Personalized therapy in Pediatric Acute Lymphocytic Leukemia: Prof. Allen Yeoh

1. ALLEN YEOH, MD
Singapore
• Associate Professor, National University Singapore
• Dr. Yeoh’s interests are in the field of treatment and biology
of childhood malignancies. Others include: Micro array
studies and minimal residual disease detection in childhood
acute leukaemias. Associate Professor Allen Yeoh is the
Principal Investigator of the multi-centre Malaysia-
Singapore ALL and AML studies. The Ma-Spore ALL 2003
study successfully used minimal residual disease
stratification to tailor the intensity of therapy with an
excellent ~80% 6-year EFS. Allen’s interest is in translational
clinical research in acute leukaemia in children. He holds
multiple awards including the American Society of
Hematology Merit Award 2001, Asian Innovation Award
2003, Singapore Clinician Scientist Awards 2005, 2008 and
2013.

2. Personalised Therapy in
Paediatric ALL
Allen Yeoh
Viva-Goh A/Prof in Paediatric Oncology
Yong Loo Lin School of Medicine
National University of Singapore

3. NCI criteria important for risk stratification
NCI Std Risk: 6yr EFS 87.1% n=284
NCI High Risk: 6yr EFS 74.8% n=192
P value=0.000
NCI Std Risk
Age 1- 9 years old AND
WBC < 50,000/uL

4. Cytogenetics and age in ALL
M
L
L

5. EFS by Age Groups
P value=0.001
1yr-9yr: 6yr EFS 84.6% n=357
>9yr: 6yr EFS 76.1% n=99
<1yr: 6yr EFS 65% n=21

6. EFS in subtypes of ALL
Years from diagnosis
876543210
EventFreeSurvival
1.0
0.8
0.6
0.4
0.2
0.0
Pre-B ALL
BCR-ABL/
censored
ALL with h
karyotype
censored
ALL with E
(1;19)-cens
ALL with T
(12;21)-cen
T-ALL-cen
Pre-B ALL
ABL/t(9;22
Pre-B ALL
BCR-ABL/
ALL with h
karyotype
ALL with E
(1;19)
ALL with T
(12;21)
T-ALL
Pre-B ALL
ABL/t(9;22
ALL Sub
Survival Functions
t(9;22)/BCR-ABL1
t(1;19)/E2A-PBX1
Hyperdip >50
TEL-AML1
OthersT-ALL

7. • Newly diagnosed NCI Standard Risk B-ALL
• Age 1-9.99 years
• Initial WBC <50,000/μL
• FISH - +4/+10 or ETV6-RUNX1
• Rapid early response – Day 8/15 and
• Day 33 MRD
• 5313 eligible pts enrolled 2005-2010
COG AALL0331 Eligibility
Maloney, ASH 2013

8. AALL0331: EFS and OS
5 yr EFS 89% (0.6%)
5 yr OS 96% (0.4%)
Maloney, ASH 2013

9. Triple trisomies OR
TEL-AML1 , &
Day 15 (or 8) marrow
M1, &
Day 29 MRD < 0.1%,
No CNS 2/3, or
testicular disease
*No triple trisomies OR
TEL-AML1, &
Day 15 (or 8) marrow
M1, &
Day 29 MRD < 0.1%
*Unless CNS 2 at dx
CNS 3
OR
Day 15 marrow M2/3,
OR
Day 29 MRD ≥ 0.1% -
1%
MLL w/RER
Steroid pretreatment
Age 1.0-9.99 years
WBC < 50,000/ul
B precursor ALL only
AALL0331: Post-Induction Treatment
Assignment
Standard Risk-HighStandard Risk-
Average
Randomized study
Standard risk-
Low
Randomized study
3 drug induction-Dex,
PEG, VCR
Maloney, ASH 2013
MRD cutoff ≥ 0.1%
used to define poor
response; now use ≥
0.01%

10. AALL0331: CCR for Risk Groups
0 2 4 6 8
0.00.20.40.60.81.0
Years
CCRprobability
2 SR Low n 1857
3 SR Average n 1500
4 SR High n 636
AALL0331
CCR by stratum
5-Year CCR rates
SR-Low 95.2% (SE 0.6%)
SR-Av 88.8% (SE 1.1%)
SR-High 85.7% (SE 1.8%)
Mattano and Maloney,

11. NCI SR + (+4/10/17) or ETV6-RUNX1
AALL 0331 – Low risk
• And no CNS or testicular leukemia, and
• rapid marrow response (<5% blasts d15 and end-IND
(MRD) <0.1%).
Intensification of Rx did not improve outcome:
• Intensification by 4 additional PEG-Asp (2500U/m2)
every 3 wks during consolidation/interim
5y CCR 96.0% (0.8) vs 94.4% (1.0) (p=0.1)
5y OS 98.3% (0.6) vs 99.3% (0.4) (p=0.05)
• Intensification by IV Capizzi MTX
3y EFS IV MTX 99.0% (0.4) vs 97.0% (0.5), p=0.16
Mattano LA, et al. ASH 2014. Abstr 793

