Changing the Treatment Story in Myelofibrosis New Science and More Choices for Challenging Cases in the JAK Inhibitor Era

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MasterClass and Case Forum Changing the Treatment Story in Myelofibrosis New Science and More Choices for Challenging Cases in the JAK Inhibitor Era

Not an official event of the 2019 ASCO Annual Meeting. Not sponsored, endorsed, or accredited by ASCO, CancerLinQ, or Conquer Cancer. Disclosures

Professor Claire Harrison has a financial Prithviraj Bose, MD, has a financial interest/relationship interest/relationship or affiliation in the form of: or affiliation in the form of: Consultant and/or Advisor for AOP Orphan Grant/Research Support from Astellas Pharma US, Inc.; Pharmaceuticals AG; Celgene Corporation; CTI Blueprint Medicines Corporation; Celgene Corporation; BioPharma Corp.; F. Hoffmann-La Roche Ltd; Novartis Constellation Pharmaceuticals; CTI BioPharma Corp.; Pharmaceuticals Corporation; Promedior, Inc.; and Sierra Oncology, Inc. Incyte Corporation; Kartos Therapeutics, Inc.; NS Pharma, Inc.; Pfizer Inc.; and Promedior, Inc. Speakers Bureau participant with Celgene Corporation and Novartis Pharmaceuticals Corporation. Honorarium from Blueprint Medicines Corporation; Celgene Corporation; and Incyte Corporation. Professor Claire Harrison does intend to discuss either non–FDA-approved or investigational use for the Prithviraj Bose, MD, does intend to discuss either following products/devices: ruxolitinib, fedratinib, non–FDA-approved or investigational use for the pacritinib, momelotinib, and other novel targeted following products/devices: ruxolitinib, fedratinib, therapies, as single-agents or combinations in different pacritinib, momelotinib, and other novel targeted myelofibrosis settings. therapies, as single-agents or combinations in different myelofibrosis setting.

This CME/MOC activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. This activity is supported by an educational grant from Celgene Corporation. Disclosures

Naveen Pemmaraju, MD, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for Celgene Corporation; LFB USA; Mustang Bio; Novartis Pharmaceuticals Corporation; Roche Diagnostics, North America; and Stemline Therapeutics, Inc. Grant/Research Support from AbbVie Inc.; Affymetrix; Cellectis; Daiichi Sankyo Company Limited; Novartis Pharmaceuticals Corporation; Plexxikon; Samus Therapeutics, Inc.; Sager Strong Foundation; and Stemline Therapeutics, Inc. Other financial interest/relationship for Dan's House of Hope, where Dr. Pemmaraju serves on the Board of Directors, and HemOnc Times/Oncology Times, where he serves as a Board Member. Naveen Pemmaraju, MD, does intend to discuss either non–FDA-approved or investigational use for the following products/devices: ruxolitinib, fedratinib, pacritinib, momelotinib, and other novel targeted therapies, as single-agents or combinations in different myelofibrosis setting.

Content Reviewers Medical Directors

Shaina Rozell, MD, MPH, has no financial PVI, PeerView Institute for Medical Education interests/relationships or affiliations in relation to this activity. Carmine DeLuca has no financial interests/relationships or affiliations in Amita B. Patel, MSN, RN, AOCNP, NP-C, has no relation to this activity. financial interests/relationships or affiliations in relation to this activity. Kathryn B. Charalambous, PhD, has no financial interests/relationships or affiliations in relation to this activity.

Other PVI associates who are in a position to have control over the content of this activity do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/MOC activity during the past 12 months.

The associates of the Medical Learning Institute, Inc., the accredited provider for this activity, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/MOC activity during the past 12 months. Visit us at PeerView.com/Myelofibrosis19

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Twitter @PeerView Need more information? Send an email to [email protected] Welcome and Introduction

Professor Claire Harrison Clinical Director - Haematology, Haemostasis, Palliative Care, Cellular Pathology Photo Guy's and St Thomas' NHS Foundation Trust Pending London, England, United Kingdom

Go online to access full [Certification Type] information, including faculty disclosures. Myeloproliferative Neoplasms

Overt PMF PV Post-ET/PV MF ET Early PMF Progressive Progressive Short term: Progressive constitutional organomegaly/ vascular events cytopenias symptoms EMH

Leukemic Time: transformation Lead time: variable; typically years (>10) 3-5 years common Premature death Symptom Burden of Myelofibrosis

Splenomegaly: 80% of patients1

MF-associated Early death prognosis: symptoms: 2 5 to 6 years 70% experience

Anemia/cytopenias: 60% to 85%

1. Cervantes F et al. Blood. 2009;113:2895-2901. 2. Tefferi A et al. Blood. 2014;124:2507-2513 . Agenda

1. MasterClass 1: the shape of MF risk assessment and treatment

2. MasterClass 2: a look at the evidence behind established and emerging JAK inhibitors

3. Case Forum: a case-based synthesis of principles and practical tips for managing MF in the JAK inhibitor era MasterClass 1

Characterizing Myelofibrosis for a Risk-Adapted Approach to Management in the JAK Inhibitor Era Prithviraj Bose, MD Associate Professor Department of Leukemia, Division of Cancer Medicine Photo The University of Texas MD Anderson Cancer Center Pending Houston, Texas

Go online to access full [Certification Type] information, including faculty disclosures. WHO Criteria for Diagnosis of Primary Myelofibrosis (PMF)1

Major criteria • Proliferation and atypia of megakaryocytes accompanied by either reticulin and/or collagen fibrosis grades 2 or 3 on a scale of 0 to 3 • Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, MDS, or other myeloid neoplasm • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker,a or absence of reactive MFb

Minor criteria • Anemia not attributed to a comorbid condition Diagnosis requires • Leukocytosis ≥11 × 109/L meeting all three major • Palpable splenomegaly criteria, and at least two • LDH increased to above upper normal limit of institutional reference range minor criterion confirmed in two consecutive • Leukoerythroblastosis determinations a In the absence of any of the three major clonal mutations, the search for the most frequent accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease. b BM fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies. 1. Arber DA et al. Blood. 2016;127:2391-2324 Pathology and Molecular Testing1

In addition to laboratory workup and symptom assessment, organizations BM aspirate and biopsy with trichrome such as the NCCN recommend and reticulin stain molecular/genetic and pathology tests to help confirm a diagnosis, including: BM cytogenetics (blood, if bone marrow is inaspirable; karyotype ± FISH)

Molecular testing for JAK2 V617F mutation; If negative, test for

CALR and MPL NGS panel JAK2 exon 12 mutations (ET or (JAK2, CALR, mutations (PV) and MF) MPL, & others)

1. NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms. Version 4.2019 . https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf. Accessed May 22, 2019. Diagnosing PPV- or PET-MF1,2

PV ET 10% progression rate per 10 years1 <4% progression rate per 10 years1 Post–PV myelofibrosis2 Post–ET myelofibrosis2 • IWG Diagnostic Criteria for post–PV myelofibrosis • IWG Diagnostic Criteria for post–ET myelofibrosis Required criteria • Documentation of previous diagnosis of PV or ET as defined by WHO criteria • Grade 2 or 3 bone marrow fibrosis (0-3 scale) or grade 3 or 4 bone marrow fibrosis (0-4 scale) Additional criteria (two required) Additional criteria (two required) • Anemia and a decrease of ≥2 g/dL from baseline • Anemia or sustained loss of need for either phlebotomy or hemoglobin level cytoreductive therapy • Leukoerythroblastosis • Leukoerythroblastosis • ≥5-cm increase in palpable splenomegaly or new • ≥5-cm increase in palpable splenomegaly or new splenomegaly splenomegaly • Increased serum LDH level • Development of ≥1 of 3 constitutional symptomsa • Development of ≥1 of 3 constitutional symptomsa a Constitutional symptoms include >10% weight loss in 6 months, night sweats, and unexplained fever (>37.5°C). 1. Tefferi A. Am J Hematol. 2008;83:491-497. 2. Barosi G et al. Leukemia. 2008;22:437-438. The Evolution of Risk Stratification Models in MF1-3

Parameter IPSS DIPSS DIPSS Plus Age >65 y    Constitutional symptoms    WBC >25 x 109/L    Hb <100 g/L   (two points)  Peripheral blasts ≥1%    Platelet count <100 x 109/L  RBC transfusion need  Unfavorable karyotype 

1. Cervantes F et al. Blood. 2009;113:2895-2901. 2. Passamonti F et al. Blood. 2010;115:1703-1708. 3. Gangat N et al. J Clin Oncol. 2011;29:392-397. IPSS Risk Stratification1

Prognostic factors 1 Survival by PMF-PS • Age >65 years 0.9 • Constitutional 0.8 symptoms 0.7 • Hb <10 g/dL 0.6 9 • Leukocytes >25 x 10 /L 0.5 • Blood blasts ≥1% 0.4 0.3

Survival, ProbabilitySurvival, 0.2 Risk groups 0.1 • Low 0 0 • Intermediate-1 1 00 24 24 48 72 48 96 12072 144 96 168 120192 216144 240 168 264 288192 • Intermediate-2 2 Time, mo • High ≥3 95% CI 95% CI 95% CI 95% CI PMF-PS = 0 PMF-PS = 1 PMF-PS = 2 PMF-PS = 3

1. Cervantes F et al. Blood. 2009;113:2895-2901. Risk Stratification: DIPSS1

1 0.9 Low 0.8 0.7 0.6 0.5 Intermediate-1 0.4

Surviving Surviving 0.3 0.2 0.1 Cumulative Cumulative Proportion High Intermediate-2 0 0 5 10 15 20 25 Time, y

1. Passamonti F et al. Blood. 2010;115:1703-1708. Risk Stratification1-3

Unfavorable Karyotypes

i(17q) +8 MK Complex karyotype -7/7q- inv(3) 11q23 rearrangement 5/5q- 12p-

1. Tefferi A et al. Leukemia. 2012;26:1439-1441. 2. Gangat N et al. J Clin Oncol. 2011;29:392-397. 3. Caramazza D et al. Leukemia. 2011;25:82-88. Prognostic Value of Driver Mutations1

JAK2 V617F vs CALR vs Triple Negative

Highest OS 1 CALR mutant (median OS 17.7 y) 0.9 JAK2 mutant (median OS 9.2 y) MPL mutant (median OS 9.1 y) CALR 0.8 Triple negative (median OS 3.2 y) 0.7 0.6 JAK2 V617F or 0.5 MPL 0.4

Survival 0.3 Triple 0.2 negative 0.1 0

Cumulative Cumulative Probability of 0 5 10 15 20 25 30 Lowest OS Time, y

1. Rumi E et al. Blood. 2014;124:1062-1069. Prognostic Value of Driver Mutations (Cont’d)1

CALR Type 1 vs Type 2 • Two types of mutations 1 CALR type 1/type 1–like – Type 1: 52 bp deletion 0.9 n = 53 0.8 Median: 26.4 (15.5-37.3) y – Type 2: 5 bp insertion 0.7 • Effect of mutation on OS 0.6 CALR type 2/type 2–like 0.5 n = 21 – Type 1 patients: OS advantage 0.4 Median: 7.4 (4.6-10.2) y JAK2 V617F HR = 4.9 (1.8-12.9) – Type 2 patients: OS comparable to 0.3 n = 251 JAK2 V617F 0.2 Median: 7.2 (5.7-8.6) y HR = 6.0 (2.7-13.4) P < .0001 0.1 N = 396 0 Proportion of Patients, % 0 5 10 15 20 25 30 Follow-Up, y

1. Guglielmelli P et al. Blood Cancer J. 2015;5:e360. “Non-Driver” Mutations1

Prognostically important genes, other than JAK2/CALR/MPL, in ET, PV, and MF

PMF

SRSF2 ASXL1 IDH2 EZH2 TP53 U2AF1 CBL

PV ET SF3B1 SH2B3

1. Tefferi A et al. Blood Adv. 2016;1:21-30. MIPSS70 and MIPSS70-Plus1 http://mipss70score.it

Key Elements • Hb <10 g/dL • WBC >25 x 109/L • HMR • PLT <100 x 109/L – ASXL1 • Blasts ≥2% – EZH2 • Fibrosis > grade 1 – SRSF2 • Constitutional – IDH1/2 symptoms • Absence of type 1- • Two or more HMR like CALR Unfavorable karyotype

1. Guglielmelli P et al. J Clin Oncol. 2018;36:310-318. The MIPSS70-Plus Version 2.0 Additionally Incorporates (Into the MIPSS70-Plus)1

Patients ≤ 70 years of age Patients of all age groups 1. “Very high risk” karyotype 2. U2AF1 Q157 mutation status 3. Sex- and severity-adjusted Hgb thresholds; and 4. Defines five prognostic categories, from very low to very high risk

Stratification by MIPSS70+ “Very high risk” karyotype • -7 • i(17q) • Inv(3)/3q21 abnormalities • 12p-/12p11.2 abnormalities • 11q-/11q23 abnormalities • Other autosomal trisomies not including +8/+9

