biologie des lal-b - ovhaihemato/aih/documents/cours...biologie des lal-b emmanuelle clappier...

Biologie des LAL-B

Emmanuelle Clappier

Service d’Hématologie biologique, hôpital Saint-Louis, AP-HP

Equipe Génome et Cancer, UMR INSERM/CNRS 944/7212, IRSL

Université Paris-Diderot

DES Hématologie

12 avril 2019

Leucémies aiguës lymphoblastiques

✓ 800 cas/an en France, moitié enfant/adulte

✓ 80% des leucémies de l’enfant

✓ 4% des hémopathies malignes de l’adulte

Données GRAALL, Huguet, JCO 2009Hunger, NEJM 2015

LALA-94

GRAALL-2003/05

LAL-B de l’enfant LAL-B de l’adulte

Identifier des cibles thérapeutiques

Stratifier le traitement

Elucider les altérations génomiques des leucémies pour:

Comprendre les mécanismes oncogéniques

Identifier des marqueurs pronostiques

t(1;19) / E2A-PBX1

t(9;22) / BCR-ABL1Chromosome Philadelphie

Les débuts de la génomique des leucémies:anomalies cytogénétiques récurrentes dans les LAL-B

t(12;21) / ETV6-RUNX1 "cryptique" détectée par FISH

fusion

AML1

ES AML1TEL

6 7 8 9

1 2 3 4 5

10 11 12 X

13 14 15

16 17 18

19 20

21 22 Y

Hyperdiploïdie "standard " +X,+4,+6,+8,+10,+14,+17,+18,+21,+21

t(4;11) / MLL-AF4

Yeoh, Cancer Cell 2002

t(9;22) / BCR-ABL1

Ph1 Fusion TEL-AML1

AML1

Split AML1TEL

6 7 8 9

1 2 3 4 5

10 11 12 X

13 14 15

16 17 18

19 20

21 22 Y

t(1;19) / E2A-PBX1

MLL break-apart

Signatures transcriptionnelles associées aux altérations fondatrices

(years)

0 2 4 6 8 10 12

0

10

20

30

40

50

60

70

80

90

100

Logrank test: p<0.0001

t(12;21) ETV6-RUNX1

n=74 (23%)

Hyperdiploidy

n=109 (34%)

Others

n=122 (38%)

t(9;22) or t(4;11)

n=19 (6%)

% EFS

Données EORTC-CLG 58881, H. Cavé

Pronostic associé aux sous-types génétiques dans les LAL-B de l’enfantAnnées 1990-2000

Pronostic des altérations « classantes »

Hyperdiploidy30-35%

ETV6-RUNX120-25%

« B-other »25-30%

TCF3-PBX1

BCR-ABL1

iAMP21MLLt

Hypo/haploidy

< 5% chacun

Paysage génomique des LAL-B Ph-neg pédiatriques en 2010

years0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100Ev

ent

free

su

rviv

al

Cohorte EORTC-CLG 58951N = 1223

Lafage-Pochitaloff, Blood 2017

Cytogénétique des LAL-B Ph-nég de l’adulte

Données GRAALL-2003/05



Hyperdiploidy30-35%

ETV6-RUNX120-25%

« B-other »25-30%

TCF3-PBX1

BCR-ABL1

iAMP21MLLt

Hypo/haploidy

< 5% chacun

years0 2 4 6 8 10

0

10

20

30

40

50

60

70

80

90

100Ev

ent

free

su

rviv

al

Données EORTC-CLG 58951N = 1223 pts

B-other:~50% des rechutes

Paysage génomique des LAL-B Ph-neg pédiatriques en 2010

CGH/SNP-array et séquençage nouvelle génération (NGS):Multiplicité des lésions oncogéniques additionnelles

Roberts, NEJM 2014

Oncogenèse multi-étape +++

Mullighan, Nature 2007

Stigmates de recombinaison RAG-médiée :

• points de cassures clusterisés

• séquences RSS-like

• addition de nucléotides (région N)

Altérations secondaires/additionnelles

Paysage génomique des LAL-B pédiatriques

Altérations initiatrices et/ou classantes

Altérations secondaires/additionnelles

High hyperdiploidy

ETV6-RUNX1

TCF3-PBX1

ERGdel

iAMP21

Low hypo/near-haploidy

MLLt

B-Other

BCR-ABL1

Hyperdiploidy30-35%

« B-other »25-30%

TCF3-PBX1

BCR-ABL1< 5%

MLLt

Hypo/haploidy

< 5% each

ERGiAMP21

ETV6-RUNX120-25%

Frequency of IKZF1 deletions in distinct BCP-ALL genetic subtypes

0

10

20

30

40

50

60

70

80

90

100

BCR-ABL1 MLL / 11q23

abn.

low hypo /

near-haploidy

iAMP21 TCF3-PBX1 ERGdel ETV6-RUNX1 High

hyperdiploidy

B-other

IKZF1

15%

% of IKZF1del in each genetic subtype

4-7

telo centro1 2 3 4 5 6 7 8

7p12.2

2-3, 2-7, D2-8, D4-8…

Whole deletion (including 7p-)

Délétions d’IKZF1

Impact pronostique des délétions d’IKZF1

86.5%

67.7%

HR = 2.41 (1.75, 3.32)

p<0.0001

(years)

0 2 4 6 8 10 12 14

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : IKZF1 deletion134 1044 984 771 511 303 129 10

52 179 159 118 84 49 13 1

Negative

Positive

92.4%

86.7%

HR = 1.67 (1.03, 2.72)

p<0.035

(years)

0 2 4 6 8 10 12 14

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : IKZF1 deletion73 1044 1010 833 567 339 152 15

21 179 172 137 105 69 21 1

Negative

Positive

Even

t-fr

ee s

urv

ival

(%)

8-y EFS

No IKZF1del

IKZF1del

n = 1223 Ph-negative BCP-ALL in childrentreated in EORTC-CLG 58951 trial (1998-2008)

Beldjord, Blood 2014;123:3739-49

N= 216 Ph-negative BCP-ALL in adultstreated in GRAALL 03/05 trials (2003-2011)

