How I Treat Myelofibrosis. Adam Mead, MD, PhD University of Oxford Oxford, United Kingdom

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1 How I Treat Myelofibrosis Adam Mead, MD, PhD University of Oxford Oxford, United Kingdom

Primary Myelofibrosis Archiv Fur Pathol.

2 cases of leukemia with peculiar blood and

Constitutional symptoms Fibrous material in

2 Primary Myelofibrosis Archiv Fur Pathol. 1879;78: cases of leukemia with peculiar blood and marrow findings Massive splenomegaly Constitutional symptoms Fibrous material in the bones 1879, Gustav Heuck ( ) Tefferi A. Leukemia. 2008;22(1):3-13

Myelofibrosis: Primary, Post-ET, and Post-PV

progressive bone marrow 1 MF-0 MF-1 MF-2 MF-3 Increased

Thrombocytopenia Peripheral blood blasts Shorter survival

polycythemia vera 1. Thiele J, et al. Haematologica.

3 Myelofibrosis: Primary, Post-ET, and Post-PV Myeloproliferative neoplasms (MPNs) characterized by progressive bone marrow 1 MF-0 MF-1 MF-2 MF-3 Increased fibrosis grade is associated with 2,3 Anemia Thrombocytopenia Peripheral blood blasts Shorter survival ET, essential thrombocythemia; MF, myelofibrosis; PV, polycythemia vera 1. Thiele J, et al. Haematologica. 2005;90(8): Thiele J, et al. Ann Hematol. 2006;85(4): Vener C, et al. Blood. 2008;111(4):

4 WHO Classification of MF Barbui T, et al. Blood Cancer J. 2015;5:e337.

stem/progenitor-cell derived Red cells PV

Progenitor ET Mks PMF Mutations in signal

5 Biologic Basis of the MPNs Chronic myeloproliferative disorders are stem/progenitor-cell derived Red cells PV Haemopoietic Stem Cell Common Myeloid Progenitor ET Mks PMF Mutations in signal transduction pathways that promote proliferation. Many are known: JAK2V617F BCR-ABL CALR MPL Neutrophils CML CML, chronic myelogenous leukemia; PMF, progressive massive fibrosis

6 What Are the Key Steps in PMF Pathogenesis? Self-renewing stem cell Lymphoid cells Myeloid cells

7 What Are the Key Steps in PMF Pathogenesis? 1. MPN-associated mutation(s) Self-renewing stem cell Lymphoid cells Myeloid cells

8 What Are the Key Steps in PMF Pathogenesis? 1. MPN-associated mutation(s) 2. MPN stem cell Self-renewal increased: Clonal advantage Lymphoid cells Myeloid cells

9 What Are the Key Steps in PMF Pathogenesis? 1. MPN-associated mutation(s) 2. MPN stem cell Self-renewal increased: Clonal advantage 3. Myeloid lineage bias and myeloproliferation: - Myeloid cells - Megakaryocytes

10 What Are the Key Steps in PMF Pathogenesis? 1. MPN-associated mutation(s) 2. MPN stem cell Self-renewal increased: Clonal advantage 3. Myeloid lineage bias and myeloproliferation: - Myeloid cells - Megakaryocytes 4. Extrinsic impact on: - BM stroma/microenvironment - Suppression of normal hematopoiesis - BM fibrosis

11 Central Role of JAK/STAT Signaling in MF MPL FLT3 CALR Vainchenker W, et al. Oncogene. 2013;32(21):

12 Disease Burden in PMF Splenomegaly Cytopenias Early death MFassociated symptoms Complications: Thrombosis Bleeding Infection EMH

13 Life Expectancy in Myeloproliferative Neoplasms Relative Survival Ratio Hultcrantz M, et al. J Clin Oncol. 2012;30(24): Hultcrantz M, et al. J Clin Oncol. 2015;33(20):

