1. Germany, Austria, Switzerland
Advances in the Treatment of AML in Children What is standard today? Practical Considerations The BFM Experience
U. Creutzig, D. Reinhard
AML-BFM Study Group
Germany, Austria, Switzerland
Czech Republic

2. Key Points of Treatment in AML
To avoid early death /TRM
Achieve Response (CR) - Induction
Longterm CCR
Consolidation/intensification
CNS therapy and maintenance
Risk adapted therapy for special groups – CBF leukemia, infants
Relapse treatment

3. Consolidation/ Intensivication
AML-BFM Standard Therapy
Special rules for FAB M3 and Down syndrome patients - SCT for HR-patients only
Ind. 1
Ind. 2
Consolidation/ Intensivication
CNS-Therapy
H A M
A I E
12 mg
A I
haM
HAE
Maintenance
1 year +
i.th. Ara-C**
Anthracyclines - Response
I will focus on treatment which is based now on the best arm our Study 98.
Therefore, I will explain this treatment, which resembles that what we do in the current study AML 2012.
Risk adapted therapy
for special groups
Relapse treatment

4. AML Studies : BFM-78/-83/-87/-93/-98/-04/-12
300mg/m²
4g/m²
400mg/m²
5.7g/m²
300mg/m²
41g/m²
mg/m²
23-41g/m²
This slide should demonstrated the developement of tretament blocks and duration during the last 30 years.
1987 a reduction of therapy was aimed to reduce toxicity. Consolidation and maintenace treatment were shortened. In addition prophylactic cranial radiation was randomised in the standard risk group.
- next slide -
450mg/m²
45g/m²
mg/m²
27g/m²
mg/m²
45g/m²
510mg/m²
45g/m²
Cumulative dosages
anthracyclines
cytarabine

5. AML-BFM Studies 78 -2004 Survival (5 years)
1.0
0.9
up to 80% today
0.8
73%
0.7
58%
0.6
0.5 P
0.4
42%
0.3
0.2
aml04_rand1.tab 01DEC10
0.1
Log-Rank p = <.0001
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
AML-BFM , SE=0.04 (N=151, 94 events)
years
AML-BFM , SE=0.04 (N=182, 93 events)
AML-BFM , SE=0.03 (N=307, 163 events)
AML-BFM , SE=0.02 (N=471, 209 events)
AML-BFM , SE=0.02 (N=472, 173 events)
AML-BFM , SE=0.02 (N=582, 125 events)

6. Early Toxicity

7. „Early Death“ by Bleeding and Leukostasis - AML-BFM 78/83
FAB
ED/Total
WBC > 100x10³/µl n %
M1/2
6/144 4
4/28 14 M3
2/11 8
-/- - M4
5/85 6
4/24 17 M5
19/80 24
14/20 70
other
-/13
total
32/333 10
22/72 31
Significance of total cell count
depends on the subtype of AML
Cancer 60:3071, 1987

8. Severe complications in case of Hyperleukocytosis
Leukostasis with respiratory insufficiency, CNS complications, renal failure,
Tumour lysis syndrome
Haemorrhage – coagulopathy with CNS – pulmonary bleeding
(decrease of plasminogen below 60%)

9. Management of pts. with Hyperleucocytosis and risk of Haemorrhage
Regular checks of coagulation parameters including fibrinogen, plasminogen, AT III and global tests
Intensive (ICU)-monitoring
gentle measures of hydration with fluid balancing
Rasburicase* or allopurinol with urine alkalinisation
no immediate compensation of anaemia (no red blood cell transf.)
fresh-frozen plasma (FFP) for patients with plasm. coagulopathy
platelet substitution
Careful blast reduction: Ara-C (40mg/m²/day); in case of poor response after 24h: dose increase to 100mg/m² cont. IV-infusion.
In case of poor response after another 24h, anthracyclines
if necessary, exchange transfusion/leukapheresis
diagnostic LP after sufficient cyroreduction
*clears uric acid from the blood

10. Induction therapy
Induction therapy should be started after reduction of blasts below cells/µl.
If cytoreduction has been insufficient, intensive treatment (induction) must be started independently of the blast count after five days latest.