1. Tefferi A et al. J Clin Oncol. 2018; 36:1769-1770. GIPSS: Genetically Inspired Prognostic Scoring System1

GIPSS-Stratified Survival Data in 641 Patients With Primary Myelofibrosis • Karyotype – Very high risk = 2 points – Unfavorable = 1 point • Driver mutations – Type 1–like CALR absent = 1 point • High-risk mutations – ASXL1 mutation = 1 point – SRSF2 mutation = 1 point – U2AF1 Q157 mutation = 1 point

1. Tefferi A et al. Leukemia. 2018;32:1631-1642. The MYSEC-PM Nomogram1,a

Covariate Points

Hgb <11 g/dL 2

Plts <150 x 109/L 1 PB blasts ≥3% 2 CALR-WT 2 Constitutional 1 symptoms

1. Put on the vertical axis the score value assigned for non-age prognostic variables 2. Put patient’s age on horizontal axis 3. Locate the combination of non-age score and age 4. The color at the location indicates the final risk category a Available at https://mysec.shinyapps.io/prognostic_model/. 1. Passamonti F et al. Leukemia. 2017;31:2726-2731. MYSEC-PM Estimate of Survival in Post-PV/ET MF1

Low risk (n = 133), not reached

Int-1 risk (n = 245), 9.3 years (95% CI: 8.1-NR)

Overall Survival, % Survival, Overall Int-2 risk (n = 126) 4.4 (95% CI: 3.2-7.9)

High risk (n = 75), 2 years (95% CI: 1.7-3.9)

No. at Risk 133 105 74 48 25 16 6 Low 245 166 104 50 20 10 6 Intermediate-1 126 70 30 15 8 2 Intermediate-2 75 25 6 1 High SMF Follow-Up Time, Years

1. Passamonti F et al. Leukemia. 2017; 31:2726-2731. Canonical and Noncanonical Actions of JAK2 and Opportunities for Therapeutic Targeting1

1. Bose P, Verstovsek S. Blood. 2017:130:115-125. Role of JAK Inhibition in MF1

JAK inhibitors improve splenomegaly, symptom burden and OS of patients with MF independent of allogeneic HCT2-4

Current status of JAK inhibitors in MF

• Ruxolitinib (approved) • Fedratinib (under regulatory review for approval) • Pacritinib (clinical hold lifted) • Momelotinib (clinical development resumed)

1. Passamonti F, Maffioli M. Blood. 2018;131:2426-2435. 2. Verstovsek S et al. J Hematol Oncol. 2017;10:55. 3. Harrison C et al. Leukemia. 2016;30:1701-1707. 4. Verstovsek S et al. J Hematol Oncol. 2017;10:156. Role of JAK Inhibition in MF (Cont’d)

JAK inhibitors have been used pre-transplant to achieve best possible response prior to conditioning1

• After HCT, JAK inhibition has emerged as a new tool in the management of patients with acute and chronic GVHD,2 with the recent FDA approval of ruxolitinib for steroid-refractory acute GVHD • Further, a small but growing body of data suggests JAK inhibitors may also serve as steroid-sparing agents3

Both before and after HCT, JAK inhibition represents an important modality for improving the outcomes of patients with MF

1. Gupta V et al. Biol Blood Marrow Transplant. 2019;25:256-264. 2. Zeiser R et al. Leukemia. 2015; 29:2062-2068. 3. Khoury HJ et al. Bone Marrow Transplant. 2018;53:826-831. Role of Allogeneic Transplant in 20191

1. Timing and sequencing of allogeneic SCT in MF can be complex and challenging

2. Allogeneic SCT remains the only curative approach for transplant-eligible patients

3. All available prognostic information and recent scoring systems should be utilized when considering allo SCT

1. McLornan DP et al. Haematologica. 2019 ;104:659-668. Comprehensive Clinical-Molecular Transplant Scoring System for MF Undergoing Stem Cell Transplantation1

Training Validation

Platelets Leukocytes Karnofsky Age ≥57 Non-CALR/MPL driver ASXL1 HLA-mismatched <150 x 109/L >25 x 109/L PS Years mutation genotype mutation unrelated donor

HR 1.6 1.57 1.50 1.65 2.40 1.42 2.08

Score 1 1 1 1 2 1 2

1. Gagelmann N et al. Blood. 2019;133:2233-2242. Toward a Consensus on Treating MF in 20191

Primary MF or PPV-MF/PET-MF Assess prognostic score Objective symptom score assessment Consideration to cytogenetics and molecular risk

Low risk Intermediate-1 Intermediate-2 High risk Consider HLA typing

Is patient a present or future allograft candidate? Asymptomatic Symptomatic watch and wait • HLA-typing and donor sourcing and consideration to timing – Can the patient be optimized pre-allograft? Ruxolitinib • Symptom burden or splenomegaly: ruxolitinib alone or combination Possible role for therapy ruxolitinib or IFN • Novel agents (eg, PRM-151 or imetelstat/novel JAK inhibitor or combination studies) Clinical needs- • Emerging JAK inhibitors/novel agents for those failing ruxolitinib in based therapy first-line therapy

Anemia management: ESA based on endogenous EPO level, IMiDs, activin receptor ligand traps, transfusions, danazol

1. Harrison CN, McLornan DP. Hematology Am Soc Hematol Educ Program. 2017;2017:489-497. MasterClass 2

Evidence-Based Treatment for Myelofibrosis— New Science and Expanding Options

Professor Claire Harrison Clinical Director - Haematology, Haemostasis, Palliative Care, Cellular Pathology Guy's and St Thomas' NHS Foundation Trust London, England, United Kingdom

Go online to access full [Certification Type] information, including faculty disclosures. JAK/STAT Signaling and Clinical Manifestations of MF1,2

Fibrosis

JAK2 JAK1

Ineffective Inflammatory hematopoiesis cytokines

Anemia Extramedullary Constitutional hematopoiesis symptoms (splenomegaly)

1. Verma A et al. Cancer Metast Rev. 2003;22:423-434. 2. Mughal TI et al. Int J Gen Med. 2014;7:89-101. 33 JAK Inhibition (Ruxolitinib): Phase 3 Clinical Trial Program

Phase 3

COMFORT-I1 COMFORT-II2 N = 309 N = 219

• Randomized, double-blind, placebo-controlled trial • Randomized, open-label trial vs best available • Conducted at multiple sites in US, Canada, (historical) therapy Australia • Conducted at multiple sites in Europe • FPFV: September 2009 • FPFV: July 2009

• Patients with PMF, PPV-MF, or PET-MF • Patients with PMF, PPV-MF, or PET-MF

• Primary endpoint: ≥35% reduction in spleen • Primary endpoint: ≥35% reduction in spleen volume from baseline to week 24 volume from baseline to week 48 • Secondary endpoints: total symptom score, • Secondary endpoints: spleen response at overall survival, duration of spleen response week 24, duration of spleen response • Exploratory endpoint: QOL • Exploratory endpoint: QOL

Highly significant reduction of spleen volume and resolution of disabling symptoms

1. Verstovsek S et al. N Engl J Med. 2012;366:799-807. 2. Harrison CN et al. N Engl J Med. 2012;366:787-798. Benefits of Ruxolitinib in a COMFORT-II Patient1

Before After 72 weeks  Spleen

 QoL

“This drug gave me my life back. I can work and enjoy life.”