14 Case 1: Clinical Heterogeneity of MF 67-year-old man Unwell: Weight loss, night sweats, and bone pain Anemic (6.8 g/dl) with leucoerythroblastic blood film 23 cm palpable splenomegaly WBC 28 with 3% blasts; normal platelet count BM shows myeloproliferation and grade 3 fibrosis JAK2 mutation positive Diagnosis = primary myelofibrosis BM, bone marrow; WBC, white blood cell

15 Case 2: Clinical Heterogeneity of MF 73-year-old woman; asymptomatic Abnormal marrow appearance on MRI 5 yrs previously Leucoerythroblastic blood film 6 cm palpable splenomegaly, asymptomatic Normal blood counts BM shows myeloproliferation and grade 3 fibrosis CALR mutation positive Diagnosis = primary myelofibrosis

16 Prognostic Risk Stratification in MF Variable IPSS DIPSS DIPSS-plus Age >65 y Constitutional symptoms Hemoglobin <10 g/dl Leukocyte count >25x10 9 /L Circulating blasts 1% Platelet count <100x10 9 /L RBC transfusion need Unfavorable karyotype +8,-7/7q-,i(17q),inv(3), -5/5q-,12p-, 11q23 rearr. 1 point each 1 point each but Hb = 2 Complex scoring IPSS, International Prognostic Scoring System; DIPSS, dynamic International Prognostic Scoring System; DIPSS-plus; a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status Cervantes F, et al. Blood. 2009;113(13): Passamonti F, et al. Blood. 2010;115(9): Gangat N, et al. J Clin Oncol. 2010;29(4):

17 IPSS Risk Groups Predict Survival Cervantes F, et al. Blood. 2009;113(13):

18 First Management Decision: Is the patient a candidate for allogeneic transplantation? Prognostic risk category Donor status Age (no specific cut-off, mostly <70 yrs) Other comorbidities Availability of other treatment options?

19 Case 3 49-year-old man Bone pains Leucoerythroblastic blood film 12 cm palpable splenomegaly; painful Hb 10.3 g/dl WBC and platelets in normal range BM shows myeloproliferation and grade 3 fibrosis JAK2 mutation negative Diagnosis = IPSS INT1 primary myelofibrosis

20 Case 3: Management Options What would be your treatment choice for this patient? 1. Symptomatic treatments, watch and wait 2. Referral for allograft 3. JAK2 inhibition with ruxolitinib 4. Further disease assessments 5. Thalidomide and prednisolone 0% 100% 0% 0% 0%

21 Mutations in PMF Median number of mutations in PV and ET = 6.5 Median number of mutations in PMF = 13 Nangalia J, et al. N Engl J Med. 2013;369(25):

22 Prognostic Value of Mutations in MF CALR mutant JAK2 mutant MPL mutant Triple negative HR = 2.29 (P<.0001) HR: 2.3 for JAK2 V617F (P<.001) 2.6 for MPL (P =.009) 6.2 for TN (P<.001) High risk: Any mutation in ASXL1, EZH2, SRSF2, IDH1/2 Rumi E, et al. Blood. 2014;124(7): Vannucchi AM, et al. Leukemia. 2013;27(9):

23 Case 3: Myeloid Panel Unpublished data JAK2/CALR/MPL mutation negative ASXL1 and SRSF2 mutations detected

24 Case 3 JAK2/MPL/CALR-mutation negative ASXL1- and SRSF2-mutation positive Sibling donor available No comorbidities = High-risk disease based on molecular markers Patient referred for allogeneic transplantation

25 Kröger N, et al. Blood. 2009;114(26):

26 Risk Factors in MF Transplantation Risk Factors (0-1 Risk) (2-3 Risks) Multivariate Risks >20 RBC Transfusions RR 4.43 (P<.01) Spleen >22 cm RR 2.71 (P =.02) ALT Donor RR 3.20 (P<.01) (N = 46: thiotepa-based reduced-intensity conditioning) Bacigalupo A, et al. Bone Marrow Transplant. 2010;45(3):

27 Use of JAK2 Inhibitors Before Transplantation for MF Patients with a good response to JAK2 inhibition have a good outcome Shanavas M, et al. Bone Marrow Transplant. 2016;22(3):

28 Second Management Decision Does the patient need treatment? What are the treatment goals? Clear indications for treatment: Symptoms (including painful splenomegaly) Cytopenias Cytoreduction Less clear indications for treatment Disease modification? Improve survival?

