CONTROL Myelofibrosis: Current Options, New Treatment Principles, and Opportunities to Leverage JAKi Platforms and Novel MOAs

Chair, Ruben A. Mesa, MD, FACP, and presenters John Mascarenhas, MD, and Naveen Pemmaraju, MD, discuss myelofibrosis in this CME/MOC/AAPA/IPCE activity titled “CONTROL Myelofibrosis: Current Options, New Treatment Principles, and Opportunities to Leverage JAKi Platforms and Novel MOAs.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3R7RBL8. CME/MOC/AAPA/IPCE credit will be available until June 30, 2025.

1. CONTROL Myelofibrosis

Current Options, New Treatment Principles, and
Opportunities to Leverage JAKi Platforms and Novel MOAs

John Mascarenhas, MD
Director, Center of Excellence in Blood Cancers

“and Myeloid Disorders 2

Myeloproliferative Disorders Program 25

Ruben A. Mesa, MD, FACP Tisch Cancer Institute, Division of >
President, Atrium Health Levine Cancer Hematology/Oncology
Executive Director, Atrium Health Wake Forest Professor of Medicine
Baptist Comprehensive Cancer Center Icahn School of Medicine at Mount Sinai
Enterprise Senior Vice President, Atrium Health New York, New York
Vice Dean for Cancer Programs, Wake Forest

University School of Medicine Naveen Pemmaraju, MD
Charles L. Spurr, Professor of Medicine, Wake Professor, Department of Leukemia, Division of
Forest University School of Medicine Cancer Medicine
Winston-Salem, North Carolina Director, Blastio Plasmacytoid Dendritic Cell
Neoplasm (BPDCN) Program
The University of Texas MD Anderson Cancer Center
Houston, Texas

Go online to access full CME/MOC/AAPA/IPCE information, including faculty disclosures.

Copyright © 2000-2024, PeerView

2. Clinical Features of Myelofibrosis‘?

Fibrosis Grade MF-3
Reticulin

DE are

osis/hemorthage
Clinical Features

Leukemic transformation

1.O'Sulivan J, Harrison CN. Mol Call Endocrinol. 2017:451:71-78, 2, Boioceh L et al, Mod Pathol, 2013:28:1577-1585, PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

3. The Modern, Comprehensive Diagnostic Workup for MF!

Current Recommendations (NCCN)

+ H&P, including spleen size by palpation, + BM cytogenetics (blood, if bone marrow is
evaluation of thrombotic/hemorrhagic events, inaspirable) (karyotype with or without FISH)

and CV risk factors + Molecular testing (blood or bone marrow) for

+ CBC with differential JAK2 V617F mutation or molecular testing using
+ Metabolic panel: uric acid, LDH, and LFTs NGS panel that includes JAK2, CALR, and MPL

4 si + Assessment of symptom burden using
+ FISH or multiplex RT-PCR (if available) a
for BCR:ABL1 to exclude CML (METS TE MENTON
: Eimmnelisnofhoodendan + Documentation of transfusion/medication history

+ BM aspirate with iron stain; BM biopsy with + HLA testing, If considering allogeneic HOT

trichrome and reticulin stain + Serum EPO and iron studies; coagulation tests

Detailed diagnostic criteria are av

lable from the ICC and WHO for PMF, PPV-MF, and PET-MF

1. NCCN Clinical Practice Guidelines in Oncology. Myeloprolferaive Neoplasms, Version 1.2024. htips:Jwww.ncen.orglrotessionals/physician_gls/pdimpn pat. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

4. Risk Stratification Has Become a Critical Aspect
of Planning for Appropriate Therapy’

Risk Stratification

Lower Risk

Primary Myelofibrosis MIPSS-70: <3
MIPSS-70+ version 2.0: <3
MIPSS-70 or MIPSS-70+ version 2.0 DIPSS-Plus: $1
(preferred) DIPSS: <2
DIPSS-Plus (if molecular testing MYSEC-PM: <14
not available)
or
DIPSS (if karyotyping not available) Higher Risk

Post-PV or Post-ET MF 0:24
'0+ version 2.0: 24
MYSEC-PM DIPSS-Plus: >1
+ DIPSS
YSEC-PM: 214

1. NOGN Cinical Practice Guidelines in Oncology. Myeloproeratwe Neoplasms. Version 1.2024. ps neen org/professionalsiphysiian_glsipdimpn pat erView.com

Copyright © 2000-2024, PeerView

5. A Number of Flexible Prognostic Models Are Available!

MIPSS-70 (for Patients With PMF Ag DIPSS-PLUS
Prognostic Variable Points Prognostic Variable Points

Hemoglobin <10 gidL. 1 DIPSS low-risk o
Leukocytes >25 x 10%L 2 DIPSS INT-1 1
Platelets <100 x 10% 2 DIPSS INT-2 2
Circulating blasts 22% 1 DIPSS high-risk 3
BMF grade 22 1 Platelets <100 x 10°/L 1
Constitutional symptoms 1 Transfusion need 1
CALR type-1 unmutated genotype 1 Unfavorable karyotype? 1
HMR mutations® 1 Risk Group Total Points

22 HMR mutations 2 Low o
Risk Group Total Points INTA 1
Low 0-1 INT-2 23
Intermediate, 24 High 46

Online calculator for DIPSS-PLUS
ps:/axmmd comvestculate/calculator

High 25

Scan the QR code here or download the Practice Aid for a quick reference,
easy-access guidelines, & all major prognostic tools for MF

* ASXL1, EZH2, SRSF2, er IDHT2.® Unfavorabie karyotype: complex kryoype o sole or two abnoraltes tat include tisomy 8-7/7 176), Se, 129» Inv)
of 11923 rearangement N
1.NCEN Clinical Practice Guidelines in Oncology. Myeloprolferaive Neoplasms, Version 1.2024. hip: /Www.ncen.orgprofessionaisiphysiian_gisfpdimpn.ps. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

6. Characterizing Established JAKi Platforms

Ruxolitinib (JAK1/2)

+ Approved for intermediate-/high-risk MF based in part on COMFORT trials?

