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

Course Director and Moderator Faculty

Professor Claire Harrison Prithviraj Bose, MD Naveen Pemmaraju, MD Guy's and St Thomas' NHS Foundation Trust The University of Texas MD Anderson Cancer Center The University of Texas MD Anderson Cancer Center London, England, United Kingdom Houston, Texas Houston, Texas

What’s Inside 3 Welcome and Introduction 4 MasterClass 1 Characterizing Myelofibrosis for a Risk-Adapted Approach to Management in the JAK Inhibitor Era 11 MasterClass 2 Evidence-Based Treatment for Myelofibrosis—New Science and Expanding Options 21 Case Forum Considerations for Selecting and Sequencing Treatment for Patients With Myelofibrosis 26 Symposium Summary and Audience Q&A

Participate in interactive questions, download activity slides, This CME/MOC activity is jointly and obtain your instant CME/MOC credit online. provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. PeerView.com/SCG900 Activity Information

Activity Description and Educational Objectives Naveen Pemmaraju, MD, has a financial interest/relationship or affiliation in the form of: The emergence of JAK inhibitor therapy for the management of myelofibrosis has offered clinicians Consultant and/or Advisor for Celgene Corporation; Incyte Corporation; LFB USA; Mustang Bio; Novartis effective targeted therapy options that can be used in different patient populations to improve Pharmaceuticals Corporation; Roche Diagnostics, North America; and Stemline Therapeutics, Inc. outcomes and ameliorate the debilitating symptoms of myelofibrosis. As additional JAK inhibitors Grant/Research Support from AbbVie Inc.; Affymetrix; Cellectis; Daiichi Sankyo Company Limited; near regulatory approval, several therapeutic questions have emerged, including those over the use Novartis Pharmaceuticals Corporation; Plexxikon; Samus Therapeutics, Inc.; Sager Strong Foundation; of multiple JAK inhibitor options in patients failing prior targeted therapy or those who present with and Stemline Therapeutics, Inc. challenging clinical features at baseline, among others. The answers to these questions will likely Other Financial or Material Support from Dan's House of Hope where Dr. Pemmaraju serves on the define the future of risk-adapted therapy in myelofibrosis and clarify treatment protocols in an era of Board of Directors and HemOnc Times/Oncolofy Times where he serves as a Board Member. (He is not several JAK inhibitor options. compensated for these roles.)

In this activity, based on a recent live symposium held in Chicago, Illinois, during the 2019 American Naveen Pemmaraju, MD, does intend to discuss either non–FDA-approved or investigational use Society of Clinical Oncology (ASCO) Annual Meeting, experts in oncology and hematology explore for the following products/devices: ruxolitinib, fedratinib, pacritinib, momelotinib, and other novel the answers to these questions via a unique MasterClass and Case Forum format, designed to offer targeted therapies, as single-agents or combinations in different myelofibrosis settings. learners a window into the scientific evidence supporting new JAK inhibitor options in myelofibrosis, while also providing a case-centric illustration of how this science can be applied in daily care. Content Reviewers This activity marries expert insight on practice-changing science with recommendations from the Shaina Rozell, MD, MPH, has no financial interests/relationships or affiliations in relation to this therapeutic “masters” and highlights how JAK inhibitor options are making a difference in patient activity. outcomes across the myelofibrosis treatment continuum. Amita B. Patel, MSN, RN, AOCNP, NP-C, has no financial interests/relationships or affiliations in relation Upon completion of this activity, participants should be better able to: to this activity. • Describe molecular and clinical features of myelofibrosis (MF) that are useful for diagnostic and prognostic assessment Medical Directors • Summarize recent efficacy and safety evidence on established and emerging JAK inhibitors and Kathryn B. Charalambous, PhD other targeted agents in the management of MF PVI, PeerView Institute for Medical Education • Select individualized, risk-adapted treatment plans for patients with symptomatic or asymptomatic MF, including those failing prior JAK inhibitor therapy Kathryn B. Charalambous, PhD, has no financial interests/relationships or affiliations in relation to this activity. Target Audience This activity has been designed to meet the educational needs of oncologists, hematologists, and Carmine DeLuca other clinicians involved in the management of myelofibrosis. PVI, PeerView Institute for Medical Education

Requirements for Successful Completion Carmine DeLuca has no financial interests/relationships or affiliations in relation to this activity. In order to receive credit, participants must view the activity and complete the post-test and evaluation form. A score of 70% or higher is needed to obtain CME/MOC credit. There are no pre- Disclaimer requisites and there is no fee to participate in this activity or to receive CME/MOC credit. Statements The information provided at this CME/MOC activity is for continuing education purposes only and is of Credit are awarded upon successful completion of the post-test and evaluation form. not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the Media: Enduring Material use of particular therapeutic agents are based on the best available scientific evidence and current Release and Expiration Dates: June 25, 2019 - June 24, 2020 clinical guidelines. No bias towards or promotion for any agent discussed in this program should be Time to Complete: 90 minutes inferred.

Faculty and Disclosure / Conflict of Interest Policy Providership, Credit, and Support Before the activity, all faculty and anyone who is in a position to have control over the content of This activity has been planned and implemented in accordance with the accreditation requirements this activity and their spouse/life partner will disclose the existence of any financial interest and/ and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint or relationship(s) they might have with any commercial interest producing healthcare goods/ providership of Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. The services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education speakers bureau membership, stock ownership, or other special relationships. Presenters will inform for physicians. participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc. for fair balance, scientific objectivity of studies mentioned in the The Medical Learning Institute, Inc. designates this enduring material for a maximum of 1.5 AMA PRA materials or used as the basis for content, and appropriateness of patient care recommendations. Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the 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 MOC Statement to the content of this CME/MOC activity during the past 12 months. Successful completion of this CME activity, which includes participation in the evaluation The associates of the Medical Learning Institute, Inc., the accredited provider for this activity, do not component, enables the participant to earn up to 1.5 MOC points and patient safety MOC credit have any financial relationships or relationships to products or devices with any commercial interest in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. related to the content of this CME/MOC activity during the past 12 months. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for Course Director and Moderator the purpose of granting ABIM MOC credit. Professor Claire Harrison Clinical Director - Haematology, Haemostasis, Palliative Care, Cellular Pathology Participation information will be shared with ABIM through the ACCME’s Program and Activity Guy's and St Thomas' NHS Foundation Trust Reporting System (PARS). Blinded individual or aggregated participant data may be shared with the London, England, United Kingdom funder of the activity.

Professor Claire Harrison has a financial interest/relationship or affiliation in the form of: Providership Consultant and/or Advisor for AOP Orphan Pharmaceuticals AG; Celgene Corporation; CTI BioPharma This CME/MOC activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Corp.; F. Hoffmann-La Roche Ltd; Novartis Pharmaceuticals Corporation; Promedior, Inc.; and Sierra Institute for Medical Education. Oncology, Inc. Speakers Bureau participant with Celgene Corporation and Novartis Pharmaceuticals Corporation. Support This activity is supported by an educational grant from Celgene Corporation. Professor Claire Harrison does intend to discuss either non–FDA-approved or investigational use for the following products/devices: ruxolitinib, fedratinib, pacritinib, momelotinib, and other novel Disclosure of Unlabeled Use targeted therapies, as single-agents or combinations in different myelofibrosis settings. The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience Faculty any reference to an unlabeled or investigational use. Prithviraj Bose, MD Associate Professor, Department of Leukemia, Division of Cancer Medicine No endorsement of unapproved products or uses is made or implied by coverage of these products The University of Texas MD Anderson Cancer Center or uses in our reports. No responsibility is taken for errors or omissions in reports. For approved Houston, Texas prescribing information, please consult the manufacturer’s product labeling.

Prithviraj Bose, MD, has a financial interest/relationship or affiliation in the form of: The materials presented here are used with the permission of the authors and/or other sources. These Grant/Research Support from Astellas Pharma US, Inc.; Blueprint Medicines Corporation; Celgene materials do not necessarily reflect the views of PeerView or any of its partners, providers, and/or Corporation; Constellation Pharmaceuticals; CTI BioPharma Corp.; Incyte Corporation; Kartos supporters. Therapeutics, Inc.; NS Pharma,Inc.; Pfizer Inc.; and Promedior, Inc. Honoraria from Blueprint Medicines Corporation; Celgene Corporation; and Incyte Corporation. About This CME/MOC Activity PVI, PeerView Institute for Medical Education, and Medical Learning Institute, Inc. are responsible Prithviraj Bose, MD, does intend to discuss either non–FDA-approved or investigational use for the for the selection of this activity’s topics, the preparation of editorial content, and the distribution of following products/devices: ruxolitinib, fedratinib, pacritinib, momelotinib, and other novel targeted this activity. Our activities may contain references to unapproved products or uses of these products therapies, as single-agents or combinations in different myelofibrosis settings. in certain jurisdictions. The preparation of PeerView activities is supported by educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI and Naveen Pemmaraju, MD Medical Learning Institute, Inc. Associate Professor, Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

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Welcome and Introduction Symptom Burden of Myelofibrosis

Professor Claire Harrison Guy's and St Thomas' NHS Foundation Trust Splenomegaly: London, England, United Kingdom 80% of patients1

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

Anemia/cytopenias: Prof. Harrison: So a warm welcome from myself and the rest of 60% to 85% the faculty this evening to this master class and case forum, which is based on the changing treatment paradigm for myelofibrosis. 1. Cervantes F et al. Blood. 2009;113:2895-2901. 2. Tefferi A et al. Blood. 2014;124:2507-2513. We’re going to be looking at new science, particularly about prognostication, and more choices for challenging cases in the JAK Just remembering that splenomegaly is very common and inhibitor era. problematic, but not in all patients. Another very, very common and difficult to manage feature is anemia, also thrombocytopenia. So we have a fantastic faculty this evening. We’ve got colleagues And despite current therapies, patients—most patients will from the MD Anderson, Dr. Bose and Dr. Pemmaraju. And I guess I ultimately die of this disease. may be an honorary MD Anderson faculty this evening. My name’s Claire Harrison. I’m from London in the UK.

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

So we’ll start with just a refresh about myelofibrosis. Remember that this is a disease which is part of a spectrum, with about 50% of patients in the community who currently with myelofibrosis will have started with one of the more indolent myeloproliferative disorders, ET or PV or the newer defined entity, prefibrotic myelofibrosis.

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

MasterClass 1 the presence of immature circulating cells and the blasts that you Characterizing Myelofibrosis see in the blood with the left shift in these conditions. for a Risk-Adapted Approach Pathology and Molecular Testing1 to Management in the JAK In addition to laboratory workup and symptom assessment, organizations BM aspirate and biopsy with trichrome such as the NCCN recommend and reticulin stain Inhibitor Era molecular/genetic and pathology tests to help confirm a diagnosis, including: BM cytogenetics (blood, if bone marrow is Prithviraj Bose, MD inaspirable; karyotype ± FISH)

The University of Texas MD Anderson Cancer Center Molecular testing for JAK2 V617F mutation; Houston, Texas 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.

WHO Criteria for Diagnosis of So, this is just a basic principle of evaluating a patient. So, Primary Myelofibrosis (PMF)1 obviously, you need a bone marrow biopsy for something like this.

Major criteria So with trichrome and reticulin staining, you always want to do • Proliferation and atypia of megakaryocytes accompanied by either reticulin and/or collagen fibrosis cytogenetics and molecular studies. Usually, you’re going to get a 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 bone marrow, so you just get it on the bone marrow aspirate. If not • 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 possible, if it’s a dry tap, get it on the blood.

Minor criteria • Anemia not attributed to a comorbid condition Diagnosis requires 9 And then the mutations. In primary myelofibrosis, 50% to 60% • Leukocytosis ≥11 × 10 /L meeting all three major • Palpable splenomegaly criteria, and at least two will have a JAK2 mutation. Twenty percent to 30% will have a CALR • LDH increased to above upper normal limit of institutional reference range minor criterion confirmed in two consecutive • Leukoerythroblastosis determinations mutation. Around 5% to 10% will have an MPL mutation, and then

a In the absence of any of the three major clonal mutations, the search for the most frequent accompanying mutations (eg, ASXL1, EZH2, TET2, about another 10% will be triple-negative. 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. So that essentially guides you. You know, if you look at the bottom Prof. Harrison: So I’m absolutely delighted to welcome to the of the slide, you obviously want to check for JAK2 V617F. If that’s stage now Dr. Bose. He’s probably familiar to you all. He’s given that there, you look for CALR exon 9 insertions or deletions, MPL lots of very nice presentations at ASH meeting, etc. And I’m going mutations. to hand the podium over to him. Welcome. And then, if it’s PV, you’ve got to think about exon 12. Remember, Dr. Bose: Thank you, Claire. Thanks, everybody, for coming. It’s that’s about 4%. The V617F is actually exon 14. So exon 12, you see really a pleasure to be here with Claire and Naveen to do this. in PV in about 4% of cases.

