ALLEN YEOH, MDSingapore

• 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.

Personalised Therapy in Paediatric ALL

Allen YeohViva-Goh A/Prof in Paediatric Oncology

Yong Loo Lin School of MedicineNational University of Singapore

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 ANDWBC < 50,000/uL

Cytogenetics and age in ALL

MLL

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

EFS in subtypes of ALL

Years from diagnosis

876543210

Eve

nt

Fre

e S

urv

ival

1.0

0.8

0.6

0.4

0.2

0.0

Pre-B ALL without BCR-ABL/t(9;22)-censored

ALL with hyperdiploid karyotype >50-censored

ALL with E2A-PBX1/t(1;19)-censored

ALL with TEL-AML1/t(12;21)-censored

T-ALL-censored

Pre-B ALL with BCR-ABL/t(9;22)-censored

Pre-B ALL without BCR-ABL/t(9;22)

ALL with hyperdiploid karyotype >50

ALL with E2A-PBX1/t(1;19)

ALL with TEL-AML1/t(12;21)

T-ALL

Pre-B ALL with BCR-ABL/t(9;22)

ALL Subtypes

Survival Functions

t(9;22)/BCR-ABL1

t(1;19)/E2A-PBX1

Hyperdip >50

TEL-AML1

OthersT-ALL

• 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

AALL0331: EFS and OS

5 yr EFS 89% (0.6%)5 yr OS 96% (0.4%)

Maloney, ASH 2013

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%

AALL0331: CCR for Risk Groups

0 2 4 6 8

0.0

0.2

0.4

0.6

0.8

1.0

Years

CC

R p

robabili

ty

2 SR Low n 1857

3 SR Average n 1500

4 SR High n 636

AALL0331

CCR by stratum

5-Year CCR ratesSR-Low 95.2% (SE 0.6%)SR-Av 88.8% (SE 1.1%)SR-High 85.7% (SE 1.8%)

Mattano and Maloney,

NCI SR + (+4/10/17) or ETV6-RUNX1AALL 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

AALL0331 Standard Risk-Low Schema

Standard DI

Maintenance

Total 2 PEG doses Total 6 PEG doses

Mattano and Maloney, AALL0331

Consolidation6MP po x 28 daysVCR day 1IT 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

0 2 4 6 8

0.0

0.2

0.4

0.6

0.8

1.0

Years

CC

R p

rob

ab

ility

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 ratesStd 94.4% (SE 1.0%)Std + int PEG 96.0% (SE 0.8%)

Mattano et al. ASH 2014 Abstr 793

14

Diagnostic ALL BM Samples (n = 327)

3-3 -2 -1 0 1 2

Gen

es f

or

cla

ss d

isti

ncti

on

(n

=271)

TEL-AML1BCR-

ABL

Hyperdiploid >

50

E2A-

PBX1

MLL T-ALL Novel

Yeoh et al. Cancer Cell 2002

Prediction Accuracy Using Support Vector Machines

SubgroupsTraining 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%

Alteration in B-cell development genes -> ALL

Ikaros del BCR-ABL1 –ve poorer outcome

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

MP dose in East Asian is lower

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

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

TPMT and NUDT15

NUDT15TPMT

Yang J, et al. J Clin Oncol 2015 early release

TPMT *3C/*3A

Yang J, et al. J Clin Oncol 2015 early release

MP dose intensity for NUDT15mutT

Yang J, et al. J Clin Oncol 2015 early release

rs116855232 NUDT15 T allele

Yang J, et al. J Clin Oncol 2015 early release

Varying times

No routineWith diary

0%

10%

20%

30%

0 1 2 3

Cu

mu

lati

ve in

cid

en

ce o

f re

lap

se

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.

00.00

Years since study exit

Cu

mu

lati

ve in

cid

ence

of

rela

pse

P = 0.020.10

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%

Interaction between ethnicity and adherence

5.3

10.5

0.90.5

0

2

4

6

8

10

12

>/=95% 94.9%-90% 89.9%-85% <85%

whites Hispanics

Haz

ard

Rat

io

Adherence rate

Adherence rate ≥90%

Risk of relapse ishigher among Hispanics c/w non-Hispanic whites

Adherence rate <90%

Risk of relapse is comparable betweenHispanics and

non-Hispanic whites

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

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

MRD response < 0.1% better

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

NECTAR T2008-002Nelarabine-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

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.

BLAst study – Blinatumumab ALL

Nicola Goekbuget, et al. ASH 2014. Abstr 379

Pediatric ChemoRx vs BMT in adult Ph-ve ALL

DFCI vs CIBMTR

Matthew D. Seftel, et al. ASH 2014. Abstr 319

Adults T- Lymphoblastic LymphomaGraall-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

Personalised MedicineCurrent

Morphology + cytochemistryFlow cytometry

B vs TCytogeneticsHyperdiploid > 50Hypodiploid < 44

OFTBCR-ABL1MLL-AF4E2A-PBX1ETV6-RUNX1

Future

Real-time PCRMRD

Multiparametric flow Flow MRD

PharmacogenomicsTPMT, NUDT15

Microarray GEPNext generation sequencing

RNA seqExome profilingWhole genome seq

Thank you