Fedratinib (JAK2/FLT3)

+ Approved for INT-2/high-risk MF; validated by JAKARTA and long-term safety evidence
(where no cases of WE were reported)?2

Pacritinib (JAK2/FLT3/IRAK1)

+ Approved for adults with adults with intermediate- or high-risk MF with platelets <50 x 109L
+ Validated by PERSIST trials*

Momelotinib (JAK1/JAK2/ACVR1)

+ Approved for intermediate- or high-risk MF patients with anemia
+ Validated by MOMENTUM study5 and subpopulation from the SIMPLIFY-1 trial®

1. Hamison C et al. N Eng J Mad. 2012:306.787:798. 2 Pardanani A e al. Br J Haematol 2021:195:244-248, 3. Pardanani A et a. ASH 2020. Abstract 3006, $
4. Mascarenhas J et al. JAMA Oncol 2018:4:652:550. 5. tps.Icicalrials govistudyINCTO$173494, 6 MtpsJiciniealtials goviet2/showNCTO1960838, PeerView.com

PeerView.com/AQJ827 Copyrig

7. Other Novel MOAs With Applications
in MF Are Being Rapidly Developed

Imetelstat (telomerase inhibitor)

Navitoclax (BCL2/BCL-

Pelabresib (BET inhibitor)

Navtemadlin (MDM2 inhibitor)

Selinexor (XPO1 inhibitor)

PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

8. Challenges With Modern Therapy

Is HCT Always the Answer?

Long-term survival
advantage with HCT was
observed for patients with
Int-1 or higher risk MF ...

... but at the cost of early
mortality!

1. Gouin K eta, Blood Adv. 2020:4:1965-1973,

PeerView.com/AQJ827

388

Adjusted
Probability, %

o8

Bae eT ROMS

231550730020

piniozosz
EE

3

Le onHer Remo

Adjusted
Probability, %
8 8

[REFPETERSETET

Adjusted
Probability, %

o B

012345 eT eo MDD
Time, y
oat isk
Her 651. 247 260212 199 175196 101 98 57 30 28 17 9
Non HOT 13771078 600 710 543301285 210 140116 78 58 41 28

PeerView.com

Copyright © 2000-2024, PeerView

9. Challenges in Optimizing Care in MF With JAKi Platforms

HR = 27 (96% Cl, 1355)
P= 006

METER: Real-world study
exploring treatment patterns,
effectiveness, and healthcare
resource use in MF

+ Survival in MF patients
after ruxolitinib
discontinuation is poor
(mOS = 14 months)?

Cumulative Survi

* o 2 a2 3% 4 © 72
+ Low platelets at the Survival Time After Discontinuation, mo
start or end of therapy ES ae 5 3 à = @

or clonal evolution

while on therapy was
associated with an
even worse prognosis?

+ Average interval from MF
diagnosis to start of initial
treatment was -8.5 months!

+ Gaps in care transition: Heat (98 a 1003)

Most patients remained on 1L
therapy through week 24...
However, 2L treatment was not
initiated until week 1561

22:
Cumulative Survival ¿8

o
on aa 2 © À
a. Survival Time After Discontinuation, mo

No
Tao
E

1. Gupta V et a. Blood. 2023:142:3205, 2. Newberry K et al. Blood. 2017,130:1125-1131. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

10. Our Goals for Today

Improve your understanding of baseline characteristics that can inform
prognostic assessment and treatment selection

Enhance your knowledge of clinical evidence supporting the integration of
JAKi platforms and agents with novel MOAs into the management of MF
across Clinical settings

Amplify your skills for developing personalized, team-driven treatment plans
that leverage JAKi-based therapies and novel agents for the management of MF

Equip you with tools to address practical aspects of modern MF management,
including prompt delivery of care, safety, and other considerations

Copyright © 2000-2024, Peerview

11. MasterClass & Case Forum 1

Leveraging Clinical Experience With Established
JAKi Options in Higher-Risk MF Care

Naveen Pemmaraju, MD

Professor, Department of Leukemia, Division of Cancer Medicine
Director, Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program
The University of Texas MD Anderson Cancer Center

Houston, Texas

2000-2024, PeerView

12. Two Contrasting Cases of Higher-Risk MF

1: Jeffrey, a 67-year-old man with PMF 2: Jeffrey, a 67-year-old man with PMF
Constitutional symptoms, Constitutional symptoms,
Splenomegaly (16 cm) Splenomegaly (16 cm)
Platelets 102 x10%L (anemia not present) Platelets 102 x10%/L (anemia not present)

Mutational testing reveals JAK2V617F, TET2, Mutational testing reveals JAK2V617F, TET2,
and ASXL1 positivity and ASXL1 positivity

Delay in finding a donor for HCT Initiates on ruxolitinib but subsequently
experiences symptoms suggesting disease
progression

What is the evidence supporting 1L and
sequential treatment with JAKi platforms?

PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

13. NCCN Guidelines: JAKi Therapy Is Well Established as an
Effective Option in Higher-Risk Disease!

Treatment for Higher-Risk MF?

