CMML: from biology to treatment · Median WBC P=0.01 28.1 x109/L 12.6 x109/L. Blood , 2013 • GM-CSF–dependent STAT5 hypersensitivity in 90% of CMML samples and is enhanced by

CMML from biology to

treatment

Pierre Fenaux

Hocircpital St Louis

Paris 7 UniversityFrance

GFM

ASH 2015

Disclosure

I have the following financial

relationships

Consultant and Contracted

Research for

Boehringer Ingelheim Celgene Corporation

Janssen Pharmaceuticals Inc Novartis

An update on CMML

bull Definition epidemiology

bull Characteristics

bull Pathophysiology

bull Differential diagnosis

bull Prognostic factors

bull Response criteria

bull treatment

An update on CMML







bull treatment

1 Persistent PB monocytosis (gt1 x109L)

bull gt 3 months

bull (gt 10 of WBC)

bull No impact of BM monocyte

2 No Phi- or BCR-ABL fusion gene

bull No eosinophilia no PDGFRAB rearrangement

3 lt20 myeloblasts or monoblasts in PB or BM

bull Including promonocytes

4 Evidence of dysplasia in one or more lineages

bull If lacking acquired clonal cytogenetic abnormality

bull or persistent monocytosis gt 3 months with exclusion of all other causes of monocytosis

bull CMML-1 lt5 PB blasts and lt10 BM blasts

bull CMML-2 5ndash19 PB blasts and 10ndash19 BM blastsVardiman Blood 2009

WHO-2008 criteria for CMML

Goasguen Haematologica 2009

Promonocytes in CMML

Epidemiology

bull Elderly patients (median age 75)

bull Male predominance (2 to 31)

bull Incidence About 20 of MDS (05 to

1100000year)

bull About 10 are therapy related

bull About 20 associated with immunological

disorders

bull 358 CMML patients of whom 39 (11) had t-CMML

bull median latency to develop t-CMML 6 years

time from outside diagnosis to MDACC referral was 15 months (range

0-80) Of thosepatients 39 (11) had prior exposureto chemotherapy andor

radiation therapy and were defined as t-CMML Clinical data of the studied

patientswereobtained at the timeof referral to MDACC Therapies that were

given to the patients were categorized into 4 groups (1) best supportive care

or cytoreductive therapy using hydroxyurea or oral etoposide (BSCCR) (2)

hypomethylating agents (HMA) such as 5-azacitidinendashbased or decitabine-

based regimens (3) AML-like induction therapy and (4) other therapies

including immunomodulatory drugs(thalidomideor lenalidomide) or tyrosine

kinase inhibitors (iMiDsTKIs) Cytogenetics and mutational analyses of

Figure 1 Survival estimate for t-CMML and de novo CMML Differences in OS duration (A) and LFS duration (B) between 319 patients with de novo CMML and 39 patients with t-CMML

BLOOD 17 OCTOBER 2013 x VOLUME 122 NUMBER 16 THERAPY-RELATED CHRONIC MYELOMONOCYTIC LEUKEMIA 2809

Original Paper

A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution

Introduction

Key Words

Abstract

Do

wnlo

ad

ed b

y

INS

ER

M D

ISC

IS

T

19

81

43

431

- 1

12

32

015

85

00

9 P

M

123 CMML 195 had at least one immune-mediated

disorder most commonly ITP gout and psoriasis

Association between CMML and vasculitis

An update on CMML







bull treatment

CMML in the adult a report of 60 cases with special reference to prognostic

factorsBr J Haematol 198765101-6

bull MF 33

bull median age 73 years

bull Splenomegaly in 32 of cases

bull hyperleucocytosis in 52 of cases

bull mean blood monocytosis 43 X 10(9)l

bull marrow blasts gt=5 57 of the cases

bull median survival was 28 months

hematological characteristics

ndash MDS

bull cytopenias

bull excess of marrow blasts

bull marrow dysplasia

bull abnormal karyotype (-7+8 rarely complex)