29 Personalised Therapy for MF Clinical Need Anemia/cytopenias Symptomatic splenomegaly Extramedullary hematopoiesis Constitutional symptoms/qol Cytoreduction Disease modification/survival ESA Danazol Thalidomide Corticosteroids Ruxolitinib Hydroxyurea Ruxolitinib Radiation therapy Ruxolitinib Corticosteroids Ruxolitinib Interferon Hydroxyurea Allogeneic SCT Ruxolitinib? Drugs / Intervention Lenalidomide (5q-) Splenectomy Radiation therapy Splenectomy ESA, erythropoiesis-stimulating agents; QoL, quality of life; SCT, stem cell transplantation

Clinical Trial Experience With Ruxolitinib in MF Primary endpoint: Proportion of patients achieving a 35% reduction in spleen volume at week 24 Secondary endpoints included: Proportion of patients

0 diary Duration of maintenance of a 35% reduction in spleen volume Primary endpoint: Proportion of patients achieving a 35% reduction in spleen volume at week 48 Secondary endpoints included:

30 Clinical Trial Experience With Ruxolitinib in MF Primary endpoint: Proportion of patients achieving a 35% reduction in spleen volume at week 24 Secondary endpoints included: Proportion of patients who had a 50% reduction from baseline at week 24 in Total Symptom Score (TSS) as measured by the modified MFSAF v2.0 diary Change from baseline to Week 24 in TSS as measured by the modified MSFAF v2.0 diary Duration of maintenance of a 35% reduction in spleen volume Primary endpoint: Proportion of patients achieving a 35% reduction in spleen volume at week 48 Secondary endpoints included: Proportion of patients achieving a 35% reduction in spleen volume at Week 24 Duration of maintenance of a 35% reduction from baseline in spleen volume COMFORT-I: Verstovsek S, et al. N Engl J Med. 2012;366(9): COMFORT-II: Harrison C et al. N Engl J Med. 2012;366(9):

COMFORT-I: Percent Change From Baseline in Spleen Volume in Individual Patients at Week 24 60 40

At week 24, ruxolitinib-treated patients had a median 33.

31 COMFORT-I: Percent Change From Baseline in Spleen Volume in Individual Patients at Week Ruxolitinib (n = 139) Placebo (n = 106) % Change From Baseline % decrease At week 24, ruxolitinib-treated patients had a median 33.0% decrease in spleen volume, and placebo-treated patients had a median 8.5% increase (P<.0001) Verstovsek S, et al. N Engl J Med. 2012;366(9):

COMFORT-I: Percent Change From Baseline in Total Symptom Score

129) Placebo (n = 103) % Change From Baseline 100 50 0-50 50%

33 COMFORT-I: Percent Change From Baseline in Total Symptom Score in Individual Patients at Week Ruxolitinib (n = 129) Placebo (n = 103) % Change From Baseline % decrease -100 Ruxolitinib-treated patients had a mean percent improvement of 46.1% in Total Symptom Score, and placebo-treated patients had a mean percent worsening of 41.8% (P<.0001) Patients with >200% increase in total symptom score are plotted as 200% increase Verstovsek S, et al. N Engl J Med. 2012;366(9):

Duration of Spleen Response Loss of response: no longer a 35% reduction that is also a >25% increase over nadir Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Ruxolitinib a BAT a 0.3 n = 78 n = 1 0.