1. Courtesy of Professor Claire Harrison. Spleen Reduction Is Independent of Driver Mutation

Efficacy of Ruxolitinib in CALR Mutated Patients in COMFORT-II2, a Regardless of JAK2 V617F Mutation1

Ruxolitinib BAT

% 20 , , 40 Percent Change From Baseline in Spleen • In CALR+ patients, a 0 20 Volume at Week 48 ≥35% reduction from 0 baseline in spleen -20 -20 volume at week 48 35% reduction from baseline was achieved by 20% Baseline From -40 -40 Primary endpoint in the ruxolitinib arm vs -60 Ruxolitinib BAT -60 JAK2V617F positive (n = 75) 0% in the BAT arm -80 JAK1V617F positive (n = 24) Change JAK2V617F negative (n = 22) JAK1V617F negative (n = 8) 1.01 + Censored

Change From Baseline, % Baseline,FromChange -100 Unknown mutation status (n = 1) Unknown mutation status (n = 2) • The Kaplan-Meier– 0.8 estimated probability • At week 48, most patients receiving ruxolitinib experienced of survival at 144 0.6 weeks was 0.76 in the spleen volume reductions, including JAK2 V617F–positive (88% 0.4 [66/75]) and JAK2 V617F–negative (91% [20/22]) patients ruxolitinib arm vs 0.50 Treatment in the BAT arm Probability 0.2 Ruxolitinib BAT 0 0 50 100 150 Time, wk

a Analysis conducted on 29/166 (17.5%) patients, with baseline mutation status assessments, who were CALR+. 1. Guglielmelli P et al. Br J Haematol. 2016 ;173:938-940. 2. Guglielmelli et al. ASH 2014. Abstract 1853. Ruxolitinib and Overall Survival: COMFORT Studies1

• The risk of death was reduced by 30% • Median OS: ruxolitinib, 5.3 years; control, 3.8 years; HR (ruxolitinib vs control) 0.70; 95% CI, 0.54-0.91; P = .0065

0.0

1. Verstovsek S et al. J Hematol Oncol. 2017;10:156. Survival Benefit Occurs in Both “HMR and LMR”…1

…But ruxolitinib does not overcome the negative survival impact of “HMR”

Survival Estimates in Patients in COMFORT-II

Stratified by Treatment and Molecular Score

1.01 0.9 0.8 0.7 0.6 Ruxolitinib LMR 0.5 Ruxolitinib HMR a a 0.4 BAT LMR Ruxolitinib Arm BAT Arm 0.3 HMR LMR HMR LMR 0.2 BAT HMR 0.1 0.79 0.85 0.58 0.71 0 Survival, Probability Survival, 0 24 48 72 96 120 144 168 192 Time, wk • In multivariate analysis of overall survival by treatment and molecular risk, the HR for treatment (ruxolitinib vs BAT) was 0.57 (95% CI, 0.30-1.08) and for LMR vs HMR the HR was 0.62 (95% CI, 0.33-1.16) a Median follow-up = 151 weeks; Kaplan-Meier estimates at 144 weeks. 1. Guglielmelli P et al. Blood. 2014;123:2157-2160. Better Spleen Response to Ruxolitinib, Better Outcome1

Ruxolitinib Events HR (95% CI) ≥10% to <25% (n = 62) 15 0.36 (0.18-0.72)

≥25% to <35% (n = 49) 7 0.25 (0.18-0.61

≥35% to <50% (n = 64) 8 0.24 (0.11-0.56) Other evidence: overall survival of patients by degree of spleen length reduction on ruxolitinib

≥50% (n = 47) 6 0.18 (0.07-0.47)

Control 1.01 0.9 ≥10% to <25% (n = 10) 0.8 3 0.7 1.02 (0.31-3.29) 0.6 ≥25% to <35% (n = 5) 2 0.5 2.79HR = 0.22(0.65 (95%-11.90) CI, 0.10 -0.51) 0.4 P = .0001 0.3 <25% reduction (n = 23) ≥35% to <50% (n = 1) 1 0.2 43.90 (4.16≥25%- but463.5) <50% reduction (n = 13)

Survival, Survival, Probability 0.1 ≥50% reduction (n = 61) 0 0.01 0.1 1 10 100 0 6 12 18 24 30 36 42 48 HR (95% CI) vs < 10% Reductiona Time, mo aCategory includes patients with a <10% reduction from baseline in spleen volume at week 24 or no assessment (ruxolitinib, n=64; control, n=189); among these patients, there were 26 deaths (events) in the pooled ruxolitinib group and 63 deaths in the control group. 1. Vannucchi AM et al. Haematologica. 2015;100:1139-1145. Weight Gain Correlates With Survival Benefit1

Before After 72 weeks  Spleen

 QoL

This patient is alive and well after 9 years. (Spleen now 179 mm)

1. Courtesy of Professor Claire Harrison. Mean Platelet Count and Hemoglobin Over Time COMFORT-I1

Platelet Count Hemoglobin

370 115

Ruxolitinib Placebo Ruxolitinib Placebo

9 110 320

105 270 100

220 g/L Hemoglobin, Platelets, x10 Platelets,

95 Mean

Mean 170 90

120 85 0 12 24 36 48 60 72 84 96 108 120 132 144 0 12 24 36 48 60 72 84 96 108 120 132 144 Time, wk Time, wk No. of Patients No. of Patients RUX 155 144 143 136 124 112 110 107 104 100 94 88 79 155 145 143 136 124 113 110 107 104 100 94 88 79 Placebo 151 128 112 82 37 151 132 113 83 37

1. Verstovsek S et al. Haematologica. 2015;100:479-488. Development of Anemia in First 12 Weeks of Therapy Does NOT Impact Survival1

