Mielofibrosiidiopatica: update diagnosticoterapeutico

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1 Mielofibrosiidiopatica: update diagnosticoterapeutico Dott.ssa M. Bergamaschi Policlinico S. Martino-IST Clinica Ematologica

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4 criteri Diagnostici WHO2016 per la PMF Criteri PREFIBROTIC /EARLY PMF OVERT PMF Criteri maggiori 1.Proliferazione della linea megacariocitariae atipia associata SENZA fibrosi reticolinica di grado > 1 associato a un incremento della cellularitàmidollare, con proliferazione dei granulociti e spesso ridotta eritropoiesi(fase di malattia cellulare, pre-fibrotica) 2.Assenza di criteri WHO per PV, LMC, MDS o altre neoplasie mieloidi 3.Presenza della mutazione JAK2V617F, CALR o MPL o di altre anomalie clonali oppure, nessuna evidenza di fibrosi midollare reattiva 1.Proliferazione della linea megacariocitariae atipia associata alla presenza di fibrosi reticolinicae/o fibrosi collagene di grado 2 o 3 2.Assenza di criteri WHO per PV, LMC, MDS o altre neoplasie mieloidi 3.Presenza della mutazione JAK2V617F, CALR o MPL o di altre anomalie clonali oppure, nessuna evidenza di fibrosi midollare reattiva Criteri minori 1. Leucocitosi 11 x Aumento dei livelli sierici di LDH 3. Anemia 4. Splenomegalia palpabile 1. Leucocitosi 11 x Leucoeritroblastosi 3. Aumento dei livelli sierici di LDH 4. Anemia 5. Splenomegalia palpabile Combinazioni diagnostiche Tutti e 3 i criteri maggiori + 1 criterio minori Tutti e 3 i criteri maggiori + 1 criteriominori

5 Klampfl T, et al. NEJM 2013 Dec 19;369(25): ; Nangalia J, et al. NEJM Dec 19;369(25):

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8 Stratificazione del rischio nella MF1

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11 MIPSS70: Mutation Enhanced Prognostic Score System for Transplant-Age Patients With MF Variables Weighted value Hb < 100 g/l WBC > /L PLT < /L PB blasts 2% Constitutional symptoms Grade 2 BM fibrosis Absence CALR Type Probability (%) Low P <.001 HMR category a 2 HMR mutations High Intermediate Risk category Score OS (y) HR Low Intermediate ( ) Survival (years) High ( ) The MIPSS70-plus score also includes unfavorable karyotype, defined as any abnormal karyotype other than normal karyotype or sole abnormalities of 20q-, 13q-, +9, chromosome 1 translocation/duplication, -Y, or sex chromosome abnormality other than -Y a HMR category was defined as having any mutation in ASXL1, EZH2, SRSF2, IDH1/2. Guglielmelli P, et al. J Clin Oncol. 2018;36(4): Reprinted with permission American Society of Clinical Oncology. All rights reserved.

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14 Covariate HR (95% CI) P value Points Age at MF diagnosis a 1.07 ( ) < Hb < 11 g/dl 2.3 ( < PLT < /L 1.7 ( ) Overall Survival in Patients With SMF Low (NR) PB blasts 3% 2.9 ( < CALR wild-type 2.6 ( ) Constitutional symptoms 1.5 ( ).03 1 a Continuous, 0.15 point/year. Int y (8.1-NR) Int y ( ) High 2.0 y ( ) Hb, hemoglobin; MYSEC-PM, Myelofibrosis Secondary to PV and ET-Prognostic Model; NR, not reached; PLT, platelet count; PB, peripheral blood; SMF, secondary MF. MYSEC-PM Calculator: Passamonti F, et al. Leukemia. 2017;31(12):

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17 2018 ELN Recommendations for the Treatment of MF Int- 2/high Ruxolitinib Yes Ruxolitinib Splenomegaly Int-1 Highly symptomatic? a First line No First line Hydroxyurea Second line Ruxolitinib Second line Drug-refractory symptomatic splenomegaly Splenectomy Low Hydroxyure a Ruxolitinib Asymptomatic, and Hb 10 g/dl, Spleen 10 cm, WBC /L, PLT /L Observation Anemia (Hb < 10 g/dl) Patient-based, depending on overall toxicity and risk Low/Int- 1 Leukocytosis or thrombocytosis Hydroxyurea Int- 2/high AlloSCT Transplant candidate Int-1 b AlloSCT (controlled settings) a Presence of local symptoms or impairment of food intake. b Refractory, transfusion-dependent anemia, blasts > 2% in 2 repeated measurements, adverse cytogenetics, or high-risk mutations. Barbui T, et al. Leukemia Feb 27. [Epub ahead of print].

18 Studi COMFORT Follow up a 5 anni Dati di sopravvivenza COMFORT II Ruxolitinib vs BAT COMFORT I Ruxolitinib vs placebo Rischio di morte è ridotto 33% vs BAT (ITT: HR, 0.67 (95% CI, ); P =.06) Harrison, C. ASH Abstract 59. Srdan Verstovsek et al. EHA 2016, abstract 452

19 Ruxolitinib per basso rischio MF: Esperienze Two studies have evaluated the use of ruxolitinib in patients with lower-risk MF In the UK ROBUST study (N = 48), similar improvements in splenomegaly and symptoms were observed across risk groups, including for patients with intermediate-1 risk MF (n = 14) 1 The global JUMP study showed that reductions in spleen length and symptom burden for patients with intermediate-1 risk MF (n = 163) were within the range observed in the overall JUMP population (N = 2233) 2 Findings from these studies suggest that patients with lower-risk MF derive clinical benefit from treatment and that ruxolitinib is an effective treatment option for these patients Mead AJ, et al. Br J Haematol. 2015;170(1): Al Ali HK, et al Haematologica 2016, Vol. 101(9):

20 Ruxolitinibe infezioni Infezione da Herpes Zoster molto comune secondaria a linfocitopenia( vaccino inattivato in arrivò) HbcAbpose HbsAgpos: profilassi con lamivudina Polmoniti infettive batteriche e cistiti ricorrenti Consigliate: vaccinazione antipneumococcicae anti-influenza inattivato PRIMA di iniziare terapia: eseguire RX torace in 2 proiezioni e dosaggio quantiferonrischio ri-attivazione TBC

21 GRAZIE PER L ATTENZIONE mica.bergamaschi@gmail.com