A A — "2

Not an HCT candidate? If HCT candidate,*°@then alloHCT

Based on
COMFORT trials
Based on
JAKARTA trial

<50 x 10%L

Pacritinib (category 1) or
Momelotinib (category 28)

Momelotinib (category 2A) or Y
Based on Pacritinib (category 28)
PERSIST-2 trial
Monitor response and
signs/symptoms of disease

Based on
MOMENTUM

* Evaluation for HOT is recommended or al patins dencaton of Higher” mutations can be helper decision-making. The selection of patents or
OHT shouldbe based on ape PS, major comarid eondtons, paycheacel sas, pan! preference, an avalaäy of caregiver, ar Fer recommended

{or planing purposes. Bndgng therapy canbe used to decrease marow last porto HCT. “JAK bars may be continue near othe start o condoning o

Improve splenomegaly and oer disease seats symptoms. *Donor selecton and condoning shoul be evaluated on a case-bpcase bes. RN

1.NCON Cinical Practice Guideines in Oncology. Myeleprolferatwe Neoplasms. Version 1.2024. tps /hwwwncen org/prfessionalsphysiian_ glspdmpn pat PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

14. ERNEST: What Is the Real-World
Impact of Ruxolitinib in MF?!
Analysis of the impact of OS: Propensity Score (PS) Matching

ruxolitinib for OS by using #0)
real-world data (n = 1,010)

Ruxolitinib
075

2
* 10-year OS after start of HU and 3

ruxolitinib in PS-matched groups 2 °°

= Hydroxyurea (HU)

* Compared with HU, ruxolitinib B 2%

was associated with a significant ® :

benefit in terms of OS o 2 4 6 8 10

ds sa Time After Start of Hydroxyurea/Ruxolitinib, y

+ Benefit was also seen in PS No. at Risk

analysis within small sample sizes #5, à 3 Ss S a 1
1. Gugleimeli P et al. Blood Adv. 2022:6:373-375. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

15. PeerView.com/AQJ827

Updates on Ruxolitinib
In the Peri- and Post-Transplant Setting!

+ 1-year GRFS = 74% po # i:
* OS, PFS, and cumulative “ = =p
incidence of NRM and disease ne ee ¿IE

relapse were, 86%, 79%, 10%, % 3 3 3 % 5 war

Se Soe Rg Y veu
and 10%, respectively 10 10
Fos z
+ Most common grade 3/4 AEs i i
anemia, thrombocytopenia, : um ES mano
A te ann
neutropenia, and a ar 2
hypertriglyceridemia ® Tim Pom Triton. AA
Bi à a pn Re ee
Sao 8 3 R F es 2 2 4 s
1. Hobbs Get al ASH 2023, stat 2103. Sins PeerView.com

Copyright © 2000-2024, PeerView

16. NCCN Guideline Recommendations for
Sequential Therapy!

Patients with higher-risk MF Clinical trial
on therapy with a JAKi

or

nn Alternate JAKi not
Monitor response and response used before (category 2B
signs/symptoms of disease ya a and menden
progression progressii
1. NCCN Cinical Practice Guidelines in Oncology. Myeloprolferative Neoplasms, Version 1.2024. hitps/Iwwnw.ncen orp/protessionals/physician_gls/patimpn pdt. PeerView.com

PeerView.com/AQ)827 Copyright © 2000-2024, PeerView

17. Fedratinib as a Sequential Option in MF Patients
Previously Treated With Ruxolitinib!

+ FREEDOM2: Patients with MF

previously treated with ruxolitinib had 100
superior SVR and symptom response 90
when treated with fedratinib compared 8 5
with BAT 2
5 70
+ The primary endpoint of SVR35 at 2 co 20001
EOC6 was met by 35.8% of patients in [7 50
the fedratinib arm compared with 6.0% = ras
of patients in the BAT arm = 40 .
£ 30
+ Most patients treated with fedratinib E 20 y
showed a reduction in spleen volume pe RETO
from baseline at EOC6 5
235% SVR at EOC6 (Primary Endpoint)
1. Harison C et al. ASH 2023. Abstract 3204 PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

18. Real-World Evidence Shows Clinical Benefits
of Sequential Therapy With Fedratinib!

Retrospective patient chart review in adults with MF who jated fedratinib
after discontinuing ruxolitinib (N = 150 eligible patients)

Best Reduction in Spleen Size During the Initial

+ Spleen size decreased by 6 Months of Fedratinib, %
19.4% to 13.2 cm at month 3 (N = 112 with palpable spleen at fedratinib initiation)
(P = .0001) and by 53.4% to ze
7.2 cm at month 6 (P = .01) of $ 60
fedratinib treatment Ds
g 20
+ 26.8% of patients had achieved 3 o om
250% spleen reduction bymonth6 = -20 Median: -9.8%
5 4 Mean: -29.2%
5 60
& #0
-100
1. Mascarenhas Jet al. Cin Lymphoma Myeloma Leuk. 2024:24:122-132 PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

19. Real-World Evidence Shows That Fedratinib
Can Be Used as a Pre-HCT Option in MF!

+ Real-world assessment of baseline characteristics and outcomes of
patients with intermediate-risk or high-risk MF receiving fedratinib after
ruxolitinib failure as a potential bridge to HCT

Inclusion criteria

+ 218 years of age

+ Diagnosed with intermediate-risk or
high-risk MF

+ Treated with RUX, then initiated
FEDR on/after August 16, 2019
+ Completed 21 cycle of FEDR
+ Discontinued FEDR to undergo HCT
+ Had 290 days of follow-up available Median follow-up (range) after FEDR initiation
9.4 months (95% Cl, 4.4-13.5)

1. Mascarenhas Jet a. ASH 2022. Abstract 2312. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

20. Real-World Evidence Shows That Fedratinib
Can Be Used as a Pre-HCT Option in MF!

+ Based on this dataset, HCT following fedratinib appears to be an
effective and safe treatment option to consider

3-Month P. FEDR Initiatioı

Paired Observations

Visita® (n = 8)
Spleen size,‘ mean (SD), cm 12.4 (7.6) 8.107) .02
No. of symptoms,* mean (SD) 2.6 (25) 2.0 (2.5) 01
EN SES ES, 2.3 (1.8) 24(G7) 93
WBC count, mean (SD) x 10%/mcL 10.4 (11.4) 6.1 (4.0) AS
Hb level, mean (SD), g/dl 8.3(1.0) 9.4 (1.0) .06
Platelet count, mean (SD) x 10%mcL 76(120) 90 (35.0) 14