So, I’ve been tasked with basically taking you through the And then you have the cases where you do not find any of these diagnosis and then prognostication, quite a bit on that, and then driver mutations. And that’s where it can be helpful to find another we’ll get into some—kind of an overview of emerging treatments, clonal marker. So the triple-negative case, many of them are going which Claire will take from there on. to have ASXL1, DET2, DNMT3A, etc, the usual suspects. And that can help you diagnose a clonal disorder. So we’ll open with the WHO criteria. So these are the diagnostic criteria, 2016, WHO classification. Not a lot of changes to the primary myelofibrosis criteria. The changes were really in PV. So here, major and minor criteria. You need all the major and two or more of the minor. So, major criteria, again: the atypia of the megs, very, very important, proliferation and atypia, not just proliferation.

Of course, the fibrosis grades, scale of 0 to 3. Prefibrotic that Claire alluded to refers to 0 and 1, and 2 and 3 is what you see in overt primary myelofibrosis. And then, of course, you go to exclude the other entities. You have to find a clonal marker. And then minor criteria: anemia, leukocytosis, splenomegaly, LDH increased, and

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Just a point about the DIPSS Plus: as you know, the Plus refers to Diagnosing PPV- or PET-MF1,2 RBC transfusion need, platelets <100, and unfavorable karyotype. PV ET What is not sometimes obvious is that in order to calculate the 10% progression rate per 10 years1 <4% progression rate per 10 years1 Post–PV myelofibrosis2 Post–ET myelofibrosis2 DIPSS Plus, you first calculate the DIPSS. And if they are at DIPSS • IWG Diagnostic Criteria for post–PV myelofibrosis • IWG Diagnostic Criteria for post–ET myelofibrosis intermediate-1, they get one point, and then you add points for Required criteria • Documentation of previous diagnosis of PV or ET as defined by WHO criteria those other three things. • 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 Similarly, if they are DIPSS low, they get zero, the DIPSS cytoreductive therapy • Leukoerythroblastosis • Leukoerythroblastosis • ≥5-cm increase in palpable splenomegaly or new intermediate-2, they get two, and if they are diffuse DIPSS high, • ≥5-cm increase in palpable splenomegaly or new splenomegaly splenomegaly • Increased serum LDH level they get three. And then you add the points for the other factors. • 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. IPSS Risk Stratification1 So, post–PV MF and post–ET MF, we have criteria for these, as well.

Prognostic factors 1 Survival by PMF-PS

The progression rate of PV to MF is higher than the progression • Age >65 years 0.9 rate of ET to MF. Now, the required criteria are fairly obvious. So • Constitutional 0.8 symptoms 0.7 • Hb <10 g/dL 0.6 9 you obviously have to have a history of PV or ET, and you have to • Leukocytes >25 x 10 /L 0.5 • Blood blasts ≥1% 0.4 have grade 2 or 3 fibrosis on the 0 to 3 scale. 0.3

Survival, Probability Survival, 0.2 Risk groups 0.1 • Low 0 0 Once you have the required criteria, you have to have two or more • 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 additional criteria, which are listed. For PV, as you would imagine, if 95% CI 95% CI 95% CI 95% CI a PV patient starts to get anemic or starts to not need phlebotomy, PMF-PS = 0 PMF-PS = 1 PMF-PS = 2 PMF-PS = 3 that is a sign, it’s a clue that they could be developing MF. So that’s 1. Cervantes F et al. Blood. 2009;113:2895-2901. the first one there. So this is the IPSS. This is the classic Cervantes paper, 10 years ago And then you have leukoerythroblastosis—that’s, again, the left now, showing you that with a very simple set of factors that you shift we talked about—splenomegaly, constitutional symptoms. already have when the patient walks into the clinic—you know For ET, there is an additional one, elevated LDH. So that, for you, is their age if they’re having symptoms, their hemoglobin, their the way to diagnose post–PV MF and post–ET MF. white count, and if they’re having circulating blasts.

And that’s all you need to divide the patients into these four classic The Evolution of Risk Stratification Models in MF1-3 risk categories: intermediate-1, intermediate-2, low, and high. And these were the criteria actually used in the COMFORT trials of Parameter IPSS DIPSS DIPSS Plus Age >65 y    ruxolitinib. Constitutional symptoms    WBC >25 x 109/L    When we talk about the intermediate-2 and high going to Hb <100 g/L   (two points)  transplant or low and intermediate-1, observation and things of Peripheral blasts ≥1%    that nature, we are usually referring to the IPSS based on its use Platelet count <100 x 109/L  RBC transfusion need  in most of these seminal studies. And you do see, you get a nice Unfavorable karyotype  separation of the survival curves using these five very simple factors.

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.

Now, risk stratification models, a number of you did say that you are using the IPSS or the DIPSS or the DIPSS Plus. These came out in 2009, 2010, and 2011, respectively. So it’s been some time, and some new models have emerged. But just to remind you, these are the parameters in these models.

Just remember that in the DIPSS, you get two points for anemia, and then just by virtue of it being called dynamic, as the name suggests, that is just to emphasize the point that the DIPSS and the DIPSS Plus can be used at any point in the disease course, whereas the IPSS was validated only at diagnosis.

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

Risk Stratification: DIPSS1 Prognostic Value of Driver Mutations1

1.01 JAK2 V617F vs CALR vs Triple Negative 0.9 Low CALR mutant (median OS 17.7 y) 0.8 Highest OS 1 0.9 JAK2 mutant (median OS 9.2 y) MPL mutant (median OS 9.1 y) 0.7 0.8 CALR Triple negative (median OS 3.2 y) 0.6 0.7

0.5 Intermediate-1 0.6 JAK2 V617F or 0.4 0.5 MPL 0.4

Surviving Surviving 0.3 Survival 0.3 0.2 Triple 0.2 0.1 negative 0.1 Cumulative Proportion Proportion Cumulative High Intermediate-2 0 0 Cumulative Probability of of Probability Cumulative 0 5 10 15 20 25 0 5 10 15 20 25 30 Lowest OS Time, y Time, y

1. Passamonti F et al. Blood. 2010;115:1703-1708. 1. Rumi E et al. Blood. 2014;124:1062-1069.

This is the DIPSS. The factors are not listed here, but they are the So now we get into the mutational era. So this is about 2014, so 5 same ones, except that anemia gets two points, and you can use years ago, when it first became clear that the driver mutation has this at any point in the disease course. And you, again, get low, an enormous impact on prognosis. So this is work from the Italians intermediate-1, intermediate-2, and high. There is pretty good showing that CALR had the best survival, triple-negative had the congruence or concordance between the IPSS and the DIPSS. worst survival, and JAK2 and MPL were almost superimposed, right For example, intermediate-2 median survival is around 4 years around in the middle. in both, and high-risk is around 2 years in both models. And I believe that Medicare uses DIPSS to decide on reimbursement for At this point, it was all CALR, not type 1 and type 2. We’ll just get to transplantation, so it becomes an extremely important practical that. And you have the median survivals where you see it ranges point. from 3 years to 18 years. And that’s just making the point that the CALR was the best, triple-negative was the worst. Risk Stratification1-3 Prognostic Value of Driver Mutations (Cont’d)1 Unfavorable Karyotypes CALR Type 1 vs Type 2

i(17q) • Two types of mutations 1 MK CALR type 1/type 1–like +8 – Type 1: 52 bp deletion 0.9 n = 53 0.8 Median: 26.4 (15.5-37.3) y – Type 2: 5 bp insertion Complex karyotype 0.7 -7/7q- • Effect of mutation on OS 0.6 CALR type 2/type 2–like inv(3) 0.5 n = 21 – Type 1 patients: OS advantage 0.4 Median: 7.4 (4.6-10.2) y 11q23 rearrangement JAK2 V617F HR = 4.9 (1.8-12.9) – Type 2 patients: OS comparable to 0.3 n = 251 5/5q- JAK2 V617F 0.2 Median: 7.2 (5.7-8.6) y 12p- HR = 6.0 (2.7-13.4) P < .0001 0.1 N = 396 0 Patients, Proportion of % 0 5 10 15 20 25 30

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. Follow-Up, y

1. Guglielmelli P et al. Blood Cancer J. 2015;5:e360. Now, we talked about karyotype, right? When we talked about DIPSS Plus, we talked about adding points for karyotype and Okay, so then it became clear that there was actually a difference low platelets, as well as transfusion need. So the unfavorable in prognosis between the types of CALR mutations—so type 1 is karyotypes are listed. the good one, and type 2 is quite adverse. Type 2 was no better than JAK2, so it was the type 1 where the survival benefit was really So, many of these you are very familiar with from AML, like limited to. monosomal and complex karyotypes, inversion 3, 5 and 7, always bad; 11q23, also almost always bad; isochromosome 17q. And then The mutant CALR gives you an abnormal carboxy terminal, which one that I think is fairly unique to this disease is the 12p-minus. I then does not bind calcium very well, because it becomes very haven’t come across that very much in other areas. positively charged, and it doesn’t bind calcium very well. And we know now that CALR actually binds to MPL, physically binds to MPL, or the thrombopoietin receptor, to drive oncogenesis.

So why would two mutations with the same effect have different prognoses? This is still not clear. It has been suggested that maybe the amount of positive charge differs based on whether they have a type 1, which is a 52-base pair deletion, or a type 2, which is a

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5-base pair insertion. These are both exon 9. Again, same effect on slides. I think it was the end of 2017 when these came out. So the the carboxy terminal, maybe some subtle differences that we don’t 70 refers to age up to 70. So, these were validated in transplant-age understand yet. patients. So, up to the age of 70.

Now, the way to look at this slide is, everything in red font refers “Non-Driver” Mutations1 to the MIPSS70-Plus. So you notice how the variables that you see Prognostically important genes, listed on the left are not all used in the MIPSS70-Plus, okay? other than JAK2/CALR/MPL, in ET, PV, and MF So, only the low hemoglobin, the blasts, the constitutional PMF symptoms, absence of type 1 CALR, the high-molecular-risk SRSF2 ASXL1 IDH2 EZH2 TP53 U2AF1 CBL mutations that I just mentioned—remember those five, ASXL1, EZH2, SRSF2, IDH1, and IDH2. Two or more of these five, and then PV ET SF3B1 SH2B3 unfavorable karyotype, those are the ones used in the MIPSS70- Plus at the bottom panel, C and D.

1. Tefferi A et al. Blood Adv. 2016;1:21-30. Panels A and B are the MIPSS70, which used all of these except the karyotype. So MIPSS70 does not rely on karyotype at all. MIPSS70- Now, this shows you on one slide the mutations, the adverse non- Plus does and eliminates the white count, the platelets, and the driver mutations, okay? So, not JAK2, MPL, CALR, but the non-driver fibrosis. Okay? mutations that are adverse in PV, ET and primary myelofibrosis. You have three categories in MIPSS70: low, intermediate, high. So, since our talk is focused on PMF, we’ll just talk about that. So You have four categories in MIPSS70-Plus: low, intermediate-1, the seven that are listed: SRSF2, ASXL1, IDH2, EZH2, TP53, U2AF1, intermediate-2, and high. and CBL. So, two splicing genes, UTAF1 and SRSF2. Quite a few epigenetic regulators, ASXL1, EZH2, IDH, as well. The MIPSS70-Plus Version 2.0 Additionally Incorporates (Into the MIPSS70-Plus)1

CBL is a negative regulator of JAK2, so if you lose CBL, you get more Patients ≤70 years of age Patients of all age groups 1. “Very high risk” karyotype 2. U2AF1 Q157 mutation status active JAK2, so that makes sense. TP53 is always bad; no stranger to 3. Sex- and severity-adjusted Hgb thresholds; and 4. Defines five prognostic categories, from very low this audience. to very high risk

And so one thing I’ll point out is that this was from the Mayo Clinic. There is a separate analysis from Dr. Vannucchi’s group in Stratification by MIPSS70-Plus “Very high risk” karyotype • -7 Italy, which defined what we call high molecular risk mutations in • i(17q) • Inv(3)/3q21 abnormalities primary myelofibrosis. And those are just a little different. • 12p-/12p11.2 abnormalities • 11q-/11q23 abnormalities • Other autosomal trisomies not including +8/+9 So, SRSF2, ASXL1, IDH2, EZH2 and, not mentioned here, IDH1. 1. Tefferi A et al. J Clin Oncol. 2018;36:1769-1770. So those were the five that were originally described as high molecular risk in Dr. Vannucchi’s paper. Okay, so there’s more. So then this evolved into what is called the MIPSS70-Plus Version 2.0. So here, as you see on the summary box MIPSS70 and MIPSS70-Plus1 on top there in black, there were three other things incorporated. http://mipss70score.it

Key Elements So one is what is called a very high-risk karyotype. So you recall • Hb <10 g/dL earlier, we talked about unfavorable karyotype. So if you look at • WBC >25 x 109/L • HMR • PLT <100 x 109/L – ASXL1 the green box at the bottom, it lists for you what is called very high • Blasts ≥2% – EZH2 • Fibrosis > grade 1 – SRSF2 risk karyotype, okay? So, some very, very bad things, again. All of • Constitutional – IDH1/2 symptoms us know that in my myeloid malignancies, those are very bad. An • Absence of type 1- • Two or more HMR like CALR additional mutation, U2AF1, came into the mix. Unfavorable karyotype And then third was that the investigators here tried to separate the anemia according to gender and severity. So let me just say 1. Guglielmelli P et al. J Clin Oncol. 2018;36:310-318. it like this. Like hemoglobin of 9 in a woman is not the same as hemoglobin of 9 in a man. So it’s actually not as bad as 9 in a man. There are some new prognostic models called MIPSS70 and So that is how they tried to further kind of tease out the anemia MIPSS70-Plus, and there’s more to come on the next couple of and see if that made a difference.

