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Prognostication in MF: From CBC to cytogenetics to molecular markers. Alessandro M. Vannucchi University of Florence, Italy. p < 0.0001. Survival is S ignificantly Shortened in PMF. Median survival: 4.6 versus 6.5 y . Cervantes F et al. JCO 2012; 24:2891-7.

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prognostication in mf from cbc to cytogenetics to molecular markers

Prognostication in MF: From CBC to cytogenetics to molecular markers

Alessandro M. Vannucchi

University of Florence, Italy

slide2

p < 0.0001

SurvivalisSignificantlyShortened in PMF

Median survival: 4.6 versus 6.5 y

Cervantes F et al. JCO 2012; 24:2891-7.

why do we n eed accurate p rognostic s cores
Why do weNeed Accurate PrognosticScores?
  • Long termremissions with the potential of beingcuredhavebeendescribedonly in patientsundergoingallogeneic HSCT
  • However, HSCT approach to MF hasseverallimitations, currently:
slide4

Risk Stratification in PMF

Cervantes et al, Blood 2009;113:2895-901

Passamonti et al, Blood 2010; 115:1703-8

Gangat N et al, J ClinOncol 2011; 29:392-7

international prognostic scoring system ipss
International PrognosticScoringSystem-IPSS

Low

Int-1

High

Int-2

Cervantes F et al. Blood 2009;113:2895-901

impact of anemia on disease progression
Impact of Anemia on Disease Progression
  • Disease-related anemia* hasbeenassociated with worseprognosis in all
  • riskscoringsystems (Lille, IPSS and derivatives)
  • RBC transfusionaldependencyisincluded in the DIPSS-plus score

Passamonti F.et al, Blood 2010; 115:1703-8

* NOT treatment-related

slide7

DynamicIPSS (DIPSS)

Passamonti F et al. Blood 2010;115:1703-8

slide8

Survival by Cytogenetic Category in PMF

At diagnosis

Beyond initialdiagnosis

CPX= complex (>3 abnormalities)

Tam C S et al. Blood 2009;113:4171-4178

slide9

"Unfavorable"Karyotype in PMF: Effect on OS

  • Unfavorable Karyo:
  • - Complex karyo,
  • - Sole or 2 abnormalities including:
  • Trisomy 8
  • -7/del(7q)
  • Del(5q)
  • Inv(3)
  • isochromosome 17q/17p-
  • 12p-
  • 11q23 abnormality

UnfavorableKaryo

M 2.0 yr

5-yr survival: 8%

FavorableKaryo

M 5.2 yr

5-yr survival: 51%

Caramazza D et al. Leukemia 2011; 25:82-88

slide10

"Unfavorable"Karyotype in PMF: Effect on LFS

FavorableKaryo

5-yr AML transformation rate: 7%

UnfavorableKaryo

5-yr AML transformation rate: 46%

Caramazza D et al. Leukemia 2011; 25:82-88

slide11

Risk Stratification in PMF

Cervantes et al, Blood 2009;113:2895-901

Passamonti et al, Blood 2010; 115:1703-8

Gangat N et al, J ClinOncol 2011; 29:392-7

slide12

DynamicIPSS-plus (DIPSS-plus)

∆ Low risk (0 adverse points)

n=66; median survival ~ 185 months

▲ Intermediate-1 risk (1 adverse point)

n=174; median survival ~ 78 months

○ Intermediate-2 risk (2 or 3 adverse points)

n=360; median survival ~ 35 months

High risk (4 or more adverse points)

n=193; median survival ~ 16 months

Survival

Lowrisk(0 variable)

M 185 mo

Int-1 risk(1 variable)

M 78 mo

High risk

(>4 variables)

M 16 mo

Int-2 risk(2-3 variables)

M 35 mo

Months

Gangat et al. J ClinOncol2011;29:392-7

slide13

Adverse Impact of MonosomalKaryotype

Normalkaryo

M 50 mo

Complexkaryo

No monosomal

M 24 mo

Sole +8

M 20 mo

Monosomal

karyo

M 6 mo

Vaidya R et al. Blood 2011;117:5612-15

slide14

“Very-High Risk” Patients: >80% Mortality

At 2 Years

Low (3%)

Int-1 (11%)

Int-2 (26%)

High (53%)

Very High (82%)

Tefferi A et al. Blood 2011; 118:4595-8

novel prognostic variables
NovelPrognosticVariables
  • SomaticMutations
  • GermlineCharacteristics
  • Cytokines
  • Otherbiomarkers (FLC, hepcidin & ferritinlevels)
slide16

JAK2 V617F Mutation and Prognosis in PMF

P=0.198

WT

V617F

N=483

Guglielmelli P et al, ASH2012

slide17

No Impact of JAK2V617Fon LeukemiaRisk

HR: 1.05 (95% CI, 0.7-1.7)

P=0.839

WT

V617F

(Competitive riskanalysis)

Guglielmelli P et al, ASH2012

blast transformation kaplan meier analysis
Blast transformation: Kaplan-Meier analysis

Barosi et al. PlosOne 2013, In press

slide19

MutationComplexity in PMF

  • 382 (79.1%) of patients presented at least one somatic mutation
  • 154 pts (32.5%) had >2 mutations
  • 31 pts (6.4%) had >3 mutations