11. Cause of Death during AML Therapy Studies AML-BFM 93 + 98 (N=902)
during aplasia: Prevention and
treatment of infections as in SCT units
experience is mandatory 3%
TRM 104 / 902 pat. = 11.5%
Creutzig et al. Early deaths and treatment-related mortality … JCO 22: 4384, 2004

12. Induction

14. ADE Induction: Improvement of Prognosis from Study -78 to -83
ED rate in aplasia ~ 4%

15. Anthracyclines Doxorubicin (ADR) Daunorubicin (DNR) DNR
Idarubicin (IDA)
Liposomal Daunorubicin (L-DNR)
Mitoxantrone (MITOX) anthracenedione derivative, structurally related to anthracyclines
Different Anthracycl. have diff. pharmacological effects and diff. (cardio-) toxicity
Problem of late cardiotoxicity
Cumulative dosage >300/400mg/m² in children
Longterm-cardiotox. in 1010 AML pat. After 11 yrs. Subclinical and clinical ~ 5 % Creutzig et al. Ped. Blood Cancer, 2007
DNR
Different Anthrac. Show diff. Pharmacology and diff. cardiotox

16. Idarubicin* - Study AML-BFM-93
ADE with DNR
30mg/m² /12h x 3 days
*30min.inf. C R A N I L
R R A D I A T I O N
Consoli-
dation
HD-A
+ VP SR S T R A I F C O N HR 1
Consoli-
dation
HD-A
+ VP
ADE
HAM
Mainten-
ance 1 y.
The main metabolite Idarubinicinol
has a high cytost. activity
has a long HLT of 57 h (Reid, 1990)
Daunorubicinol HLT 28 h
Activity in the CNS R1
R 2
AIE with IDA
12mg/m²/d x 3 days
*30min.inf.
* since h inf.
AIE HR 2
Consoli-
dation
HD-A
+ VP
HAM
The main metabolite Idarubinicinol
has a high cytostatic activity
a long HLT of 57 h (Reid, 1990) - Daunorubicinol HLT 28 h
activity in the CNS

17. Results: AML-BFM 93* ADE - AIE random. EFS 1.0 0.9 0.8 0.7 .57, SE=.04
Blasts day 15 after
ADE >5% vs. AIE >5% = 35% vs. 19%
p= 0.003
0.9
0.8
0.7
.57, SE=.04
0.6 P
0.5
.51, SE=.04
0.4
0.3
Dose of 60mg DNR : 12mg IDR = 5 : 1
equipotent – CR and pEFS
after IDR:
Duration of aplasia
Severe infections
0.2
ash1099.kam 15NOV99
0.1
Log-Rank p = .31
0.0 1 2 3 4 5 6 7
years
ADE (N=175, 82 events)
AIE (N=183, 76 events)
*Creutzig et al Leukemia 2001

18. Liposomal Daunorubicin – L-DNR Introduction of a less cardiotoxic anthracyclines
DNR within a liposomal delivery system
L-DNR accumulates at sites of abnormal vascular permeability (leukemic stem cells in the BM)
The liposome preparation is very stable, allowing the drug to retain activity in multi-resistant leukaemia
low AUC relation
in the heart,
HLP
Peak level
HLP = Plasma Half life time

19. Randomized introduction of liposomal daunorubicin (L-DNR) in a higher equivalent dose than idarubicin during induction*
AIE (3x 12 mg/m² IDR) (equiv. 60 mg DNR)
vs.
ADxE (3x 80 mg/m² L-DNR)
Aim: to improve prognosis
by a higher L-DNR equivalent dose than idarubicin during induction
without increasing toxicity
*Creutzig et al BLOOD 2013

20. Induction ADxE – AML-BFM 2004
Ara-C mg/m²/day cont. Inf.
Ara-C 12 x 100 mg/m² every 12h, 30min. Inf.
L-DNR 3 x 80 mg/m²* x3 days
Etoposid 3 x 150 mg/m²*/day LP
Ara-C IT age-dependent
days
*60 min infusion

21. Results - Randomization L-DNR
ADX N=257
AIE
N=264 N %
ED/TRM after ind. 2
0.8 10
3.8
no increase of cardio-
toxicity
despite higher cumulative
anthracycline dose

22. Conclusion: Induction
Induction is most important
To decrease the blast cell burden fast and substantially
To achieve remission
And longterm remission
Drug intensity should be high!
But (cardio-) toxicity and infections during aplasia have to be considered

