Risk Stratification of Patients with Myelofibrosis and the Role of Transplant

Alessandro M. VannucchiSection of Hematology,

University of Florence, Italy

Survival in PMF: the IPSS Cohort

N= 1,054

Median: 69 mo (95% CI, 61-76)

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

reference

0.0

0.2

0.4

0.6

0.8

1.0P

roba

bilit

y

0 2 4 6 8 10 12 14 16 18 20 22 24 26Years

1980 - 1995 1996 - 2007

Whole series: actuarial survival (± 95% CI)according to period of diagnosis

p < 0.0001

Improving Survival Trends in PMF

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

Median survival: 4.6 versus 6.5 y

Variable IPSS DIPSS DIPSS-plusAge >65 y

Constitutional symptoms

Hemoglobin <10 g/dL

Leukocyte count >25x109/L

Circulating blasts > 1%

Platelet count <100x109/L

RBC transfusion need

Unfavorable karyotype+8,-7/7q-,i(17q),inv(3), -5/5q-,12p-, 11q23 rearr.

Cervantes et al, Blood 2009;113:2895-901Passamonti et al, Blood 2010; 115:1703-8

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

Risk Stratification in PMF

International Prognostic Scoring System-IPSS

Low

Int-1Int-2High

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

Points Median survival

(mo)

Low 0 135

Int-1 1 95

Int-2 2 48

High >3 27

Dynamic IPSS (DIPSS)

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

Points Median survival

(mo)

Low 0 Not reach.

Int-1 1-2 170

Int-2 3-4 48

High 5-6 18

DIPSS-Plus

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

Risk group

No.predictors

Median survival, y

Low 0 15.4

Int-1 1 6.5

Int-2 2-3 2.9

High >4 1.3

Vaidya R et al. Blood 2011;117:5612-5615

Prognostically Detrimental Effect of Monosomal Karyotype

“Very-High Risk” Patients: >80% MortalityAt 2 Years

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

Low (3%)

Int-1 (11%)

Int-2 (26%)High (53%)

Very High (82%)

Very-High risk variables

• monosomal karyotype

• inv(3)/i(17q)

or any 2 of the following:

• PB blasts >9%

• WBC >40x109/L

• other unfavorable karyotype

Improving Survival Trends in PMF

0.0

0.2

0.4

0.6

0.8

1.0

Re

lativ

e s

urv

ival

0 1 2 3 4 5 6 7 8 9 10Years from diagnosis

1980-1995 1996-2007

IPSS risk groups high & intermediate-2Relative survival by year of PMF diagnosis

0.0

0.2

0.4

0.6

0.8

1.0

Re

lativ

e s

urv

ival

0 1 2 3 4 5 6 7 8 9 10Years from diagnosis

1980-1995 1996-2007

IPSS risk groups low & intermediate-1Relative survival by year of PMF diagnosis

0.0

0.2

0.4

0.6

0.8

1.0

Re

lativ

e s

urv

ival

0 1 2 3 4 5 6 7 8 9 10Years from diagnosis

1980-1995 1996-2007

Age >= 65 yearsRelative survival by year of PMF diagnosis

0.0

0.2

0.4

0.6

0.8

1.0

Re

lativ

e s

urv

ival

0 1 2 3 4 5 6 7 8 9 10Years from diagnosis

1980-1995 1996-2007

Age < 65 yearsRelative survival by year of PMF diagnosis

1980-1995

1996-2007

1980-1995

1996-2007

1980-1995

1996-2007

1980-1995

1996-2007

Age <65 y Age >65 y

IPSS Int-2/HighIPSS Low/Int-1

P=0.01 P=0.02

P=0.02 P=0.11

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

Causes of Death in PMF

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

31%

19%

14%

10%

5%

4%

4%

13%

Causes of Death in PMF

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

31%

19%

14%

10%

5%

4%

4%

13%

Risk of Leukemia Transformation in MF

Bjorkholm M et al, JCO 2011; 29: 2410-15.

SIR(95%CI)

Primary Myelofibrosis 63.8(42.7-91.6)

DIPSS Predicts Progression to Leukemia in PMF

Passamonti F et al, Blood 2010; 116:2857-8

• The risk of progression to blast phase is 7.8-fold (Int-2) or 24.9-fold (High) higher compared with Low/Int-1 category

Guglielmelli P et al. Blood 2011; 118;19:5227-34

• In multivariate analysis, EZH2 mutated status was an IPSS-independent variable significantly associated with reduced OS (P=0.016)

P< 0.001

EZH2 WT

EZH2 mut

P= 0.028

EZH2 WT

EZH2 mut

Ove

rall

Surv

ival

Leuk

emia

-fre

e Su

rviv

al

• Mutations of EZH2 are found in 6% of PMF subjects

Prognostic Impact of Mutations in PMF

Risk-Adapted MF Treatment Algorithm

Obtain DIPPS/DIPPS-plus score

Interm-2 / High risk

Asymptomatic Symptomatic

Observation

•Conventional drug therapy• Ruxolitinib*

Consider SCT

Investigationaldrug therapy

Refractory

NOMyA: <45-50y RI : 45-65y

YES

•Conventional drug therapy• Ruxolitinib*

Refractory

MyA, MyeloablativeRI, Reduced Intensity

Low risk / Interm-1

* FDA approved for Interm/high-risk

Myeloablative

Allogeneic SCT for Myelofibrosis

Pts Med. Age OS TRM

Guardiola (1999) 55 42 47% (5y) 27%

Deeg (2003) 56 43 58% (3y) 32%

Ballen (2010) Sibling 170 45 39% (5y) 22% MUD 117 47 31% (5y) 42%

Allogeneic SCT for Myelofibrosis

Rondelli (2005) 21 54 85% (2.5y) 10

Kröger (2005) 21 53 84% (3y) 16 Bacigalupo (2010) 46 51 45% (5y) 24

Alcalby (2010) 162 57 22% (5y) 22

Gupta (ASH2012) 222 55 37% (5y) ---

Reduced intensity Pts Med. Age OS (%) TRM (%)

A «High-Risk Feature» for Transplant Outcome

Low risk= 0-1 variablesHigh risk= >2 variables

Bacigalupo A, BMT 2010; 45:458-63 ; Bacigalupo et al, ASH2012

Updated this ASH, 70 patients. Actuarial 10-yr survival is 66% vs 20% for low vs high risk (P<0.001), due to both higher TRM (38% vs 9%) and relapse related deaths (35% vs 21%)

Variable HR

Spleen >22 cm 2.8

RBC units >20 3.9

Alternative donor 3.4

Scott B L et al. Blood 2012;119:2657-2664

OS After SCT is Predicted by DIPPS Score

«Lille scoring system rather than DIPSS is a better predictive of overall mortality after allo SCT using reduced intensity conditioning» Gupta V, ASH2012High-risk category: RR 2.22 vs low-risk

Potential Impact of JAK2 Inhibitors on MF Treatment Pathway

McLornan DP, BJH 2012; 157:413-25

Conclusions

• High-performance clinical risk score systems (IPSS and derivatives) allow risk stratification of PMF patients

• Novel cytogenetic and molecular information might improve categorization

• Risk stratification is useful for therapeutic decisions, mainly for referral to SCT, the only curative approach

• SCT performance is better in low risk categories• SCT repositioning in the JAK2 inhibitors era?