34 Duration of Spleen Response Loss of response: no longer a 35% reduction that is also a >25% increase over nadir Probability Ruxolitinib a BAT a 0.3 n = 78 n = Events 34 (43.6%) Censored 44 (56.4%) 1 (100%) Time, Years Ruxolitinib, n = BAT, n = Median duration of response: ruxolitinib, 3.2 years The Kaplan-Meier estimated probability of maintaining response 3 years, 0.51 (95% CI, ) 5 years, 0.48 (95% CI, ) a For patients who achieved a 35% reduction at any time during randomized treatment; crossover patients are not summarized. Harrison CN, et al. Blood. 2015;126: Abstract

35 Mean Platelet Count and Hemoglobin Level Over Time Following Ruxolitinib Initiation Platelet Count Hemoglobin Mean Platelets (x10 9 /L) Ruxolitinib Placebo Ruxolitinib Placebo Mean Hemoglobin (g/l) Weeks Number of patients RUX PBO Weeks Number of patients Verstovsek S, et al. Haematologica. 2015;100(4):

36 Myelofibrosis and Cytopenias (N = 364) Tx Dep 24% Hb - Normal 25% N.B. Varying times NL Hb Men 13.5 g/dl Women 12 g/dl WBC < Normal 10% Hb <10g/dL- Tx Dep 18% Hb 10g/dL - Normal 33% PLT = % PLT < 50 9% WBC Normal 90% PLT = % PLT > % Emanuel RM, et al. J Clin Oncol. 2012;30(33):

37 Dose Reduction of Ruxolitinib Correlates With Reduced Efficacy Verstovsek S, et al. Haematologica. 2013;98(12):

38 Case 4: Management of Cytopenias 68-year-old female Presented with JAK2+ (90% allele burden) PV 10 years ago Aspirin and venesection Multiple thrombotic events: Lifelong warfarin 9 years after diagnosis phlebotomy requirements declined but remained transfusion independent Severe pruritus and bone pains Increasing splenomegaly New onset thrombocytopenia (warfarin switched to LMWH) Hb 11.5; WBC 12; Platelets 52 3% circulating blasts BM: grade 3 fibrosis and myeloproliferation No other mutations on myeloid panel Diagnosis = DIPSS INT-1 risk post-pv MF

39 Case 4: Management Options 1. Thalidomide and prednisolone 2. Splenectomy 3. Referral for allograft 4. JAK2 inhibition with low-dose ruxolitinib 5. Experimental treatment option

40 Case 4: Management Options 1. Thalidomide and prednisolone 2. Splenectomy 3. Referral for allograft 4. JAK2 inhibition with low-dose ruxolitinib 5. Experimental treatment option 11.3% 5.2% 2.1% 70.1% 11.3%

41 What Can be Done for MF Thrombocytopenia? Danazol (25%-30% responses) Limited durability Thalidomide and prednisolone (20% response) Limited durability Splenectomy? Limited durability Thrombopoietin agents? (may enhance fibrosis) Cervantes F, et al. Br J Haematol. 2005;129(6): Tefferi A et al. Blood. 2000;95(7):

42 What About Other Novel JAK2 Inhibitors in MF? Kinase Pacritinib Ruxolitinib Momelotinib JAK JAK JAK NR TYK NR FLT Different JAK inhibitors have different affinity for JAK family members Likely different off-target effects, eg, thiamine uptake with fedratinib Possibly different interactions as a consequence of other genetic features, eg, CALR

43 Distinct Properties of Pacritinib Inhibits some interesting targets in myelofibrosis in addition to JAK2 FLT3 IRAK1 Lack of significant myelosuppression in early-phase clinical trials Lack of JAK1 inhibitory activity Will this correlate with reduced immunosuppression and withdrawal syndrome?

Phase III Trials With Pacritinib Eligibility criteria PERSIST-1 Primary or Secondary MF (Int 1 or higher) No prior treatment with JAK2

excluding ruxolitinib Primary endpoint % of patients achieving 35% reduction in spleen size from baseline to week 24* Enrollment

Clinic Cancer Center, AZ, USA Claire Harrison, MD, Guy s Hospital, London, UK * Crossover from BAT allowed after progression or

44 Phase III Trials With Pacritinib Eligibility criteria PERSIST-1 Primary or Secondary MF (Int 1 or higher) No prior treatment with JAK2 inhibitors Stratified for platelet counts of 100,000/µL and 50,000/µL 2:1 Randomization* n~320 Pacritinib Best available therapy (BAT) excluding ruxolitinib Primary endpoint % of patients achieving 35% reduction in spleen size from baseline to week 24* Enrollment complete: N = 327; topline data Q Sites: ~90 in Europe, Australia, Russia, and USA Principal investigators: Ruben Mesa, MD, Mayo Clinic Cancer Center, AZ, USA Claire Harrison, MD, Guy s Hospital, London, UK * Crossover from BAT allowed after progression or assessment of the primary endpoint National Institutes of Health. Available at: Accessed: June 6, 2016.