OS in patients with or without an Hb decrease of 30 g/L at week 12

1.01 0.9 0.8 Ruxolitinib (drop in Hb ≤30 g/L) Ruxolitinib (drop in Hb >30 g/L)a 0.7 Control (drop in Hb ≤30 g/L) 0.6 0.5 Control (drop in Hb >30 g/L)a 0.4 0.3 0.2 0.1 Survival, Survival, Probability 0 0 50 100 150 Time, wk No. at Risk Ruxolitinib (drop in Hb ≤30 g/L) 143 118 101 62 Ruxolitinib (drop in Hb >30 g/L)a 29 18 13 4 Control (drop in Hb ≤30 g/L) 121 110 91 62 Control (drop in Hb >30 g/L)a 124 106 93 57 a Includes patients who became transfusion dependent in the first 12 weeks of treatment but were independent at baseline. 1. Al-Ali HK et al. Leuk Lymphoma. 2016;57:2464-2467. Infections and Ruxolitinib: Immunosuppression?

COMFORT STUDIES: Hepatitis B increased UTIs, URTIs, and reactivation herpes reactivation

PML Cryptococcus

Rux

TB Toxoplasma reactivation Current Status: Ruxolitinib in MF

• A highly effective drug benefiting many patients • Data from 2,233 patients in JUMP trial at American Society of Hematology (ASH) Annual Meeting in 2017 (Al-Ali et al)1 • Anemia and thrombocytopenia may limit effective dosing1-3 • Infections: 5% herpes zoster, atypical infections (eg, reactivation of TB)1,3,4 • Nonmelanoma skin cancer more prevalent (vs BAT) in RESPONSE4 • Recent link to NHL reported • Lack of evidence of disease modification in low-risk MF • Definition of failure variable in clinical trials, unclear in clinical practice

1. Al-Ali HK at al. Haematologica. 2016;101:1065-1073. 2. Verstovsek S et al. J Hematol Oncol. 2017:10:156. 3. Harrison CN et al. Leukemia. 2016;30:1701-1707. 4. Vannucchi AM et al. New Engl J Med. 2015;372:426-435. British Guidelines for Myelofibrosis and Use of JAK inhibitors1

Includes Symptoms Spleen Hematological Toxicity infection No Clear Continue ruxolitinib Clear Yes

Yes Suboptimal Consider Suboptimal No continuing ruxolitinib Yes No Minimal Equivocal Yes No None None Yes Stop ruxolitinib

1. Reilly JT et al. Br J Haematol. 2014;167:418-420.

Identification/Management of Progression/Resistance on Ruxolitinib

Feature Treatment Options • Threshold: beyond baseline, ↑ by 5 cm, more symptomatic • Optimize dose of ruxolitinib Spleen • Switch to alternative JAK inhibitor • Consider splenectomy • Review cause (eg, mood disturbance, other medications) • Optimize dose of ruxolitinib Symptoms • Consider alternative treatments (eg, steroid, antihistamine) • Switch to alternative JAK inhibitor • Exclude other causes (eg, drug–drug interaction) More anemia or • Determine if it needs treating thrombocytopenia • Add EPO, danazol, thalidomide • Determine the threshold for treatment Leukocytosis • Add hydroxycarbamide • Threshold depends on rate of rise 10%/15%/20% Blasts • Expectant, consider adding HMA or rarely AML induction

Prognosis After Ruxolitinib Discontinuation1

1.0 HR = 4.1 (95% CI, 1.8-9.5); P = .001 1.0 HR = 2.7 (95% CI, 1.3-5.8); P = .006 0.8 0.8

Plt ≥100 No clonal evolution at FU Survival 0.6 Plt <100 Survival 0.6 Clonal evolution at FU Censored Censored 0.4 0.4

0.2 0.2 Cumulative Cumulative 0.0 Cumulative 0.0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Survival After Discontinuation, mo Survival After Discontinuation, mo Plts <100 median survival 11/12 Clonal evolution median survival 6/12

No. at risk No. at risk Plt ≥100 23 12 7 4 3 1 0 No CE 28 16 4 4 2 1 0 Plt <100 33 10 4 0 CE 14 3 3 1 0

1. Newberry KJ et al. Blood. 2017;130:1125-1131. JAK Inhibitors and Status of Development in Myelofibrosis as Lead Indication

Combo trials Derailed in earlier phase 3 now re-entering phase 3

Selective Approved JAK1, Active Ruxolitinib Active in combo? late phase Toxicity second line Pacritinib • neuro Fedratinib; Momelotinib • pancreas Active mid phase Active Failed Itacitinib early phase BMS-911543 NS018 LY2784544

Lestaurtinib AZD1280 XL019 Fedratinib MOA

• Fedratinib is a small-molecule, ATP-competitive kinase inhibitor that is potent against both wild-type and mutant JAK2 • Fedratinib is highly selective for JAK2 – Less potential for off-target side effects through inhibition of other members of the JAK family?

H N S NH O O O N N

N N H JAKARTA: Phase 3 Study Design1

Week 24 or disease Placebo progression before week 24: Daily oral doses, crossover to fedratinib • Aged ≥18 years 4-week cycle • Diagnosis of 400 or 500 mg (1:1) – Primary MF – Post–PV MF Fedratinib 400 mg – Post–ET MF R Daily oral doses, • Intermediate 2 or 4-week cycle Week 24 EOT high-risk status (EOC6) • Splenomegaly Fedratinib 500 mg Daily oral doses, 4-week cycle

1 cycle = 4 weeks

1. Pardanani A et al. JAMA Oncol. 2015;1:643-651. Primary Endpoint:

Spleen Response (ITT Population)1

45 40.2

40 36.5 35 Confirmed 30 25 20 15 10

in Spleen Volume, % Volume, Spleen in 5 1 0

Patients With ≥35% Reduction ≥35% With Patients Placebo Fedratinib Fedratinib (n = 96) 400 mg 500 mg (n = 96) (n = 97)

35/96 and 39/97 patients in the fedratinib 400-mg and 500-mg groups vs 1/96 in the placebo group (P < .001)

1. Pardanani A et al. JAMA Oncol. 2015;1:643-651. Symptom Responses: Change in TSS by Group1

-20

-40 From Baseline, % Baseline, From Placebo Median Change in TSS Change Median -60 Fedratinib 400 mg Fedratinib 500 mg -80 0 4 8 12 16 20 24 Time, wk

