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Risk Stratification of P atients with M yelofibrosis and the R ole of T ransplant

Risk Stratification of P atients with M yelofibrosis and the R ole of T ransplant. Alessandro M. Vannucchi Section of Hematology , University of Florence, Italy. Survival in PMF: the IPSS Cohort. reference. Median : 69 mo (95% CI, 61-76). N= 1,054.

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Risk Stratification of P atients with M yelofibrosis and the R ole of T ransplant

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  1. RiskStratification of Patients with Myelofibrosis and the Role of Transplant Alessandro M. Vannucchi Section of Hematology, University of Florence, Italy

  2. Survival in PMF: the IPSS Cohort reference Median: 69 mo (95% CI, 61-76) N= 1,054 Cervantes F et al. Blood 2009;113:2895-901.

  3. p < 0.0001 ImprovingSurvivalTrends in PMF Median survival: 4.6 versus 6.5 y Cervantes F et al. JCO 2012; 24:2891-7.

  4. 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

  5. International PrognosticScoringSystem-IPSS Low Int-1 High Int-2 Cervantes F et al. Blood 2009;113:2895-901

  6. DynamicIPSS (DIPSS) Passamonti F et al. Blood 2010;115:1703-8

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

  8. PrognosticallyDetrimentalEffect of MonosomalKaryotype Vaidya R et al. Blood 2011;117:5612-5615

  9. “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

  10. ImprovingSurvivalTrends in PMF Age <65 y Age >65 y 1996-2007 1996-2007 1996-2007 1996-2007 1980-1995 1980-1995 1980-1995 1980-1995 P=0.01 P=0.02 IPSS Low/Int-1 IPSS Int-2/High P=0.02 P=0.11 Cervantes F et al. JCO 2012; 24:2891-7.

  11. Causes of Death in PMF 13% 4% 4% 5% 10% 14% 19% 31% Cervantes F et al. Blood 2009;113:2895-901

  12. Causes of Death in PMF 13% 4% 4% 5% 10% 14% 19% 31% Cervantes F et al. Blood 2009;113:2895-901

  13. Risk of LeukemiaTransformation in MF Bjorkholm M et al, JCO 2011; 29: 2410-15.

  14. DIPSS PredictsProgression to Leukemia in PMF • The risk of progression to blastphaseis 7.8-fold (Int-2) or 24.9-fold (High) highercompared with Low/Int-1 category Passamonti F et al, Blood 2010; 116:2857-8

  15. Prognostic Impact of Mutations in PMF • Mutations of EZH2 are found in 6% of PMF subjects P< 0.001 P= 0.028 Leukemia-free Survival OverallSurvival • In multivariate analysis, EZH2mutated status was an IPSS-independentvariablesignificantlyassociated with reduced OS (P=0.016) Guglielmelli P et al. Blood 2011; 118;19:5227-34 EZH2 WT EZH2 WT EZH2 mut EZH2 mut

  16. Risk-AdaptedMF Treatment Algorithm Obtain DIPPS/DIPPS-plus score Low risk / Interm-1 Interm-2 / High risk Consider SCT Asymptomatic Symptomatic NO YES MyA: <45-50y RI : 45-65y • Conventional • drugtherapy • Ruxolitinib* • Conventional • drugtherapy • Ruxolitinib* Refractory Refractory Investigational drugtherapy Observation MyA, Myeloablative RI, ReducedIntensity * FDA approved for Interm/high-risk

  17. Allogeneic SCT forMyelofibrosis Myeloablative 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%

  18. Allogeneic SCT forMyelofibrosis Reducedintensity Pts Med. Age OS (%) TRM (%) 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) ---

  19. A «High-RiskFeature» for TransplantOutcome Low risk= 0-1 variables High risk=>2 variables Updatedthis ASH, 70 patients. Actuarial 10-yr survivalis 66% vs 20% for low vs high risk (P<0.001), due to bothhigher TRM (38% vs 9%) and relapse relateddeaths (35% vs 21%) Bacigalupo A, BMT 2010; 45:458-63 ; Bacigalupo et al, ASH2012

  20. OS After SCT isPredictedby DIPPS Score «Lille scoringsystemratherthan DIPSS is a betterpredictive of overallmortalityafter allo SCT usingreducedintensityconditioning» Gupta V, ASH2012 High-riskcategory: RR 2.22 vs low-risk Scott B L et al. Blood 2012;119:2657-2664

  21. Potential Impact of JAK2 Inhibitors on MF Treatment Pathway McLornan DP, BJH 2012; 157:413-25

  22. Conclusions • High-performance clinicalrisk score systems (IPSS and derivatives) allowriskstratification of PMF patients • Novel cytogenetic and molecular information might improve categorization • Riskstratificationisuseful for therapeuticdecisions, mainly for referral to SCT, the only curative approach • SCT performance isbetter in lowriskcategories • SCT repositioning in the JAK2 inhibitors era?

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