Acute Lymphoblastic Leukemiain AYAsNicolas Boissel

Hematology Department, AYA Unit

Saint-Louis Hospital, Paris, France

Lugano, 11 May 2018

Discolures of commercial support

Name of Company

Research support

Employee Consultant Stockholder Speaker’sBureau

Advisory Board

Other

AMGEN X X X

PFIZER X

NOVARTIS X X

SANOFI X

SERVIER X X

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Age-Specific SEER Incidence Rates, 2009-2013

AYA

ALL – Incidence by age

ALL - Survival by ageSEER registry

Keegan TH, Cancer. 2016 Apr 1;122(7):1009-16

1992-19962002-2006

AYA

Year of diagnosis :

ALL in AYA : specificity & issues

• A specific biology of ALL in AYA

• Treatment heterogeneity

• Maintenance therapy and adherence

• Specific short- and long-term toxicities

• Suboptimal health insurance

• Less inclusion in trials

Age and primary abnormalities in B-cell ALL

Moorman A, in Harrison CJ. Br J Haematol 2009;144:147–56

2000

Age and primary abnormalities in B-cell ALL

• t(9;22) / BCR-ABL1

• Hypodiploidy/near-triploidy

• KMT2A(MLL)-r

• iAMP21

• t(17;19) / TCF3-HLF

• Ph-like :

• CRLF2-r, ABL-class…

• MEF2D-r

Iacobucci et Mullighan, J Clin Oncol. 2017 Mar 20;35(9):975-983

Primary abnormalities with high-risk features2017

BCR-ABL1-like & Ph-like in children

Den Boer M et al., Lancet Oncol. 2009 Feb; 10(2): 125–134Harvey RC, et al. Blood. 2010;116:4874–84

COALL-92/97 CCG 1961

Signaling pathways in Ph-like ALL

Iacobucci et Mullighan, J Clin Oncol. 2017 Mar 20;35(9):975-983

Genetic landscape of Ph-like ALL

Hunger S & Mullighan C, Blood. 2015 Jun 25; 125(26): 3977–3987

Ph-like ALL : an AYA disease ?

Herold, N Engl J Med 2014

Translocation involving IGH@ locus :t(X;14)(p22;q32) or t(Y;14)(p11;q32)

Interstitial PAR1 deletion: P2RY8-CRLF2 fusion

Russel , Blood. 2009 Sep 24;114(13):2688-98.Mullighan, Nat Genet. 2009 Nov;41(11):1243-6.Yoda, PNAS 2010 Jan 5;107(1):252-7.

Point mutation

in the CRLF2 gene

7% in children, 50% in Down syndrome

CRLF2 deregulation

JAK2 mutation in 50% of cases

Roberts, Cancer Cell. 2012 Aug 14;22(2):153-66.

Fusion transcripts activating kinases

• JAK2-translocations: 3/15 (20%)• ABL1-translocations: 5/15 (33%)• IGH@-translocations: 4/15 (27%)

Kinase Rearrangements and Therapeutic Targets in Ph-like ALL

Pui CH, Clin Lymphoma Myeloma Leuk. 2017 Aug;17(8):464-470.Lengline E, Haematologica. 2013 Nov;98(11):e146-8.

EBF1 exon 15 PDGFRB exon 11

EBF1-PDGFRB

fusion transcript

174 bp

100 bp

300 bp

Figure 1

8.6 Mbdeletion

A

B

C

5q33

imatinib

BMT

Min

ima

l re

sid

ua

l d

ise

ase

10-1

10-2

10-3

10-4

10-5

Time from diagnosis

(days)50 100 150

induction consolidation

Figure 2

10-0

200 250

French GRAALL strategy to detect kinase activation in BCP-ALL

Personal communication, Emmanuelle Clappier

GENETIC GROUPS

High hyperdiploidyETV6-RUNX1TCF3-PBX1BCR-ABL1iAMP21MLL translocationsERG deletionTCF3-HLFLow hypodip. / Near trip.

B-OTHER CRLF2 deregulation

PRIMARY WORKUP- Karyotype and/or DNA index and/or CGH-array- RQ-PCR and/or FISH for recurrent translocations- ERGdel genomic PCR- RQ-PCR CRLF2 and P2RY8-CRLF2

ABL-class JAK-classUnknown

SECONDARY WORKUP- FISH (ABL1/2, PDGFRB, JAK2)- RT-MLPA (ABL1, EBF1-PDGFRB,…)

EXPLORATORY WORKUPRNAseq / Exome

Kinase sequencing

Minimal/measurable residual disease (MRD) in ALL

Years

1012

10-6

2

1010

108

106

104

102

100

10-4

10-2

= 100%

0

Relapse

Consolidation

Induction

Number

of blast cells

Maintenance

10-0

Residual disease

Morphology

MRDtools

MRD techniques

• IgH/TcR rearrangement

‐ MolBiol, PCR (DNA)

• Leukemic blast phenotype

‐ Flow-Cytometry (blast cells)

• Fusion genes

‐ BCR-ABL1

‐ MolBiol, RT-PCR (RNA)

• Next-generation sequencing

Post-induction MRD

Beldjord K, et al. Blood 2014;123:3739–49

5y-OS: MRD

Age and post-induction MRDin children (>1y) and AYAs

MRD

MRD1

Age and increasing risk of failurein children (>1y) and AYAs with Ph- ALL

Hough R, Br J Haematol. 2016 Feb;172(3):439-51.

