MIELOFIBROSI. Massimo Breccia (Roma)

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1 MIELOFIBROSI Massimo Breccia (Roma)

2 Definizione Neoplasia mieloproliferativa cronica caratterizzata da marcate alterazioni fibrose dello stroma midollare, fino ad un quadro di fibrosi serrata, eventualmente accompagnata da osteosclerosi, conemopoiesi in sedi eterotope, aumento dei progenitori emopoietici circolanti, con presenza di elementi mieloidi, eritroidi, e megacariocitari immaturi e di progenitori in circolo (=leucoeritroblastosi).

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5 NATURAL HISTORY OF CMD CHRONIC MYELOGENOUS LEUKEMIA (CML) IDYIOPATIC MYELOFIBROSIS (FLORID PHASE) POLICITEMIA VERA ESSENTIAL THROMBOCYTEMIA ACCELERATED PHASE SPENT (HYPERFIBROTIC) MPD BLASTIC (ACUTE) PHASE MAJOR THROMBOTIC EVENT

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12 Possibili terapie nella MFI Per anemia: androgeni, corticosteroidi, farmaci immnunomodulanti (talidomide, lenalidomide, pomalidomide) Per leucocitosi e splenomegalia: terapia citoriduttiva (idrossiurea, splenectomia, radioterapia) Trapianto di cellule staminali Farmaci inibitori di JAK2

13 Ruxolitinib 13

14 L alterazione del signaling di JAK1 e JAK2 è responsabile delle manifestazioni cliniche della MF JAK2 JAK1 Citochine infiammatorie Mieloproliferazione Fibrosi Emopoiesi extramidollare (splenomegalia) Eritropoiesi inefficace Sintomi costituzionali Verstovsek S, et al. N Engl J Med. 21; 363:

15 COMFORT I Trial Design COMFORT: COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment Randomized, double blind, multicenter phase III study conducted in USA, Canada, and Australia Patients with Randomize PMF, PPV-MF, or PET-MF N = 39 1:1 IPSS intermediate 2 or high risk Palpable spleen 5 cm Platelet count 1 x 1 9 /L JAK2V617F positive or negative Ruxolitinib 15 or 2 mg oral BID* n = 155 Placebo n = Ongoing 21 Discontinued 78 Ongoing 37 Discontinued 36 Crossed over Open-label ruxolitinib extension phase Qualifying events: 25% increase in spleen volume from baseline (before week 24, must be accompanied by worsening symptoms) Primary endpoint: 35% reduction of spleen volume from baseline to week 24 Secondary endpoints: Symptom score, overall survival, duration of spleen response, QoL *3 patients not evaluable for safety included in ITT analysis of efficacy. IPSS, International Prognostic Scoring System 1. Verstovsek S, et al. N Engl J Med. 212;366:799 87; 2. Verstovsek S, et al. N Engl J Med. 212;366: (supplemental appendix). 15

16 Endpoint primario: Ruxolitinib riduce di oltre il 35% il volume splenico* in una percentuale significativamente superiore di pazienti vs placebo o BAT 1,2 Studio COMFORT-I vs placebo Studio COMFORT-II vs BAT COMFORT-I 1 (settimana 24) COMFORT-II 2 (settimana 48) 5 41,9% p<,1 5 p<,1 Responder (%) Ruxolitinib (n=155),7% Placebo (n=153) Responder (%) % Ruxolitinib (n=217) % BAT (n=72) * Valutazione mediante MRI/CT Verstovsek S, et al. N Engl J Med 212; 366(9): ; 2. Harrison C, et al. N Engl J Med 212; 366(9):

17 COMFORT-I Durability of spleen volume reduction 1. Kaplan-Meier curve of durability of spleen volume reduction Probability % reduction (n=9) 35% reduction Weeks from onset No. at risk % reduction: Time from first 35% reduction to <35% reduction and 25% increase from nadir. 1% reduction: Time from first 35% reduction to <1% reduction from baseline. 9/155 (58%) had a 35% reduction at any time point during the study 64% maintained a 35% reduction for at least 2 years Verstovsek S, et al. Haematologica. 213;98(12):

18 COMFORT-I Spleen volume reduction and patient-reported outcomes Spleen Volume Reduction correlates with Patient-Reported Outcomes (Week 24) Ruxolitinib Placebo Mean % change in TSS (95% CI) Total Symptom Score <1% 1 <35% 35% Worsening Improvement Mean change in score (95% CI) PROMIS Fatigue Scale <1% 1 <35% 35% Worsening Improvement Mean % change in score (95% CI) Global Health Status/QoL <1% 1 <35% 35% Worsening Improvement Mean PGIC score (95% CI) Patient Global Impression of Change <1% 1 <35% 35% No Change Increasing Improvement Mesa RA, et al. Blood. 211;118(21): Abstract 3842.