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

The bottom right panel is how the MIPSS70-Plus Version 2.0 can So, what you do is you add up the points on the right. They’re reclassify or re-stratify patients above and beyond the MIPSS70- fairly simple. It’s just hemoglobin, platelets, blasts, CALR wild-type. Plus, okay? So it’s sort of an improvement on it. I think it gets a little Remember, CALR wild-type is a bad thing, right? CALR mutation onerous to have that many models. But then, the field is rapidly is good. So CALR wild-type and constitutional symptoms. You evolving. add those up, and then you plot the age of the patient on the nomogram shown. So, once you have the age and you have the GIPSS: total of those points, you have your prognostic score. And there Genetically Inspired Prognostic Scoring System1 are websites for all of these. And I’ve been using this for my post- GIPSS-Stratified Survival Data in 641 PV, post-ET patients. Patients With Primary Myelofibrosis • Karyotype – Very high risk = 2 points – Unfavorable = 1 point 1 • Driver mutations MYSEC-PM Estimate of Survival in Post-PV/ET MF – Type 1–like CALR absent = 1 point • High-risk mutations – ASXL1 mutation = 1 point Low risk (n = 133), not reached – SRSF2 mutation = 1 point – U2AF1 Q157 mutation = 1 point

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

Overall Survival, % Survival, Overall 1. Tefferi A et al. Leukemia. 2018;32:1631-1642. 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)

So then we have GIPSS. So we are not done with this. So GIPSS is 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 the Genetically Inspired Prognostic Scoring System, and GIPSS SMF Follow-Up Time, Years is—I will say this, GIPSS—intuitively you kind of like it, because 1. Passamonti F et al. Leukemia. 2017; 31:2726-2731. there are no clinical variables. So, as you would imagine, it gives you a nice separation of the Now, obviously, you cannot do this the day you meet the patient, curves for, you know, four prognostic categories, as we are used to but this is entirely clinical variable-free. It’s all genomics. It’s seeing. karyotype and mutations. And you give them points and you get a nice separation of the curves. Canonical and Noncanonical Actions of JAK2 and Opportunities for Therapeutic Targeting1 I will mention here that Andrew Kuykendall from Moffitt has now published that GIPSS outperforms DIPSS. So it was a nice comparison that they did. I’m not aware of any other such comparisons having been done recently. It showed that GIPSS outperformed DIPSS.

The MYSEC-PM Nomogram1

Available at https://mysec.shinyapps.io/prognostic_model/. 1. Bose P, Verstovsek S. Blood. 2017;130:115-125. Covariate Points

Hgb <11 g/dL 2 Plts <150 x 109/L 1 So now, just a word about treatment. You know, this is an PB blasts ≥3% 2 CALR-WT 2 enormous area. There are many, many, many drugs being Constitutional 1 developed and, you know, Claire will, of course, talk about some of symptoms the emerging JAK inhibitors and other therapies.

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 So, this is just trying to show you that there are many other 4. The color at the location indicates the final risk category 1. Passamonti F et al. Leukemia. 2017;31:2726-2731. pathways being targeted. I’ll just mention a few that have been tried in trials. HDAC inhibitors were disappointing. We’ve had some All right, and then a word about post–PV MF or post–ET MF. This nice results with some IMiDs, as well as azacitidine. There are trials deserves mention because these are different diseases. So then ongoing of navitoclax, the Bcl-2/Bcl-xL inhibitor. No results in the primary myelofibrosis, generally the prognosis of post–PV MF public domain yet. and post–ET MF is better than primary myelofibrosis. So there is a dedicated model for this. Thankfully, there’s only one major There have been some encouraging data with PI3 kinase-δ model at this time. So it’s called the MYSEC-PM— Myelofibrosis inhibitors. Those of you who do breast cancer would be aware of Secondary to PVR or ET prognostic model. the CDK4/6 inhibitors. That’s also a promising strategy, at least in

8 Go online to complete the post-test and evaluation for CME/MOC credit PeerView.com/SCG900 Changing the Treatment Story in Myelofibrosis: New Science and More Choices for Challenging Cases in the JAK Inhibitor Era the lab. And not shown here are actually many other targets, like of studies, and this has become standard practice. And usually, at bromodomain inhibitors, LSD1 inhibitors, PARP inhibitors, etc. So, least at our institution, we will taper the dose over 5 to 7 days, and lots of synergistic concepts, but we need to wait and see what then start conditioning the next day. pans out in the clinic. And then, 2 weeks ago, ruxolitinib got approved for acute GVHD, corticosteroid refractory. So from that standpoint, perhaps it can Role of JAK Inhibition in MF1 be used after transplant. But I do want to be careful here and mention that we don’t have data from a myelofibrosis standpoint JAK inhibitors improve splenomegaly, symptom burden and OS of patients with MF independent of allogeneic HCT2-4 of post-transplant ruxolitinib. So what we do is pretransplant ruxolitinib and, like I just said, taper it and start the conditioning. Current status of JAK inhibitors in MF And now, in the new era of GVHD, maybe post-transplant

• Ruxolitinib (approved) ruxolitinib. They can be steroid—ruxolitinib can be steroid- • Fedratinib (under regulatory review for approval) sparing, as well. • Pacritinib (clinical hold lifted) • Momelotinib (clinical development resumed) Role of Allogeneic Transplant in 20191

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

So, just a very high-level overview of what JAK inhibition does in 2. Allogeneic SCT remains the only curative approach for myelofibrosis. As you are all aware, they improve splenomegaly. transplant-eligible patients They improve symptom burden and, importantly, overall survival. 3. All available prognostic information and recent Overall survival has been shown in the COMFORT-I and -II long- scoring systems should be utilized when considering term analyses at 5 years to have been improved with ruxolitinib allo SCT versus placebo or best available therapy. The references are available there for you.

1. McLornan DP et al. Haematologica. 2019;104:659-668. There are a few new JAK inhibitors in development. Fedratinib is actively being considered for regulatory approval. Pacritinib is now So, this is just about allo transplant, and just remember that, you back in business. There was a clinical hold, as you may be aware know, again, this is the only curative modality, and, you know, we of, and that has been lifted, and the drug has resumed active actually do myeloablative conditioning. Many places do reduced development in patients with platelets <50, which might be a intensity. There are obviously a lot of factors that need to be niche population where ruxolitinib is currently not approved. considered when you decide to send somebody for transplant.

Momelotinib has been resurrected, as well. You might recall, this Usually, intermediate-2 and high-risk, or intermediate-1 with is the drug, I think, from ASCO two years ago. This is the drug that adverse, say, mutations, karyotype, red cell transfusion need, can improve anemia potentially to some degree. So we’ll see what etc. So there’s obviously a lot of factors that go into the decision- happens with these. making.

Comprehensive Clinical-Molecular Transplant Scoring Role of JAK Inhibition in MF (Cont’d) System for MF Undergoing Stem Cell Transplantation1

Training Validation 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 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. 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. 1. Gagelmann N et al. Blood. 2019;133:2233-2242.

And then just a word about transplant. Obviously, that remains a Now, there was, at ASH 2018, and also now published in Blood, very important modality in myelofibrosis. So the typical practice is there is another prognostic scoring system, but this has a twist. to keep the ruxolitinib going until the conditioning starts. There’s This is for determining outcomes after transplant. So this is not not a lot of high-quality evidence for this, but there are a number

9 Changing the Treatment Story in Myelofibrosis: New Science and More Choices for Challenging Cases in the JAK Inhibitor Era to decide who to send to transplant, but this is to determine Audience Q&A: Question 1 outcomes after transplant.

Which risk score should I use for newly diagnosed patients, You see the variables listed at the bottom: platelets, leukocytes, and when should I calculate another risk score? performance status, age, again, JAK2 being worse than CALR, MPL. ASXL1. And of course, the donor type with regards to HLA, giving you a very nice separation of overall survival. Not shown here is that this model can also predict nonrelapse mortality, so that was also shown in the presentation. This comes from Germany, from Nicolaus Kröger’s group.

Toward a Consensus on Treating MF in 20191

Primary MF or PPV-MF/PET-MF Assess prognostic score Prof. Harrison: So, thank you very much. That was really fantastic. Objective symptom score assessment Consideration to cytogenetics and molecular risk So, a good question here, which risk score should I use for newly

Low risk Intermediate-1 Intermediate-2 High risk diagnosed patients, and when should I do another risk score? And I Consider HLA typing want to supplement that question, because I also use these scores Is patient a present or future allograft candidate? Asymptomatic Symptomatic watch and wait • HLA-typing and donor sourcing and consideration to timing online, but sometimes I run into the problem that, you know, – Can the patient be optimized pre-allograft? Ruxolitinib • Symptom burden or splenomegaly: ruxolitinib alone or combination therapy Possible role for sometimes they give me a vastly different estimate for a patient. • Novel agents (eg, PRM-151 or imetelstat/novel JAK inhibitor or ruxolitinib or IFN combination studies) Clinical needs- • Emerging JAK inhibitors/novel agents for those failing ruxolitinib in based therapy first-line therapy So I might have a patient sitting in front of me that with one score Anemia management: ESA based on endogenous EPO level, IMiDs, activin receptor ligand traps, transfusions, danazol might get a 5-year survival of, you know, 60%, but using another 1. Harrison CN, McLornan DP. Hematology Am Soc Hematol Educ Program. 2017;2017:489-497. score, it might be down at 30%. So, could you answer the question, and then talk a little bit about how you handle the kind of different So, finally, toward a consensus on treating MF, you’re already aware predictions from the different scores? of this. Intermediate-2 and high is where you typically consider transplant, although you may want to in some intermediate-1s, like Dr. Bose: Sure. I don’t know if I can give you a very intelligent we just discussed. answer to this, but what I do is that I actually still use the old ones, okay? So I still use the DIPSS or DIPSS Plus. And then I Irrespective of their risk category, if they are symptomatic, you always consider the molecular aspects. So, triple-negative, ASXL1, need to consider ruxolitinib. This is now in the NCCN guidelines. SRSF2, and the things we talked about. And that is how I form an So, low, intermediate-1, whatever the case may be. If they are impression of whether I need to send them to transplant. symptomatic, you would consider ruxolitinib. I have actually not been using yet the MIPSS or, you know, the And then there are some patients where anemia is their main GIPSS or whatever. But MYSEC-PM I have been using. Again, that’s a problem. And there you may want to do anemia-directed therapy. relatively uncluttered field. That’s the only main model in post-PV, This is also endorsed by the NCCN guidelines. Just a word on post-ET. So I’m using that. But for primary MF, I’m just using the old the anemia management. The usual agents—most of these are ones, and then incorporating this information. accessible to you. Prof. Harrison: I think that was a very intelligent answer. Thank But I do want to mention luspatercept, because you heard about it you very much. at ASH 2018 plenary session. Luspatercept was positive in a trial in MDS. So, we have data with a very similar agent called sotatercept, which has looked good in myelofibrosis. I have presented that a few times.

And so this class of drugs, called activin receptor ligand traps, might be a novel way of improving anemia in patients who are on ruxolitinib, or even who are not on ruxolitinib. So that is something to look forward to in terms of drug development.

And I think that might be it. There are obviously many other novel agents that we can talk about later. Thank you.