Toft N, Leukemia. 2018 Mar;32(3):606-615.

UKALL-2003 NOPHO-2008

Age and increasing risk of TRMin adults (18-59y) with Ph- ALL

18-24y 25-34y 35-45y 46-54y 55-59y

Cumulative incidence of failure(primary resistance, relapse)

Cumulative incidence of TRM(induction death, death in CR1)

Leukemia-related events Treatment-related events

Huguet F. , JCO 2018, in press

Event-free survival

Children Adults Elderly

Cu

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M/F

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TRM and CI of Failure according to age and treatment intensity

Children Adults Elderly

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Treatment Intensity : Low/Medium/HighTRMFailure

Treatment Intensity : Low/Medium/HighTRMFailure

AYA

Age

(yr)

Pts CR

(%)

EFS

(%)

France1 FRALLE 93 15-20 77 94 67

LALA 94 100 83 41

Netherland2 DCOG 15-18 47 98 69

HOVON 44 91 34

UK3 ALL97 15-17 61 98 65

UKALLXII 67 94 49

Sweden4 NOPHO92 15-20 36 99 74

Adult ALL Group 23 90 39

USA5 CCG 16-20 197 90 63

CALGB 124 90 34

Paediatric vs. adult therapyin adolescents 15–20 yr

1. Boissel N, et al. J Clin Oncol 2003;21:774–80; 2. De Bont JM, et al. Leukemia 2004;18:2032–5;3. Ramanujachar R, et al. Pediatr Blood Cancer 2007;48:254–61;

4. Hallböök H, et al. Cancer 2006;107:1551–61; 5. Stock W, et al. Blood 2008;112:1646–54

Impact of age-based care organizationon the outcome of AYA 18-39y

Siegel SE, JAMA Oncol. 2018 Feb 15.

Five-Year Relative Survival Rate by Single Year of Age at Diagnosis, 2000 to 2007 (SEER)

AYA in “pediatric-inspired” trials

TrialPatients

N

Age range

years

Median age

yearsCR

Early

death

Death in

CRHSCT EFS/DFS/CRD

years

OS

years

PETHEMA ALL-96 81 15-30 20 98% 1% 1%# 0%# 6 EFS, 61% 6 69%

HOVON (FRALLE 93) 54 17-40 26 91% 4% NR 35% 2 EFS, 66% 2 72%

FRALLE 2000 89 15-29 19 99% NR NR 28% 5 EFS, 61% 5 66%

JALSG ALL202-U 139 16-24 19 94% 5% 4% 15% 5 DFS, 67% 5 73%

Intergroup C10403 296 17-39 24 NR NR NR NR 2 EFS, 66% 2 78%

DFCI 01-175 74 18-50* 28* 86% 1% NR 21% 4 EFS, 58% 4 67%

A-BFM (MDACC) 106 13-39 22 93% 1% 8% 10% 3 CRD, 70% 5 60%

HyperCVAD (MDACC) 102 15-40 27 98% 1% 7% 6% 3 CRD, 67% 5 60%

Modified DFCI 91-01** 42 18-35 NR 98% 0% NR NR 3 DFS, 77% 3 83%

GMALL 07/03** 887 15-35 NR 91% 4% NR 43% 5 CRD, 61% 5 65%

GRAALL-2003/2005** 502 15-35 24 97% NR NR NR 5 EFS, 59% 5 65%

NOPHO-2008 221 18-45 NR NR 1% 6% NR 5 EFS, 74% 5 78%

5y-OS 60-78%

Death in CR7-9%Boissel N & Baruchel A, Blood 2018, in press

HSCT10-43%

Adolescents in recent pediatric trials

Boissel N & Baruchel A, Blood 2018, in press

Trial Patients Age rangeMedian

ageCR

Early

death

Death

in CRHSCT EFS OS

(N) years years years years

CCG-1961 262 16-21 NR 95% 2% 3% 4% 5 72% 5 78%

DFCI 9101/9501 51 15-18 16.2 94% 4% 2% NR 5 78% 5 81%

Total Therapy XV 45 15-18 NR 98% 0% 7% 11% 5 86% 5 88%

UKALL-2003 229 16-24 NR 97% NR 6% 6.1% 5 72% 5 76%

FRALLE-2000 186 15-19 16.1 96% 2% 2% 12% 5 74% 5 80%

5y-OS 78-88%

Death in CR4-7%

HSCT4-12%

Differences in outcomein adolescents with ALL:

Schiffer CA. J Clin Oncol 2003;21:760–1

“Paediatricians administer these treatments with a military

precision on the basis of a near-religious conviction about

the necessity of maintaining prescribed dose and

schedule come hell, high water, birthdays, Bastille Day, or

Christmas.”