19 COMFORT-I 3-year follow-up Survival advantage versus placebo Overall survival by treatment group 1, Randomized to ruxolitinib Randomized to placebo ruxolitinib* Probability,8,6,4 HR=,69 IC 95%:,46 1,3 P=,67 N. di morti: ruxolitinib = 42; placebo = 54 Median follow-up: 149 weeks,2 Percent of at-risk placebo who crossed over or discontinued No at risk Months Ruxolitinib BAT *By Week 8, all patients originally randomized to placebo discontinued or crossed over to ruxolitinib therapy Overall survival favored patients originally randomized to ruxolitinib compared with patients originally randomized to placebo Verstovsek S. American Society of Hematology 55th Annual Meeting. Abstract 396. Available at:

20 Overall Survival by JAK2V617F Mutation Status JAK2V617F-Positive JAK2V617F-Negative Survival Probability.6.4 HR=.54 (95% CI:.3,.98) Survival Probability.6.4 HR=.65 (95% CI:.26, 1.63).2.2 Ruxolitinib (n=113) Placebo (n=123) Weeks Ruxolitinib (n=4) Placebo (n=27) Weeks Verstovsek S ASH Annual Meeting 212. Abstract 8 2

21 COMFORT II Trial Design COMFORT: COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment Randomized, open label, multicenter phase III study conducted in Europe Patients with Randomize PMF, PPV-MF, or PET-MF N = 219 2:1 IPSS intermediate 2 or high risk Palpable spleen 5 cm Platelet count 1 x 1 9 /L JAK2V617F positive or negative Ruxolitinib 15 or 2 mg oral BID n = 146 Best available therapy (BAT) n = Ongoing 26 Discontinued 29 Extension phase 31 Ongoing 24 Discontinued 18 Crossed over Ruxolitinib crossover and extension phase Qualifying events: splenectomy or progressive splenomegaly (25% increase in volume from on-study nadir) Primary endpoint: 35% reduction of spleen volume from baseline to week 48 Secondary endpoints: Spleen response at week 24, duration of spleen response Exploratory endpoint: QoL *Best available therapy as selected by investigator, including possibility of combination therapy, no therapy, or changing therapy over the course of the trial. Harrison CN, et al. N Engl J Med. 212;366:

22 2 COMFORT II Change in spleen volume Change from baseline in spleen volume over time Ruxolitinib BAT (excluding crossover) BAT (including crossover) Mean % change from baseline Week Ruxolitinib n = BAT Excluding patients who crossed over to ruxolitinib n = BAT Including patients who crossed over to ruxolitinib n = BAT patients who crossed over to ruxolitinib had reductions in spleen volume after crossover Cervantes F, et al. Blood. 213;122(25):

23 COMFORT II Duration of spleen response Sustained spleen reductions 35% with ruxolitinib continued therapy Probabiltiy No. of patients Ruxolinitib 75 BAT 1.2 Events 31 (41.3%) (.%).1 Censored 44 (58.7%) 1 (1%) Weeks (time from first 35% reduction) a Ruxolitinib n = Includes randomized and extension phases for patients randomized to ruxolitinib; crossover patients are not included. Duration of maintenance was estimated only for patients who achieved 35% reduction in spleen volume. a The first spleen assessment by MRI was at 12 weeks (earliest possible response). 75 patients (51%) in the ruxolitinib arm achieved a 35% reduction in spleen volume 6 of these patients achieved a response after the primary endpoint (after 48 weeks of treatment) The median duration of spleen response has not been reached with 151 weeks of follow up Cervantes F, et al. Blood. 213;122(25):

24 Ruxolitinib aumenta la sopravvivenza verso BAT 1 Probabilità 1,,9,8,7,6,5 Ruxolitinib Studio COMFORT-II verso BAT Dati a 3,5 anni 1 Curve di Kaplan-Meier di sopravvivenza globale per gruppo di trattamento 1 BAT,4 Ruxolitinib BAT,3 N. di pazienti ,2,1 Eventi Censored 4 (27,4%) 16 (72,6%) 4 (41,1%) 43 (58,9%),,5 1, 1,5 2, 2,5 3, 3,5 4, 4,5 5, N. a rischio Ruxolitinib BAT Anni Mod da Ref 1 Riduzione del 42% del rischio di morte verso BAT (HR=,58, IC 95%:,36-,93) 1 4 decessi (27.4%) nel braccio ruxolitinib vs 3 (41.1%) nel braccio BAT 1 Probabilità stimata di sopravvivrenza pari a,71 (IC 95%,,63-,78) nel braccio ruxolitinib e,54 (IC 95%,,41-,65) nel braccio placebo 1 I dati a 3,5 anni confermano i benefici delle analisi precedenti 1 1. Harrison C. et al. EHA 214 Abs P Medica day I 1 Sett15 Business Use Only

25 Studi COMFORT Pooled Analysis della sopravvivenza globale Benefici in termini di sopravvivenza rispetto a BAT 1, Ruxolitinib Control Probabilità di sopravvivenza,8,6,4,2 Riduzione del 35% del rischio di morte vs controllo Settimane N. Ruxolitinib Controllo I pazienti trattati negli studi COMFORT con ruxolitinib hanno presentato una sopravvivenza maggiore rispetto ai pazienti che hanno ricevuto placebo o BAT Vannucchi AM, et al. Abs presented at ASH 213 #282; available at Indice

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27 6 anni, maschio, sintomi costituzionali, grado 3 fibrosi, milza 2 cm (IPSS alto rischio), JAK2 +. Inizia Ruxo 2 mg BID e raggiunge una risposta splenica completa. Dopo 17 mesi di terapia, assenza di fibrosi secondo criteri WHO Matteo Molica e Massimo Breccia, Ann Hematol 214

28 Nuovi inibitori in sperimentazione

29 PERSIST-1: Reduction of Spleen Volume 35% at Wk 24 Significantly greater percentage of pts in the pacritinib arm reached the primary endpoint Change From Baseline (%) Mesa RA, et al. ASCO 215. Abstract LBA76. Reprinted with permission. Pacritinib (n = 168) Best available therapy (n = 85) Patients 35% decrease Pts Reaching Primary Endpoint, % Population PAC BAT P Value ITT Evaluable* *Baseline + Wk 24 spleen assessment by MRI or CT.