Spleen ze was measured a FEDR non sf parts ad le month post FEDR tan ste patents.» Corser ony the most eet iin
recorded spleen size between 61 and 120 days post FER ination, Al patients had received 23 mont of FEDR treatment “Statistical comparison of mean values by

paved test “Centimeters above the costal margin." Symptoms were repo fo 7 patents at FEDR nao and 6 patents athe Son post EDR ation il yy 7,

Y Mascarennas Jet al ASH 2022. Abstract 2312. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

21. Practical Guidance on Delivering
Therapy With JAKi Platforms: Ruxolitinib

Starting dose by baseline platelet count
+ >200 x 10%/L: 20 mg BID

« 100 to 200 x 10%L: 15 mg BID

« 50 to >100 x 10%/L: 5 mg BID

Safety Considerations

+ Thrombocytopenia, anemia, and neutropenia: Manage by dose
reduction, interruption, or transfusion

+ Assess patients for signs and symptoms of infection and initiate
appropriate treatment promptly

+ Serious infections should have resolved before starting therapy

PeerView.com

PeerView.com/AQ)827 Copyright © 2000-2024, PeerView

22. Practical Guidance on Delivering
Therapy With JAKi Platforms: Fedratinib

Recommended Dosage

+ 400 mg orally once daily with or without food

Safety Considerations

+ Frequency and severity of Gl AEs can be reduced via early
implementation of Gl prophylaxis (eg, antiemetics)

+ Monitoring thiamine levels before fedratinib initiation and periodically
during therapy is recommended (thiamine supplements can be useful)

PeerView.com

PeerView.com/AQ)827 Copyright O 2000-2024, Peerview

23. Case Forum: A Newly Diagnosed Patient With PMF

4. Jeffrey, a 67-year-old man with PMF
Constitutional symptoms,
Splenomegaly (16 cm)

Platelets 102 x10%L (anemia not present)

Mutational testing reveals JAK2V617F, TET2,
and ASXL1 positivity

Delay in finding a donor for HCT

PeerView.com/AQJ827

Discussion

What available frontline options would
you consider for this patient?

4 Would you consider a JAKi prior to
HCT? Or just a JAKi?

v How would you select between
available JAKi regimens?

PeerView.com

Copyright © 2000-2024, PeerView

24. Case Forum: A Patient Experiencing Symptoms on a JAKi

Discussion

Y What are the sequencing options for
this patient post-ruxolitinib?

Y Isa ruxolitinib dose adjustment an
option or do current symptoms rule
that out?

v What factors would favor sequencing
to other available JAKi options?

PeerView.com/AQJ827

. Jeffrey, a 67-year-old man with PMF
Constitutional symptoms,
Splenomegaly (16 cm)
Platelets 102 x10%L (anemia not present)

Mutational testing reveals JAK2V617F, TET2,
and ASXL1 positivity
Initiates on ruxolitinib but subsequently

experiences symptoms suggesting disease
progression

PeerView.com

Copyright © 2000-2024, PeerView

25. Take-Homes: Two Contrasting Cases of Higher-Risk MF

1: Jeffrey, a 67-year-old man with PMF, 2: Jeffrey, a 67-year-old man with PMF
splenomegaly, and baseline platelets initiating treatment on ruxolitinib who

>100 x10°/L experiencing a delay in subsequently experiences loss of
finding a donor for HCT response / progression

Recommendations Recommendations
«= HCT can still be considered at a latter w Current guidelines support transitioning to
time, but treatment is needed now due to an alternative JAKi in this setting
donor delay Subsequent HCT could still be considered

w Evidence supports upfront JAKi therapy
with agent such as ruxolitinib or fedratinib

PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

26. MasterClass & Case Forum 2
The Personalized Treatment Reality in MF Care
Guidance on Addressing Patient Needs With
Newer JAKi Platforms

Ruben A. Mesa, MD, FACP

President, Atrium Health Levine Cancer ~~

Executive Director, Atrium Health Wake Forest Baptist Comprehensive Cancer Center /
Enterprise Senior Vice President, Atrium Health
Vice Dean for Cancer Programs, Wake Forest University School of Medicine
Charles L. Spurr, Professor of Medicine, Wake Forest University School of Medicine
Winston-Salem, North Carolina

© 2000-2024, PeerView

27. What if Jeffery Had Presented With Baseline Anemia?

Jeffrey, a 67-year-old man with PMF
+ Constitutional symptoms

Splenomegaly (16 cm)

Platelets 102 x109/L
Mutational testing reveals JAK2V617F, TET2, and ASXL1 positivity
Additional findings include: Hb 6.5 g/dL

What is the evidence supporting JAKi options
when anemia or thrombocytopenia present?

PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

28. 2024 NCCN Guideline Updates for MF-Associated Anemia!

Controlled on
a JAKi

Presence of
symptomatic
splenomegaly and/or
constitutional
symptoms

Not Controlled

1.NCON Clinical Practice Guideines in Oncology. Myeloprolfeatve Neoplasms, Version 12024. ts ww nen orgprotessionalsphysician_ s/pétimpn pat

PeerView.com/AQJ827

Other Recommended
Regimens

Useful in certain
Circumstances

Preferred

+ Ruxolitinib

combination + Change to

en > Add luspatercept momelotinib
Clinical Trial | Add ESA (ifserumEPO - Change to
<500 mU/mL) pacritinib

> Danazol (category 2B)

Preferred Other Recommended Regimens.