IKZF1del

No IKZF1del

Clappier E, et al. Leukemia 2015;29:2154–61

IKZF1 deletion is a marker of poor outcome in B-other ALL

Forest-plot analysis

EORTC-CLG 58951 study

Clappier E, et al. Leukemia2015;29:2154–61

B-other

87/354 IKZF1del (25%)

HR=2.22 (1.45, 3.39)

p=0.0002

79.0%

56.4%

years0 2 4 6 8 10 12 14

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : IKZF1 deletion

51 264 240 176 119 75 37 336 90 74 55 40 24 6 1

NegativePositive

8-y EFS

IKZF1 intragenic deletionBP-PCR +/- CGH

Risk classification in GRAALL-2014

MRD1 ≥ 10-4 et <10-3

Oncogenetics

TP1

TP2

High risk criteria

Very High Risk criteria

MRD2 ≥ 10-4

MRD1 ≥ 10-3

MLL/KMT2A rearrangementKaryo, FISH, bio mol

MRD

High hyperdiploidy

ETV6-RUNX1

TCF3-PBX1

ERGdel

iAMP21

Low hypo/near-haploidy

MLLt

B-Other

BCR-ABL1

Hyperdiploidy30-35%

« B-other »25-30%

TCF3-PBX1

BCR-ABL1< 5%

MLLt

Hypo/haploidy

< 5% each

ERGiAMP21

ETV6-RUNX120-25%

Hyperdiploidy5-10%

ETV6-RUNX1

« B-other »~50%

TCF3-PBX1

BCR-ABL1~25%

iAMP21

MLLt~10%

Hypo/haploidy

< 5% each

LAL-B pédiatriques LAL-B adultes

Groupes génétiques des LAL-B de l’adulte et de l’enfant

LAL Ph-like (BCR-ABL1-like) : un groupe de mauvais pronostic

Den Boer, Lancet Oncology 2009

Den Boer, Lancet Oncology 2009Harvey, Blood 2010

ProB signatureFrequent IKZF1 deletions (40-90%)

Mutations JAK

Shochat, J Exp Med 2011

Altérations génétiques ciblant l’axe CRLF2-IL7R-JAK2-STAT5

Translocations IGH@-CRLF2t(X;14)(p22;q32) ou

t(Y;14)(p11;q32)

Délétion interstitielle PAR1 fusion P2RY8-CRLF2

Mutations IL7R

Dérégulation CRLF2Russel LJ, et al. Blood 2009

Yoda A, et al. Proc Natl Acad Sci 2010

➢ Signalisation dérégulée potentiellement « ciblable » par des inhibiteurs de JAK, PI3kinase, mTOR

Russel LJ, et al. Blood 2009

Mullighan CG, et al. Proc Natl Acad Sci 2009

ruxolitinib

rapamycine

Peeters P et al., Blood 1997Reiter A et al., Cancer Res 2005De Braekeleer E et al., Leukemia 2007Poitras JL et al., Chromosomes & Cancer 2008Hidalgo-Curtis C et al., Genes, Chrom & Cancer 2008Soler G et al., Leukemia 2008Ernst E et al., British Journal of Haematology 2011Kakadia PM et al., Leukemia 2011Kobayashi K et al., British J of Haematology 2014Lilljebjorn U et al., Leukemia 2014Roberts KG, et al. N Engl J MedKawamura M et al., Genes, Chrom & Cancer 2015Yano M et al., British J of Haematology 2015…

Partenaires

ATF7IPBCREBF1ETV6FOXP1LSM14AMEF2DNUMA1NUP214PAX5PCM1RANBP2RCSD1SFPQSHIP1SNX2SSBP2STRN3SPTBN1ZC3HAV1ZMIZ1ZMYM2 … Roberts KG, et al. Cancer Cell 2012

Kinases

ABL1

ABL2

PDGFRB

PDGFRA

CSF1R

JAK2

NTRK3

LYN

SYK

FLT3

FGFR1…

Fusions impliquant des kinases: partenaires variés +++

Pronostic des LAL Ph-like chez l’adulte

Jain, Blood 2017

Roberts, JCO 2017

0.00

0.20

0.40

0.60

0.80

1.00

Ove

rall

Sur

viva

l

13 10 5 4 3 1 1 1 0 0 Number at risk

0 1 2 3 4 5 6 7 8 9Time(years)

Hunger, Blood 2015

Jain, Blood 2017

GRAALL, unpublished data

Peeters P et al., Blood 1997Reiter A et al., Cancer Res 2005De Braekeleer E et al., Leukemia 2007Poitras JL et al., Chromosomes & Cancer 2008Hidalgo-Curtis C et al., Genes, Chrom & Cancer 2008Soler G et al., Leukemia 2008Ernst E et al., British Journal of Haematology 2011Kakadia PM et al., Leukemia 2011Kobayashi K et al., British J of Haematology 2014Lilljebjorn U et al., Leukemia 2014Roberts KG, et al. N Engl J MedKawamura M et al., Genes, Chrom & Cancer 2015Yano M et al., British J of Haematology 2015…

Partenaires

ATF7IPBCREBF1ETV6FOXP1LSM14AMEF2DNUMA1NUP214PAX5PCM1RANBP2RCSD1SFPQSHIP1SNX2SSBP2STRN3SPTBN1ZC3HAV1ZMIZ1ZMYM2 … Roberts KG, et al. Cancer Cell 2012

Kinases

ABL1

ABL2

PDGFRB

PDGFRA

CSF1R

JAK2

NTRK3

LYN

SYK

FLT3

FGFR1…

Fusions impliquant des kinases: partenaires variés +++

Kinases de classe ABL

-> sensibilité aux inhibiteurs

de type imatinib

BCR-ABL1High hyperdiploidyLow hypodiploidyMLL fusionsiAMP21 ERGdel (DUX4)CRLF2 deregulationTCF3-PBX1ETV6-RUNX1TCF3-HLF ABL1 fusionsJAK2 fusionsPDGFRB fusionsPAX5 fusionsZNF384 fusions

… all known fusion beeing detected by RT-MLPA

KaryotypeFISH

RNA-seq

BP-PCR IKZF1del , ERGdel

RQ-PCR CRLF2, EPOR

CGH-arrayRT-MLPA

No classifying lesion identifiedand

Poor treatment response

Stratégie de diagnostic prospectif centralisé des altérations génétiques Ph-like pour une prise en charge thérapeutique précoce

