1.36 0.41

CHC1L || Regulator of chromosome condensation (RCC1) and

BTB (POZ) domain containing protein 2 -0.91 -0.21 -0.01 -1.1 1.00

RIMS3 || Regulating synaptic membrane exocytosis 3 -0.51 -0.07 -0.63 -2.48 0.42

GPR109A || G protein-coupled receptor 109A NA NA 1.42 1.7 NA




Interleukin 15 (IL-15)

• chromosome 4q21

• proinflammatory cytokine sharing many biological functions of IL-2

• expressed by multiple tissues and cell types including leukemic

blasts

• regulates T and natural killer cell activation and proliferation

• activates proinflammatory functions of PMN cells (as opposed to

IL-2)

• RNA and protein expression is upregulated in PBMNC in patients

with chronic progressive Multiple Sclerosis

Leukemic IL-15 expression in diagnostic BM of ALL patients

without (CNS1) and with (CNS3) leukemic CNS involvement

Validation analysis by RQ-PCR

P < 0.001 P < 0.001

1726N =

CNS3CNS1

Inte

rle

ukin

-15

exp

ressio

n (

a.u

.)

400

300

200

100

0

1326N =

CNS3CNS1

Inte

rle

ukin

-15

exp

ressio

n (

a.u

.)

400

300

200

100

0

Patients included inmicroarray analysis

Independent setof patients

6.93

(2.55-18.83)<0.001

153.25

(10.37-2264.69)<0.001

75.76

(7.69-769.23)

16

(53.3)

4

(7.7)IV

1.30

(0.62-2.72)0.011

22.03

(1.57-153.85)0.017

14.22

(1.60-126.58)

9

(30.0)

12

(23.1)III

0.41

(0.15-1.10)0.130

6.39

(0.51-59.17)0.200

4.46

(0.45-4.39)

4

(13.3)

17

(32.7)II

0.09

(0.01-0.65)1.001.00

1

(3.3)

19

(36.5)I

Likelihood ratio (95% CI)PP

CNS3n=30

CNS1n=52

IL-15 quartiles

Multivariateodds ratio (95% CI)

Univariateodds ratio (95% CI)

Number of subjects and prevalence (%)

Uni- and multivariate associations and likelihood ratios for IL-15 expression quartiles and

CNS status in 82 childhood ALL patients

Is IL-15 expression relevant for CNS relapse?

Patients from trial ALL-BFM 2000 that were initially CNS-negative (CNS1) with subsequent isolated or combined CNS relapse were compared to CNS1 patients with a minimum follow-up of three years.

CNS Disease in Childhood ALL

Characteristics at initial diagnosis of 44 CNS1 patients in longterm remission and 22 CNS1 patients relapsing with CNS involvement

Number of subjects and prevalence (%)

0.0075 (22.7)15 (34.1)high risk

14 (63.6)11 (25.0)intermediate risk

3 (13.6)18 (40.9)standard riskTreatment group

0.1082 (9.1)TEL/AML1 positive

0.1082 (9.1)-BCR/ABL positive

0.8083 (13.6)7 (15.9)T-ALLType

19 (86.4)37 (84.1)B-precursorImmunopheno-

0.4407 (31.8)12 (27.3)> 100,000

5 (22.7)9 (20.5)50,000 - < 100,000

4 (18.2)16 (36.4)10,000 - < 50,000 WBC count/µl

6 (27.3)7 (15.9)< 10,000 Presenting

0.1445 (22.7)18 (40.9)female

17 (77.3)26 (59.1)maleSex

0.5877 (31.8)17 (38.6)> 10

15 (68.2)27 (61.4)1 - < 10 Age (years)

PRelapseRemission

IL-15 expression in leukemic blasts at initial diagnosis predictssubsequent relapse with involvement of the CNS

P < 0.001

2244N =

RelapseRemission

Inte

rle

ukin

-15

exp

ressio

n (

a.u

.)

400

300

200

100

0

Odds ratio* for IL-15 expression levels above the median = 13.80, 95% CI 3.38-56.31, P < 0.001*controlling for gender, age and WBC at diagnosis, immunophenotype, presence of BCR/ABL or TEL/AML1 fusion transcripts (yes/no), and treatment group

Conclusions from the CNS/IL-15 study

• IL-15 expression characterizes CNS involvement at initial diagnosis

of childhood ALL.

• IL-15 predicts CNS relapse in patients classified as CNS1 at initial

diagnosis by morphological criteria.

• IL-15 has excellent diagnostic potential for assessing CNS status in

ALL.

• Analysis of IL-15 expression opens new perspectives for adaptation

of CNS-directed therapy in childhood ALL.