45 In the phase III PERSIST-1 trial of pacritinib (PAC) vs best available therapy (BAT) patients with myelofibrosis treated with pacritinib were noted to experience all of the following EXCEPT: 1. 24% of evaluable PAC-treated patients achieved SVR greater than or equal to 35% 0% 2. PAC-treated patients with baseline thrombocytopenia showed a lower incidence of spleen and symptom responses 68.8% 3. Treatment-emergent diarrhea was highest in week 1-8 (grade 3/4 = 2.7%) and lower in other time intervals. For patients who crossed over from BAT, a similar trend was seen 18.8% % patients treated with PAC vs 0% BAT became red blood cell transfusion independence 12.5%

46 Spleen Volume Reduction 35% At Week 24 As Assessed by MRI/CT ITT population: 19.1% vs 4.7%, PAC vs BAT (P =.0003) Evaluable population a : 25.0% vs 5.9%, PAC vs BAT (P =.0001) Change From Baseline, % PAC (n = 168) BAT (n = 85) Patients b 35% decrease a Evaluable population: patients had both baseline and week 24 spleen assessment by MRI or CT; n = 168 for PAC and n = 85 for BAT. b As of last patient s 24-week visit. BAT, best available therapy; CT, computed tomography; ITT, intent to treat; MRI, magnetic resonance imaging; PAC, pacritinib Mesa RA, et al. J Clin Oncol. 2015;33(Suppl): Abstract LBA7006. Vannucchi AM, et al. Blood. 2015;126: Abstract 58.

47 PERSIST-1: Spleen Volume Reduction 35% ITT PAC BAT Evaluable a 40% 40% P =.0370 Patients 30% 20% P = % P = % P = % 30% 20% P = % 33.3% P = % 10% 4.7% 10% 5.9% 0% All Pts 0% 0% <50,000/μL <100,000/μL 0% All Pts 0% 0% <50,000/μL <100,000/μL Platelet Counts Platelet Counts a Patients had both baseline and week 24 spleen assessment by MRI or CT; n = 168 for PAC and n = 85 for BAT. Mesa RA, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA7006.

48 PERSIST-1: 50% Reduction in TSS a At Week 24 ITT population: 24.5% vs 6.5%, PAC vs BAT (P<.0001) Evaluable b population: 40.9% vs 9.9%, PAC vs BAT (P<.0001) Change From Baseline, % PAC (n = 132) BAT (n = 71) Evaluable b Patients 50% decrease a v1.0 and v2.0 combined; b Patients had both baseline and week 24 TSS value; n = 132 for PAC and n = 71 for BAT. Mesa RA, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA7006.

PERSIST-1: 50% Reduction in TSS a At Week 24 by Baseline Platelet Counts ITT b PAC BAT Evaluable c Patients 50% 40% 30% 20% 10% P =.4086 20.0% 6.3% P =.0677 P =.0004 25.0% 24.3% 8.8% 5.

49 PERSIST-1: 50% Reduction in TSS a At Week 24 by Baseline Platelet Counts ITT b PAC BAT Evaluable c Patients 50% 40% 30% 20% 10% P = % 6.3% P =.0677 P = % 24.3% 8.8% 5.5% 50% 40% 30% 20% 10% P = % 11.1% P = % 16.7% P< % 7.5% 0% 0% <50,000/μL <100,000/μL 100,000/μL <50,000/μL <100,000/μL 100,000/μL a v1.0 and v2.0 combined; b n = 220 for PAC and n = 107 for BAT; c Patients had both baseline and Week 24 TSS value; n = 132 for PAC and n = 71 for BAT. Mesa RA, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA7006.