ndash MPN

bull Splenomegaly

bull Extra hematological disease (serous effusions cutaneous

lesions)

bull increased WBC counts

bull monocytosis (gt1000mm3)

bull immature myeloid cells in the blood (myelocytes

metamyelocytes)

laquo dysplastic raquo CMML WBC lt 13GL

laquo proliferative raquo CMML WBC gt 13Gl

Haematologica 2011

Flow Cytometry as diagnostic tool

Selimoglu-Buet et al Blood 2015

CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16

Peripheral blood human monocyte subsets

MO2 CD14+CD16+

Intermediate

monocytes

Age-matched controls CMML reactive monocytosis

CMML monocytosis is made mostly of classical (MO1)

monocytes

CD14

CD16

CMML MDS MDS MPN

Before AZA After AZA

CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA

Response to hypomethylating agents

includes a decrease in MO1 subset

Respond

ers (N=7)

Molecular abnormalities in 80 CMML

RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1

Frequency of mutations (Itzykson JCO

2013)

Gene Ndeg pts studied Mutation

TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)

U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5

genotype phenotype Correlations(Itzykson JCO 2013)

bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations

bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations

bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC

bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)

bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)

bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)

An update on CMML


bull Characteristics classification





bull treatment

CMML clonal architecture

1 ndash Early clonal dominance

2 - Linear acquisition of mutations

3 - Growth advantage to the more mutated cells with differentiation

TET2 SRSF2 KRAS

Itzykson R et al Blood 2013


4 - Some branching events mostly due to

mitotic recombination


Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2

GM-CSF hypersensitivity in CMML

GM-CSF hypersensitivity is present in only some

CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60

Itzykson et al Blood 2013

Median WBC

P=001

281 x109L

126 x109L

Blood 2013

bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations

bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential

Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype

bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)

bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages

a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes

JCI 2011

bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment

ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML

bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG

sequences and specific histone modifications in the genepromoter

bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression

bull 167 differentially methylated regions

(DMRs) of DNA at baseline distinguished

responders from nonresponders using

NGS

These DMRs were primarily localized to

nonpromoter regions and overlapped with

distal regulatory enhancers

An update on CMML







bull treatment

CMML differential diagnosis

bull Reactive monocytosis (infectionshellip)

bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip

bull MDS evolving to CMML

bull Monocytosis during transition from MPN or MDS to M4 or M5 AML

bull Other MDSMPN



CMML 2 or M4 or M5 AML

bull Clinical findings ndash Cutaneous involvement

ndash Gingival hypertrophy

bull Coagulopathy (DIC)

bull WBC gt 100Gl

bull Auer rods

bull Mutationsndash FLT3 ITD

ndash NPM1

An update on CMML







bull treatment

Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988

bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors

ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype

ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly

bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with

82 accuracyndash Longer term survival (at 42 months) predicted by initial

PB leukocyte count

CMML laquo Scores raquo

bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)

bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)

bull GFM score (JCO 1988)

bull IPSS

bull MD Anderson score (Blood 2002)

bull Italian ndashSpanish score (CPSS) (Blood 2012)

bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)

bull R-IPSSbull Recent cooperative efforts

Prognostic value of mutations univariate analysis (Itzykson JCO 2013)

120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1

N agrave risque Mois

Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)

favorableunfavorable

01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)

Prognostic score including gene

mutations

Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts

Itzykson et al JCO 2013

0-4 low5-7 int8-11 high

bull N=1832 8 centers

bull 80 CMML 1

bull 75 marrow blasts better cut off than 10

bull All prognostic scores valid

bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)

bull After correction for Hb ndash circulating blasts

ndash Plts

ndash Karyotype

ndash ASXL1 (P = 00114)

ndash CBL (P = 0003) mutations as independently prognostic

bull N=261 CMML aged lt65 years

bull In multivariable analysis

ndash lower HB (P = 001)

ndash higher circulating blast (P = 0002)


ndash SRSF2 mutations (P = 0008)