Search for fusion genes

Reads

LSM14A ex6 TGATAACAAGAGACAAGTAGGTGAAAAGCTCCGGGTCTTAG ABL1 ex3

SPTBN1 ex9 TCATCTCTGACATCAACAAGAAGCCACGTTACGAGATCCAG PDGFRB ex12

NRF1 ex10 TGGAGTCCAAGATGCTAATGTTATGAACTATTAACAGAAAA JAK2 ex19

ZNF566 ex4 AACAAGAGGCCAGTGGCCAGTTGAACTTAGCTCATTAAGGG JAK2 ex9

ZEB2 ex10 ACATAAATACGAACACACAGATTATGAACTATTAACAGAAA JAK2 ex19

ETV6 ex4 GCATCAGAACCATGAAGAAGATGTGCAGCACATTAAGAGGA NTRK3 ex15

CREBBP ex14 AAGGGGAGCCCAGGTCTGAGGTAGAATGGAAGAATCTCACT ZNF384 ex3

EP300 ex6 GCGGCCCATGAGCAACATGAAAAGTTCAGGAGCCCTGGAAA ZNF384 ex3

RNA-seq analysis for « B-other » ALL cases

Efficacy of Tyrosine Kinase Inhibitors therapy in patients with Philadelphia-like Acute Lymphoblastic Leukemia harboring ABL-class fusions

Lengliné, et al., Haematological2013Duployez et al., Haematologica 2016Tanensi et al. , manuscript in preparation

Retrospective study on 24 patientsTreated with TKI firstline (n=19) or at relapse (n=5)


Lengliné, et al., Haematological2013Duployez et al., Haematologica 2016Tanensi et al. , manuscript in preparation


Tanensi et al. , manuscript in preparation



3-years OS 77%

Tanensi et al. , manuscript in preparation



3-years OS 77%

-> Recommendation for the treatment of patients with Ph-like ALL ABL-class in the GRAALL 2014 trial:Imatinib 600 mg in association with chemo