Changes in Platelet Levels, Hemoglobin, and RBC Transfusion Dependence Over Time 60 Patients With

Hgb <10 g/dl Mean Hgb (g/dl) (± SEM) 1,a PAC Mean Platelets 10 9 /L (± SEM) 50 40 30 20 10 BAT P

5 BAT 0 BL 3 4 8 12 16 20 24 Weeks 8 BL 3 4 8 12 16 20 24 Weeks At baseline, 15.9% of PAC and 14.

Patients Patients Achieving RBC Transfusion Independence 1 30% 25% 20% 15% 10% 25.7% P =.

0% BAT, best available therapy; BL, baseline; Hgb, hemoglobin; PAC, pacritinib; RBC, red blood

50 Changes in Platelet Levels, Hemoglobin, and RBC Transfusion Dependence Over Time 60 Patients With Baseline Platelets <50,000/μL Mean Platelets 10 9 /L (± SEM) 1,a PAC 10 Patients With Baseline Hgb <10 g/dl Mean Hgb (g/dl) (± SEM) 1,a PAC Mean Platelets 10 9 /L (± SEM) BAT P =.0034 b p= b Mean Hgb (g/dl) (± SEM) BAT 0 BL Weeks 8 BL Weeks At baseline, 15.9% of PAC and 14.0% of BAT patients were RBC transfusion dependent, per Gale criteria ( 6 units/90 days 2 ) Patients Patients Achieving RBC Transfusion Independence 1 30% 25% 20% 15% 10% 25.7% P =.043 PAC BAT 5% a By central laboratory. b Based on linear regression using mixed model. 0% BAT, best available therapy; BL, baseline; Hgb, hemoglobin; PAC, pacritinib; RBC, red blood cell 0% 1. Mesa RA, et al. J Clin Oncol. 2015;33(Suppl): Abstract LBA Gale RP, et al. Leuk Res. 2011;35(1):8-11. Vannucchi AM, et al. Blood. 2015;126: Abstract 58.

51 Incidence of Diarrhoea Over Time on PERSIST 1 Mesa RA, et al. J Clin Oncol. 2016;34(suppl): Abstract 7067

52 OS in patients with plts <50 Harrison C, et al. J Clin Oncol. 2016;34(suppl): Abstract 7066

53 Case 4: Management of Cytopenias Patient commenced pacritinib 400 mg daily as part of the PERSIST-1 study 20% spleen volume reduction after 24 weeks Good symptomatic response: Pruritus Fatigue Platelet count remained stable at over 18 months

54 Pacritinib is not approved for use in the UK

55 As of 9 th February 2016, studies with pacritinib put onto a full clinical hold by FDA; further outcomes awaited. Main areas of concern: Bleeding epistaxis and intracranial Cardiac failure and atrial fibrillation New drug application has been withdrawn Pacritinib is not approved for use in the UK

56 Case 4: Management of Cytopenias Pacritinib discontinued Rapid increase in symptoms (back to baseline level) 5 mg bd ruxolitinib caused worsening of the thrombocytopenia within 1 week Currently awaiting compassionate use pacritinib or PRM151 trial

57 Do JAK2 inhibitor treatments have a disease-modifying effect? Should their use be considered in less-symptomatic patients?

58 COMFORT-I OS: Rank-Preserving Structural Failure Time (RPSFT) Analysis Ruxolitinib Probability Placebo Ruxolitinib Placebo-RPSFT HR = 0.36 (95% CI: ) Weeks RPSFT is a recognized method to estimate HR after adjusting for crossover 1-5 Hazard ratio of 0.36 is consistent with the hypothesis that ITT analysis underestimates the survival benefit of ruxolitinib relative to true placebo 1. Robins J, et al. Commun Stat Theory Meth. 1991;20: Demetri GD et al. Clin Cancer Res 2012;18(11): National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance Issued September 23, Sternberg CN, et al. Eur J Cancer. 2013;49(6): National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance Issued February Verstovsek S, et al. Haematologica. 2015;100(4):