ndash Mayo-French cytogenetic stratification (P = 004)

negatively impacted survival

An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML

bull Treatment of symptomatic disorders

ndash Myeloproliferation

ndash Cytopenias

bull laquo disease modifying raquo drugs

ndash Chemotherapy

ndash Hypomethylating agents (HMAs)

bull Allogeneic SCT

bull laquo targeted drugs raquo

bull N=94 (Spanish and Dusseldorf registries)

bull Erythroid response (ER) in 64 and RBC-TI in 31

bull median duration 7 months (range 0ndash88)

bull CPSS and EPO level significantly associated with ER (P = 0003)

bull In CPSS low- or int 1-risk

ndash absence of RBC TD

ndash EPO level

Treatment of thrombocytopenia

bull Peripheral thrombocytopenia

bull Hypomethylating agents

bull TPO agonist receptors

ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)

Treatment of proliferative CMML

CMML with poor prognostic factors (Wattel Blood 1996)

1)If WBC le13 Gl

- IPSS int-2 or high

2) If gt13 Gl

at least 2 of the following criteria

-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl

-Thrombocytopenia lt100 Gl

-Splenomegaly (SMG)

OR

-Extramedullary lesions (EML)

A randomized trial of hydroxyurea

versus VP16 in adult advanced CMMLWattelBlood 1996

bullN= 105

bullHydroxyurea yields 60 RR (1 CR) but

mainly minor responses vs 35 RR for

etoposide

Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML

Median survival 20 vs 12 months

HMAs in CMML

-n= 76

-55 CMML1 and 45 CMML2

-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly

-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both

bull 33 (43) responses including 13 CR ()

bull Median survival 29 months

bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)

ndash marrow blasts gt10 (p = 005)

bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival

bullbull

Matched-pair analyses

-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)

-longer OS for azacitidine first- line

vs HY first-line

(median 277 vs 62

Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011

bull Inclusion criteria

(1) age gt 18

(2) CMML (WHO 2008 criteria)

(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high

ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5

bull Hb lt10gdL

bull platelets lt 100000mm3

bull abnormal cytogenetics

bull SMG gt5 cm below costal margin

bull Extra medullary disease

Decitabine in advanced CMML a phase 2

trialT Braun Blood 2011

bull 39 advanced CMML

bull Median number of cycles 10

bull Overall response rate 38 ( 10 CR 21

marrow CR 8 stable with HI)

bull OS 48 at 2 years

bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)

bull Median OS 275 months

two-gene classifier (ASXL1SRSF2) stratifying

patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)




NGS




DACOTA phase III trial DAC vs HY in advanced CMML

bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates

ndash Gene mutationsndash Gene expressionndash Gene methylation

bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)

Allogeneic SCT in CMML

bull 73 patients transplanted between 1992 and 2009median age 53 yrs

bull 36 palpable splenomegaly

bull 61 CMML-1 39 CMML-2

bull 48 13 and 9 good int and poor riskkaryotype

bull 43 RIC

bull 3-year OS NRMEFS and CIR 32 36 29 and 35

Year of transplant lt2004 and

palpable splenomegaly

unfavorable

prognostic factors

BJH 2015

bull N=513 median age 53 allo before 2010

bull Conditioning standard (n = 249) RIC (n = 226)

bull Donors related (n = 285) or unrelated (n = 228)

bull Disease status at transplantation CR (122 patients) no CR (344)

bull 4-year NRM 41 relapse 32 RFS 27 OS 33

bull CR at transplantation associated with better

bull N=83 from 1991 to 2013

bull 41 received CT 37 HMA beforeallo SCT

laquo Targeted raquo treatments in CMML

bull Farnesyl transferase inhibitors

ndash Tipifarnib (15 CR) (Blood 2007)

ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)

bull JAK2JAK1 inhibitors

bull Anti GM-CSF antibodies (KB 003)

bull MEK inhibitors

bull IDH 1 IDH2 targeted drugs

Cooperative efforts on CMML

bull MDSMPN group of the International MDS Foundation

bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML

Groupe Francophone

des Myeacutelodysplasies

bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)

bull Biological groups M Fontenay C Preudhomme

E Solary O Bernard

bull Website www gfmgrouporg

bull Online registry of French MDS cases

bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net

Disclosure

I have the following financial

relationships

Consultant and Contracted

Research for

Boehringer Ingelheim Celgene Corporation

Janssen Pharmaceuticals Inc Novartis

An update on CMML







bull treatment

An update on CMML







bull treatment


bull gt 3 months

bull (gt 10 of WBC)














Epidemiology




1100000year)



disorders















Original Paper


Introduction

Key Words

Abstract

Do

wnlo

ad

ed b

y

INS

ER

M D

ISC

IS

T

19

81

43

431

- 1

12

32

015

85

00

9 P

M




An update on CMML







bull treatment



bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




An update on CMML







bull treatment

An update on CMML







bull treatment


bull gt 3 months

bull (gt 10 of WBC)














Epidemiology




1100000year)



disorders















Original Paper


Introduction

Key Words

Abstract

Do

wnlo

ad

ed b

y

INS

ER

M D

ISC

IS

T

19

81

43

431

- 1

12

32

015

85

00

9 P

M




An update on CMML







bull treatment



bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




An update on CMML







bull treatment


bull gt 3 months

bull (gt 10 of WBC)














Epidemiology




1100000year)



disorders















Original Paper


Introduction

Key Words

Abstract

Do

wnlo

ad

ed b

y

INS

ER

M D

ISC

IS

T

19

81

43

431

- 1

12

32

015

85

00

9 P

M




An update on CMML







bull treatment



bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard





bull gt 3 months

bull (gt 10 of WBC)














Epidemiology




1100000year)



disorders















Original Paper


Introduction

Key Words

Abstract

Do

wnlo

ad

ed b

y

INS

ER

M D

ISC

IS

T

19

81

43

431

- 1

12

32

015

85

00

9 P

M




An update on CMML







bull treatment



bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard






Epidemiology




1100000year)



disorders















Original Paper


Introduction

Key Words

Abstract

Do

wnlo

ad

ed b

y

INS

ER

M D

ISC

IS

T

19

81

43

431

- 1

12

32

015

85

00

9 P

M




An update on CMML







bull treatment



bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




Epidemiology




1100000year)



disorders















Original Paper


Introduction

Key Words

Abstract

Do

wnlo

ad

ed b

y

INS

ER

M D

ISC

IS

T

19

81

43

431

- 1

12

32

015

85

00

9 P

M




An update on CMML







bull treatment



bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard


















Original Paper


Introduction

Key Words

Abstract

Do

wnlo

ad

ed b

y

INS

ER

M D

ISC

IS

T

19

81

43

431

- 1

12

32

015

85

00

9 P

M




An update on CMML







bull treatment



bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




Original Paper


Introduction

Key Words

Abstract

Do

wnlo

ad

ed b

y

INS

ER

M D

ISC

IS

T

19

81

43

431

- 1

12

32

015

85

00

9 P

M




An update on CMML







bull treatment



bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




An update on CMML







bull treatment



bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard






bull MF 33








ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard





ndash MDS

bull cytopenias




ndash MPN

bull Splenomegaly


lesions)




metamyelocytes)



Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




Haematologica 2011



CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard






CD1

4

MO1 CD14+CD16-

Classical monocytes

CD14lowCD16high

non-classical

monocytes

MO3

Healthy

donors

MO1 lt 94

MO2 + MO3

gt 6 C

D16


MO2 CD14+CD16+

Intermediate

monocytes



monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard






monocytes

CD14

CD16

CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




CMML MDS MDS MPN


CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard





CD14

CD

16

0 3 6 9 12 15 1875

80

85

90

95

100Threshold

94

MO

1 (

o

f to

tal

mo

no

cyte

s)

AZA



Respond

ers (N=7)


RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard





RAS

CBL JAK

2

Signal

transduction

EZH2

TET2

Epigenetic

N

NH2

N O

ASXL1

IDH

DNMT3A

A Exon 2

Splicing e

ZRSR2

U2AF1

SRSF2

SF3B1


2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard





2013)


TET2 262 151 (58)

SRSF2 220 101 (46)

ASXL1 312 125 (40)

RUNX1 263 39 (15)

NRAS 263 29 (11)

CBL 264 27 (10)

JAK2 263 21 (8)

KRAS 263 20 (8)

ZRSF2 189 15 (8)

IDH2 229 13 (6)

SF3B1 220 13 (6)









An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard











An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




An update on CMML







bull treatment





TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard








TET2 SRSF2 KRAS






Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard








Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




Padron Blood 2014

Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




Grb2

SosRas

Ras

GTP

Nf1Raf

MEK

ERK

Cbl

AP1

GM-CSF

Shc

Shp2



CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard





CMML cases

Controcircles LMMC

0

20

40

60

80

No

mb

re

de

co

lon

ies

Serum-free medium

GM-CSF 10 ngmL

90

29

P=001

Controls CMM

L

Nu

mb

er

of

co

lon

ies

RIT1

40

60


Median WBC

P=001

281 x109L

126 x109L

Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




Blood 2013







JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard








JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




JCI 2011









NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard







NGS




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




An update on CMML







bull treatment






bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard









bull Other MDSMPN







bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard










bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard








bull WBC gt 100Gl

bull Auer rods


ndash NPM1

An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




An update on CMML







bull treatment







PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard










PB leukocyte count





bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard








bull IPSS






120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard





120 3624 48 60

0

20

4

0

10

0

60

8

0

Months

Cu

mu

lative

Pro

ba

bility o

f S

urv

iva

l

0 6 12 18 24 30 36 42 48 54 60

00

02

04

06

08

10

187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0

125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1

187

125

134

68

84

29

50

10

19

6

5

1


Su

rvie

Glo

ba

le (

)

ASXL1 sauvage

ASXL1 muteacute

OS

P lt 00001

P lt 005 P lt 001 P lt 0001

OS

LFS

(CI 95)


01 10 100

U2AF1

SF3B1

IDH2

ZRSR2

KRAS

JAK2

CBL

NRAS

RUNX1

ASXL1

SRSF2

TET2

HR (95 CI)


mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard





mutations





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard





bull 80 CMML 1





ndash Plts

ndash Karyotype











An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard












An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




An update on CMML







bull treatment

An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




An update on CMML







bull treatment

Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




Treatment of CMML



ndash Cytopenias


ndash Chemotherapy


bull Allogeneic SCT








ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard










ndash EPO level








1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard











1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard






1)If WBC le13 Gl


2) If gt13 Gl


-BM blasts ge5

-karyotype abnormal

-Hb lt 10 grdl


-Splenomegaly (SMG)

OR




bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard






bullN= 105



etoposide



HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




HMAs in CMML

-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




-n= 76









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard









bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




bullbull




vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard







vs HY first-line

(median 277 vs 62



(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard






(1) age gt 18




bull Hb lt10gdL



















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard


















NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard











NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard







NGS













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard













bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard









bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard








bull 43 RIC




unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard






unfavorable

prognostic factors

BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard




BJH 2015















bull MEK inhibitors





Groupe Francophone




E Solary O Bernard












bull MEK inhibitors





Groupe Francophone




E Solary O Bernard










bull MEK inhibitors





Groupe Francophone




E Solary O Bernard







Groupe Francophone




E Solary O Bernard




Groupe Francophone




E Solary O Bernard




Documents

CMML: from biology to treatment · Median WBC P=0.01 28.1 x109/L 12.6 x109/L. Blood , 2013 • GM-CSF–dependent STAT5 hypersensitivity in 90% of CMML samples and is enhanced by