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Audience Q&A: Question 2 MasterClass 2 Evidence-Based Treatment for For a patient who is on treatment and becomes anemic, when calculating the DIPSS score, do you give two points for anemia? Myelofibrosis—New Science and Expanding Options

Professor Claire Harrison Guy's and St Thomas' NHS Foundation Trust London, England, United Kingdom

Prof. Harrison: And then there’s a second question about treatment-associated anemia. So this is a really good question, JAK/STAT Signaling and because most of our treatments, particularly JAK inhibitors— Clinical Manifestations of MF1,2 ruxolitinib, particularly—will cause anemia. So, if you’ve got a patient who’s on treatment, and they become anemic, and you’re doing the DIPSS score, do you give them two points for anemia? Fibrosis JAK2 JAK1

Dr. Bose: Yeah, I think, absolutely great question. So when DIPSS Ineffective Inflammatory hematopoiesis cytokines was developed, there was no ruxolitinib, right? So a paper came out in 2010. Ruxolitinib was approved in 2011. So definitely, that Anemia Extramedullary Constitutional hematopoiesis symptoms was not taken into account when this was developed. (splenomegaly)

So I think not just anemia, also constitutional symptoms. So, say 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. 1 they are already on ruxolitinib, and their symptoms are all gone. So then, how do you factor that in? Maybe before ruxolitinib they had Prof. Harrison: So, I’m going to expand a little bit more on a lot of symptoms. evidence-based treatment for myelofibrosis, take a look back, but also a look forward. Certainly, the models were not derived in a ruxolitinib era. So I don’t think the answer is really known here. But when we say that Both JAK1 and JAK2 activation may well be important for the you can use the DIPSS at any point, that is true, because that is how principal manifestations of myelofibrosis. So, JAK2 being linked it was developed back then. But there was no ruxolitinib. to ineffective erythropoiesis, then extramedullary hemopoiesis and the other manifestations, such as anemia, and we think that One thing I will say from the COMFORT study is, we do know that many patients develop constitutional symptoms because of the ruxolitinib-induced anemia is not prognostically bad. So that was inflammatory status of the disease, which is probably linked to very clearly shown, two papers on this. So disease-associated JAK1 signaling, although there’s less evidence perhaps behind anemia is very different from ruxolitinib-induced anemia. So that. There certainly does seem to be efficacy in terms of inhibiting maybe we should not be giving two points for anemia if we feel it’s JAK and the effects on symptoms. all ruxolitinib, which, again, is hard to know, you know, how much is ruxolitinib, how much is the disease.

Prof. Harrison: Okay, great. Well, thank you very much.

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

JAK Inhibition (Ruxolitinib): Spleen Reduction Is Independent of Driver Mutation Phase 3 Clinical Trial Program

Phase 3 Efficacy of Ruxolitinib in CALR Mutated Patients in COMFORT-II2, a COMFORT-I1 COMFORT-II2 1

N = 309 N = 219 Regardless of JAK2 V617F Mutation Ruxolitinib BAT

% 20 , 40 Percent Change From Baseline in Spleen • Randomized, double-blind, placebo-controlled trial • Randomized, open-label trial vs best available • In CALR+ patients, a 0 20 Volume at Week 48 • Conducted at multiple sites in US, Canada, (historical) therapy ≥35% reduction from 0 baseline in spleen -20 Australia • Conducted at multiple sites in Europe -20 volume at week 48 35% reduction from baseline was achieved by 20% From Baseline -40 • FPFV: September 2009 • FPFV: July 2009 -40 Primary endpoint in the ruxolitinib arm vs -60 Ruxolitinib BAT 0% in the BAT arm -60 • Patients with PMF, PPV-MF, or PET-MF • Patients with PMF, PPV-MF, or PET-MF -80 JAK2 V617F positive (n = 75) JAK2JAK1V617F V617F positivepositive (n(n == 24)24) Change JAK2 V617F negative (n = 22) JAK2JAK1V617F V617F negativenegative (n(n == 8)8) 1.01 + Censored

Change From Baseline,% -100 Unknown mutation status (n = 1) Unknown mutation status (n = 2) • The Kaplan-Meier–

0.8 • Primary endpoint: ≥35% reduction in spleen • Primary endpoint: ≥35% reduction in spleen estimated probability • At week 48, most patients receiving ruxolitinib experienced of survival at 144 0.6 weeks was 0.76 in the volume from baseline to week 24 volume from baseline to week 48 spleen volume reductions, including JAK2 V617F–positive (88% 0.4 ruxolitinib arm vs 0.50 Treatment • Secondary endpoints: total symptom score, • Secondary endpoints: spleen response at [66/75]) and JAK2 V617F–negative (91% [20/22]) patients Probability in the BAT arm 0.2 Ruxolitinib BAT overall survival, duration of spleen response week 24, duration of spleen response 0 • Exploratory endpoint: QOL • Exploratory endpoint: QOL 0 50 100 150 Time, wk Highly significant reduction of spleen volume and resolution of disabling symptoms

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

So, I’m going to whiz through very quickly ruxolitinib. As I’ve We also know that for JAK inhibition that spleen reduction is mentioned already, we’re now quite a long time from the approval independent of driver mutation. So regardless of whether the of ruxolitinib, which was based on the two phase 3 studies, patient has a JAK2, a CALR or, indeed, is triple-negative, these COMFORT-I and COMFORT-II. patients will still get benefit from these agents.

And this is largely data from the COMFORT-II study that you can Benefits of Ruxolitinib in a COMFORT-II Patient1 see in this slide.

Before After 72 weeks  Spleen Ruxolitinib and Overall Survival: COMFORT Studies1

 QoL • 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

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

1. Courtesy of Professor Claire Harrison.

0.0 Really, the benefits of this drug are summed up pretty much in this slide, which is from one of my patients in London. The patient had 1. Verstovsek S et al. J Hematol Oncol. 2017;10:156. a very nice response in terms of splenomegaly and improvements in quality of life. You also note that she’s put on weight. And there’s Now, the first speaker referred to overall survival benefit. This was a nice quote relating to her quality of life. not something that was a primary endpoint for the COMFORT studies but is something that we have observed in treating And actually, I just saw this patient a few weeks ago. So she’s now patients. around 120 weeks. She’s still on ruxolitinib, but we might refer to her a bit later on. Her spleen’s now a little bit bigger, and she’s got And this is a publication that we made from a landmark analysis a few symptoms, but she’s still pretty happy on the drug. across the two studies showing, even accounting for crossover, that the risk of death was reduced by about 30%, and the survival benefit for patients is somewhere between 2 and 3 years. Now, this has been criticized because it wasn’t a primary endpoint in the studies, but it’s been shown in subsequent analyses, which I don’t have time to touch on in great detail here, but, for example, in matched pair analysis which has been performed from the COMFORT cohorts.

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Interestingly, you’ll note here that we didn’t see the same nice Survival Benefit Occurs in Both “HMR and LMR”…1 separation that was seen in the MD Anderson study. And that …But ruxolitinib does not overcome the negative survival impact of “HMR” actually increasing reduction in spleen volume was not clearly Survival Estimates in Patients in COMFORT-II Stratified by Treatment and Molecular Score associated with an additive survival benefit. In my clinical practice,

1.01 I’m aiming to get the best response in terms of spleen and 0.9 0.8 0.7 symptoms for patients. But obviously, that’s individualized. 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 1 0 Survival, Probability Survival, Weight Gain Correlates With Survival Benefit 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 Before After 72 weeks (95% CI, 0.30-1.08) and for LMR vs HMR the HR was 0.62 (95% CI, 0.33-1.16)  Spleen a Median follow-up = 151 weeks; Kaplan-Meier estimates at 144 weeks. 1. Guglielmelli P et al. Blood. 2014;123:2157-2160.

 QoL

The survival benefit for patients occurs regardless of what their mutational status is. So you know now what high molecular risk means. It means that the patient has one of the five mutations that we listed out earlier. This patient is alive and well after 9 years. (Spleen now 179 mm) And what you see on this slide is the patients who have a high 1. Courtesy of Professor Claire Harrison. molecular risk who were treated with ruxolitinib have a better survival than the patients who were on the best available therapy. You saw this lady’s images a few slides back, but I use this to point These are data from COMFORT-II. So, ruxolitinib is able to uplift out to you that if your patient is gaining weight, what subsequent the survival advance for both groups of patients, whether they’re post hoc analysis of COMFORT-I showed was that patients who low or high molecular risk. But it does not overcome the negative gain weight with ruxolitinib tend to be the patients that have a impact of high molecular risk mutations. survival benefit. So, again, that’s an important clinical tip for you. If your patient is gaining weight, that’s a good sign. Better Spleen Response to Ruxolitinib, Better Outcome1 Of course, you have to watch out for cardiovascular disease, and Ruxolitinib Events HR (95% CI) you have to be thinking about managing that. But it’s a useful soft ≥10% to <25% (n = 62) 15 0.36 (0.18-0.72) sign. ≥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) Mean Platelet Count and Control 1.01 0.9 1 ≥10% to <25% (n = 10) 0.8 Hemoglobin Over Time COMFORT-I 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) Platelet Count Hemoglobin ≥35% to <50% (n = 1) 1 0.2 43.90 (4.16≥25%- but463.5) <50% reduction (n = 13) Survival, Probability 0.1 ≥50% reduction (n = 61) 370 115 0 Ruxolitinib Placebo Ruxolitinib Placebo 0.01 0.1 1 10 100 0 6 12 18 24 30 36 42 48 /L

9 110 320 HR (95% CI) vs <10% Reductiona Time, mo 105 270 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 100 patients, there were 26 deaths (events) in the pooled ruxolitinib group and 63 deaths in the control group. 220 Hemoglobin, g/L Platelets, x 10 1. Vannucchi AM et al. Haematologica. 2015;100:1139-1145. 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 Another thing that was observed, actually, first of all by the group 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 at the MD Anderson was that the survival benefit of the patient Placebo 151 128 112 82 37 151 132 113 83 37 appeared to be linked to the degree of spleen reduction. So what you see in this box here on the bottom right of the slide is the 1. Verstovsek S et al. Haematologica. 2015;100:479-488. palpable spleen length reduction. So this was more than 50%, 25% to 50%, and less than 25% spleen reduction. So that’s something An adverse aspect of using ruxolitinib is the on-target effect of you can easily do in the clinic, just put a hand on the patient’s causing anemia and thrombocytopenia. And this is a limitation in abdomen. clinical practice, as we’ll come to discuss shortly. You’re probably mostly familiar with the fact that the platelet count will reduce by And here are similar data from a landmark analysis of the around 40% and doesn’t really get better over time. If it’s getting COMFORT studies snapshot—how are the patients’ spleen worse over time, for me, that’s a sign that my—I’m worried the volumes at 24 weeks? And for those patients who had at least patient might be progressing. a 10% reduction in spleen volume, there was a survival benefit associated with ruxolitinib, but not with the control arm therapy. And we’ve touched on already the subject of anemia, which tends to behave in a slightly different way. You tend to get a nadir around week 18, returning toward, but not back to, baseline.

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

So, most patients who are stable on ruxolitinib will have, you Current Status: Ruxolitinib in MF know, a relatively stable hemoglobin. If the patient’s becoming progressively anemic, that’s another sign that their disease is • A highly effective drug benefiting many patients progressing. • 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 Development of Anemia in First 12 Weeks of • Infections: 5% herpes zoster, atypical infections (eg, reactivation of TB)1,3,4 1 Therapy Does NOT Impact Survival • Nonmelanoma skin cancer more prevalent (vs BAT) in RESPONSE4 • Recent link to NHL reported OS in patients with or without an Hb decrease of 30 g/L at week 12 • Lack of evidence of disease modification in low-risk MF 1.01 0.9 Ruxolitinib (drop in Hb ≤30 g/L) 0.8 a • Definition of failure variable in clinical trials, unclear in clinical practice 0.7 Ruxolitinib (drop in Hb >30 g/L) Control (drop in Hb ≤30 g/L) 0.6 0.5 Control (drop in Hb >30 g/L)a 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. 0.4 4. Vannucchi AM et al. New Engl J Med. 2015;372:426-435. 0.3 0.2 0.1 Survival, Probability Survival, 0 0 50 100 150 Time, wk No. at Risk So, summary of current status of ruxolitinib on this slide. We’ve 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 got lots of data from very large studies and real-world evidence Control (drop in Hb >30 g/L)a 124 106 93 57 for the use and benefit of this drug, but we still have problems. We 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. have problems with anemia, problems with thrombocytopenia. Infections can be difficult for these patients. We’ve had progressive We touched on these data earlier. Here is a landmark analysis, multifocal leukoencephalopathy, for example. again, done across the studies looking, again, at, what about anemia in the first 12 weeks. So if a patient’s on ruxolitinib, who And we’re also seeing a small signal for nonmelanoma skin got a 30-g fall in their hemoglobin at 12 weeks, this did not really cancers, though primarily that’s in patients who have already had impact on survival. This is a drug effect. But clearly, those patients premalignant skin lesions who have been heavily treated with on the control arm who had progressive anemia, those patients hydroxyurea. It is important to do a dermatological review for your did worse. patients.

There has recently been a link to non-Hodgkin’s lymphoma, but Infections and Ruxolitinib: Immunosuppression? there have been subsequent publications, including data from the MD Anderson, suggesting that the risk, if it’s present, may well be very small, and certainly in our London cohort, we haven’t seen COMFORT STUDIES: Hepatitis B increased UTIs, URTIs, and reactivation any aggressive non-Hodgkin’s lymphomas. But that’s something herpes reactivation that still needs to be looked at. PML Cryptococcus

Rux British Guidelines for Myelofibrosis and Use of JAK inhibitors1 TB Toxoplasma reactivation Includes Symptoms Spleen Hematological Toxicity infection No Clear Continue ruxolitinib Clear Yes

No

Yes The other downside of ruxolitinib, or upside in terms of graft Suboptimal Consider Suboptimal No continuing versus host disease, are risks of infection and other aspects of ruxolitinib Yes immunosuppression. So that’s a downside of this drug which we No Minimal Equivocal need to be managing in clinical practice. Yes No None None Yes Stop ruxolitinib 1. Reilly JT et al. Br J Haematol. 2014;167:418-420.