59 COMFORT-II: Overall Survival After 3.5 Years (EHA 2014) Probability Patients Events Censored 0.0 Ruxolitinib (27.4%) 106 (72.6%) BAT (41.1%) 43 (58.9%) Years Ruxolitinib BAT Ruxolitinib, n = BAT, n = HR = 0.58; 95% CI, ; log-rank test P =.022. P value for log-rank test is provided for descriptive purposes and was not adjusted for multiple comparisons Harrison C et al. Haematologica. 2014;99(suppl1): Abstract P403

burden and reduction of BM fibrosis in 1 patient

60 Reduction of JAK2V617F Allele Burden and Resolution of BM Fibrosis With Ruxolitinib Reduction of allele burden and reduction of BM fibrosis in 1 patient Wilkins BS, et al. Haematologica. 2013;98(12):

Trial Design: ReTHINK Rux vs Placebo (MF DIPSS LR/ HMR+) Screening Treatment Phase MF Patients Spleen 5 cm below

bid Ruxolitinib 5/15/20 mg bid PFS2 Survival Follow-Up Inclusion Population: Hb >10 g/dl; transfusion

(90 events) Secondary Endpoints PFS-2, Safety &Tolerability, QOL, OS * If progression is achieved by spleen or

61 Trial Design: ReTHINK Rux vs Placebo (MF DIPSS LR/ HMR+) Screening Treatment Phase MF Patients Spleen 5 cm below LCM HMR+ (ASXL1, EZH2, SRSF2 or IDHI1/2) N = 320 1:1 Ruxolitinib 10 mg bid Placebo PFS1* Ruxolitinib 5/15/20 mg bid Ruxolitinib 5/15/20 mg bid PFS2 Survival Follow-Up Inclusion Population: Hb >10 g/dl; transfusion independent ANC >1, WBC <15000 Blast <1% Platelets >75,000 MPN10 15 (individual items 3) Primary Endpoint: PFS-1 (90 events) Secondary Endpoints PFS-2, Safety &Tolerability, QOL, OS * If progression is achieved by spleen or symptoms National Institutes of Health. Available at: Accessed: June 8, 2016.

62 Potential Disease Modification Must Be Balanced Against Risk of Treatment Complications Eg, immune dysfunction with JAK1/2 inhibition Increased rate of infections, eg, UTIs, VZV with ruxolitinib Multiple different opportunistic infections reported during ruxolitinib therapy Development, activation, and migration of monocyte-derived dendritic cells significantly impaired following exposure to ruxolitinib Wide range of effects on T-cell subsets Drug-induced attenuation of cytokine-mediated NK cell activation, proliferation, and functional capability Primarily a JAK1 inhibitory effect? Will pacritinib be different? Barosi G, et al. Blood. 2013;122: Abstract Yajnanarayana SP, et al. Blood. 2013;122: Abstract Heine A, et al. Blood. 2013;122(7): Keohane C, et al. Blood. 2013;122: Abstract Massa M, et al. Leukemia. 2014;28(2): Schönberg K, et al. Blood. 2013;122: Abstract 16. Stuebig T, et al. Blood. 2013;122: Abstract 2001.

63 The Future: Novel Therapies and Combination Partners for JAK Inhibitors Pomalidomide Lenalidomide Danazol Azacytidine Decitabine Pi3 Kinase SMO inhibitors HDAC panobinostat/givinostat Pentraxin analogue PRM151 Transplantation Interferon Telomerase inhibitors (imetelestat) In whom to trial these agents, and how to pick a successful combination? Is spleen reduction the optimum target?

Classical Ph-1neg myeloproliferative neoplasms: Ruxolitinib in myelofibrosis. Francesco Passamonti Università degli Studi dell Insubria, Varese

Classical Ph-1neg myeloproliferative neoplasms: Ruxolitinib in myelofibrosis Francesco Passamonti Università degli Studi dell Insubria, Varese DIPSS during f-up IPSS at diagnosis Diagnose MF and genotype