23. Remission - AML Complete Remission (CR):
Bone marrow (BM) blasts < 5%
absence of blasts with Auer rods
absence of extramedullary disease
absolute neutrophil count > 1.0 x 109/L (1000/µL)
platelet count > 80 x 109/L (100,000/µL) independence of red cell transfusions
Nonresponse (NR)/Resistant disease:
Failure to achieve CR (stated after 6 weeks / after HAM) at the end of intensification
CR can be confirmed
by morphology together with MRD

24. LP should be done on day 1, to avoid too high doses in the CNS together with HD-Arac
2. InduCtion with HAM Aim: to eradicate remaining leukemic cells AML-BFM 93

25. AML-BFM 83-93: 10-Year EFS of HR Patients 1.0 0.9
Additional treatment with HAM
0.8
HD Ara-C combinations, e.g. HAM
3-4 blocks of intensification
can improve survival
0.7
0.6 P
0.5
.41, SE=.03
0.4
0.3
.31, SE=.03
0.2
beratung.kam 25APR03
0.1
Log-Rank p = .02
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
years
AML-BFM (N=339, 233 events)
AML-BFM (N=310, 179 events)

26. Intensification (consolidation)

27. Study AML-BFM 98 + + Consolidation H A M A I E Rand II HAE Rand III
Special rules for FAB M3 and Down syndrome patients - SCT for HR-patients only
Ind. 1
Ind. 2
Consolidation
12 Gy
vs. 18 Gy
H A M
A I E
12 mg
Rand II
HAE
Except
M 3 + DS
Rand III
Maintenance
1 year +
i.th. Ara-C**
A I
haM
Rand I +
G-CSF* +
G-CSF*

28. AML-BFM 98 Randomization Cycles EFS (5 years)
1.0
0.9
2-Cycle vs. 6-Week Consolidation
0.8
0.7
0.6
.51, SE=.04
0.5 P
.50, SE=.04
0.4
0.3
Tendency for less toxicity with 2-cycle therapy
0.2
0.1
Log-Rank p = .66
0.0 1 2 3 4 5 6 7
years
2-Cycles (N=199, 95 events)
Consolidation (N=191, 85 events)

29. Still discussion, how many intensive courses including induction are needed.
Our experience with <5 courses in pts. with t(8;21) were unfavorable.
MRC results showed no benefit of the 5th course, but courses were different. HD -
Cytarabine 3 g/m²
Day 1 3
every 12
hours
: 3
hour
infusion
for a total of 6
doses
Etoposide
Phosphate 125 mg/m²/d
Day 2,3,4,5 60
minute
Cytarabine IT
Day 0
Cytarabin
e IT in age
related dosages
< 1
year
20 mg ; 1
< 2
years
26 mg
34 mg
>3
40 mg 6 LP
BMP
Days
HAE
HAE

30. CNS Therapy 10x, no triple together with HD-Ara-c
Most CNS relapses occur early in median before CNS-RT was scheduled
Risk factors
Young age <2 years and high WBC
Combined with intensified chemotherapy elements CNS efficiency could be improved
More high-dose cytarabine and liposomal daunorubicin have been introduced in the AML-BFM treatm. schedules since study -93
CNS-RT is replaced by triple i. th. therapy in CNS neg. pts.
to avoid RT-related long-term sequelae
10x, no triple together with HD-Ara-c

31. Maintenance BFM studies: 6-TG daily 40mg/m²
Ara-C s.c. 40mg/m² x4 every 4 weeks - 1 year
Study AML-BFM 12:
Randomization 2 months vs. 1 year maintenance

32. Risik groups Definition Risk-adapted treatment Special Groups for treatment
Core binding factor (CBF) AML
Infants

33. Risk classification by morphology, cytogenetics
and response on day in the AML-BFM studies
M1/2 Auer, M3, M4eo or
t(8;21), t(15;17), inv(16)
Other
FLT3 ITD (M3 excl.)
FAB SR+
BM day 15
>5%
Yes (M3 excl.) No SR HR
35%
65% 33
BJH 1999

34. t(8;21) +/- HAM OS EFS lower CI of relapse with HAM
No HAM scheduled OS
EFS
lower CI of relapse with HAM
Creutzig, BLOOD 118;2011

35. inv(16) EFS OS Creutzig, BLOOD 118;2011
No difference with or without HAM
Creutzig, BLOOD 118;2011