Guglielmelli P et al, ASH2012

slide20

Mutations Associated with Reduced Overall Survival

in Multivariate Analysis

EZH2

ASXL1

WT

WT

Mut

Mut

P= 0.0008

P< 0.0001

SRSF2

WT

Mut

P< 0.0001

Guglielmelli P et al, ASH2012

slide21

Mutations Associated with Leukemia

in Multivariate Analysis

EZH2

ASXL1

WT

Mut

Mut

WT

P=.003

HR=1.98 (95%CI: 0.88-4.46)

P<.0001

HR=2.5 (95%CI: 1.51-4.13)

SRSF2

IDH1/2

Mut

Mut

WT

WT

P=.007

HR= 2.73 (95%CI: 1.34-5.55)

P<.0001

HR= 2.66(95%CI: 1.10-6.47)

* Competitive Risk Analysis

Guglielmelli P et al, ASH2012

slide22

A "Molecularly High-Risk" Status Associates with ReducedOverallSurvival

P<0.0001

  • EZH2
  • ASXL1
  • SRSF2
  • IDH1/2

Low Risk

High Risk

HR= 2.29 (95%CI: 1.65-3.19)

  • In the “molecularly high-risk” category, overall survival was 81 months (range: 61.9-99.5) compared with 148 months (range: 52.5-243.2) in the “molecularly low-risk” category (P<0.0001). Mutivariate analysis.

Guglielmelli P et al, ASH2012

slide23

A "Molecularly High-Risk"Status AssociatesWith LeukemiaTransformation

High Risk

  • EZH2
  • ASXL1
  • SRSF2
  • IDH1/2

Low Risk

P<0.0001

HR 2.96 (95%CI:1.85-4.76)

  • In the “molecularly high-risk” category, leukemia-free survival was 129 months (range: 90-168) compared with 323 months (range: 194-452) in the “molecularly low-risk” category (P<0.0001) – Competitive risk analysis

Guglielmelli P et al, ASH2012

slide24

The "Molecularly High-Risk" Status Contributes to Refined IPSS Categorization

IPSS (LOW-INT1)

IPSS (INT2-HIGH)

P= 0.017

P= 0.002

Low Risk

Low Risk

High Risk

High Risk

Guglielmelli P et al, ASH2012

slide25

The "Molecularly High-Risk" Status Predicts for LeukemiaRiskwithin IPSS Categories

IPSS (LOW-INT1)

IPSS (INT2-HIGH)

P= 0.001

P= 0.01

High Risk’

High Risk

Low Risk

Low Risk

Guglielmelli P et al, ASH2012

slide26

ABSTRACT #430

Prognostic Interactions Between SRSF2, ASXL1, and IDH Mutations in Primary Myelofibrosis and Determination of Added Value to Cytogenetic Risk Stratification and DIPSS-Plus

Terra L Lasho, MT, (ASCP)1*, Naseema Gangat, MD1*, Christy Finke, BS1*, Rebecca R. Laborde, PhD1*, Curtis A Hanson, MD2*, Rhett P Ketterling, MD3*, Ryan A Knudson3*, Animesh Pardanani, MBBS, PhD1 and Ayalew Tefferi, MD1

slide27

The A3669G Polymorhism of GlucocorticoidReceptorContributes to BlastTransformation in PMF

  • The A3669G allele is a susceptibility allele for PMF (HR 1.6-1.8)
  • The G/G allele associated with a «more-myeloproliferative» phenotype

OS*

BT*

0.47 per 100 pt-yr

N=274

N=21

13.6 per 100 pt-yr

77.6mo vs 298mo; P=0.049

76.7mo vs 261mo; P=0.018

remainedsignificant in multivariate

*, restricted to JAK2V617Fpospts, n=295

Barosi G et al, Blood 2012; 120:3112-7

slide28

AbnormallyIncreased IL-8 and IL2R Plasma Levels Are PrognosticallyDetrimental

Int-1 (n=27)

All (n=127)

Int-2 (n=70)

Treatment naive

(n=90)

Tefferi A et al. JCO 2011;29:1356-1363

slide29

Plasma Free Light Chain (FLC) LevelsPredictSurvival in PMF

FCL

FCL +/- IL-8 and/or IL-2R

< 3.78 mg/dL

Bothnormal

Bothabnormal

> 3.78 mg/dL

Eitherabnormal

Bothabnormal

Levelsabove or below the ROC cutoff (3.78 mg/dL)

Pardanani A et al. JCO 2012;30:1087-94

slide30

Conclusions

  • Prognosticscores in OMF are needed for therapeuticchoices
  • At present, they are mainlyreserved for HSCT decision
  • Mostusedscores are based on clinical and hematologicvariables
  • Cytogeneticshasbeen show to add to clinicalscores
  • Molecularcharacterizationmay help refineclinicalscores, be cost-effective and overcometechnicallimitations of conventionalcytogenetics
slide31

Acknowledgments

Contributors

Section of Hematology, University of Florence

Paola Guglielmelli

FlaviaBiamonte

Tiziana Fanelli

Ambra Spolverini

Maria Chiara Susini

Giada Rotunno

Alessandro Pancrazzi

Lisa Pieri

Mario Cazzola - Pavia

Gianni Barosi - Pavia

Francisco Cervantes - Barcelona

Andrea Reiter - Mannheim

Andrew Duncombe - Southampton

Katerine Zoe - Athens

Nick Cross - Salisbury