Alessia Tieghi. Ematologia ASMN- IRCCS Reggio Emilia

Transcript

1 Alessia Tieghi Ematologia ASMN- IRCCS Reggio Emilia

2 Tossicità ematologica dei JAK2 inibitori Ruxolitinib: COMFORT I COMFORT II Ruxolitinib: Studio JUMP Reggio Emilia Considerazioni

3 1. Cervantes, et al. Blood. 2009;113(13): ; 2. Passamonti, et al. Blood. 2010;115(9): ; 3. Gangat N, et al. J Clin Oncol. 2011;29:

4 Tefferi, et al. Blood. 2011;117(13)

5 Causes of death 4% 4% 5% 10% 13% 14% 19% 31% Cervantes et al, Blood 2009; 113:

6 Effect of Ruxolitinib on Erythropoiesis EPO The JAK/STAT pathway is a major regulator of erythropoiesis primarily through erythropoiejn (EPO)- mediated JAK2 acjvajon Ruxolitinib JAK2 P STAT JAK2 P STAT SOCS-1 Cell membrane RuxoliJnib- mediated inhibijon of JAK2 acjvity, regardless of V617F mutajon status, leads to decreased erythropoiesis PI3K AKT P STAT P STAT RAS Cytoplasm RAF P FOXO P mtor P ERK MEK P P STAT STAT Erythropoiesis Target genes Nucleus Nuclear membrane 6

7

8 La dose iniziale raccomandata di ruxolitinib è basata sulla conta piastrinica Conta piastrinica Dose iniziale > /mm 3 20 mg BID per os /mm /mm /mm /mm 3 Uso concomitante di inibitori del citocromo CYP3A4, in caso di deficit renale grave o scompanso epatico di qualsiasi grado 15 mg BID per os Massimo 5 mg BID per os* Ridurre la dose iniziale bid del 50% Dose massima Ruxoli4nib: 25 mg BID 1. JAKAVI Riassunto delle CaraYerisJche del ProdoYo; 2. Verstovsek S. Leuk Lymphoma. 2013

9 Dose changes Platelet Count 100,000 to less than 125,000/mm 3 75,000 to less than 100,000/mm 3 50,000 to less than 75,000/ mm 3 25 mg twice daily 20 mg twice daily 10 mg twice daily 5 mg twice daily Dose at Time of Platelet Decline 20 mg twice daily 15 mg twice daily 10 mg twice daily 5 mg twice daily 15 mg twice daily New Dose 10 mg twice daily 5 mg twice daily No Change No Change No Change 10 mg twice daily 5 mg twice daily No Change No Change 5 mg twice daily No Change

10 Hematological Safety Laboratory parameter All grades Ruxolitinib N=155 COMFORT-I 1 COMFORT-II 2 Placebo N=151 Ruxolitinib N=146 Best available therapy N=73 % % % % % % % % Grade All Grade All Grade All 3 grades 3 grades 3 grades Grade 3 Anemia Thrombocytopenia Neutropenia The most frequently reported hematological adverse reactions in the phase 3 COMFORT studies included anemia (82.4%), thrombocytopenia (69.8%), and neutropenia (15.6%) 1. Verstovsek S, et al. N Engl J Med. 2012;366(9): Harrison C, et al. N Engl J Med. 2012;366(9):

11

12 Mean daily dose of Ruxolitinib All Ruxolitinib (n=155) 15 mg BID starting dose (n=55) 20 mg BID starting dose (n=100) Daily Dose (mg BID) BL Weeks Approximately 70% of patients had dose adjustments during the first 12 weeks of therapy Patients achieved a stable dose with longer-term Verstovsek S, et al. N Engl J Med 2012;366:

13 Incidence of Anemia e Thrombocytopenia Grado 3 / 4 Ruxolitinib Grade 3 Ruxolitinib Grade 4 Placebo Grade 3 Placebo Grade 4 Anemia Thrombocytopenia All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis; therefore, data for patients receiving placebo is shown for 0 <6 months only

14 Mean Hemoglobin Levels Over Time Mean Percentage Change From Baseline Ruxolitinib Placebo -20 BL Weeks Mean hemoglobin nadirs after 8 12 weeks of therapy and recovers to a new steady state which remains stable with longer-term therapy

15 Hemoglobin Levels Over Time By Ruxolitinib Titrated Dose <10 mg BID 10 mg BID 15 mg BID 20 mg BID BL Patients titrated to 10 mg BID after nadir hemoglobin showed faster and more complete return of hemoglobin to pretreatment levels

16 Overall Survival by Ruxolitinib 10 mg BID Titrated Dose Survival Probability Ruxolitinib 10 mg BID (n=26) Ruxolitinib >10 mg BID (n=85) Placebo (n=128) 0 BL Weeks Survival of patients titrated to 10 mg BID was comparable to those treated with higher doses of ruxolitinib

17 RBC Transfusions Over Time 50 Proportion of patients with RBC transfusion in prior month Percentage of Patients Ruxolitinib Placebo 0 BL Weeks From First Ruxolitinib Dose By Week 36, the proportion of ruxolitinib-treated patients receiving RBC transfusions decreased to the level seen with placebo and remained stable thereafter

18 Mean Platelet Counts Over Time Platelet counts remain stable with longer-term therapy Mean Percentage Change From Baseline Ruxolitinib Placebo -60 BL Weeks Median platelet count at baseline: Ruxolitinib, /L; Placebo, /L.