ZD

+

321

0-1-2-3

Classifying alterations

BCR-ABL1-likeKMT2A

B_

SL

06

7B

_S

L0

61

B_

SL

05

0B

_S

L0

52

B_

SL

13

8B

_S

L1

69

B_

SL

03

2B

_S

L0

60

B_

SL

09

3B

_S

L0

23

B_

SL

06

3B

_S

L0

76

B_

SL

01

1B

_S

L0

06

B_

SL

03

1B

_S

L0

37

B_

SL

11

1B

_S

L0

13

B_

SL

15

5B

_S

L0

42

B_

SL

10

7B

_S

L1

28

B_

SL

07

4B

_S

L1

08

B_

SL

16

5B

_S

L0

46

B_

SL

00

2B

_S

L1

27

B_

SL

02

2B

_S

L1

09

B_

SL

06

9B

_S

L0

71

B_

SL

11

8B

_S

L1

40

B_

SL

12

3B

_S

L0

98

B_

SL

14

5B

_S

L1

46

B_

SL

10

3B

_S

L0

21

B_

SL

01

4B

_S

L0

30

B_

SL

05

3B

_S

L1

35

B_

SL

08

6B

_S

L1

14

B_

SL

05

5B

_S

L1

61

B_

SL

05

8B

_S

L0

09

B_

SL

01

5B

_S

L1

53

B_

SL

03

6B

_S

L1

42

B_

SL

04

4B

_S

L1

34

B_

SL

12

1B

_S

L0

16

B_

SL

04

7B

_S

L1

20

B_

SL

15

2B

_S

L0

99

B_

SL

13

7B

_S

L1

43

B_

SL

08

7B

_S

L0

51

B_

SL

06

2B

_S

L0

88

B_

SL

13

0B

_S

L0

27

B_

SL

07

0B

_S

L0

96

B_

SL

09

4B

_S

L1

10

B_

SL

09

7B

_S

L1

06

B_

SL

01

0B

_S

L1

67

B_

SL

06

4B

_S

L1

31

B_

SL

03

8B

_S

L0

80

B_

SL

11

7B

_S

L0

25

B_

SL

08

5B

_S

L0

54

B_

SL

06

6B

_S

L1

16

B_

SL

02

8B

_S

L0

03

B_

SL

04

5B

_S

L0

04

B_

SL

13

3B

_S

L0

84

B_

SL

02

0B

_S

L1

12

B_

SL

01

8B

_S

L0

17

B_

SL

02

4B

_S

L0

34

B_

SL

00

5B

_S

L0

68

B_

SL

07

7B

_S

L0

75

B_

SL

11

9B

_S

L0

08

B_

SL

05

7B

_S

L1

36

B_

SL

16

6B

_S

L1

49

B_

SL

07

8B

_S

L1

25

B_

SL

10

5B

_S

L0

29

B_

SL

15

4B

_S

L0

33

B_

SL

14

7B

_S

L1

70

B_

SL

08

9B

_S

L1

64

B_

SL

04

0B

_S

L0

95

B_

SL

05

6B

_S

L1

48

B_

SL

03

5B

_S

L1

59

B_

SL

17

2B

_S

L1

56

B_

SL

01

2B

_S

L0

91

B_

SL

12

6B

_S

L1

29

B_

SL

05

9B

_S

L1

32

B_

SL

00

1B

_S

L0

90

B_

SL

06

5B

_S

L0

26

B_

SL

04

8B

_S

L1

68

B_

SL

08

2B

_S

L0

19

B_

SL

14

1B

_S

L1

57

B_

SL

16

0B

_S

L1

39

B_

SL

10

0B

_S

L0

79

B_

SL

04

9B

_S

L0

07

B_

SL

03

9B

_S

L0

73

B_

SL

12

2B

_S

L1

63

B_

SL

10

1B

_S

L1

51

B_

SL

14

4B

_S

L1

50

B_

SL

17

4B

_S

L0

43

B_

SL

09

2B

_S

L1

02

B_

SL

12

4B

_S

L1

71

B_

SL

17

3B

_S

L1

04

B_

SL

08

3B

_S

L1

13

B_

SL

11

5B

_S

L0

72

USP32P1G PM 6BCO L6A3CXCL12HLA- DRB6HLA- DQ A2ZNF516FAM 171A1B3G NT5CREB5DI RAS1PLK2RG S16SPRY1SO CS3G PR183RG S1RG S2HSPA1BI TG A9SERPI NE1SNAI 1EFNB1XI RP1PER1EG R1EG R2EG R3BHLHE40FO SBDLL1HBEG FSI K1ATF3G RASPM AFFNR4A1BRE- AS1FO SL2NR4A2NR4A3PVRL2RTP5ELL2SG K1I FI T2SNX9DUSP8SYTL3PELI 1ERM NTNFPTG S2CXCL8ADMI ER3PLI N2UNC13BCEBPAADG RE2M YRI PFLT3ABHD17CEM P1SPRY2ADM 2N4BP3ETV5PDG FAI RX1LAM B2CACNA2D4CSF1RCCNA1M M P14NI NLCLEC11AAI F1LCO L5A1DDR1STAG 3CLEC14ANO S2BCL6BFLT4CD9S100A16HSPG 2PALMHTRA3UG T3A2LO C101928841LG R6LO C728175ZNF185CYG BM N1LCN8I FI 44LCPAM D8CO BLTM CC3ANKRD33BKI AA1462FAM 101BWDFY3LPAR6DO CK6CNN3NXNC6or f 25M M P17RASD1FAM 69BCALN1SI PA1L2SM AD1NPR1WFS1EG FL7ERGSHANK3I TG A6CD34DAPK1TDRD9PTPRDFRM D4ATTC28SPP1RG S18VNN1ATP9ASALL4G ATA3TFPIPCDH10ESAMM AST4VASH2CASC15DEF8H1F0FSCN1AG AP3NPDC1CDH11M ACRO D2PPM 1HPVRL1CSM D1ARHG AP24BTNL9KLF11LO C729737TNS1CYBBPADI 2M POCEACAM 6TUBB6SYTL2I G LL5SEL1L3M CO LN2M ARCKSKI AA0125ANXA5M S4A1TTNLTBTESSH2D1AAHNAKG PRI N3FCRL1M TSS1S100A10FCG R3AG NLYPRF1G ZM BTCF7CD6RO RAI TKVCANI TG A2BPPBPLG ALS1LM NACRI P1SELLM PEG 1THBS1I FI TM 1JCHAI NBM P3PTCH1F13A1ARHG EF12M YH10SPATS2LALDH1A1FLT1DCHS1AASSLO C284581G NG 11KLF4FAT1UNC79VLDLRSERI NC2LI NC01226DDI T4LHS3ST4SO X7G LDCLO C613266LO C728989HDG FRP3PCDH9STAP1CHST2PTPRMAG AP1CLEC12ALHFPL2M PPED2RG M BSDK1PCDH17SHRO O M 3SDC2M LLT4FM NL2APBB2M TCL1SNX25NETO 1FSTL4M DG A1PO U4F1KI AA0226LAKAP12LI NC01163LG R5PTG DRANKRD30BTM PRSS15CO L24A1CDH4NPR3SPO N1PLCB4TI NAG L1PREX2SETBP1TBC1D9SLI TRK4CYB5R2O VCH2G O LG A8AG O LG A8BM YEF2M CTP2I KZF2CRM P1SULF2LAM A3I G F2BP2SO X11ZNF711NRN1LI NC00689M YT1LDO CK1SCN3ACDC42BPBCECR2PLEKHG 4BRG S9M CAMM TSS1LCPXM 1KCNQ 5NFATC4ATP1A3DTX1RASAL1PTPN14NEG R1USP53SYNMCD96EVPLNAV2M EG F10KI R3DX1PDG FRBKCNA5ABCA9PTPRKSYT1APBA1NPYFG FR1CO L27A1ARHG AP32PHG DHPARD3ADG RA3SLI T2I G F2BP3THSD7AI FNLR1VAT1LLAM P5CAM K2DI RF4EFEM P1TENM 4G PR176RPS17M AP1BPAX8- AS1USP6PRO M 1M YO 10G REM 1YES1CD109KCNK17LCN10LCN6FZD6PLCH1TI AM 2KLF8BAALCNEI L1STAB1SH3BP5DPEP1PLEKHG 1PFKFB2CDC42EP3I RX2RCAN1I D3EPHA7NT5EPO N2SO CS2PCLOCTG FLI NC01013CHST15BLACEP2RY14CYTL1PLVAPFAM 69CECM 1TSPAN7SLC2A5ELFN2LI NC00114M YO 1BTM EM 236VWA2NRXN3M UC4ADG RF1ADG RG 1DENND3PRXEPAS1ARHG EF17PALD1NRP1BM P2SEM A6ATP53I NP1M M ERI M S3ARPP21LRI G 1PEG 10RAPG EF5ARHG AP29KHDRBS3ATP10AAHRKCTD12KLF9SCM L1NKAI N4NPTX1M YO 7BCPNE7M YO 18BSDK2SCN4AFAM 150BAO X2PTCL6TCL1BLO C101927697RAG 1BAHCC1VPREB1TCL1ADNTTI G LL1VPREB3

Genetic alteration

PAX5 P80R

Other PAX5 mutations

PAX5 deletion

DDDD- - D- DD- DDD- - D- - DD- ZZ- ZZZZZ- ZZZ- ZZZZZZZZZ- ZZ- Z- - - - - - - - - - - - - - - - - KKKKKB- - - - - - - - HHBBBBBBBBBBBBBBBB- B- B- - - - - - - - - B- - - - - L - - P- - - L - PM- - - - - L - - - B- - - - - - - - - - - - - - P- Z- - MB- - - - - - - B- - B

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ++++++++++++++- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - - - - - - - - - - + - - + - - - - - - - - - - - - - - - - - - - - - - - +++- - - - - - - - ++ - - - . - - - - - - - - - - - - - - - - - + - - - - - - - - - - - - - - - - - - - - - - + - - - - +++- - . - - - - - - + - - - - - - - - - - - - - - - - - - - + - - - - - - - - - - + - - - - - - - - - - - - -

. . . . - ++ - . + . . + - . - . + - - . . . . + . - . - . . . - + . . - - . - + . . - . . . - - - - - - - ++++++++- - . . . . . . - . . . . . + . . . - + - + . . . - . - - - . . - . + - - - - . - . - - - - + - - . . . ++++ . - . . . - - - - - - . . . . . - . . . . . . - + - - + . - . ++ . + . . . - . . . . . + . . . . . . .