+ Pacritinib
+ Ruxolitinib combination

+ Clinical Trial > Luspatercept
+ Momelotinib > ESAs (if serum EPO <500
mU/mL)

> Danazol (category 2B)

PeerView.com

Copyright © 2000-2024, PeerView

29. NCCN Guideline Updates MF-Associated Anemia
With No Symptomatic Splenomegaly!

Clinical trial (preferred)

Management of MF- or

associated anemia with Luspatercept
no symptomatic ESAs (if serum EPO <500 mU/mL)

splenomegaly and/or Danazol

constitutional symptoms Rule outítreat Momelotinib (category 2B)
coexisting Pacritinib (category 2B)
causes =
Lenalidomide + prednisone for
del(5q) (category 2B)
1. NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasms. Version 1.2024. htpshwww.ncen orglprotessionals/physician_gs/pdtimpn pet. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

30. Phase 3 MOMENTUM Trial Assessed
Momelotinib in the Post-JAKi Setting in MF!

Primary Endpoint

Momelotinib

Previously treated AS
with JAKi wi
Symptomatic (TSS 210) Momelotinib
Anemic (Hb <10 g/dL and 200 mg daily
platelets 225 x 109/L)
N = 195 Danazol

600 mg daily + plac
(n= 65)

+ Primary endpoint: TSS response rate at week 24
+ Secondary endpoints: TI rate at week 24, splenic response rate (SRR) at week 24
All primary and key secondary endpoints met2$

1. hitpsieiniatals goviet2show NCTO4173404, 2. Verstorsek Set al. Lancet. 2023:401:269-280. 3, Mesa R et al. ASCO 2022. Abstract 7002. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

31. MOMENTUM: Week 24 Symptom Responses
Were Sustained Through Week 48'

Momelotinib Group Who Continued Treatment Danazol Group Who Crossed Over

100 mAtweek 24 (momelotinib) mAtweek48 (momelatinib) — 100 mAtweek 24 (danazol) mAtweek 48 (momelotinib)
x 80 80
¿
Eso 60
8

4 40
i 0
e 20 20

o 0
TSS Response Transfusion SVR235% SVR225% TSSResponse Transfusion SVR235% SVR225%
Independence Independence

+ Week 24 TSS response was 25% in the MMB group and 9% in the DAN group

+ No new safety signals emerged with long-term follow-up

1.Gerds À et al Lancet Haematol 2023,10:0735-0748, PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

32. MOMENTUM: Survival Analysis and Updates!

Randomized pred Open ia! pred
100 oo
Mona
so E.
®
so E
E
3
“ = 0
5 $
¿on
6 5®
o o
ur BEE 0 40 40 0 6 1 0 66 10 ove
Time Since Randomization, wk —

Con:

tent OS outcomes with the ori

1.Gerds A et al. Lancet Haematol 2023;10.0735-6748. 2. Mesa R et al, ASCO 2028, Abstract 8571

PeerView.com/AQJ827

Momelotinib __Danszol
Patents o 18 =
Evens.n 5 $
‘Censor 5 7
À HR (05% cH) 0.12 (001-108)

12 16 20 24 26 32 36 40 44 48 62 56 60 64 68 72 76 60 84
Time Since Randomization, wk

inal unadjusted analysi

PeerView.com

Copyright © 2000-2024, PeerView

33. How Does Momelotinib Impact Quality of Survival?!

Key Takeaways

+ Patients treated with momelotinib
(versus ruxolitinib or BAT)

— Spent less time reliant on RBC
transfusions

- More time free from
transfusions and anemia
events

+ Anemia benefit with momelotinib
suggests improved quality of
survival for MF patients

1. Mesa Ret al, ASH 2023, Abstract 1626,

PeerView.com/AQJ827

Survival Distribution Function Estimate

Ruxolitinib
10

08
06
04
02
0 Momelotinib _
08
08
04
02

o
0 14 28 42 56 70 84 98 112 126 140 154
Time in Each Health State, d
HTD WTWIR MPostLFs

PeerView.com

Copyright © 2000-2024, PeerView

34. Luspatercept Shows Efficacy
In the Setting of MF-Induced Anemia!

en Primary Treatment Period
+ Phase 2 trial assessing erythroid maturation agent ‘Primary endpoct Secondary endpoint
luspatercept in patients with MF-associated
anemia + TD'

+ Safety profile of luspatercept consistent with
previous studies

Patients, %

+ Treatment with luspatercept induced
improvements in anemia and transfusion burden

in all cohorts
Cohort! Cohart3A Cohat? _CohataB
No RUX RUX No RUX RUX
(2) (00) me mem
Use of luspatercept for MF-induced anemia in
Non-TD (Anemia) TO

TD patients with TD on JAK2i therapy is being
assessed in the phase 3 INDEPENDENCE study?

+ Primary endpoint: anemia response

+ Secondary endpoints: Non-TD cohorts, mean Hg
increase 21.5 g/dL from baseline; TD cohorts, 250%
reduction in RBC transfusion burden from baseline

1. Gerds A et al ASCO 2023. Abstract 7016. 2. tips cinicalrals govlet/showiNCTO4717414, PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

35. Pacritinib Induced Robust Spleen/Symptom Responses
in Patients With MF and Low Baseline PLTs'

PERSIST-2 tested pacritinib 400 mg QD or 200 mg BID vs
BAT (including JAK1/2 inhibitors) in MF!

ITT Population Patients With Platelets <50 x 109L
SVR 235%! 250% reduction in SVR 235%! 250% reduction in
modified TSS?2 modified TSS?"
meee mars a
P=.001
2
PAC an mg BAT PAC a mg BAT FACE mn mg er Pie m mg BAT

+ The proportions of patients with much improved or very much improved scores were
57% with pacritinib 200 mg BID vs 28% with BAT
+ excludes India! symptom sores fr redness fom MPN-SAF TSS v20; wein petal aa for ther AK inners

1: Mascarennas Jet al JAMA Oncol 2018:4:652-659, 2. Data on Fle. CTI Biopharma Corp, Pacinb Cinical Overview. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

36. PERSIST-2: Adverse Event Profile’

Adverse Events page 200 El

(n= 106)
Any-grade AE: nts in either arm, %
Diarrhea 48 15
Thrombocytopenia 34 24
Nausea 32 "
Anemia 24 15
Peripheral edema 20 15
Vomiting 19 5
Fatigue 17 16
Grade 23 AEs in >5% of patients in either arm, %
Thrombocytopenia 32 18
Anemia 22 14
Neutropenia i 5
Pneumonia 7 3
Serious AEs in >3% of patients in either arm, %
Anemia 8 3
Thrombocytopenia 6 2
Pneumonia 6 4
Congestive heart failure 4 2

HPSSIed, per standardized MedORA queres.