12. AALL0331 Standard Risk-Low Schema
Standard DI
Maintenance
Total 2 PEG doses Total 6 PEG doses
Mattano and Maloney, AALL0331
Consolidation
6MP po x 28 days
VCR day 1
IT MTX x3
SR-Low is good genetics
and good response
(MRD<0.1%)
3 drug induction
Day 1-36
Consolidation
Interim MP
Consolidation + 2 PEG
Interim MP + 2 PEG

13. 0 2 4 6 8
0.00.20.40.60.81.0
Years
CCRprobability
LRAsp LRAsp IV arms n 928
LRS LRS IV arms n 929
AALL0331 SR-Low Group
CCR by PEG regimen
One sided P value 0.1341
AALL0331 SR-Low: No Benefit with
Intensified Pegasparaginase
5-Year CCR rates
Std 94.4% (SE 1.0%)
Std + int PEG 96.0% (SE 0.8%)
Mattano et al. ASH 2014 Abstr 793

14. 14
Diagnostic ALL BM Samples (n = 327)
3-3 -2 -1 0 1 2
Genesforclassdistinction(n=271)
TEL-AML1BCR-
ABL
Hyperdiploid >
50
E2A-
PBX1
MLL T-ALL Novel
Yeoh et al. Cancer Cell 2002

15. Prediction Accuracy Using
Support Vector Machines
Subgroups
Training Set
Apparent Accuracy
Test Set
True Accuracy Sensitivity Specificity
T-ALL
E2A-PBX1
TEL-AML1
BCR-ABL
MLL rearrangement
Hyperdiploid > 50
100%
100%
98%
96%
100%
93%
100%
100%
99%
97%
100%
96%
100%
100%
100%
83%
100%
100%
100%
100%
98%
98%
100%
93%

16. Alteration in B-cell development genes -> ALL

17. Ikaros del BCR-ABL1 –ve poorer outcome

18. IKZF1 del plus
deletion in PAX5, CDKN2A, CDKN2B or PAR1 and absence of ERGdel
• 6% of ALL cases.
• 5y-EFS IKZF1plus 50%±0.06 vs 86%±0.01
• 5y-CIR 45%±0.06 vs 11%±0.01
5y-EFS 5y-cum relapse
• MRD SR 94%±0.06 6%±0.10
• MRD IR 38%±0.09 62%±0.10
• MRD HR 27%±0.13 55%±0.17
p<0.0001 p<0.0001
Elif Dagdan et al. ASH Abstr 131

19. MP dose in East Asian is lower

20. 6MP ( mg/m2/day) MTX (mg/m2/week) ANC (x109/L)
WT (n=40) 44.5 17.6 2.27
TPMT mutant *3C(A719G) (n=2) 20.7 16 2.4
44.5±2.4
17.6±0.9
2.27 ±0.1
20.7±1.2
16±1.4
2.4±0.3
0
5
10
15
20
25
30
35
40
45
50
Average
Dose Intensity by TPMT Genotype
NUHS Oral Chemotherapy in maintenance in ALL
P=0.032
P=0.712

21. TPMT mutation in 3.1%
Ma-Spore ALL 2003 study
Ethnic
TPMT Chinese Indian Malay Others Total
Wild Type
247
(95.4%)
44
(93.6%)
202
(93.5%)
34
(100%)
527
(94.8%)
*3C (A719G)
8
(3.1%)
2
(4.3%)
6
(2.8%)
0
(0%)
16
(2.9%)
*6 (A539T)
1
(0.4%)
0
(0%)
0
(0%)
0
(0%)
1
(0.2%)
NA
3
(1.1%)
1
(2.1%)
8
(3.7%)
0
0%)
12
(2.1%)
Total 259 47 216 34 556

22. TPMT and NUDT15
NUDT15TPMT
Yang J, et al. J Clin Oncol 2015 early release

23. TPMT *3C/*3A
Yang J, et al. J Clin Oncol 2015 early release

24. MP dose intensity for NUDT15mutT
Yang J, et al. J Clin Oncol 2015 early release

25. rs116855232 NUDT15 T allele
Yang J, et al. J Clin Oncol 2015 early release

26. Varying
times
No routineWith diary

29. 0%
10%
20%
30%
0 1 2 3
Cumulativeincidenceofrelapse
Years since study exit
Cumulative Incidence of Relapse by Adherence
Adherence ≥ 95%
Adherence < 95%
p=0.0003
non-adherers at 3.2-fold increased risk of relapse ( p=0.007),
after adjusting for sociodemographic/clinical variables
The adjusted risk of relapse attributable to non-adherence was
52% for this cohort that entered maintenance in 1st CR.