-3.0 -2.9 -2.8 -2.7 -2.6 -2.5 -2.4 -2.3 -2.2 -2.1 -2.0 -1.9 -1.8 -1.7 -1.6 -1.4 -1.3 -1.2 -1.1 -1.0 -0.9 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0

ZNF384DUX4/ERG


ZNF384 fusion BCR-ABL1-like rearrangement Low hypodiploidy PAX5 fusionDUX4 rearrangement MLL/KMT2A rearrangement Hyperdiploidy MEF2D fusion

BK

-

LH

.

PM

BCR-ABL1-likeDUX4/ERG ZNF384

Gene expression profiling


ZD

+

321

0-1-2-3


BCR-ABL1-likeKMT2A

B_

SL

06

7B

_S

L0

61

B_

SL

05

0B

_S

L0

52

B_

SL

13

8B

_S

L1

69

B_

SL

03

2B

_S

L0

60

B_

SL

09

3B

_S

L0

23

B_

SL

06

3B

_S

L0

76

B_

SL

01

1B

_S

L0

06

B_

SL

03

1B

_S

L0

37

B_

SL

11

1B

_S

L0

13

B_

SL

15

5B

_S

L0

42

B_

SL

10

7B

_S

L1

28

B_

SL

07

4B

_S

L1

08

B_

SL

16

5B

_S

L0

46

B_

SL

00

2B

_S

L1

27

B_

SL

02

2B

_S

L1

09

B_

SL

06

9B

_S

L0

71

B_

SL

11

8B

_S

L1

40

B_

SL

12

3B

_S

L0

98

B_

SL

14

5B

_S

L1

46

B_

SL

10

3B

_S

L0

21

B_

SL

01

4B

_S

L0

30

B_

SL

05

3B

_S

L1

35

B_

SL

08

6B

_S

L1

14

B_

SL

05

5B

_S

L1

61

B_

SL

05

8B

_S

L0

09

B_

SL

01

5B

_S

L1

53

B_

SL

03

6B

_S

L1

42

B_

SL

04

4B

_S

L1

34

B_

SL

12

1B

_S

L0

16

B_

SL

04

7B

_S

L1

20

B_

SL

15

2B

_S

L0

99

B_

SL

13

7B

_S

L1

43

B_

SL

08

7B

_S

L0

51

B_

SL

06

2B

_S

L0

88

B_

SL

13

0B

_S

L0

27

B_

SL

07

0B

_S

L0

96

B_

SL

09

4B

_S

L1

10

B_

SL

09

7B

_S

L1

06

B_

SL

01

0B

_S

L1

67

B_

SL

06

4B

_S

L1

31

B_

SL

03

8B

_S

L0

80

B_

SL

11

7B

_S

L0

25

B_

SL

08

5B

_S

L0

54

B_

SL

06

6B

_S

L1

16

B_

SL

02

8B

_S

L0

03

B_

SL

04

5B

_S

L0

04

B_

SL

13

3B

_S

L0

84

B_

SL

02

0B

_S

L1

12

B_

SL

01

8B

_S

L0

17

B_

SL

02

4B

_S

L0

34

B_

SL

00

5B

_S

L0

68

B_

SL

07

7B

_S

L0

75

B_

SL

11

9B

_S

L0

08

B_

SL

05

7B

_S

L1

36

B_

SL

16

6B

_S

L1

49

B_

SL

07

8B

_S

L1

25

B_

SL

10

5B

_S

L0

29

B_

SL

15

4B

_S

L0

33

B_

SL

14

7B

_S

L1

70

B_

SL

08

9B

_S

L1

64

B_

SL

04

0B

_S

L0

95

B_

SL

05

6B

_S

L1

48

B_

SL

03

5B

_S

L1

59

B_

SL

17

2B

_S

L1

56

B_

SL

01

2B

_S

L0

91

B_

SL

12

6B

_S

L1

29

B_

SL

05

9B

_S

L1

32

B_

SL

00

1B

_S

L0

90

B_

SL

06

5B

_S

L0

26

B_

SL

04

8B

_S

L1

68

B_

SL

08

2B

_S

L0

19

B_

SL

14

1B

_S

L1

57

B_

SL

16

0B

_S

L1

39

B_

SL

10

0B

_S

L0

79

B_

SL

04

9B

_S

L0

07

B_

SL

03

9B

_S

L0

73

B_

SL

12

2B

_S

L1

63

B_

SL

10

1B

_S

L1

51

B_

SL

14

4B

_S

L1

50

B_

SL

17

4B

_S

L0

43

B_

SL

09

2B

_S

L1

02

B_

SL

12

4B

_S

L1

71

B_

SL

17

3B

_S

L1

04

B_

SL

08

3B

_S

L1

13

B_

SL

11

5B

_S

L0

72


Genetic alteration

PAX5 P80R


PAX5 deletion


- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ++++++++++++++- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - - - - - - - - - - + - - + - - - - - - - - - - - - - - - - - - - - - - - +++- - - - - - - - ++ - - - . - - - - - - - - - - - - - - - - - + - - - - - - - - - - - - - - - - - - - - - - + - - - - +++- - . - - - - - - + - - - - - - - - - - - - - - - - - - - + - - - - - - - - - - + - - - - - - - - - - - - -

. . . . - ++ - . + . . + - . - . + - - . . . . + . - . - . . . - + . . - - . - + . . - . . . - - - - - - - ++++++++- - . . . . . . - . . . . . + . . . - + - + . . . - . - - - . . - . + - - - - . - . - - - - + - - . . . ++++ . - . . . - - - - - - . . . . . - . . . . . . - + - - + . - . ++ . + . . . - . . . . . + . . . . . . .

-3.0 -2.9 -2.8 -2.7 -2.6 -2.5 -2.4 -2.3 -2.2 -2.1 -2.0 -1.9 -1.8 -1.7 -1.6 -1.4 -1.3 -1.2 -1.1 -1.0 -0.9 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0

ZNF384DUX4/ERG



BK

-

LH

.