A consequence of better regimens?

Better doctors?

Both?

FRALLE 2000, 15–19 yrAdult vs. paediatric centres

Cluzeau T et al, ASH 2012, abstract 3561

0

,2

,4

,6

,8

1

0 1 2 3 4 5 6 7 8

▬▬ Paediatric------ Adultp=.0004

83%

56%

0

,2

,4

,6

,8

1

0 1 2 3 4 5 6 7 8

Years

▬▬ Paediatric------ Adultp=.0001

82%

41%

EFS

(%)

OS

(%)

Differences in- Age Yes, but not relevant- ALL characteristics No- Doctors, facilities Yes, but which mechanism?

Years

Adherence to 6-MP during maintenance Paediatric COG study

Bhatia S, et al. J Clin Oncol 2012;30:2094–101

VariableEstimated

Adherence (%)P

Time on study, months < .001

1 94.7 —

2 93.1 < .001

3 92.5 < .001

4 91.6 < .001

5 91.0 < .001

6 90.2 < .001

Age at study participation < .001

< 12 years 93.1

≥ 12 years 85.8

Household structure .001

Multiple caregivers 93.1

Single mother 80.6

Ethnicity < .001

Non-Hispanic whites 94.8

Hispanics 88.4

Adherence

Impact of age on major toxicities NOPHO-2008

Toft N, Leukemia. 2018 Mar;32(3):606-615.

Avascular Necrosis (AVN)A major issue in Adolescents with ALL

• The risk of AVN is correlated to the cumulative dose of corticosteroids.

• Asparaginase and high-dose MTX mayincrease the risk of AVN

• Other factors associated with risk of AVN are :• older age (>10 yr),

• Higher BMI,

• continuous steroid administration,

• HSCT, GvHD.

• AVN incidence rate is about 20% for patients > 15 yr in pediatric trials.

Relling MV et al., J Clin Oncol. 2004 Oct 1;22(19):3930-6.

Mattano LA et al., Lancet Oncol 13 (9): 906-15, 2012.

by age

Alternate weekvs.

Continuous

0

5

10

15

20

25

30

10 Gy 12 Gy 14-15.75 Gy BuCy

0

5

10

15

20

25

30

10 Gy 12 Gy 14-15.75 Gy BuCy

Ovarian function after HSCT for ALL

• Infertility is common after SCT

• Persistent ovarian failure is shown in more than 80% of female after myeloablative regimen and almost all patients after Bu-Cy.

• Incidence of pregnancy less than 3%

• Increased risk for maternal and fetal complications after TBI-based regimen

Sanders JE et al., Blood. 1996 Apr 1;87(7):3045-52

Salooja N et al., Lancet. 2001 Jul 28;358(9278):271-6.

% p

atie

nts

Pregnancy

Ovarian recovery

TBI

Recovery of spermatogenesis after HSCT

Rovò A et al.,

Haematologica. 2013 Mar;98(3):339-45

Risk factors for azoospermia

ConclusionAYA with ALL

• The transition between children and adult ALL biology occurs in AYA patients.

• Adolescents aged 15–20 years should be treated in paediatric trials

• Young adults benefit from full paediatric or paediatric-inspired approaches. Upper age limit to adopt such strategies should be prospectively explored.

• Rapid screening for targetable and/or high-risk diseases may help to offer early access to precision medicine.

• AYA programs should be developed :

‐ to offer specific psychological & social support,

‐ to maintain engagement in school, education & workplace (re)integration

‐ to ensure fertility preservation and survivorship care plan

Biologists

C. AbbalV. AsnafiM. BakkusL. BarangerK. BeldjordMC. BénéML. BoullandH. Cavé JM. CayuelaA. ChasseventE. ClappierE. DelabesseN. GrardelM. LafageE. MacIntyreB. SchäferJ. Soulier

Clinicians

N. BoisselT. BraunA. BuzynJY. CahnY. ChalandonP. ChevallierA. DelannoyN. DhédinM. Escoffre-BarbeC. GardinC. Graux

Coordination

V. LhéritierN. IfrahH. Dombret

Biostatistics

J. LejeuneS. Chevret

… All GRAALL investigators

D. HeimU. HessF. HuguetA. HuynhM. HunaultT. LeguayS. LeprêtreJP. MarolleauS. MauryP. RousselotX. ThomasJP. VernantN. Vey