+ Diarrhea with pacritinib most often occurred

during weeks 1-8, was manageable, and
resolved within 1-2 weeks

Neurological AEs and opportunistic infections
rarely reported with pacritinib

Grade 23 Events (Pooled?)

=PAC 200 mg BID mBAT

Bleeding

Cardiac

Safety outcomes with pacritinib were similar
for those with <50 x 10°/L vs 50-100 x 10%/L.
platelets at baseline

1. Mascarenhas Jet a. JAMA Oncol. 2018,4:662-050.

PeerView.com/AQJ827

PeerView.com

Copyright © 2000-2024, PeerView

37. Can Lower-Dose Ruxolitinib Be Effective
in Patients With Low Platelet Counts?!

+ A phase 2 study assessed the
safety and efficacy of ruxolitinib in
patients with MF and low platelet
counts (50-100 x 109/L)

+ Ruxolitinib was initiated at
5 mg twice daily with gradual
up-titration based on response and
hematologic parameters

+ Improvements in spleen volume
and symptoms were greatest with
ruxolitinib 10 mg twice daily

1.Talpaz M et a. Ci Lymphoma Myeloma Leuk. 2022:22:336-346,

PeerView.com/AQJ827

Median Change From
Baseline, %

Median Change From
Baseline, %

2

¿38358

n=16

n=2 n=27 n=6
A El

$ mg QD or
5 mg BID

n=17

SmgAM10mg 10mgBID 10mgAMISmg Total
PM PM or 15 mg BID
Final Titrated Dose Group

n=1 n=29 n=6

5 mg QD or
$ mg BID

SmgAM/0mg 10mgBID 10mgAWISmg Total
PM PM or 15 mg BID

Final Titrated Dose Group
PeerView.com

Copyright © 2000-2024, PeerView

38. Momelotinib in MF: Practical Considerations

Recommended Dosage

* 200 mg orally once daily with or without food

Safety Considerations

The most common AEs reported in studies to date are thrombocytopenia,
hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea

Monitor for signs and symptoms of infection

Thrombocytopenia and neutropenia: Manage by dose reduction or interruption
Hepatotoxicity: Obtain liver tests before therapy initiation and periodically

throughout treatment

PeerView.com/AQJ827

PeerView.com

Copyright © 2000-2024, PeerView

39. Practical Guidance on Delivering
Therapy With JAKi Platforms: Pacritinib

Recommended Dosage
+ 200 mg orally twice daily

Safety Considerations

+ Avoid in patients with active bleeding; hold prior to surgical procedures

+ For significant diarrhea: antidiarrheals, dose reduction, or dose interruption
* Thrombocytopenia: Manage by dose reduction or interruption

« Avoid use in patients with baseline QTc >480 ms

+ Interrupt and reduce dosage in patients who have a QTcF >500 ms

PeerView.com

PeerView.com/AQ)827 Copyright O 2000-2024, Peerview

40. Case Forum: What if Jeffery Had
Presented With Baseline Anemia?

Jeffrey, a 67-year-old man with PMF
Constitutional symptoms
Splenomegaly (16 cm)

Platelets 102 x10%/L
Mutational testing reveals JAK2V617F, TET2, and ASXL1 positivity
Additional findings include: Hb 6.5 g/dL

Discussion
+ What would be your first choice for this patient with baseline anemia?
- Does anemia impact treatment decisions in MF?
+ How would you select between available JAKi therapies?
- If momelotinib, what is your clinical experience thus far with dosing and AE management?
If the patient had presented with low baseline platelets, how would your choices change?

PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

41. Take-Homes: A Patient With MF-Induced Anemia

Jeffrey, a JAKi-naive 67-year-old man who presents PMF, splenomegaly

constitutional symptoms, and baseline ane

Recommendations
+ This patient's symptoms are not yet controlled on a JAKi

+ Momelotinib is an approved option that could address this patient's symptoms and anemia
(supported by MOMENTUM)

+ If this patient had been started on a JAKi for symptom control, adding luspatercept is
another potential option (NCCN)

+ In the setting of baseline thrombocytopenia, options such as pacritinib or dose-modified
ruxolitinib could be considered

PeerView.com

PeerView.com/AQ)827 Copyright O 2000-2024, Peerview

42. MasterClass & Case Forum 3
Emerging Opportunities for MF
CONTROL With Novel MOAs

John Mascarenhas, MD

Director, Center of Excellence in Blood Cancers and Myeloid Disorders
Myeloproliferative Disorders Program

Tisch Cancer Institute, Division of Hematology/Oncology

Professor of Medicine

Icahn School of Medicine at Mount Sinai

New York, New York

2000-2024, PeerView

43. A Patient With High-Risk MF
With Loss of Response to JAKi Therapy

Sarah, a 71-year-old woman with HR MF (not eligible for HCT)
CALR type 2 mutation present
Treatment with 1L ruxolitinib

Sequenced to alternative JAKi after 2 years due to loss of response
Increasing splenomegaly (now 11 cm)

Is this a setting where newer MOAs can make a difference?

PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

44. Augmenting JAKi Responses:
Add-On Therapy With Navtemadlin in MF

+ Improvements in SVR with ruxolitinib plus
navtemadiin in patients with primary or
secondary TP53 wild-type MF who experienced
suboptimal response to ruxolitinib alone?