1. Pardanani A et al. JAMA Oncol. 2015;1:643-651. JAKARTA: Hematologic and Nonhematologic Events1

Adverse Events, Fedratinib 400 mg (n = 96) Fedratinib 500 mg (n = 97) Placebo No. (%) All Grades Grade 3 or 4 All Grades Grade 3 or 4 All Grades Grade 3 or 4

Nonhematologic

Diarrhea 63 (66) 5 (5) 54 (56) 5 (5) 15 (16) 0

Vomiting 40 (42) 3 (3) 53 (55) 9 (9) 5 (5) 0

Nausea 61 (64) 0 49 (51) 6 (6) 14 (15) 0

Constipation 10 (10) 2 (2) 17 (18) 0 7 (7) 0

Asthenia 9 (9) 2 (2) 15 (16) 4 (4) 6 (6) 1 (1)

Abdominal pain 14 (15) 0 12 (12) 1 (1) 15 (16) 1 (1)

Fatigue 15 (16) 6 (6) 10 (10) 5 (5) 9 (10) 0

Dyspnea 8 (8) 0 10 (10) 1 (1) 6 (6) 2 (2)

Weight decrease 4 (4) 0 10 (10) 0 5 (5) 0

Hematologic

Anemia 95 (99) 41 (43) 94 (98) 58 (60) 86 (91) 24 (25)

Thrombocytopenia 60 (63) 16 (17) 55 (57) 26 (27) 48 (51) 9 (9)

Lymphopenia 54 (57) 20 (21) 63 (66) 26 (27) 50 (54) 19 (21)

Leukopenia 45 (47) 6 (6) 51 (53) 15 (16) 18 (19) 3 (3)

Neutropenia 27 (28) 8 (8) 42 (44) 17 (18) 14 (15) 4 (4)

1. Pardanani A et al. JAMA Oncol. 2015;1:643-651. JAKARTA-2: Open-Label Study With Fedratinib1

• Aged ≥18 years • Intermediate-2 or high-risk Fedratinib status Once daily, starting dose 400 mg – Primary MF Consecutive 4-week cycles – Post–PV MF – Post–ET MF • Platelet count ≥50 x 109/L • Permitted dose adjustments = 200-600 mg/day • Received RUX for ≥14 days • Dose up-titration permitted if <50% reduction in • Discontinued RUX ≥14 days spleen volume by palpation to ECO6 prior to starting fedratinib • Dose-titration permitted in event of toxicity • Patients who continued to benefit clinically could remain on study until the occurrence of disease RUX RUX progression or unacceptable toxicity resistant intolerant

Classification made by treating physician

1. Harrison CN et al. Lancet Haematol. 2017;4:e317-e324. Fedratinib Is Effective in Patients With MF Previously

Treated With Ruxolitinib: Results From JAKARTA-21

120 Resistant Intolerant Other

100 80

60 60 40 Spleen 40 Symptoms 20 atECOG 20 0

0 SAF -

-20 -20 MS

Relative to to % Baseline, Relative -40 -40 in -60 -60 Change in Spleen Volume atECOG Changein Spleen Volume -80

Relative to to % Baseline, Relative -100 Change

Fedratinib: orphan drug designation for the treatment of secondary and primary myelofibrosis; currently under FDA priority review for treatment of MF

1. Harrison CN et al. Lancet Haematol. 2017;4:e317-e324. JAKARTA-2 Reanalysis at ASCO 20191

• In original JAKARTA-2 analysis, Main Findings fedratinib demonstrated ≥35% • 79/97 enrolled patients (81%) met the more SVR in patients resistant or stringent criteria for RUX R/R (n = 65, 82%) or intolerant to RUX per investigator intolerance (n = 14, 18%) assessment

• Reanalysis employed a more Clinically meaningful reductions in stringent definition of RUX failure splenomegaly and symptom burden in patients with MF who met more stringent criteria

• Updated poster on Monday, • SVRR = 30% June 3, 8:00 AM • Symptoms RR = 27% • Safety consistent with prior reports FREEDOM-1 study also underway

1. Harrison CN et al. ASCO 2019. Abstract 7057. Review of Encephalopathy Cases1

• Across nine fedratinib trials enrolling 670 MPN or solid tumor patients 1. Fedratinib does not appear • Five potential WE patients to increase risk for thiamine • One subject had malnutrition related to protracted deficiency beyond its potential nausea and vomiting, as well as clinical signs and to exacerbate malnutrition MRI findings consistent with WE through poor management of preventable GI events • Two subjects likely experienced WE, both of which recovered without a dose interruption, suggesting 2. Proper management of GI is fedratinib does not inhibit thiamine absorption an important component of • Two subjects inconclusive or not supportive of WE care for patients on fedratinib

No clear link between WE and fedratinib

1. Harrison CN et al. Blood. 2017;130:4197. Pacritinib in MF: PERSIST Phase 3 Trials

PERSIST-11 Pacritinib • Primary/secondary MF 400 mg once daily • Primary endpoint (week 24): • No exclusion for R ≥35% SVR baseline Plt 2:1 • Secondary endpoint: BAT • No prior JAK2 ≥50% reduction in TSS N = 327 (excluding RUX) inhibitors allowed

PERSIST-22 Pacritinib 400 mg once daily • Primary/secondary MF • Coprimary endpoints (week • Plt ≤100,000/mcL R Pacritinib 24): ≥35% SVR and ≥50% 1:1:1 • Prior JAK2 inhibitors 200 mg twice daily reduction in TSS allowed BAT N = 311 (including RUX)

1. Mesa RA et al. Lancet Haematol. 2017;4:e225-e236. 2. Mascarenhas J et al. JAMA Oncol. 2018;4:652-659. Pacritinib PERSIST-2 Results: Spleen Volume Reduction1

Pacritinib 400 mg Pacritinib 200 mg Ruxolitinib Other BAT once daily twice daily (n = 22) (n = 28) (n = 51) (n = 57) 80

-20 35% decrease

-40 Mean: -21.0 Mean: -4.6 Change% From Baseline, Mean: -19.8 Median: -4.5 -60 Median: -19.0 Median: -23.0

-80 Patient Groups

1. Mascarenhas J et al. JAMA Oncol. 2018;4:652-659. Pacritinib PERSIST-2 Results: Total Symptom Score Reduction1

Pacritinib 400 mg Pacritinib 200 mg Ruxolitinib Other BAT once daily twice daily (n = 22) (n = 29) 175 (n = 51) (n = 55)

150

125

100

-25 50% decrease

Change% From Baseline, -50 Mean: -18.2 Mean: -33.6 Mean: -3.9 -75 Median: -27.0 Median: -41.0 Median: -15.0 -100 Patient Groups