36. AML - BFM 2004 Infants (<2y)
BMP
Day
~ ~140
MRD MRD MRD MRD MRD MRD a
MRD
18 Gy 1
Induction 1
ADxE
Induction 2
HAM
AI/ 2
CDA
haM
Maintenance 1 year
cytarabine IT
1,2
Intensification
Consolidation
AIE R1 AI R3 R2 SR HR
HAE
SCT from HLA
identical
siblings
BFM 2004 Version 03/2004 S
12 Gy
Infants: Drug dosage was generally calculated according to
bodyweight. Dose per kg = m² dose : 30 HD
Ara
C was dose adjusted to age
(from 20% in the <3
month
to 60% in >11
olds).
Reduced desaminase and low clearance

37. Favorable cytogenetics
Patient Data
Infants
N=108
1-2 y.
N=112
2-10 y.
N= 286
p-value %
(chi)
Gender m:f
48:52
50:50
52:48
0.73
WBC
>100,000/µl 26 21 13
0.009
FAB M4/5 60 59 18
<0.0001
FAB M7 19 22 5
CNS pos. 23 7
Extramed. organ involv. 34 31 20
0.007
Favorable cytogenetics 4 9 35
11q23/MLL pos. 51 44

38. Age Groups – Total- AML-BFM 98+04 EFS (5 years) 1.0
0.9
0.8
0.7
0.6
0.5 P
0.4
0.3
infant.tab 12NOV10
0.2
0.1
Log-Rank p = .0090
0.0 1 2 3 4 5 6 7 8 9 10 11 12
years
Age < 1 year , SE=0.05 (N=108, 60 events)
Age 1-<2 years 0.46, SE=0.05 (N=112, 60 events)
Age >=2 years 0.57, SE=0.03 (N=286, 120 events)

39. 95% infants are HR pts. Age Groups AML-BFM 98+04 EFS (5 years)
HR Groups
1.0
0.9
0.8
95% infants are HR pts.
0.7
0.6
0.5 P
0.4
0.3
infant.tab 12NOV10
0.2
0.1
Log-Rank p = .83
0.0 1 2 3 4 5 6 7 8 9 10 11 12
years
Age < 1 year , SE=0.05 (N=103, 57 events)
Age 1-<2 years 0.44, SE=0.05 (N= 95, 53 events)
Age >=2 years 0.46, SE=0.04 (N=164, 88 events)

40. Age< 10 years HR Survival after Relapse (5 years)
1.0
0.9
Results after relapse were even better in infants!
Infants can tolerate intensive relapse treatment!
0.8
0.7
0.6
0.5 P
0.4
0.3
infant.tab 01DEC10
0.2
0.1
Log-Rank p = .024
0.0 1 2 3 4 5 6 7 8 9 10
years
Age < 1 year , SE=0.08 (N= 35, 18 events)
Age 1-<2 years 0.25, SE=0.07 (N= 36, 26 events)
Age >=2 years 0.35, SE=0.07 (N= 57, 35 events)

41. Conclusion Infants are generally HR patients Risk factors:
similar in infants and 1-2 year olds
different in older HR children (e.g. cytogenetics)
Infant age is no independent RF
Intensive AML treatment is feasible in infants
Toxicities can be managed
Outcome is excellent:
5-year OS rate of 79% partly due to salvage therapy after non-/partial response and relapse
However some unfavorable MLL types especially t(4;11) are much more frequent in ALL

42. Risik stratification by genetics
AML-BFM 2012
t(8;21), t(15;17), inv(16)
NK NPM1 /CEBPA dm
others HR
(~20%)
adverse
-5, -7, del(5q), abn(3q)
complex karyotype
t(7;12)(q35;p13)
t(4;11)(q21;q23)
t(6;11 )(q27;q23)
t(5;11)(q35;p15)
t(10;11)
12p abn.
t(9;22)
WT1mut/FLT3-ITD
SR + blast count day 28 > 15% IR
IR + persistence of blasts (>5%) after 2. induction HR IR HR SR OS
<50%
OS >90%
OS ~60%