One of the problems we have is to decide when is a patient failing ruxolitinib, and how to maximize benefit. This is how we’ve kind of put our thoughts on this across in the British guidelines, looking at benefit, the two aspects of benefit, symptoms and spleen. And then toxicity, including infections, but mainly hematological toxicity.

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Identification/Management of or patients who have evidence of clonal evolution at the time of Progression/Resistance on Ruxolitinib discontinuation have a very poor prognosis, less than 11 and 6 Feature Treatment Options months, respectively. • Threshold: beyond baseline, ↑ by 5 cm, more symptomatic • Optimize dose of ruxolitinib Spleen • Switch to alternative JAK inhibitor • Consider splenectomy JAK Inhibitors and Status of Development in • Review cause (eg, mood disturbance, other medications) • Optimize dose of ruxolitinib Symptoms Myelofibrosis as Lead Indication • Consider alternative treatments (eg, steroid, antihistamine) • Switch to alternative JAK inhibitor Combo • Exclude other causes (eg, drug–drug interaction) trials More anemia or Derailed in earlier phase 3 • Determine if it needs treating thrombocytopenia now re-entering phase 3 • Add EPO, danazol, thalidomide Selective • Determine the threshold for treatment Approved Leukocytosis JAK1, • Add hydroxycarbamide Active Ruxolitinib Active in combo? late phase • Threshold depends on rate of rise 10%/15%/20% Toxicity second line Blasts Pacritinib • Expectant, consider adding HMA or rarely AML induction • neuro Fedratinib; Momelotinib • pancreas Active mid phase Active Failed Itacitinib early phase BMS-911543 NS018 LY2784544

And this is a kind of more practical guide to something I use in Lestaurtinib AZD1280 terms of thinking about patients. There are no current guidelines XL019 which give you clear data to suggest your patient might be failing this drug. And so, for myself, I’m looking at various different aspects and thinking about, how much might this have So what about other JAK inhibitors? This is a summary slide, and progressed? we’re going to focus in the next few slides mainly on these three drugs: pacritinib, fedratinib, and momelotinib. These have all So, just to pick out, for example, a patient whose spleen is been perhaps somewhat derailed in earlier testing, and are now increasing, how much is it increasing? Has it just gone back to reentering phase 3 studies. And fedratinib is on an accelerated baseline? Is it symptomatic or not? So that’s something I would be approval path. thinking about. So let’s take a look at the data with them before thinking about I might be optimizing the dose of ruxolitinib, thinking about what more we’re doing with ruxolitinib, for example. another JAK inhibitor. So there are several different therapies in clinical trials in this context. Or indeed, I might even use Fedratinib MOA splenectomy for patients; although in our practice, we don’t use that very often. In the interest of time, I’ll move on, because we’ll • Fedratinib is a small-molecule, ATP-competitive kinase inhibitor return to some of these things later. 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 Prognosis After Ruxolitinib Discontinuation1 members of the JAK family?

H N S NH O O O N N

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 N 0.8 0.8 Plt ≥100 No clonal evolution at FU N H 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 So this is the structure of fedratinib. Like ruxolitinib, it’s an ATP- Survival After Discontinuation, mo Survival After Discontinuation, mo Plts <100 median survival 11/12 Clonal evolution median survival 6/12 competitive kinase inhibitor. It’s more selective for JAK2 than 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 JAK1. Potentially it might have less off-target effects, although it’s 1. Newberry KJ et al. Blood. 2017;130:1125-1131. interesting to note that the benefits of fedratinib are quite similar to ruxolitinib. And let’s take a look at them now. Something that’s very important to understanding clinical practice is that if you stop ruxolitinib for your patient, they are likely to have a poor prognosis. They will get a rebound in their spleen and symptoms, and that’s something we need to manage in clinical practice. You heard already how that’s managed going into transplant.

But you also need to think about which patients are likely to have the worst prognosis, and this, nice data, again, from the MD Anderson suggests that those patients who are thrombocytopenic

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

different doses of fedratinib. And you can see, again, that the two JAKARTA: Phase 3 Study Design1 different doses are quite equivalent here, and you can see, again, progressive symptom responses. Week 24 or disease Placebo progression before week 24: Daily oral doses, crossover to fedratinib • Aged ≥18 years 4-week cycle Something that’s a little bit interesting here is, again, you see a • Diagnosis of 400 or 500 mg (1:1) – Primary MF rapid reduction in symptoms, but that the symptom responses – Post–PV MF Fedratinib 400 mg Daily oral doses, – Post–ET MF R 4-week cycle appear to continue to improve with fedratinib. • Intermediate 2 or Week 24 EOT high-risk status (EOC6) • Splenomegaly Fedratinib 500 mg Daily oral doses, 4-week cycle JAKARTA: 1 1 cycle = 4 weeks Hematologic and Nonhematologic Events

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 1. Pardanani A et al. JAMA Oncol. 2015;1:643-651. 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 So we completed a phase 3 study, which was published several Constipation 10 (10) 2 (2) 17 (18) 0 7 (7) 0 Asthenia 9 (9) 2 (2) 15 (16) 4 (4) 6 (6) 1 (1) years ago now, called the JAKARTA study. This was the last 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 placebo-controlled study that was done in myelofibrosis with a Dyspnea 8 (8) 0 10 (10) 1 (1) 6 (6) 2 (2) Weight decrease 4 (4) 0 10 (10) 0 5 (5) 0 JAK inhibitor. At the time when patients, who were very similar to 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) the COMFORT patients, went into the study, two different doses of 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) fedratinib were used, and the primary endpoints of the study were Neutropenia 27 (28) 8 (8) 42 (44) 17 (18) 14 (15) 4 (4) similar to the COMFORT studies. 1. Pardanani A et al. JAMA Oncol. 2015;1:643-651.

Primary Endpoint: Toxicity of fedratinib—important to point out that there is perhaps Spleen Response (ITT Population)1 a little bit less thrombocytopenia, but definitely anemia occurred,

45 and there was some easy-to-manage GI toxicity. 40.2

40 36.5 35 Confirmed 30 25 1 20 JAKARTA-2: Open-Label Study With Fedratinib 15 10 • Aged ≥18 years

in Spleen Volume, % Volume, Spleen in 5 1 • Intermediate-2 or high-risk Fedratinib 0

Patients With ≥35% Reduction ≥35% With Patients status Placebo Fedratinib Fedratinib Once daily, starting dose 400 mg – (n = 96) 400 mg 500 mg Primary MF Consecutive 4-week cycles (n = 96) (n = 97) – Post–PV MF – Post–ET MF 35/96 and 39/97 patients in the fedratinib 400-mg and 500-mg groups • Platelet count ≥50 x 109/L • Permitted dose adjustments = 200-600 mg/day vs 1/96 in the placebo group (P < .001) • Received RUX for ≥14 days • Dose up-titration permitted if <50% reduction in

1. Pardanani A et al. JAMA Oncol. 2015;1:643-651. • Discontinued RUX ≥14 days spleen volume by palpation to EOC6 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 You can see that we saw very impressive spleen responses with RUX RUX progression or unacceptable toxicity resistant intolerant fedratinib, perhaps a little bit more than ruxolitinib, although one Classification made by treating physician would need to be cautious about cross-trial comparisons. And it’s 1. Harrison CN et al. Lancet Haematol. 2017;4:e317-e324. important here to note that the design of this study involved a second confirmatory spleen volume assessment. We did a second-line study with fedratinib called JAKARTA-2. At that time, and still today, we have no clear guidance for which patients are failing or which ones have resistance or intolerance. Symptom Responses: Change in TSS by Group1 But this was very open in terms of—it was investigator-decided intolerance. And we published these data a couple of years ago. 20

0

-20

-40 From From Baseline, % Placebo MedianChange in TSS -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.

And here is a graph just showing you symptom responses with change in total symptom score, according to placebo or the two

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Fedratinib Is Effective in Patients With MF Previously Review of Encephalopathy Cases1 Treated With Ruxolitinib: Results From JAKARTA-21

120 Resistant Intolerant Other • Across nine fedratinib trials enrolling 670 MPN or

100 solid tumor patients 80 1. Fedratinib does not appear • Five potential WE patients to increase risk for thiamine 60 60 deficiency beyond its potential 40 • One subject had malnutrition related to protracted Spleen Symptoms 40 nausea and vomiting, as well as clinical signs and to exacerbate malnutrition 20 20 MRI findings consistent with WE through poor management of 0 0 preventable GI events -20 -20 • Two subjects likely experienced WE, both of which Relative Relative to Baseline, % -40 in MFSAF in MFSAF at ECOG recovered without a dose interruption, suggesting -40 -60 2. Proper management of GI is fedratinib does not inhibit thiamine absorption an important component of Change in Spleen Volume at ECOG Change in Spleen Volume -60 -80 Relative Relative to Baseline, % -100 • Two subjects inconclusive or not supportive of WE care for patients on fedratinib Change

Fedratinib: orphan drug designation for the treatment of secondary and primary myelofibrosis; No clear link between WE and fedratinib currently under FDA priority review for treatment of MF

1. Harrison CN et al. Lancet Haematol. 2017;4:e317-e324. 1. Harrison CN et al. Blood. 2017;130:4197.

For me, it was very striking, the benefit that my patients were This drug was halted in clinical development because of several having in the whole-patient cohort with this agent second line. cases of Wernicke’s encephalopathy, and we presented some data And here you can see that the graphic basically divides patients as looking at Wernicke’s encephalopathy for these patients at the to whether they’re resistant or intolerant. And you can see that the ASH meeting. benefit’s occurring for the two different classes. There were nine fedratinib trials open at the time the drug went on a full clinical hold, with almost 700 patients. There were five JAKARTA-2 Reanalysis at ASCO 20191 potential Wernicke’s encephalopathy patients. One subject

• In original JAKARTA-2 analysis, fedratinib demonstrated ≥35% SVR Main Findings definitely had Wernicke’s encephalopathy, but this patient, as in patients resistant or intolerant to RUX per investigator assessment • 79/97 enrolled patients (81%) you can see summarized on the slide, had clear risk factors. They – Reanalysis employed a more stringent definition of RUX failure met the more stringent criteria

for RUX R/R (n = 65, 82%) or were malnourished, they refused NG feeding, they had protracted Spleen Volume and Symptom Response Rates intolerance (n = 14, 18%) ITT Population RUX Failure Cohort Sensitivity Cohort nausea and vomiting, and this patient definitely had Wernicke’s. (N = 97) (n = 79) (n = 66) Clinically meaningful reductions in splenomegaly Patients, % Patients, % Patients, % N N N and symptom burden in (95%CI) (95%CI) (95%CI) patients with MF who met There were two further subjects who were actually on 31 30 36 more stringent criteria SVRR 97 79 66 (22%, 41%) (21%, 42%) (25%, 49%) • SVRR = 30% the JAKARTA study who likely did experience Wernicke’s • Symptoms RR = 27% Symptoms 27 27 32 90 74 62 RR (18%, 37%) (17%, 39%) (21%, 45%) • Safety consistent with prior encephalopathy, but both of them recovered without dose reports interruption, suggesting that fedratinib may well not inhibit FREEDOM-1 study also underway 1. Harrison CN et al. ASCO 2019. Abstract 7057. thiamine absorption, and neither of these patients have any long- lasting problems. At this meeting, we’re presenting a reanalysis of the JAKARTA-2 data for a couple of reasons: First of all because there are other So it’s difficult to be certain about whether there is a clear link, studies now using different definitions of resistance or intolerance, and certainly there’s a risk management strategy for this toxicity so we’ve gone back through and reanalyzed our data and been in the FREEDOM studies, and it highlights the fact that it’s really more strict. And also, in the original data set, we imputed the data important to assess nutrition for your patient. that were missing. Pacritinib in MF: PERSIST Phase 3 Trials So you can see a poster at this meeting, and I’ve summarized the findings on the right-hand side, still striking benefits for PERSIST-11 Pacritinib • Primary/secondary MF patients. And just to call out that the FREEDOM-1 study is currently 400 mg once daily • Primary endpoint (week 24): • No exclusion for R ≥35% SVR underway in North America with fedratinib. 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.

So let’s take a quick look at pacritinib. Pacritinib has also completed two phase 3 studies. This drug has been evaluated specifically for patients who are particularly thrombocytopenic. And in the next slide, I’m going to show you data from the

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

PERSIST-2 study, which enrolled patients exclusively who were Rationale for Further Development of Pacritinib thrombocytopenic and may have had prior JAK inhibitors.