1. Mascarenhas J et al. JAMA Oncol. 2018;4:652-659. Pacritinib PERSIST-2 Safety1

Clinical hold lifted

PAC QD PAC BID BAT AE Serious TEAEs n = 104 n = 106 n = 98 Any SAE 48 (46) 50 (47) 30 (31) SAEs referred to in the FDA clinical hold notification CHF 1 (1) 4 (4) 2 (2) Atrial fibrillation 3 (3) 0 3 (3) Cardiac arrest 2 (2) 0 0 Epistaxis 2 (2) 2 (2) 1 (1) Subdural hematoma 2 (2) 0 0

1. Mascarenhas J et al. ASH 2016. Abstract LBA-5. Rationale for Further Development of Pacritinib

• Dual inhibition of JAK2 and FLT3 Based on current data and MOA, and activity inhibiting other pacritinib may have a potential role in inflammatory pathways such as the management of patients with MF IRAK1 and CSF1R and anemia–thrombocytopenia (an unmet medical need in this setting)1-3 • Evidence from the PERSIST trials and earlier studies

• PAC203 study, evaluating the safety and efficacy of three pacritinib dosing schedules in patients with MF previously treated with ruxolitinib, is now fully enrolled4

• Phase 3 study of pacritinib in adult patients with MF and who have severe thrombocytopenia (platelets <50,000/mcL) also planned

1. Mesa RA et al. Lancet Haematol. 2017;4:e225-e236. 2. Mascarenhas J et al. JAMA Oncol. 2018;4:652-659.3. Dean JP et al. Blood. 2013;122:395. 4. https://clinicaltrials.gov/ct2/show/NCT03165734. Accessed May 29, 2019. Momelotinib: Mechanism of Action1,2

Momelotinib: a selective Rational candidate for treatment of MF small-molecule inhibitor of based on JAK1 and JAK2 • Inhibitory activity against wild-type JAK and the JAK2Val617Phe mutant

• Inhibition of bone morphogenic protein receptor kinase activin A receptor, type I (ACVR1)–mediated hepcidin expression that stimulated erythropoiesis

1. Tyner JW et al. Blood. 2010;115:5323-5340. 2. Pardanani A et al. Leukemia. 2009;23:1441–1445. SIMPLIFY-1: Momelotinib vs Ruxolitinib1

Spleen

MMB RUX 215 217 n (184 evaluable) (204 evaluable) Spleen response, % 26.5 29 P = .011; MMB is noninferior to RUX

Symptoms

MMB RUX

211 211 n (174 evaluable) (190 evaluable) Response rate, % 28.4 42.4 P = .98; MMB is inferior to RUX

1. Mesa R et al. J Clin Oncol. 2017;35:3844-3850. SIMPLIFY-2: Momelotinib vs BAT in Ruxolitinib-Failing Patients With MF1

24-Week Spleen Response in Individual Patients

SIMPLIFY-2 Momelotinib group BAT group (n = 70) (n = 39) Phase 3 study assessing the efficacy and safety of momelotinib vs BAT in patients with MF who

had suboptimal responses No ruxolitinib (n = 4) or hematological toxicity with ruxolitinib (N = 156) 35% decrease Proportion difference of 0.01 Change in Spleen Volume From Baseline, % Baseline, From Volume Spleen in Change (95% CI, 0.09-0.10) P = .90

(7/104) 7% (3/52) 6% Number of Patients Meeting at Least 35% Reduction in Spleen Volume 1. Harrison CN et al. Lancet Haematol. 2018;5:e73-e81. Challenging Scenarios: Evidence-Guided Solutions

• Ruxolitinib + ESA ± danazol ± IMiD Anemia • Consider pacritinib* or momelotinib* or luspatercept* or sotatercept* and CPI 610 being tested

<50 x109/L: consider ruxolitinib ± danazol ± IMiD consider pacritinib* Thrombocytopenia

<50 x109/L refractory to ruxolitinib: consider pacritinib* Challenging Scenarios: Evidence-Guided Solutions (Cont’d)

• Dose escalation or switch to alternative JAK inhibitor (eg, fedratinib as per Progression of symptoms JAKARTA-2) or spleen on ruxolitinib • Trial of combination therapy • Allo SCT if applicable (best before progression)

• Perhaps continue ruxolitinib; evidence of benefit (Massarova ASH 2017) Progression to accelerated or blast phase • Combination ruxolitinib and HMAs • Intensive chemo and allo SCT if appropriate Other Potential Treatment Targets in MF

• NESTIN positive cells in the JAK/STAT pathway stem cell niche1 dysregulation JAK, CALR, MPL • Estrogen signalling1 Splicing machinery Transcription factors SF3B1, SRSF2, U2AF1 IKZF1, CUX2, FOXP1, Epigenetics and TP53, ETV6, NF-E2 • BET inhibitors histone modifications TET2, IDH1, IDH2, 2 DNMT3A, ASXL1, EZH2 • Pentraxin-2 analog (PRM-151)

• Imetelstat (telomerase inhibitor); molecular and histological Metalloproteinases remissions3 – 27% OR in JAK2mut ↓ CXCL12 ↑ Proinflammatory cytokines – 32% OR in ASXL1mut ↑ VEGF ↑ IL-1 – 38% CR in SF3B1/U2AF1mut

? prolongs survival in triple negative disease Estrogen signaling

1. Arranz L et al. Nature. 2014;512:78-81. 2. Verstovsek S et al. ASCO 2014. Abstract 7144. 3. Tefferi A et al. New Engl J Med. 2015;373:908-919. Combinations With Ruxolitinib Being Pursued in Clinical Trials

• Allogeneic HCT • Hh inhibitors (sonedegib, glasdegib, • Danazol (androgenic steroid) visemodegib) • Erythropoietin-stimulating agents • RAD001 (everolimus) • GS-6624 (LOXL2) • MEK inhibitor • Azacitidine/decitabine • PRM-151 • Panobinostat/pacrinostat • Navitoclax • BKM120/alt PI3 kinase inhibitors • Luspatercept • SL-41 • PARP and BET inhibitors

But, who to test? What endpoints? Take-Home Thoughts on JAK Inhibitor–Based Treatment of MF

• Beginning with the approval of ruxolitinib, JAK inhibitors have established a role in the management of symptomatic MF

• Other JAK inhibitors in development – Fedratinib under FDA review; efficacy in MF and patients progressing on ruxolitinib, currently available in FREEDOM study – Pacritinib an important action for patients with thrombocytopenia – Momelotinib an important signal for anemia