PM



-> PAX5 P80R mutation

PAX5 deletions

ZD

+

321

0-1-2-3


BCR-ABL1-like

PAX5 P80RPAX5 other mutations

KMT2A

B_

SL

06

7B

_S

L0

61

B_

SL

05

0B

_S

L0

52

B_

SL

13

8B

_S

L1

69

B_

SL

03

2B

_S

L0

60

B_

SL

09

3B

_S

L0

23

B_

SL

06

3B

_S

L0

76

B_

SL

01

1B

_S

L0

06

B_

SL

03

1B

_S

L0

37

B_

SL

11

1B

_S

L0

13

B_

SL

15

5B

_S

L0

42

B_

SL

10

7B

_S

L1

28

B_

SL

07

4B

_S

L1

08

B_

SL

16

5B

_S

L0

46

B_

SL

00

2B

_S

L1

27

B_

SL

02

2B

_S

L1

09

B_

SL

06

9B

_S

L0

71

B_

SL

11

8B

_S

L1

40

B_

SL

12

3B

_S

L0

98

B_

SL

14

5B

_S

L1

46

B_

SL

10

3B

_S

L0

21

B_

SL

01

4B

_S

L0

30

B_

SL

05

3B

_S

L1

35

B_

SL

08

6B

_S

L1

14

B_

SL

05

5B

_S

L1

61

B_

SL

05

8B

_S

L0

09

B_

SL

01

5B

_S

L1

53

B_

SL

03

6B

_S

L1

42

B_

SL

04

4B

_S

L1

34

B_

SL

12

1B

_S

L0

16

B_

SL

04

7B

_S

L1

20

B_

SL

15

2B

_S

L0

99

B_

SL

13

7B

_S

L1

43

B_

SL

08

7B

_S

L0

51

B_

SL

06

2B

_S

L0

88

B_

SL

13

0B

_S

L0

27

B_

SL

07

0B

_S

L0

96

B_

SL

09

4B

_S

L1

10

B_

SL

09

7B

_S

L1

06

B_

SL

01

0B

_S

L1

67

B_

SL

06

4B

_S

L1

31

B_

SL

03

8B

_S

L0

80

B_

SL

11

7B

_S

L0

25

B_

SL

08

5B

_S

L0

54

B_

SL

06

6B

_S

L1

16

B_

SL

02

8B

_S

L0

03

B_

SL

04

5B

_S

L0

04

B_

SL

13

3B

_S

L0

84

B_

SL

02

0B

_S

L1

12

B_

SL

01

8B

_S

L0

17

B_

SL

02

4B

_S

L0

34

B_

SL

00

5B

_S

L0

68

B_

SL

07

7B

_S

L0

75

B_

SL

11

9B

_S

L0

08

B_

SL

05

7B

_S

L1

36

B_

SL

16

6B

_S

L1

49

B_

SL

07

8B

_S

L1

25

B_

SL

10

5B

_S

L0

29

B_

SL

15

4B

_S

L0

33

B_

SL

14

7B

_S

L1

70

B_

SL

08

9B

_S

L1

64

B_

SL

04

0B

_S

L0

95

B_

SL

05

6B

_S

L1

48

B_

SL

03

5B

_S

L1

59

B_

SL

17

2B

_S

L1

56

B_

SL

01

2B

_S

L0

91

B_

SL

12

6B

_S

L1

29

B_

SL

05

9B

_S

L1

32

B_

SL

00

1B

_S

L0

90

B_

SL

06

5B

_S

L0

26

B_

SL

04

8B

_S

L1

68

B_

SL

08

2B

_S

L0

19

B_

SL

14

1B

_S

L1

57

B_

SL

16

0B

_S

L1

39

B_

SL

10

0B

_S

L0

79

B_

SL

04

9B

_S

L0

07

B_

SL

03

9B

_S

L0

73

B_

SL

12

2B

_S

L1

63

B_

SL

10

1B

_S

L1

51

B_

SL

14

4B

_S

L1

50

B_

SL

17

4B

_S

L0

43

B_

SL

09

2B

_S

L1

02

B_

SL

12

4B

_S

L1

71

B_

SL

17

3B

_S

L1

04

B_

SL

08

3B

_S

L1

13

B_

SL

11

5B

_S

L0

72


Genetic alteration

PAX5 P80R


PAX5 deletion


- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ++++++++++++++- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - - - - - - - - - - + - - + - - - - - - - - - - - - - - - - - - - - - - - +++- - - - - - - - ++ - - - . - - - - - - - - - - - - - - - - - + - - - - - - - - - - - - - - - - - - - - - - + - - - - +++- - . - - - - - - + - - - - - - - - - - - - - - - - - - - + - - - - - - - - - - + - - - - - - - - - - - - -

. . . . - ++ - . + . . + - . - . + - - . . . . + . - . - . . . - + . . - - . - + . . - . . . - - - - - - - ++++++++- - . . . . . . - . . . . . + . . . - + - + . . . - . - - - . . - . + - - - - . - . - - - - + - - . . . ++++ . - . . . - - - - - - . . . . . - . . . . . . - + - - + . - . ++ . + . . . - . . . . . + . . . . . . .

-3.0 -2.9 -2.8 -2.7 -2.6 -2.5 -2.4 -2.3 -2.2 -2.1 -2.0 -1.9 -1.8 -1.7 -1.6 -1.4 -1.3 -1.2 -1.1 -1.0 -0.9 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0

ZNF384DUX4/ERG PAX5P80R



PAX5 alterationsPositive Negative Not available

BK

-

LH

.