• Dual inhibition of JAK2 and FLT3 Based on current data and MOA, and activity inhibiting other Pacritinib PERSIST-2 Results: pacritinib may have a potential role in inflammatory pathways such as 1 the management of patients with MF IRAK1 and CSF1R Spleen Volume Reduction and anemia–thrombocytopenia (an 1-3 • Evidence from the PERSIST trials Pacritinib 400 mg Pacritinib 200 mg unmet medical need in this setting) Ruxolitinib Other BAT once daily twice daily and earlier studies (n = 22) (n = 28) (n = 51) (n = 57) 80

60 • PAC203 study, evaluating the safety and efficacy of three pacritinib dosing schedules in 40 patients with MF previously treated with ruxolitinib, is now fully enrolled4 20 • Phase 3 study of pacritinib in adult patients with MF and who have severe 0 thrombocytopenia (platelets <50,000/mcL) also planned -20 35% decrease

-40 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. Mean: -4.6 4. https://clinicaltrials.gov/ct2/show/NCT03165734. Accessed May 29, 2019. Change From Baseline, % Mean: -19.8 Mean: -21.0 Median: -4.5 -60 Median: -19.0 Median: -23.0

-80 Patient Groups It’s potentially of interest because not only does it inhibit JAK2, but 1. Mascarenhas J et al. JAMA Oncol. 2018;4:652-659. it also has effects on CSF1R and IRAK. And if the data hold true with regard to benefits for thrombocytopenic patients, and perhaps There were two dosing strategies for pacritinib in this study. And some benefits for anemia, this could represent an important niche here you see the spleen volume reduction. Just taking a look at therapy for our patients. the right-hand side of this slide, you can see that this is the best available therapy arm, and many of these patients continued to Momelotinib: Mechanism of Action1,2 receive ruxolitinib. But pacritinib was superior in terms of spleen volume reduction in this study. Momelotinib: a selective Rational candidate for treatment of MF small-molecule inhibitor of based on Pacritinib PERSIST-2 Results: JAK1 and JAK2 • Inhibitory activity against wild-type JAK Total Symptom Score Reduction1 and the JAK2Val617Phe mutant

Pacritinib 400 mg Pacritinib 200 mg Ruxolitinib Other BAT once daily twice daily • Inhibition of bone morphogenic protein (n = 22) (n = 29) 175 (n = 51) (n = 55) receptor kinase activin A receptor, type I 150 (ACVR1)–mediated hepcidin expression 125 that stimulated erythropoiesis 100

75

50

25

0 1. Tyner JW et al. Blood. 2010;115:5323-5340. 2. Pardanani A et al. Leukemia. 2009;23:1441-1445. -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 I also want to touch on momelotinib, because I think this is also Patient Groups an important and interesting agent. This drug, like ruxolitinib, 1. Mascarenhas J et al. JAMA Oncol. 2018;4:652-659. inhibits both JAK1 and JAK2, but it also has an important hepcidin- mediated action that potentially stimulates erythropoiesis. And also in terms of symptom score. SIMPLIFY-1: Momelotinib vs Ruxolitinib1 Pacritinib PERSIST-2 Safety1 Spleen Clinical hold lifted MMB RUX 215 217 n PAC QD PAC BID BAT (184 evaluable) (204 evaluable) AE Serious TEAEs n = 104 n = 106 n = 98 Spleen response, % 26.5 29 Any SAE 48 (46) 50 (47) 30 (31) P = .011; MMB is noninferior to RUX SAEs referred to in the FDA clinical hold notification CHF 1 (1) 4 (4) 2 (2) Symptoms Atrial fibrillation 3 (3) 0 3 (3) MMB RUX 211 211 n Cardiac arrest 2 (2) 0 0 (174 evaluable) (190 evaluable) Epistaxis 2 (2) 2 (2) 1 (1) Response rate, % 28.4 42.4 Subdural hematoma 2 (2) 0 0 P = .98; MMB is inferior to RUX 1. Mesa R et al. J Clin Oncol. 2017;35:3844-3850.

1. Mascarenhas J et al. ASH 2016. Abstract LBA-5. So this drug has also completed two phase 3 studies. The first was Some concerns were highlighted with pacritinib in terms of cardiac a first-line study head to head with ruxolitinib where momelotinib events. However, these have been refuted by the FDA, and this was designed—the study was designed to show that it was drug is also currently ongoing in further studies. noninferior to ruxolitinib for splenomegaly. But in this study, it was inferior in terms of symptom management.

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SIMPLIFY-2: Momelotinib vs BAT Challenging Scenarios: in Ruxolitinib-Failing Patients With MF1 Evidence-Guided Solutions (Cont’d)

• Dose escalation or switch to alternative JAK inhibitor (eg, fedratinib as per SIMPLIFY-2 Progression of symptoms JAKARTA-2) or spleen on ruxolitinib • Trial of combination therapy Phase 3 study assessing • Allo SCT if applicable (best before the efficacy and safety progression) of momelotinib vs BAT in patients with MF who had suboptimal responses • Perhaps continue ruxolitinib; evidence of or hematological toxicity benefit (Massarova ASH 2017) Progression to accelerated with ruxolitinib (N = 156) • Combination ruxolitinib and HMAs or blast phase • Intensive chemo and allo SCT if appropriate

1. Harrison CN et al. Lancet Haematol. 2018;5:e73-e81.

In a second-line study, interestingly, momelotinib was superior For patients who have progressive symptoms on splenomegaly, to best available therapy, which was predominantly ruxolitinib. there are a number of options which we’re going to touch on in Only these four patients were not receiving ruxolitinib in terms of the later part of this session, and then progression to accelerated symptom responses. What you see on this slide is spleen, but there or blast phase remains problematic. My preferred management for was definitely superiority for symptoms. these patients, if I’m not going to take them down an aggressive path, is to use hypomethylating agent with ruxolitinib. Very rarely Challenging Scenarios: would we go to intensive chemotherapy and allogeneic stem cell Evidence-Guided Solutions transplant in that setting.

• Ruxolitinib + ESA ± danazol ± IMiD Other Potential Treatment Targets in MF Anemia • Consider pacritinib* or momelotinib* or luspatercept* or sotatercept* and CPI 610 being tested • NESTIN positive cells in the JAK/STAT pathway stem cell niche1 dysregulation JAK, CALR, MPL • Estrogen signalling1 Splicing machinery Transcription factors SF3B1, SRSF2, U2AF1 9 IKZF1, CUX2, FOXP1, <50 x10 /L: Epigenetics and TP53, ETV6, NF-E2 • BET inhibitors consider ruxolitinib ± danazol ± IMiD histone modifications TET2, IDH1, IDH2, 2 consider pacritinib* DNMT3A, ASXL1, EZH2 • Pentraxin-2 analog (PRM-151) Thrombocytopenia • Imetelstat (telomerase inhibitor); <50 x109/L refractory to ruxolitinib: molecular and histological consider pacritinib* 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 So, just thinking about evidence-guided solutions for challenging Estrogen signaling scenarios in clinical management, anemia remains a problem. 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. And so when I’m managing patients with ruxolitinib who are anemic, I sometimes add in an ESA or danazol or an IMiD. There’s Now, we’re going to touch on other potential treatment targets. an ongoing study with pomalidomide. If these patients are eligible There are many of them. And that some of them have got really for a clinical trial, I might consider pacritinib, momelotinib, or exciting data, some of which is going to be shown at this meeting. luspatercept, and also, the BET inhibitor CPI 610 is also showing some benefit for anemia. Combinations With Ruxolitinib Being Pursued in Clinical Trials

If the patient has thrombocytopenia—this is a particularly • Allogeneic HCT • Hh inhibitors (sonedegib, glasdegib, challenging clinical scenario—I am a little bit more adventurous • Danazol (androgenic steroid) visemodegib) in using ruxolitinib in patients with platelets well below 50. But • Erythropoietin-stimulating agents • RAD001 (everolimus) • MEK inhibitor I might consider adding, for example, danazol to support their • GS-6624 (LOXL2) • Azacitidine/decitabine • PRM-151 platelet count. And in patients who are thrombocytopenic • Panobinostat/pacrinostat • Navitoclax refractory to ruxolitinib, pacritinib is a reasonable option and will • BKM120/alt PI3 kinase inhibitors • Luspatercept be available in a clinical trial shortly. • SL-41 • PARP and BET inhibitors

But, who to test? What endpoints?

We’re also pursuing combinations with ruxolitinib. And there are many of them, and this list is not exhaustive.

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

But the problem we have in the field is, who should we be selecting for these combinations? If we select patients who are Audience Q&A: Question 4 already progressing on ruxolitinib, we may be selecting patients that are too difficult to treat, where we might see a benefit in a JAK-naïve patient. What do you recommend for treating a patient who develops anemia and thrombocytopenia while being treated with ruxolitinib?

And what endpoint should we use? We are collecting lots of data, but we really need some better surrogate endpoints for our patients.

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 Dr. Bose: I think I’ll just add, somebody asked about, again, what • Other JAK inhibitors in development – Fedratinib under FDA review; efficacy in MF and patients progressing to do about anemia and thrombocytopenia on ruxolitinib, and on ruxolitinib, currently available in FREEDOM study Claire already touched on most of this. One thing we recommend – Pacritinib an important action for patients with thrombocytopenia is thalidomide 50 mg/day. In fact, Claire did one of the earlier trials – Momelotinib an important signal for anemia on this. • Combinations of JAK inhibitors with other treatment modalities are also being assessed (HMAs, IMiDs) And we are currently doing a trial, us and Sloan-Kettering, where we just add 50 mg/day of thalidomide to ruxolitinib, and particularly for the platelets, you know, where you—there’s not So my take-home thoughts based on this section of this evening much else that you can do. You know, you go danazol and ESA for are that, clearly, JAK inhibitors have an established role in the anemia. But for the platelets, that seems to be a nice intervention. management of symptomatic myelofibrosis. We’ve taken a look at other JAK inhibitors that are in development, all of which will be available in clinical trials. But at the present time, fedratinib is available in the FREEDOM study, as I’ve already mentioned. And combinations of other therapies are also of interest.

Audience Q&A: Question 3

Is it necessary to repeat a bone marrow biopsy in the course of disease?

Perhaps there’s a question here about, is it necessary to repeat a bone marrow biopsy in the course of disease? So I don’t know whether the faculty want to answer that, but for myself, I wouldn’t unless I thought the patient was progressing or in a clinical trial.

Dr. Pemmaraju: Exactly right. I think this concept of either “routine bone marrow biopsies” or what you’re used to in AML or in MDS may not always apply to our patients with MPN. So look for things like clear disease progression, changing of disease states. But I would not recommend doing them on a routine basis unless there was a clinical need to do that.

20 Go online to complete the post-test and evaluation for CME/MOC credit PeerView.com/SCG900 Changing the Treatment Story in Myelofibrosis: New Science and More Choices for Challenging Cases in the JAK Inhibitor Era

Case Forum Illustrating the Principles of MF Treatment Considerations for Selecting and in the JAK Inhibitor Era (Cont’d) Sampling of emerging JAK inhibitors

Sequencing Treatment for Patients Phase 3 evidence; • Efficacy in MF, including in JAKARTA/JAKARTA-2 ruxolitinib-failing patients Fedratinib With Myelofibrosis Under regulatory review Naveen Pemmaraju, MD

The University of Texas MD Anderson Cancer Center • Efficacy in MF (patients Houston, Texas Phase 3 EVIDENCE; with low baseline platelets) Pacritinib PERSIST trials

As you’ve heard here from the speakers, a sampling of these Illustrating the Principles of MF Treatment emerging JAK inhibitors is really kind of creating excitement for us in the JAK Inhibitor Era and our patients. You heard about the data with fedratinib, with Where we are in 2019 phase 3 data completed several years ago, the JAKARTA studies, now—and all this is under regulatory review, as you heard from • In higher-risk setting, Intermediate or alloSCT remains a Claire. The concept here is that, are you going to be using other Ruxolitinib approved potentially curative option high-risk MF JAK inhibitors, either in the frontline setting or in the relapsed/ refractory? Let’s see how the process goes.

• ↑ risk of opportunistic infections Lower starting doses in And then the pacritinib drug. Again, you have phase 3 and phase Safety considerations certain situations • Cytopenias: manage by dose reduction, 2 data showing efficacy for this, and particularly here, possibly interruption, or transfusion the niche area of below platelets, thrombocytopenic, which is an urgent unmet medical need for the ruxolitinib-treated patient. So let’s await these data as the year unfolds. Prof. Harrison: Okay. So I think this section of this evening is going to be fun. I’m going to hand over to Naveen, who’s going to Ellen, an Older Patient be talking about selecting and sequencing treatment. So, here you Receiving Treatment for MF go. Ellen is 75 years old, fit She starts treatment and active, with After at least 3 months with ruxolitinib Dr. Pemmaraju: Thank you, Claire. Thanks to the organizers here. confirmed MF Thank you, Dr. Bose. This has been a great session to be a part of. • PS of 1 • 20-mg dose twice daily • Rising splenomegaly So what I want to do is change it up a little bit here, and let’s do a • Constitutional bit more of an interactive—let’s synthesize the information that symptoms, • She initially tolerates • Return of constitutional splenomegaly, normal treatment well symptoms we heard from Claire and Prithvi, and be able to put it all together. platelets at baseline For the first time in our field, we need to start thinking about sequencing combinations, what to do after the frontline failure or intolerance.