43. AML-BFM 2012 AIE R R SR IR* HR Special rules for APL
Induction 1
Induction 2
Course 3
Course 4
Course 5
MT 8 wks. Cytarabin i.th.
Inv(16) AI
haM
HAE SR R
t(8;21)/
t(1;11) NPM1 CEBPA dm
HAM AI
haM
HAE
MT 1 year Cytarabin i.th.
AIE R
ADxE
vs CDxA
Clofarabin
IR* AI
HAM
haM
HAE
Clofarabine 40mg – 5 days (day 4-8) HR
HAM AI
haM
alloMSD /MUD
BMP
day MRD MRD MRD MRD MRD
Week
Special rules for APL
*in FLT3-ITD pos. pts. Interval therapy with sorafenib

44. Conclusion Treatment
Total strategy of intensive induction, consolidation and intensification (4-6 courses)
Effective therapy elements: HD Ara-C + anthracycline (Mitox)
And some months of maintenance ?
toxicity reduction by
Initial strategies to avoid early death
justifiable cumulative anthracycline doses
risk-adapted SCT
experiences in the management of therapeutic problems

46. Relapsed AML Affects 30-40% of initial patients achieving CR
Bone marrow usually involved, CNS in 10-15%
50% early, 50% late (< vs >1 year from diagnosis)
Prognosis after relapse has improved considerably

48. DNX-FLAG

49. Kaspers, JCO 2013
Median follow-up pts at risk 4 yrs

50. Survival (4 years) in early and late relapses
Relapsed AML 2001/01
Survival (4 years) in early and late relapses
1.0
0.9
CR2
early rel. 53%
late rel. 73%
0.8
0.7
0.6
0.5
0.45, SE=0.03 P
0.4
rez_fin.tab 13MAY11
0.3
0.2
0.26, SE=0.03
0.1
Log-Rank p = <.0001
0.0 1 2 3 4 5 6 7 8 9
years
Rel.< 1 Year from diagnosis (n=263, 191 events)
Rel.>=1 Year from diagnosis (n=250, 134 events)

51. 4- year survival after relapse according to cytogenetics
1.0
0.9
inv16
0.8
0.7
t(8;21)
0.6
0.5 P
0.4
0.3
0.2
rez_fin.tab 04MAR10
0.1
Log-Rank p = <.0001
0.0 1 2 3 4 5 6 7 8
years
Normal 0.31, SE=0.04 (N=135, 86 events)
t(8;21) 0.65, SE=0.06 (N= 66, 22 events)
inv(16) 0.76, SE=0.09 (N= 29, 6 events)
t(9;11) 0.23, SE=0.11 (N= 18, 13 events)
other 11q , SE=0.07 (N= 50, 35 events)
other 0.31, SE=0.04 (N=190, 127 events)

52. Relapsed AML 2001 Study Patients Survival with or without CR2
1.0
0.9
0.8
0.7
0.6
0.5 P
0.49, SE=0.04
0.4
ibfm0407.tab 20APR07
0.3
0.2
0.14, SE=0.04
0.1
Log-Rank p = <.0001
0.0 1 2 3 4 5 6
years
No CR2 (N=125, 97 events)
CR (N=208, 86 events)

53. 5-year survival after relapse according to
blast counts at day 28
1.0
0.9
Relapsed AML 2001
0.8
Creutzig, Haematologica 2014
0.7
0.6
0.5
0.44, SE =0.03 P
0.4
cyto_1607.tab 29SEP17
0.3
0.2
0.1
Log-Rank p = <.0001
0.10, SE =0.03
0.0 1 2 3 4 5 6 7
years
BM 28 <= 20% (N=384,206 events)
BM 28 > 20% (N=123,108 events)

55. Int. Relapsed AML 2010 DNX-FLA-GO
Reinduction
L-DNR mg/m²/d day 1,3, min infusion
Fludarabine 30 mg/m²/d day 1 to 5
30min infusion
Cytarabine mg/m² day 1 to hr infusion
Gemtuzumab Ozogamicin 4.5mg/m² day hr infusion
Cytarabine/Pred/Mtx i.th. day 0
LP BMP
<1 year
1<2years
2<3years
≥ 3 years
Cytarabin
16 mg
20 mg
26 mg
30 mg
MTX
6 mg
8 mg
10 mg
12 mg
Pred
4 mg
day

56. Conclusion After achieving CR2
After relapse treatment response by BM on day 28 is a strong and independent prognostic factor
pts. who are very unlikely to be cured may be eligible for more intensive /experimental treatment
After achieving CR2
Indication for allo-SCT (MFD and MUD) for every patient
Thank`s for your attention!