‘SVR Change From Baseline to Week 24 by
‘Central Review MRUCT, %

‘Baseline Spleen Volume, em?
3549 650 2400 1,932 1822 1.580 1.375 1,955 2885 2.111 3,380

1, Mascarenhas Jet al EHA 2023, Abstract $210 PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

45. BOREAS: Navtemadlin in R/R MF To JAKi Treatment!

Arm 1
Navtemadlin (KRT-232)

240 mg 7 days ON, 21 days OFF (28-day cycle)
(n= 188)

Patients with primary or secondary MF
who are R/R to JAKi treatment

2:1 randomization
(n= 282) Arm 2:

Best available therapy

Patient stratification:
+ MF type (primary vs secondary)
+ Baseline TSS (s10 vs >10)

Best available therapy options include
hydroxyurea, chemotherapy, or supportive care.
JAKi aro excluded

Primary Endpoint

+ Spleen volume reduction (SVR) 235% at week 24 by MRI/CT

1.Verstovsek S et al. Future Oncol. 2022:18:2999-2009. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

46. POIESIS Will Test the Add-On Therapy With Navtemad
the Setting of Suboptimal Response to Ruxolitinib

Phase 3 randomized, double-blind, placebo-controlled study of navtemadlin added to ruxolitinib in
JAK inhibitor—naive patients with MF who have suboptimal response to ruxolitinib

Enrollment====>> Ruxolitinib Run-in Period===> Screening} Phase 3 Start=} Week 24 MRIMFSAF

‘Suboptimal Response
to Rucolitinib MF Patients Ruxoltinib Monotherapy ARMA
Who are Jak — |_| 2 18 but ©25 weeks ofteatment Navtemadlin 240 mg QD
SUR > 0% but < 35% and Inhibitor ‘on stable ( 8 weeks) nur de
155 reduction > 0% but< 50% | Tratmentnaive cose Ruxoltin
Endotstudy
Co-primary Endpoints: Secondary Endpoints:
‘Spleen Volume Reduction and TSS Best Spleen and TSS response at any time
Improvement Rate at Week 24 after start of on
en Spleen response dura
+ RBC transfusion usage and dependent to

+ SVR3S by Central Review MRUCT
+ TSSS0 Improvement by MFSAF v4.0

independent
+ Overall survival

PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

47. Pro-Survival BCL2 Proteins, Including BCL-XL,
Are Overexpressed in the MPN Setting’

+ In preclinical studies, the synergy
between navitoclax and JAK1/2 ECS) Ruxolitinib
inhibitors has been shown to

induce death of malignant cells 0
STAT3/5 Navitoclax ‘scie

is

+ The addition of navitoclax to
ruxolitinib in patients with
suboptimal responses to ruxolitinib
monotherapy has demonstrated
preliminary efficacy, safety, and
evidence of disease modification

Apoptosis

1. PemmarajuN et al. Lancet Haematol 2022:9:0434-0444. 2. Tognon R et al. J Hematol Oncol 2012.52. 3. Guo J tl. PoS One. 2015.10:00114363, ~~.
4. Breccia M et al. Ann Hematol. 2017:96:387-391. 5. Refic et al. AACR 2022. Poster 5339. 6. Harrison CN et al. J Clin Oncol. 2022:40:1671-1680. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

48. Phase 2 REFINE Trial: Add-On Therapy With Navitoclax in
Patients With MF and Suboptimal Response to Ruxolitinib*

N = 34 adult patients with intermediate-/high-risk MF who had progression or suboptimal

response on stable ruxolitinib dose (210 mg twice daily)
+ Patients received navitoclax at 50 mg once daily followed by escalation to a maximum of 300 mg

+ SVR35 was achieved by 26.5% of {Patents une achieved SVRIS and TSSSO at 7
patients at week 24 and by 41% of El mcm BETT 3
patients at any time on study en Pia -

8 20) m Patents who achieved SVRIS at week 24, or 3

+ 250% reduction in TSS was achieved & 4 | 15950 21veck 24, or BMF grade improvement at 9

in 41% of patients f°
Lo

+ BMF improved by 1-2 grades in 33% of 3 0

evaluable patients E
E

+ Reversible thrombocytopenia without =
clinically significant bleeding was the A ig
most common adverse event (88%)

KBCOEFOMTIKUMNOPORSTUVWKY ZA
Patients (n = 28)
1.Harison CN etal. J Clin Oncol. 2022:40:1671-1680. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

49. Telomerase Inhibition as a Target in MF‘?

Apoptosis of
malignant cells
Malignant Malignant
hematopoietic a
OPS progenitor cel

-0-
x

Imetelstat inhibits Recovery of normal
telomerase RBCs, WBCs, and
activity platelets enabled

1. Asal A et a. Cancer Ros. 2003:83(14)3931-2939, 2 Herbert BS etal. Oncogene, 2005:24(33)5262-5268,

PeerView.com/AQJ827

Imetelstat binds to RNA template,
preventing maintenance of telomeres

Telomerase

RNA template

Imetelstat

—
Telomere

MOA
Potent competitive inhibitor of telomerase activity
‘Structure: proprietary 13-mer thio-phosphoramidate (NPS)
‘oligonucleotide, with covalently-bound lipid tail to increase
cell permeability

Disease-modifying potential: selective Kling of malignant
stem and progenitor cells enabling normal blood cell
production

PeerView.com

Copyright © 2000-2024, Peerview

50. Activity of Imetelstat in Patients With R/R MF (IMbark Trial)

+ Patients randomized to receive 10
imetelstat 9.4 mg/kg or 4.7 mg/kg IV 09
once every 3 weeks! er
+ Atweek 24, spleen and symptom o
response rates were 10.2% and 32.2% E os Imetelstat 9.4 mg/kg
in the 9.4-mg/kg arm A
z
+ Treatment with imetelstat 9.4 mg/kg led 304
to a median OS of 29.9 months and BMF 3 03
E

improvement in 40.5% of patients er :
En Eimeteistat 47 mgikg

+ Safety (9.4 mg/kg dose): reversible os wha | eos
hematologic grade 23 TEAES included: &
0 6 2 © À oo 3
- Anemia (39%) une “neon Sixty m0
mm O
- Thrombocytopenia (41%) meta dmg 59 53 4 a 2 a o
- Neutropenia (32%)
1. Mascarenhas y eta. J Gin Oncol. 2021:30:2881-2892. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

51. IMbark: Improvement in BMF and Association With OS

OS Association With Change or
Stabilization in BMF

+ Biomarker and BMF assessments
suggested selective effects on the
malignant clone!