PM

Pro80Arg

Gene expression profilingGene mutation analysis


Passet et al., Blood 2019

0.00

0.20

0.40

0.60

0.80

1.00

Ove

rall

Su

rviv

al

14 10 10 10 9 9 5 1 1 0PAX5P80R

298 140 107 87 64 43 25 8 4 0No PAX5P80R

Number at risk

0 1 2 3 4 5 6 7 8 9Time(years)

P=0.036

Biological and clinical features associated with PAX5 P80R

0.00

0.20

0.40

0.60

0.80

1.00

Overa

ll S

urv

ival

0 1 2 3 4 5 6 7 8 9

Time(years)

PAX5P80R

No PAX5P80R

B_

SL12

0B

_SL

152

B_

SL01

602

9-00

5602

1-03

54B

_SL

099

1304

4B

_SL

121

B_

SL13

715

112

B_

SL04

402

1-00

2701

5-02

26B

_SL

143

008-

0382

1650

40B

_SL

134

1500

113

054

B_

SL04

7B

_SL

142

B_

SL03

600

5-01

12B

_SL

087

B_

SL05

112

044

1146

1112

045

1508

712

078

RNA-seqCGH-array

Targeted NGSSanger PAX5

PAX5 P80R

PAX5 2nd allele

CDKN2A loss

IKZF1 deletion

Signaling

NRAS

KRAS

IL7R

PTPN11

P2RY8-CRLF2

FLT3

NF1

JAK2

PTPRC

SH2B3

PAX5 P80R PAX5 2nd allele CDKN2A loss IKZF1 deletion

Homozygous

Heterozygous

Deleted

Mutated

Monoallelic

Biallelic

Whole

Intragenic

Negative

Not available

Passet et al., Blood 2019

✓ Inactivation of PAX5 2nd allele, CDKN2A loss, RAS signalling

✓ Good response to treatment, favorable outcome

Hyperdiploidy

Hypo/neartriploidy

MLLr

Other

PAX5P80R

TCF3-PBX1

Genomic classification at RNA-seq era: update GRAALL-2014-B on 310 patients

BCR-ABL1-like18%

MLL/KMT2A16%

Low hypodiploidy10%

High hyperdiploidy7%

DUX4/ERG6%

ZNF384 fusion6%

PAX5 P80R6%TCF3-PBX1

4%MYC+/-BCL2

3%

IGH-CEBP3%ETV6-RUNX1

2%

PAX5 fusion2%

New2%

iAMP211%

TCF3-HLF1%

MEF2D-BCL91%

Other12%

ZD

+

321

0-1-2-3


BCR-ABL1-likeKMT2A

B_

SL

06

7B

_S

L0

61

B_

SL

05

0B

_S

L0

52

B_

SL

13

8B

_S

L1

69

B_

SL

03

2B

_S

L0

60

B_

SL

09

3B

_S

L0

23

B_

SL

06

3B

_S

L0

76

B_

SL

01

1B

_S

L0

06

B_

SL

03

1B

_S

L0

37

B_

SL

11

1B

_S

L0

13

B_

SL

15

5B

_S

L0

42

B_

SL

10

7B

_S

L1

28

B_

SL

07

4B

_S

L1

08

B_

SL

16

5B

_S

L0

46

B_

SL

00

2B

_S

L1

27

B_

SL

02

2B

_S

L1

09

B_

SL

06

9B

_S

L0

71

B_

SL

11

8B

_S

L1

40

B_

SL

12

3B

_S

L0

98

B_

SL

14

5B

_S

L1

46

B_

SL

10

3B

_S

L0

21

B_

SL

01

4B

_S

L0

30

B_

SL

05

3B

_S

L1

35

B_

SL

08

6B

_S

L1

14

B_

SL

05

5B

_S

L1

61

B_

SL

05

8B

_S

L0

09

B_

SL

01

5B

_S

L1

53

B_

SL

03

6B

_S

L1

42

B_

SL

04

4B

_S

L1

34

B_

SL

12

1B

_S

L0

16

B_

SL

04

7B

_S

L1

20

B_

SL

15

2B

_S

L0

99

B_

SL

13

7B

_S

L1

43

B_

SL

08

7B

_S

L0

51

B_

SL

06

2B

_S

L0

88

B_

SL

13

0B

_S

L0

27

B_

SL

07

0B

_S

L0

96

B_

SL

09

4B

_S

L1

10

B_

SL

09

7B

_S

L1

06

B_

SL

01

0B

_S

L1

67

B_

SL

06

4B

_S

L1

31

B_

SL

03

8B

_S

L0

80

B_

SL

11

7B

_S

L0

25

B_

SL

08

5B

_S

L0

54

B_

SL

06

6B

_S

L1

16

B_

SL

02

8B

_S

L0

03

B_

SL

04

5B

_S

L0

04

B_

SL

13

3B

_S

L0

84

B_

SL

02

0B

_S

L1

12

B_

SL

01

8B

_S

L0

17

B_

SL

02

4B

_S

L0

34

B_

SL

00

5B

_S

L0

68

B_

SL

07

7B

_S

L0

75

B_

SL

11

9B

_S

L0

08

B_

SL

05

7B

_S

L1

36

B_

SL

16

6B

_S

L1

49

B_

SL

07

8B

_S

L1

25

B_

SL

10

5B

_S

L0

29

B_

SL

15

4B

_S

L0

33

B_

SL

14

7B

_S

L1

70

B_

SL

08

9B

_S

L1

64

B_

SL

04

0B

_S

L0

95

B_

SL

05

6B

_S

L1

48

B_

SL

03

5B

_S

L1

59

B_

SL

17

2B

_S

L1

56

B_

SL

01

2B

_S

L0

91

B_

SL

12

6B

_S

L1

29

B_

SL

05

9B

_S

L1

32

B_

SL

00

1B

_S

L0

90

B_

SL

06

5B

_S

L0

26

B_

SL

04

8B

_S

L1

68

B_

SL

08

2B

_S

L0

19

B_

SL

14

1B

_S

L1

57

B_

SL

16

0B

_S

L1

39

B_

SL

10

0B

_S

L0

79

B_

SL

04

9B

_S

L0

07

B_

SL

03

9B

_S

L0

73

B_

SL

12

2B

_S

L1

63

B_

SL

10

1B

_S

L1

51

B_

SL

14

4B

_S

L1

50

B_

SL

17

4B

_S

L0

43

B_

SL

09

2B

_S

L1

02

B_

SL

12

4B

_S

L1

71

B_

SL

17

3B

_S

L1

04

B_

SL

08

3B

_S

L1

13

B_

SL

11

5B

_S

L0

72


Genetic alteration

PAX5 P80R


PAX5 deletion


- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ++++++++++++++- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- - - - - - - - - - - - - - - - - - - - - - - - + - - + - - - - - - - - - - - - - - - - - - - - - - - +++- - - - - - - - ++ - - - . - - - - - - - - - - - - - - - - - + - - - - - - - - - - - - - - - - - - - - - - + - - - - +++- - . - - - - - - + - - - - - - - - - - - - - - - - - - - + - - - - - - - - - - + - - - - - - - - - - - - -

. . . . - ++ - . + . . + - . - . + - - . . . . + . - . - . . . - + . . - - . - + . . - . . . - - - - - - - ++++++++- - . . . . . . - . . . . . + . . . - + - + . . . - . - - - . . - . + - - - - . - . - - - - + - - . . . ++++ . - . . . - - - - - - . . . . . - . . . . . . - + - - + . - . ++ . + . . . - . . . . . + . . . . . . .