So, to review what we’ve seen here so far, in 2019, what you’ve Now, let’s start to kind of work through some problems together. seen from Claire and Prithvi is that we have one currently Now, these are patients that—I don’t want to get too hung up on approved targeted JAK inhibitor, the ruxolitinib, and that’s in the the details of the exact cases, but I want to bring up these three intermediate- or high-risk space with allo transplant always in the buckets that we’re talking about. So, the concept of somebody background for your most aggressive patients, for their disease who’s truly failing a JAK inhibitor pretty quickly after you should courses, and then maybe this concept of lower starting doses see maximum effect, thinking about what to do for other JAK in certain situations, somewhat guided by the package insert, inhibitors, thinking about how to add an agent on a clinical trial, somewhat by clinical experience. thinking about a brand-new non-JAK inhibitor. So, let’s look at some of these patients. And then there are these patients who have situations, special situations where they either cannot take a JAK inhibitor in the The first patient is a typical patient I see in the clinic, a 75-year- frontline setting, or they develop cytopenias, infections, other old woman who’s fit, active, performance status of 1 by ECOG, situations that may necessitate the switch to something else. And but does have constitutional symptoms directly because of the without FDA approvals, what does one switch to? myelofibrosis. This patient is started on standard of care ruxolitinib

21 Changing the Treatment Story in Myelofibrosis: New Science and More Choices for Challenging Cases in the JAK Inhibitor Era at the package insert recommended dose with normal platelets. Dr. Pemmaraju: Yes. See, that’s brilliant. And so that’s a really She tolerates this well. practical way to apply, right? Because the molecular data seem to be so theoretical, and now not necessarily adhering to scoring And timing-wise, let’s just say in the first year, first 3 to 6 months systems per se, but this kind of thinking, that is brilliant, actually. after a reasonable period of time of seeing where you should see maximum effect, the patient rapidly starts to have splenomegaly, And, Dr. Bose, what do you think about the different side-effect return of constitutional symptoms, which had gone away. And so profiles as you think about the JAK inhibitors? Claire and you both the thinking is, is that potentially an initially sensitive patient to brought up, nicely—Claire, you had brought up that some of JAK inhibitor prior, we did not have other JAK inhibitors—what these JAK inhibitors are hitting other targets, so you mentioned does one do in this first situation? pacritinib hitting FLT3. Fedratinib, I believe, has bromodomain activity. Case Forum 1 Newer JAK Inhibitors an Option for Ellen Dr. Bose, what do you see as far as these so-called off-target effects and how that guides our management?

Ellen exhibits lack of Emerging JAK inhibitors/clinical trials are likely response to ruxolitinib treatment options in this setting Dr. Bose: Well, you know, the bromodomain inhibition by

• Supported by JAKARTA-2 findings fedratinib is interesting, because, again, we have synergism • Other emerging JAK inhibitors with potential between ruxolitinib and other bromodomain inhibitors. But then Use of fedratinib is applications in this case include pacritinib or an appropriate we don’t know how much that is—we really have no idea how momelotinib next step • Clinical trials (eg, JAKi + HMA or + PI3Ki) much that is contributing to the clinical data we’ve seen. also an option

Discussion: How can we best explain the difference among established and emerging JAK inhibitors to patients like Ellen? Now, with pacritinib, you know, that seems like there is a niche for it. You know, the <50, as you pointed out, the lack of myelosuppression. Momelotinib, you know, we have seen some So, as you think through your patient, maybe this is a patient that improvement in anemia, right, so that clearly—and with the whole actually could benefit from a subsequent or second JAK inhibitor. activin receptor story, that might be something that is unique to it. And we’ve seen some of the data here today, right? So clinical trials with the fedratinib, pacritinib, momelotinib. And again, this And I think with fedratinib, I think what really we need to see is concept of maybe someone’s having a suboptimal response, and that if in the second-line setting we truly have responses in spleen so the so-called add-back clinical trials, which Claire and I and and symptoms, the reanalysis that Claire pointed out showed others are starting to lead, potentially an option here. about 30% responses. So, that clearly would fill an unmet need.

But the question, before we move on to thinking about the Robert, a Patient on Long-Term suboptimal and the failing after all the JAK inhibitors are used, is, Therapy With Ruxolitinib how do we best explain the difference among the established JAK Robert is a 70-year-old inhibitor, ruxolitinib, and the emerging ones that are coming up— Within the past At the most recent man diagnosed with MF 6 months clinic visit fedratinib, pacritinib, momelotinib? So I wanted to pause to kind of 5 years earlier • 4.5-year treatment get people’s thoughts on that. • Increasing spleen size history of ruxolitinib • Intermittent return of (now 8 cm below costal • Successful several constitutional margin) If I can turn to my panelists, in the absence of molecular—this management of symptoms (fatigue and • Falling counts (platelets constitutional symptoms joint/bone pain) is the same problem—a good problem, I would say—we had in now at 55 x109/L) and splenomegaly CML, where there is still no molecular exact directing thing, do you envision, once we have two to four JAK inhibitors, will there be a molecular way to decide, or is it more of a clinical feel? Dr. Harrison, if you can lead us? Dr. Pemmaraju: Very helpful. So let’s move on to the second case. Prof. Harrison: I don’t think there’s any evidence at the moment. Really great discussion. So, again, we’re thinking about these three or so different buckets that our patients may fall in. So this is a Dr. Pemmaraju: Right. gentleman who comes to the clinic, 70-year-old man. This patient’s had myelofibrosis now for 5 or 6 years, has been on JAK inhibitor Prof. Harrison: About molecular data particularly linking for 4 or 5 years. Successfully has managed the constitutional response. But there are data linking the presence of high symptoms and splenomegaly that presented. molecular risk mutations to likely durability of response and time to treatment failure. I believe that came from your center, I think. But now, after 4 or 5 years, the patient is starting to have the intermittent return of the constitutional symptoms, classically

22 Go online to complete the post-test and evaluation for CME/MOC credit PeerView.com/SCG900 Changing the Treatment Story in Myelofibrosis: New Science and More Choices for Challenging Cases in the JAK Inhibitor Era what we see in the clinic: fatigue and the joint and bone pain, at the impact upon the patient undertaking a clinical trial. Many splenomegaly. But the caveat here—and as you do see in the real patients travel a long way for these studies. world—is that the cytopenias now are below 100. So possibly, right, trying to trigger us to think about preventing immediately, So we go through very carefully what the potential benefits “Let’s go to a second JAK inhibitor.” and side effects might be and what the different options for patients are. I think that we’re fortunate in the moment that we Case Forum 2 have several clinical trials open for patients. But it can be very Clinical Trial–Based Therapy bewildering for them, so we do try to take a lot of time doing that.

Robert is a candidate for second-line therapy, Many novel targeted strategies are being Dr. Pemmaraju: That’s very helpful. And again, in the absence of eager to pursue developed in clinical trials molecular or other guiding forces—and these are new agents— another option what Claire brings up is this—the logistical or the financial Options currently being assessed include agents concerns, which is very real, and also a new thing that’s emerging Clinical trial–based promoting apoptosis (SMAC mimetics), therapy therapies targeting CD123, telomerase for Dr. Bose and I in the clinic is IV versus oral. recommended inhibitors, anti-fibrotic agents (PRM-151)

Discussion: How can we counsel Robert on the best option Some of the new drugs require hospitalization now. Some require to pursue in a clinical trial? multiple visits, more than what any of us have been used to in either the pharmaceutical or the medical side. And so it’s a whole new era for our patients with myelofibrosis. This is completely sort So, in this patient who, let’s say for our discussion here, is failing of real-world practical considerations. So that’s very, very helpful. JAK inhibitor, may not be able to qualify for another JAK inhibitor, what does one do? And this is the bulk of my research focus with Well, and then there’s this third bucket that’s now starting to our group at MD Anderson. This is someone who you may start to become an emerging area in our field. Of course, I’ve already given think about clinical trial for. away kind of the answer. This is something I’m trying to illustrate, this so-called intermediate response—not responding and not The concept here, as both Claire and Prithvi showed very nicely, quite failing the drug. Let’s call it suboptimal for our discussion. is that there are many clinical trials in our field. Most of these are in the phase 1 setting, some now in the phase 2. And there’s an Susan, a Patient assortment of those, and we’ll go through them in the subsequent With Suboptimal Response slides. Susan, a 55-year-old Further Susan Starts on woman presents with Testing Shows Ruxolitinib But thinking about promotion of apoptosis, targeting the • WBC: 32 x 109/L • 20-mg dose twice daily • 15% weight loss microenvironment, CD123, telomerase with imetelstat targeting • Blasts: <1% • After 6 months, spleen • Splenomegaly 12 cm has improved but remains • Hb: 14.5 g/dL the fibrosis itself. So, if you have access to or have referral to a below costal margin 3 cm below costal margin • Platelets: 367 x 109/L clinical trial option in the absence of a JAK inhibitor is something. • No sibling donor • Intermittent constitutional • LDH: 675 units And so the question, of course, which we don’t have a great symptoms answer now, is how do you counsel your patients about a clinical Additionally, biopsy results and mutational trial? And I’m particularly interested in hearing the differences in analyses confirm a diagnosis of PMF England versus America—how does that work? So, Claire, I’d like to start with you. How does the counseling for a clinical trial come up in the clinic, and how do you broach that topic? So this is a young woman, 55 years old, who has constitutional symptoms, splenomegaly at baseline. No clear pathway for a Prof. Harrison: Okay, so I think for many patients, they think that stem cell transplant immediately, and so comes to you for initial a clinical trial is the best option, because a new therapy must be management. better. So, and for—many patients haven’t really thought about clinical trial before, and they don’t really understand the concept. Counts are shown here, just kind of to try to get us thinking about abnormal blood counts, not just always anemia, but here someone So we try to have several conversations with them. We have several with leukocytosis, so adverse factors based on that. Elevated LDH, different members of the team that will talk to them. We try not to which a lot of us have only access to in the initial visit. just give them a big patient information sheet and send them off. So you start on JAK inhibitor frontline, and after 3 to 6 months, I think really it’s about looking at the patient, thinking about what yes, there’s spleen improvement, but, ah, there’s still a little bit of you’ve got available, and thinking about how fit the patient is. And splenomegaly left. Not quite enough to be called a remission, not also, the number of visits that the patient has to come for. So there quite enough to fail and move on, and what exactly are you going were some very nice data that were done by the Italians, looking to move on to?

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

And the constitutional symptoms are not the magic bullet that Dr. Bose: No, I think it’s actually—you know, it’s an important you’re used to with the other patients. She is still having serious area to address, because, you know, you have—again, completely intermittent constitutional symptoms that are affecting the quality agree with you—no one has been able to agree on a ruxolitinib of life. So what do you do in this situation? failure definition. But then, you know, there is the suboptimal concept, and then there is the frank failure, which, again, there is Case Forum 3 not, you know, a clear demarcation between those two. Combination Therapy via a Clinical Trial But then we are seeing responses, like I will add to your list, Susan is a there is, at this meeting and at EHA this year, the first data on a classic case of Some benefit from JAK inhibitor therapy, but “suboptimal response” lack of complete success suggests a need for bromodomain inhibitor, CPI 610, as Claire alluded to, which is more potent management based on synergism in the lab. So there are all these trials. I think Many trials are testing JAK inhibitor–based it’s very—this is a popular strategy now. Many, many new agents Combination-based combination in MF—Susan is likely a good clinical trials candidate for such options: ruxolitinib + HSP90; being done this way, where you add them on. So, yeah, thank you. an option ruxolitinib + navitoclax; ruxolitinib + PI3K

Discussion: Which experimental combination might be Potential Algorithm for Treatment of MF After the best options for Susan? 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 Well, this is this suboptimal response that we, as investigators, are 4. Determine candidacy for splenectomy (rare) trying to carve out with all of the stakeholders in the field. Number Failure because of Candidate for Transplant inadequate JAK clinical trial candidate one thing, as my co-panelists will tell you, is we don’t have a great inhibitor dose participation definition. Each clinical trial is showing a different definition. Not necessarily about agreement, it’s just that there may not be an Proceed Risk–benefit assessment of Proceed accordingly higher JAK inhibitor dose or accordingly objective, scientific way to determine a frontline intolerance or alternative JAK inhibitor or JAK inhibitor combination suboptimal response.