19 COMFORT- 1: 3- year update of ruxolitinib Ruxolitinib (n = 155) Placebo (n = 151) Placebo Placebo Ruxolitinib (n=111) Median exposure, weeks Still on treatment, n (%) 77 (49.7) 0 57 (51.4) Crossed over, n (%) 111 (73.5) Discontinued, n (%) 78 (50.3) 40 (26.5) 54 (48.6) Primary reasons for discontinuation, n (%)* Death 15 (19.2) 7 (17.5) 11 (20.4) Adverse event 15 (19.2) 9 (22.5) 8 (14.8) Consent withdrawn 12 (15.4) 7 (17.5) 11 (20.4) Disease progression 18 (23.1) 13 (32.5) 15 (27.8) 1 anemia, 1 thrombocytopenia 1 anemia, 1 thrombocytopenia Verstovsek et al., Blood 2013 vol. 122 no

20 Verstovsek S et al. Blood 2013;122:396 20

21

22

23 1% anemia, 3,6 % thrombocytopenia

24 Dose Intensity by Starting Dose mg bid: n = mg bid: n = In the 20 mg bid group, the median daily dose remained stable to week 48 (39.7 mg) and then decreased slightly over Jme (34.3 mg/day at week 144) In the 15 mg bid group, the median dose intensity decreased over the first 24 weeks of therapy then stabilized at 20 mg/day (20.8 mg/day at week 144) Dose intensity = cumulative dose/duration of exposure

25 Laboratory Data: Hemoglobin Levels Over Time Baseline g/dl 8.0 n = Ruxolitinib BAT In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 weeks of treatment and then recovered to levels similar to those in the BAT

26 Red Blood Cell Transfusions Percentage of Patients Receiving PRBC Transfusions Ruxolitinib n = BAT n =

27 Laboratory Abnormalities: Platelets New or worsened platelet abnormalities n (%) Ruxolitinib Randomized n = 146 BAT Randomized n = 73 Ruxolitinib Cross-over n = 45 Total Ruxolitinib a n = 191 Platelets Grade 1 45 (30.8) 11 (15.1) 7 (15.6) 52 (27.2) Grade 2 41 (28.1) 5 (6.8) 12 (26.7) 56 (29.3) Grade 3 11 (7.5) 4 (5.5) 9 (20.0) 23 (12.0) Grade 4 3 (2.1) 3 (4.1) 2 (4.4) 7 (3.7) a Includes ruxolitinib randomized + extension and crossover from BAT. Higher proportion of patients had worsening to grade 3-4 thrombocytopenia after crossover from BAT to ruxolitinib (24.4%)

28 Studio NOVARTIS CINC424A2401 Pazienti UOC Ematologia Reggio Emilia

29 Study design Adult pa4ents with primary MF, post- PV MF, or post- ET MF regardless of prior treatment Ruxoli4nib treatment un4l disease progression, commercial availability, or 24 months from last pa4ent first visit Baseline Plt count > /L Ruxoli4nib 20 mg PO BID Baseline Plt count /L Ruxoli4nib 15 mg PO BID Baseline Plt count /L Ruxoli4nib 5 mg PO BID Follow- up period 28 days following last dose

30 PAZIENTI TOTALI REGGIO EMILIA 18 PROTOCOLLO JUMP 14 D.M. 08 maggio Età media, anni (range) 64 (52-75) PMF 6 PET- MF 6 PPV- MF 6 DIPSS: High Risk 5 Int Int- 1 2 Durata trayamento, seemane (mediana) 50 (28-108) PazienJ in trayamento 8 Screening failure 2 Cause di interruzione: Progressione ( 5 pazienj: 31%; 2 decessi) LAM (1 paziente; 6%) TMO (1 paziente; 6%)

31 Mean Daily dose of Ruxolitinib over time 45 Dose iniziale 20mg BID (15) Dose iniziale 15 mg BID (1) 40 Dose Giornaliera (mg Totali) Weeks

32 Mean hemoglobin levels over time 5 Decremento medio percentuale rispetto al baseline Weeks

33 Mean platelet counts over time Decremento medio percentuale rispetto al baseline,0-15,0-30,0-45,0-60, Weeks

34 Mean white blood cells counts over time 0 Decremento medio percentuale rispetto al baseline Weeks

35 Caso clinico 1: paziente con necessità di trasfusioni WBC Plt Dose INC424 Unità trasfuse Hb (g/dl)

36 Caso clinico 2: neutropenia febbrile (mg BID) Iperpiressia, crisi convulsiva Febbre Bronchite, oltre 39 C febbre oltre 39 C

37 Talpaz M. et al

38 Distribution of Ruxolitinib daily dose over the 24 weeks study period

39 Efficacy results at 24 weeks

40 Changes in hematologic parameters

41

42 CONCLUSIONI RUXOLITINIB - Frequente citopenia (anemia e trombocitopenia) - Insorgenza precoce (nadir dopo 8-12 settimane) - Tendenza alla stabilizzazione nel lungo periodo - Trattamento: riduzione della dose (10mg BID), trasfusioni - Rara causa di sospensione del trattamento - Uso di Epo e G- CSF? - Dose iniziale?