30. 0
0.00
Years since study exit
Cumulativeincidenceofrelapse
P = 0.02
0.10
0.20
0.30
1 2 3 4 5
0.25
0.15
0.05
Cumulative Incidence of Relapse by Ethnicity
Hispanics: 16.5%
Caucasians: 6.3%

31. Interaction between ethnicity and adherence
5.3
10.5
0.9
0.5
0
2
4
6
8
10
12
>/=95% 94.9%-90% 89.9%-85% <85%
whites Hispanics
HazardRatio
Adherence rate
Adherence rate ≥90%
Risk of relapse is
higher among
Hispanics c/w
non-Hispanic whites
Adherence rate <90%
Risk of relapse is
comparable between
Hispanics and
non-Hispanic whites

32. MP compliance important
• Schedule >95% important.
• Regular routine dosis better – better
complianc.
• With food or dairy or at night not critical for
high dose MP 75 mg/m2 per day. Not sure if
lower doses matters.
• Not need to be too strict – regular more impt

33. COG AALL0433
Intermediate risk relapse
• early isolated CNS/testicular relapse (<18 m), or
late BM/combined relapse (≥36 m) of B-ALL
• N = 271 eligible patients
• 0.1% end-induction MRD predict outcome
• late BM relapse MRD- after induction 3-yr EFS of
80.4 ± 4.7% - no need SCT
• SCT for
– Late BM relapse and MRD +ve
– Early isolated extramedulary relapse -
Lew G, et al. ASH 2014. Abstr 684

34. MRD response < 0.1% better

35. Early bilateral isolated testicular
relapse poor outcome – BFM ALL-REZ
• ALL-REZ trials (1983-2013) = 1603 boys
• Testicular = 302 (18.8% of boys). Isolated testicular 8.4%.
• No difference in timing compared to combined relapse.
• Rx Affected testes 24Gy, other side 15-18Gy. Reinduction and full Rx.
• 5y EFS Isolated testicular 0.70±0.04 better outcome
than combined relapse (0.54±0.04, p=0.005)
• Multivariate poorer outcome:
– Time to relapse,
– Bilateral testicular relapse
– Combine BM and testicular relapse
• Subsequent relapse mainly in BM.
Christiane Chen-Santel, et al. ASH 2014. Abstr 68

36. NECTAR T2008-002
Nelarabine-Etoposide-Cycloph in T-acute lymphoblastic relapse
• NEL 650 mg/m2,
• CPM 440 mg/m2 and
• ETOP 100 mg/m2, each given daily for 5 days
No IT 7 days prior or 21 days after NEC
19 patients with relapsed/refractory T-ALL/LL
T-ALL 44% response
T-LL 25% response
James Whitlock et al. ASH 2014. Abstr 795

37. BLAST – Blinatumumab ALL
Single arm, Phase II study.
• N= 116 ALL patients with MRD positive > 10-3
• Blinatumomab 15 µg/m²/day was given by
continuous IV infusion for 4 weeks
• complete MRD response (negative MRD ≥ 10-4
after 1 cycle)
• 59% grade ≥ 3 SAE and 27% grade ≥4 SAEs
– pyrexia (15%), tremor (7%), aphasia (5%),
encephalopathy (5%), atypical pneumonia
• Most respond by 1 cycle.

38. BLAst study – Blinatumumab ALL
Nicola Goekbuget, et al. ASH 2014. Abstr 379

39. Pediatric ChemoRx vs BMT in adult Ph-ve ALL
DFCI vs CIBMTR
Matthew D. Seftel, et al. ASH 2014. Abstr 319

40. Adults T- Lymphoblastic Lymphoma
Graall-Lysa LL03
• 131 T-LL patients
• 5y EFS 61% and 5y-OS 66%.
• IPI-score had no prognostic value,
• Raised LDH (71% pts)
– lower EFS (HR = 2.8 [1.3 – 6.1]) and
– OS (HR = 3.5 [1.4 – 9.1])
• AlloSCT did not improve outcome
Stephane Lepretre et al. ASH 2014. Abstr 371

41. Personalised Medicine
Current
Morphology
+ cytochemistry
Flow cytometry
B vs T
Cytogenetics
Hyperdiploid > 50
Hypodiploid < 44
OFT
BCR-ABL1
MLL-AF4
E2A-PBX1
ETV6-RUNX1
Future
Real-time PCR
MRD
Multiparametric flow
Flow MRD
Pharmacogenomics
TPMT, NUDT15
Microarray GEP
Next generation sequencing
RNA seq
Exome profiling
Whole genome seq

42. Thank you