-3.0 -2.9 -2.8 -2.7 -2.6 -2.5 -2.4 -2.3 -2.2 -2.1 -2.0 -1.9 -1.8 -1.7 -1.6 -1.4 -1.3 -1.2 -1.1 -1.0 -0.9 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0

ZNF384DUX4/ERG



BK

-

LH

.

PM

???



-> New genetic subtype to be explored

LAL-B Ph+

Ph. Rousselot, unpublished data

M o n th s

BC

R-A

BL

IS

%

-6 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0

0 .0 0 1

0 .0 1

1

1 0

1 0 0

U n d e te c ta b le

M M R

0

AutoHSCT

IM Nilotinib

MRD1

IgH0.01

IgH neg IgH neg

BLINATUMOMAB

MRD positivity after auto-SCT 36y female, Ph+ ALL, e1a2

-6

-4

-2

0

-6 -4 -2 0

IgTcr

BC

R.A

BL

Neg

100%

10%

1%

0,01%

0,001%

0,1%

10010-110-210-410-5 10-3

PnqNeg

Ig/TCR

High number of discordant results between BCR-ABL1 and Ig/TCR

n=101 n=12

n = 433 samples

rp = 0.47

77 patients

BCR-ABL1/ABL1 transcripts

(Positive

not quantifiable)

-6

-4

-2

0

-6 -4 -2 0

IgTcr

BC

R.A

BL

-6

-4

-2

0

-6 -4 -2 0

IgTcr

BC

R.A

BL


Neg

100%

10%

1%

0,01%

0,001%

0,1%

BM PB

10-110-210-410-5 10-3

PnqNeg

Ig/TCR100

n=181 samples

rp=0.60

n=252 samples

rp=0.38

More discordant results in peripheral blood than in bone marrow

n=36 n=61

-> In agreement with lower levels of B-cell ALL MRD in PB than in BM (van der Velden, Leukemia 2002)

MRD1

-6

-4

-2

0

-6 -4 -2 0

IgTcr

BC

R.A

BL

n=116

MRD2

-6

-4

-2

0

-6 -4 -2 0

IgTcr

BC

R.A

BL

MRD3

-6

-4

-2

0

-6 -4 -2 0

IgTcr

BC

R.A

BL

MRD4

-6

-4

-2

0

-6 -4 -2 0

IgTcr

BC

R.A

BL

n=126 n=96 n=95


Ig/TCR

Dissociation persists at late timepoints

-> In agreement with persistance of BCR-ABL1 clonal hematopoiesis after

lymphoblasts clearance

Nagel, Blood 2017

BCR-ABL1–positive cells outside the B-lineage compartment

are found in 40% of adult patients with Ph-ALL

-6

-4

-2

0

-6 -4 -2 0

IgTcr

BC

R.A

BL

Neg

100%

10%

1%

0,01%

0,001%

0,1%

10010-110-210-410-5 10-3

PnqNeg

Ig/TCR

36/77 (47%) patients have dissociated kinetics:

≥ 1 log difference at ≥ 2 timepoints

n=101 n=12

n = 433 samples

rp = 0.47

77 patients


1 log

36 patients

(Positive

not quantifiable)

Patients with dissociated kinetics exhibit

distinct clinico-biological features

Dissociated

N=36

Parallel

N=41P-value

Median age, years 45 48 0.66

Male/female ratio 2,6 1,05 0.067

Organ infiltration 11/34 [32] 10/35 [29] 0.80

WBC, G/L [quartiles] 27.1 [9.2;69.9] 12.3 [6.4;27.0] 0.056

Neutrophils, G/L [quartiles] 4.5 [2.0;9.5] 1.8 [0.8;2.8] 0.0009

Lymphocytes, G/L [quartiles] 3.1 [2.1;5.8] 2.8 [1.8;3.9] 0.20

Monocytes, G/L [quartiles] 0.4 [0.1;1.1] 0.1 [0;0.2] 0.019

Blast, G/L [quartiles] 8.4 [1.6;33.1] 6.9 [1.3;24.4] 0.5

Blast % in BM [quartiles] 84 [76;92] 92 [85;95] 0.028

Major BCR [%] 17/36 [47] 5/41 [12] 0.0009

IKZF1 intragenic deletion [%] 16/36 [44] 31/41 [76] 0.0094

Non leukemic

Chronic or pre-leukemic

Acute leukemic

Differenciation

Transformation

HSC Pro-B Pre-B Immature B

V(D)J rearrangements

IKZF1del

CML-like disease in relation with occurrence of BCR-ABL1 in

an early/non B-committed hematopoietic progenitor

CML-like Ph+ALL

BCR-ABL1

Consistant data at diagnosis in Nagel, Blood 2017

Clinical relevance of a BCR-ABL1 clonal hematopoiesis

after blast clearance ?

✓ Prognostic relevance of BCR-ABL1 clonal hematopoiesis ?

✓ Therapeutic management ?

✓ Different MRD marker for different therapeutic decision

Remerciements

Laboratoire d’HématologieUnité Hématologie moléculaire et

bioinformatiqueHôpital Saint-Louis, IUH

Marie PassetRathana KimIbrahima Ba

Samuel Quentin

François SigauxJean Soulier

All GRAALL investigators and biologists

Colombe Saillard, Mario Bargetzi, Xavier Thomas, Carlos Graux, Yves Chalandon, Thibaut Leguay, Etienne Lengliné, Johanna Konopacki Mathilde Hunault, Eric Delabesse, Marina Lafage, Cédric

Pastoret, Nathalie Grardel, Vahid Asnafi

Nicolas BoisselVéronique Lhéritier

Hervé Dombret

biologie des lal-b - ovhaihemato/aih/documents/cours...biologie des lal-b emmanuelle clappier...

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