1. Pardanani A et al. Blood. 2018;132:492-500. But the good thing is, in this setting there are emerging clinical trials. For example, there is combination with ruxolitinib and other Dr. Pemmaraju: So, as we conclude the session, I tried to put agents, and this is the so-called add-back strategy, just meaning together something of an algorithm. I’d love to hear what that you’re adding back another agent to the ruxolitinib and everyone has to say. Again, this is so much art of medicine here. keeping it on. But what I was thinking about is, what do I do—2019, heading into 2020, patient is clearly failing or is suboptimal to a JAK inhibitor? And to the credit of everyone in this field, there are multiple trials now where you’re allowed to be on your JAK inhibitor—so, say, So, first thing that we may not talk about enough is, stem cell ruxolitinib—for an X period of time, usually mandated as 3 months transplant remains this sort of potentially curative option. Yes, or longer—and then on top of that, you’re able to add in the study it may not be for everybody, but we have to think about that. drug, which I think is revolutionary. I think that’s pretty amazing. And we’ve talked about that here. So, intermediate- to high-risk patient, young, fit, good performance status. Some examples are shown here. There are some data with the heat shock 90 protein class. There’s an ongoing clinical trial that we’re a Number two is outright failure. We’ve talked about that, switching part of. Claire and I are part of this Bcl-xL strategy, adding back the to a novel non-JAK inhibitor clinical trial. Number 3 is someone navitoclax. PI3 kinase has been tested before, so on and so forth. who you think is still JAK-sensitive, has the blood count. So you go to a subsequent JAK inhibitor. And then finally, the suboptimal So, basically, the bottom line here is, no matter how you describe add-back strategy, where you keep the JAK inhibitor and you’re or define ruxolitinib or JAK inhibitor intolerance in a suboptimal moving on in one of these novel clinical trials. So I think that kind way or response, each of these clinical trials has their criteria, and of summarizes what we’ve been talking about. they’re allowing patients to go on already on commercial supply JAK inhibitor.

So, Dr. Bose, I wanted to turn to you. What are your thoughts about this? This is not something commonly seen in the other fields. Usually, we’re used to, “Come off of whatever drug you’re on; go on the new one.” What are your thoughts on this add-back strategy?

24 Go online to complete the post-test and evaluation for CME/MOC credit PeerView.com/SCG900 Changing the Treatment Story in Myelofibrosis: New Science and More Choices for Challenging Cases in the JAK Inhibitor Era

Novel Therapies in MPNs: And then activation of TP53, or really modulation of the TP53, Moving Beyond JAK Inhibitors John Mascarehnas and Ron Hoffman leading these efforts with • Promotion of apoptosis the MDM2 inhibition, actually in PV as well as possibly even in – SMAC mimetics/IAP antagonists (LCL161; ph2; NCT02098161): n = 44, myelofibrosis. So that’s something exciting to pay attention to. 30% ORR R/R MF, median OS not yet reached1 – Bcl-xL inhibition (Navitoclax; ph2; NCT03222609) Novel Therapies in MPNs: • Targeting of hematopoietic stem cell/micro-environment Moving Beyond JAK Inhibitors (Cont’d) – CD123 inhibition (SL-401; ph2; NCT02268253) – HSP90 inhibition (PU-H71; ph1; NCT03373877) • Bromodomain and extra-terminal (BET) inhibitors – Being assessed in MF and other malignancies (INCB057643; NCT02711137) • Activation of TP53 pathway – MDM2 inhibition (idasanutlin, ph 2 (PV); NCT03287245) • Targeting fibrosis and associated cytokines – Pentraxin (PRM-151; ph 2; NCT01981850) 1. Pemmaraju N et al. ASH 2017. Abstract 256. – TGF-β modulation – Aurora Kinase A inhibition: alisertib

So, as we conclude together, I wanted to give you some more • Telomerase inhibition1,2 details on some of these agents that we had mentioned before. – 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) We tried to pull together some of the recent data, and we’ve listed the clinicaltrials.gov number for your future reference. 1. Tefferi A et al. New Engl J Med. 2015;373:908-919. 2. Mascarenhas J. ASH 2018. Abstract 685.

So, this is sort of my own, but I think a lot of us kind of think Dr. Bose nicely mentioned the bromodomain, the BET inhibitor about these this way. So, from the lab to the clinic. So, the first class. This is a really nice scientific story. Dr. Bhalla at our institution group I picked out for us to talk about is apoptosis promoters, or and others have shown that in the lab in both myelofibrosis and promoters of cell death. This is a class of drugs somewhat known post–MPN AML, maybe there’s activity of this. And so now, just as the SMAC mimetics or IAP antagonists, inhibitors of apoptosis now coming into the clinic. That’s very exciting. protein. Targeting the fibrosis itself, Serge Verstovsek and others, Dr. This particular trial we highlight is an investigator-initiated study Esterov, have been key in leading this. Kind of a really interesting that I’m leading at our center. We have enrolled close to 50 concept. Is this a primary or secondary phenomenon in patients. And we are showing responses in patients with relapsed/ myelofibrosis? So, lots of different ways to target that. refractory myelofibrosis, as I presented at ASH oral presentation the last 2 years. I think the TGF-β superfamily modulation is really important. Dr. Bose has led some of those studies. Now even Dr. Mascarehnas Importantly, in this small study, investigator-initiated, single-site, with the new approaches. median overall survival not yet reached. It’s important, because we believe that people who have truly failed a JAK inhibitor as a front And then how about this, this aurora kinase A inhibition, which line may only have an overall survival of 14 to 16 months, as shown actually was just recently published in Cancer Discovery? This is the by our group in Moffitt. So, something to think about as we review work of John Crispino at Northwestern, the alisertib, and Mayo these single-agent nonrandomized studies. Clinic involved, as well. A nice publication showing activity there.

Bcl-xL inhibition I mentioned. We’re part of an ongoing study, so And then finally, the telomerase story—what an interesting we look forward to seeing results of that. story that’s been. It first came out in the New England Journal of Medicine, now 4 years ago, by Dr. Tefferi, presented by John Now, what about this microenvironment? That’s caught attention Mascarehnas at ASH this past year. A large study, actually, 100- in a lot of fields, including in AML and lymphomas. We’re part of a some patients. Again, this same concept that the median overall study leading CD123 inhibition with the SL-401 tagraxofusp, which survival had not yet been reached, or if it has, it’s getting now to 30 our group led the FDA approval for in a rare blood cancer called months. And so again, at different dose levels, suggesting activity. blastic plasmacytoid neuritic-cell neoplasm. And the concept is targeting CD123. So that’s in phase 2 testing, presenting a poster here at ASCO.

HSP90 inhibition, this is based on some really nice science, primarily led by Memorial Sloan-Kettering, the Chiosis Lab, showing that as a single agent or in combination with ruxolitinib, the PU-H71 may have activity, and so that’s being pursued in the clinical trial format.

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

Ongoing Research Into JAK Inhibitor Symposium Summary and Combination Approaches Audience Q&A

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

RUX + HSP90i (MF) NCT03373877 Prithviraj Bose, MD RUX + Bcl-xLi (MF) NCT03222609 Naveen Pemmaraju, MD RUX + PI3Ki (MF) NCT01730248

RUX + THAL (MF - frontline & R/R) NCT03069326 RUX + HDACi (Pracinostat) (MF) – frontline Audience Q&A: Question 5

Would you stop ruxolitinib if a patient’s numbers of squamous cell lesions increases?

So, as we conclude together, we think about these single agents in combination. Claire and Prithvi have both nicely mentioned the ruxolitinib plus hypomethylator approach. Interestingly, not only did we use it in the blast or accelerated phase, but actually this trial that we published just a few months ago in Blood, believe it or not, is in the chronic phase MF as a frontline approach. Ruxolitinib for 3 months, then the azacitidine is added right after that. And seven to ten of those patients on the study actually had a spleen response after the azacitidine was added. So, check that paper out. Prof. Harrison: So, here is a good practical question about squamous cell cancer of the skin. So, I’d like to ask you, Naveen, We’ve talked about all of these other studies. Dr. Bose, you nicely maybe, could you just comment on, would you stop ruxolitinib if mentioned the ruxolitinib-thalidomide that you’re leading with your patients get increasing numbers of squamous cell lesions? Memorial Sloan-Kettering. Again, frontline approach as well as a relapsed/refractory arm. And so these are some of the approaches Dr. Pemmaraju: So, for me, in the clinic, I have not done that. I here. think it’s a real issue. We know that from the long-term COMFORT studies that you and Serge have completed, and even in the PV study, as well, clinically it comes up.

So, you’re talking about a median age 60-, 70-, 80-year-old patients, many of whom have risk factors for these nonmelanoma skin cancers. And then definitely—you know, an increased signal. I have not yet stopped based on squamous cell or basal cell carcinomas, even though they’re common.

What I have been doing, I will say, is two things. One is greater awareness and education up front, interestingly, when I prescribe a JAK inhibitor. So I am mentioning it there, in addition to viral infections and all that. And two, a lot more partnership with the dermatologist, interestingly. That’s not something that I routinely used to do.

I’m not advocating or saying that every patient needs to go see the dermatologist as a baseline, but it is something that’s been useful, and to have a regular dermatologist as part of the team, if you will. And I have to say that, no, I have not stopped on the basis of this. I’d be curious to hear what both of you think, but something to monitor.

Prof. Harrison: Yeah. Prithvi, do you want to—

Dr. Bose: So, I’ve actually gone down on the dose. I can think of one patient in whom it’s a really serious problem, recurrent. And

26 Go online to complete the post-test and evaluation for CME/MOC credit PeerView.com/SCG900 Changing the Treatment Story in Myelofibrosis: New Science and More Choices for Challenging Cases in the JAK Inhibitor Era now he had this prior to ruxolitinib, okay? And it may have gotten Well, you know, I think you have to mention it, of course. And worse. Recurrent lesions requiring repeated surgical excision. regarding the papers, as the person sending the question stated, there were, I think, two papers that showed inhibition, and then He’s responded very well to ruxolitinib in terms of spleen and there was at least one paper that did not show inhibition. symptoms and has been therefore reluctant to come off and explore another agent. But I’ve gone down to 10 BID, hoping that Prof. Harrison: Yeah. that’ll hold his response and give him fewer of these. Dr. Pemmaraju: Right. Dr. Pemmaraju: Interesting. Dr. Bose: And it is very rare, as Claire and Kat Jamieson have Prof. Harrison: Okay, that’s interesting. shown. There was only one confirmed case. So I don’t think it’s a huge concern, but obviously, if somebody’s malnourished and, Dr. Pemmaraju: That’s interesting. you know, alcohol and things like that, one has to be much more vigilant, probably not put them on the FREEDOM trial, and—but, you know. Audience Q&A: Question 6 Prof. Harrison: Yeah. Did Wernicke’s encephalopathy occur more on one dose regimen versus another? Did fedratinib affect thiamine uptake? Dr. Pemmaraju: I agree with this. I think, Claire, based on your very nice analysis, which really went back and did this deep dive, what I got out of it is that there were cases of metabolic encephalopathy, but that might be more because of GI malnutrition, either from the cancer state itself or other comorbidities.

So I think what it just allows me to do is have a greater recognition of who’s the patient I’m putting on fedratinib, and then maybe Prof. Harrison: There were a couple of questions about Wernicke’s monitoring a little bit closer for these GI nutrition and GI upset encephalopathy. The first question was, did it occur more on one than I probably would have done previously. dose than another? And then there was also a question about a publication about the effect of fedratinib on thiamine uptake. So, Prof. Harrison: So I think in the trial, there is not routine I might take first bash at that, and then maybe you guys might tell supplementation. me what you’re going to do about your patients on the FREEDOM study. Dr. Pemmaraju: Right, right.

So almost exclusively all of the cases, or putative cases, occurred Prof. Harrison: But there is routine screening of thiamine levels, on the 500-mg dose of fedratinib. And so going forward in the yeah. Good. clinical trials, the dose selected will be 400 mg. So I think our time here has drawn to a close. Thank you very much And then just lastly, a comment about the paper that was for you, the audience, in being so interactive. And thank you very published on the impact of fedratinib on thiamine uptake. An much, Prithvi and also Naveen, for excellent presentations. And I initial paper was published that suggested there was an impact wish you all a successful ASCO meeting. Thank you. on the THTR transporter. Actually, in a subsequent study, which in the presence of human serum, we didn’t see an effect on thiamine Narrator: This activity has been jointly provided by Medical uptake. Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. So I think practically we do not commonly see thiamine deficiency in our patients, and it will be checked in the trial. But I just wanted to ask you guys, what will you be doing for patients treated with fedratinib? What will you tell your patients?

Dr. Bose: So, yes, we are participating in FREEDOM, and what I don’t know off the top of my head right now is if routine thiamine supplementation is part of the plan. I hadn’t heard it talked about. So it’s not? Okay.

27 CME/MOC Changing the Treatment Story in Myelofibrosis: New Science and More Choices for Challenging Cases in the JAK Inhibitor Era

Based on a panel discussion and on data from recent medical literature. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView or any of its partners, providers, and/or supporters.

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.

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