• Combinations of JAK inhibitors with other treatment modalities are also being assessed (HMAs, IMiDs) Case Forum Considerations for Selecting and Sequencing Treatment for Patients With Myelofibrosis

Naveen Pemmaraju, MD Associate Professor, Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

Go online to access full [Certification Type] information, including faculty disclosures. Illustrating the Principles of MF Treatment in the JAK Inhibitor Era Where we are in 2019

• In higher-risk setting, Intermediate or alloSCT remains a Ruxolitinib approved high-risk MF potentially curative option

• ↑ risk of opportunistic infections Lower starting doses in Safety considerations certain situations • Cytopenias: manage by dose reduction, interruption, or transfusion Illustrating the Principles of MF Treatment in the JAK Inhibitor Era (Cont’d) Sampling of emerging JAK inhibitors

Phase 3 evidence; • Efficacy in MF, including in JAKARTA/JAKARTA-2 ruxolitinib-failing patients Fedratinib Under regulatory review

• Efficacy in MF (patients Phase 3 EVIDENCE; with low baseline platelets) Pacritinib PERSIST trials Ellen, an Older Patient Receiving Treatment for MF

Ellen is 75 years old, fit She starts treatment and active, with After at least 3 months with ruxolitinib confirmed MF • PS of 1 • 20-mg dose twice daily • Rising splenomegaly • Constitutional symptoms, • She initially tolerates • Return of constitutional splenomegaly, normal treatment well symptoms platelets at baseline Case Forum 1 Newer JAK Inhibitors an Option for Ellen

Ellen exhibits lack of Emerging JAK inhibitors/clinical trials are likely response to ruxolitinib treatment options in this setting

• Supported by JAKARTA-2 findings • Other emerging JAK inhibitors with potential Use of fedratinib is applications in this case include pacritinib or an appropriate momelotinib next step • Clinical trials (eg, JAKi + HMA or + PI3Ki) also an option

Discussion: How can we best explain the difference among established and emerging JAK inhibitors to patients like Ellen? Robert, a Patient on Long-Term Therapy With Ruxolitinib

Robert is a 70-year-old Within the past At the most recent man diagnosed with MF 6 months clinic visit 5 years earlier • 4.5-year treatment • Increasing spleen size history of ruxolitinib • Intermittent return of (now 8 cm below costal • Successful several constitutional margin) management of symptoms (fatigue and • Falling counts (platelets constitutional symptoms joint/bone pain) now at 55 x109/L) and splenomegaly Case Forum 2 Clinical Trial–Based Therapy

Robert is a candidate for second-line therapy, Many novel targeted strategies are being eager to pursue developed in clinical trials another option

Options currently being assessed include agents Clinical trial–based promoting apoptosis (SMAC mimetics), therapy therapies targeting CD123, telomerase recommended inhibitors, anti-fibrotic agents (PRM-151)

Discussion: How can we counsel Robert on the best option to pursue in a clinical trial? Susan, a Patient With Suboptimal Response

Susan, a 55-year-old Further Susan Starts on woman presents with Testing Shows Ruxolitinib • WBC: 32 x 109/L • 20-mg dose twice daily • 15% weight loss • Blasts: <1% • After 6 months, spleen • Splenomegaly 12 cm has improved but remains • Hb: 14.5 g/dL below costal margin 3 cm below costal margin • Platelets: 367 x 109/L • No sibling donor • Intermittent constitutional • LDH: 675 units symptoms

Additionally, biopsy results and mutational analyses confirm a diagnosis of PMF Case Forum 3 Combination Therapy via a Clinical Trial

Susan is a classic case of Some benefit from JAK inhibitor therapy, but “suboptimal response” lack of complete success suggests a need for more potent management

Many trials are testing JAK inhibitor–based Combination-based combination in MF—Susan is likely a good clinical trials candidate for such options: ruxolitinib + HSP90; an option ruxolitinib + navitoclax; ruxolitinib + PI3K

Discussion: Which experimental combination might be the best options for Susan? Potential Algorithm for Treatment of MF After Failure of JAK Inhibitor Therapy1

1. Determine circumstances of JAK inhibitor failure 2. Determine candidacy for allogeneic SCT 3. Determine candidacy for clinical trial participation 4. Determine candidacy for splenectomy (rare)

Failure because of Candidate for Transplant inadequate JAK clinical trial candidate inhibitor dose participation

Proceed Risk–benefit assessment of Proceed accordingly higher JAK inhibitor dose or accordingly alternative JAK inhibitor or JAK inhibitor combination

1. Pardanani A et al. Blood. 2018;132:492-500. Novel Therapies in MPNs: Moving Beyond JAK Inhibitors

• Promotion of apoptosis – SMAC mimetics/IAP antagonists (LCL161; ph2; NCT02098161): n = 44, 30% ORR R/R MF, median OS not yet reached1 – BCL-xL inhibition (Navitoclax; ph2; NCT03222609)

• Targeting of hematopoietic stem cell/micro-environment – CD123 inhibition (SL-401; ph2; NCT02268253) – HSP90 inhibition (PU-H71; ph1; NCT03373877)

• Activation of TP53 pathway – MDM2 inhibition (idasanutlin, ph 2 (PV); NCT03287245)

1. Pemmaraju N et al. ASH 2017. Abstract 256. Novel Therapies in MPNs: Moving Beyond JAK Inhibitors (Cont’d)

• Bromodomain and extra-terminal (BET) inhibitors – Being assessed in MF and other malignancies (INCB057643; NCT02711137)

• Targeting fibrosis and associated cytokines – Pentraxin (PRM-151; ph 2; NCT01981850) – TGF-β modulation – Aurora Kinase A inhibition: alisertib

• Telomerase inhibition1,2 – Imetelstat ph2 results 9.4 mg/kg IV every 3 weeks, n = 107; median 0S in 9.4 mg/kg arm has not been reached (R/R MF)

1. Tefferi A et al. New Engl J Med. 2015;373:908-919. 2. Mascarenhas J. ASH 2018. Ongoing Research Into JAK Inhibitor Combination Approaches

MDACC: MF (Masarova et al Blood 2018) RUXO + AZA – frontline (MF) and MDS/MPN-U

RUXO + HSP90i (MF) NCT03373877

RUXO + BCL-xLi (MF) NCT03222609

RUXO + PI3Ki (MF) NCT01730248

RUXO + THAL (MF- frontline & R/R NCT03069326

RUXO + HDACi (Pracinostat) (MF) – frontline Please remember to complete and submit your Post-Test and Evaluation for CME/MOC credit. Missed anything?

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