• Our data suggest a role for IL-15 in the pathogenesis of leukemic

CNS involvement.

• IL-15 may serve as a potential therapeutic target in ALL.

Cario G, Izraeli S, Teichert A, Rhein P, Skokowa J, MorickeA, Zimmermann M, Schrauder A, Karawajew L, Ludwig WD, Welte K, Schunemann HJ, Schlegelberger B, Schrappe M,

Stanulla M (2007)

High interleukin-15 expression characterizes childhoodacute lymphoblastic leukemia with involvement of the CNS.

J Clin Oncol 25: 4813-4820

Funding from BMBF (Bonn), Young Investigator Faculty Grant (Kiel), M. Schickedanz

Foundation (Fuerth)





– Ph+ ALL (2000)



• inadequate early response: I-BFM (2006)

N = 326

Pts recruited within 10y from 10 study groups

��

N = 497

Patients enrolled in participating centers ofone of the 13 study groups and institutionsbetween 1983 and 1995.

Patient population (11q23)

Outcome by age (11q23)

11q23: Outcome by regimen: Chemo vs SCT

��

N = 139 (less than 45 chromosomes)= 130 (Ph neg. ALL)

Pts recruited in 10y from 10 study groups

��

��

��





– Ph+ ALL (2000)



• inadequate early response: I-BFM (2006)

Argentina (GATLA), Austria (BFM-A), Czech Republic (CPH), Germany (BFM-G), Hungary (HPOG), Italy (AIEOP)

Patients enrolled from 4/95 to 12/2000.

VHR-ALL: Patient characteristics by treatment

Conclusions

• Currently, initial patient characteristics are of limited valuefor risk assessment as response to treatment isheterogenous in all subgroups, even in well-definedsubsets of ALL (e.g. in Ph+ ALL).

• Thus, even more-refined ways to determine the patient at (increased) risk to relapse are needed– to save others from (unnecessary) therapy

– to identify those HR patients who may need alternative therapy(e.g. hSCT).

• Treatment is effective but too toxic (and no change in sight!).

• Relapsed patients are at high risk to (eventually) die of thedisease.

• Thus, effective prevention is a most relevant issue.

AcknowledgmentsAcknowledgments

Dept. of Pediatrics, University Medical Dept. of Pediatrics, University Medical

Center SchleswigCenter Schleswig--Holstein, Campus KielHolstein, Campus Kiel

Andre Andre SchrauderSchrauder

GunnarGunnar CarioCario

Alexander ClaviezAlexander Claviez

Anja MAnja Möörickericke

Caroline SchwarzCaroline Schwarz

Dept. of Pediatric Hematology/ Oncology, Dept. of Pediatric Hematology/ Oncology,

Medical School Medical School HannoverHannover

Martin Stanulla Martin Stanulla

Karl WelteKarl Welte

Institute of Human Institute of Human GeneticsGenetics, Heidelberg, Heidelberg

Thomas FlohrThomas Flohr

Claus R. Claus R. BartramBartram

ReferenceReference laboratorieslaboratories

WolfWolf--Dieter Ludwig, Richard Dieter Ludwig, Richard RateiRatei

JochenJochen HarbottHarbott

ALLALL--BFM 2000 BFM 2000 StudyStudy CommitteeCommittee

ParticipatingParticipating centerescenteres fromfrom G/CH/AG/CH/A

AIEOPAIEOP--BFM Trial Steering CommitteeBFM Trial Steering Committee

Helmut GadnerHelmut Gadner

Martin SchrappeMartin Schrappe

Giuseppe Giuseppe MaseraMasera

Valentino Valentino ConterConter

Statistical analysisStatistical analysis

Martin ZimmermannMartin Zimmermann

Maria Maria GraziaGrazia ValsecchiValsecchi

MRD Task Force of IMRD Task Force of I--BFMBFM--SG:SG:

Jacques J.M. van DongenJacques J.M. van Dongen

Andrea Andrea BiondiBiondi, Giovanni , Giovanni CazzanigaCazzaniga

Renate PanzerRenate Panzer--GrGrüümayermayer

Claus R. BartramClaus R. Bartram

Deutsche JoDeutsche Josséé Carreras LeukCarreras Leukäämiemie--Stiftung e.V.Stiftung e.V.

BMBF: KPOH (BMBF: KPOH (CompetenceCompetence NetworkNetwork PedOncPedOnc))

Deutsche Krebshilfe

Documents

Risk-adapted stratification and treatment of childhood ALL · 2014. 4. 24. · 99 MRC-ALL 97/99 UKALL-R3 COALL-06-97 FRALLE 2000 EORTC-CLG 58951 NOPHO ALL-2000 (pre-)BMT ALL adult