Survival, Probability

Time on Study, mo

No, at Risk
Yes » 8 6 ww ons o
No 3% OS M 27 #8 3 o

1. Mascarenhas J eta. J Gin Oncol. 2021:39:2881-2892. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

52. IMpactMF Will Further Assess Imetelstat in R/R MF!

Treatment Period
Until disease progression, unacceptable
toxicity, or consent withdrawal

Screening
(28 days)

EOT vi
within 30 days
post-last dose

Post
treatment
follow-up

Refractory MF
Int2/high-risk

If PD, eligible
for crossover
to imetelstat

N=~320 Best available therapy
INV-selected non-JAK

inhibitor therapy

+ Primary endpoint: OS
+ Key secondary endpoints include: symptom response, PFS, spleen response,
improvement in BM fibrosis, safety, among others

1.Mascarenhas Jet al. EHA 2029. Abstract 2037,

PeerView.com/AQJ827 Copyright © 2000-2024, PeerView

53. Will Test Imetelstat Add-On Therapy!

MYF1001 Phase 1/1b Study

PART 4 (Phase 1)

Treatment Period

Int1/Int2/High-risk MF un Until disease progression, unacceptable toxicity, ~~ à
JAK-inhibitor naive ue consent withdrawal pa
Ruxolitinib
Pre-study entry 5-25mg BID
>12 (max 24) week Ruxolitinib tx + Imetelstat
(24 weeks at stable dose) Imetelstat BOIN design 4 dose levels:
4.7,6.0,7.5, 9.4 mg/kg IV Q28 days
End-of- Post.

PART 2 (Phase 1b)
Int1/Int2/High-risk MF
JAK-inhibitor naive

1.Bradiey Teta. Blood. 2022:140:3041-3942.

PeerView.com/AQJ827

Ruxolitinib

Ruxolitinib
>12 (max 24) 525mg BID
weeks with 4

weeks at stable sien tee a

dose pe

Treatment _ Treatment
Visit Follow-Up
Within 30 days Every 12
postlastdose weeks

PeerView.com

Copyright © 2000-2024, PeerView

54. Can Newer Mechanisms Make
a Difference in 1L Settings?

Copyright © 2000-2024, PeerView

55. The Phase 3 MANIFEST-2 Trial Tested the Addition of the
BETi Pelabresib to Ruxolitinib in JAKi-Naive MF

Primary endpoint met

Update from ASCO 20241: SVR35 response at Week 24 was significantly
greater in patients treated with pelabresib + ruxolitinib vs placebo + ruxolitinib

MM Peisbrest + ruottnd (= 171) II Placebo + uno (n= 1899) 177 poputation
2 Pelabresib+ Placebo +
i so Ruxolitinib Ruxolitinib
B (N=214) (N=216)
A ee 65.9% 35.2%
3° Difference? <.001
3 ifferenc:
A 30.4 (21.6, 39.3)
ic (95% Cl)
8 ssw redución *
so
A Mean % change
E in spleen -50.6 -306
4 volume (n= 171) (n= 183) Nas
00 at Week 24°
95% CI [| -53.2, 48.0 | -33.7, -27.5

Data cutoff date: August 31, 2023. Spleen volume assessed by centra ead.

"Waterfall plots represent patents who have baseline and Week 24 data. ° Calculated by stated Cochran-Mantel-Haenszel est. Patients without Week 24

assessment are considered nonresponders. *SVRIS response at any time and percentage change in spleen volume at Week 24 are exploratory endpoints.

4 Rampal Ret al ASCO 2024. Abstract 6502.

PeerView.com/AQJ827

Copyright © 2000-2024, PeerView

PeerView.com

56. MANIFEST-2: Improvement of Reticulin Fibrosis

Grade in Central Read by Week 24 With Pelabresib!

Pelabresib + ruxolitinib (n = 94)

38.3%

improved

Pelabresib +
ruxolitinib

Worsened 21 grade (%) 17.0

Improved 21 grade (%) 38.3

1. Rampal Ret al. ASCO 2024. Abstract 6502.

PeerView.com/AQJ827

Placebo + ruxolitinib (n = 83)

25.3%
eae improved
unchang
ed
21.7%
worsened

Placebo + Differencet
ruxolitinib (95% Cl)

277

253

PeerView.com

Copyright © 2000-2024, Peerview

57. TRANSFORM-1: Adding Navitoclax to Ruxolitinib
Improved Spleen Responses in the 1L Setting!

+ Navitoclax + ruxolitinib led to an SVRgswo4 rate that was twice as high as
placebo + ruxolitinib

+ SVR;srate at any time was substantially greater with NAV + ruxolitinib than
placebo + ruxolitnib

x0
<7 SVR at Week 24 (ITT)
[ic
g so
S| 30
Se
Ë 63.2% (n=79) | 31.5% (n=40)
o
; in
¿2
E ee s =
33
¿| 50
En
Ss
NAV + RUX (n = 114) Placebo + RUX (n = 106)
1.Pemmaraju N et al. ASH 2023. PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

58. Case Forum: A Patient With High-Risk MF
With Loss of Response to JAKi Therapy

Sarah, a 71-year-old woman with HR MF (not eligible for HCT)
CALR type 2 mutation present
Treatment with 1L ruxolitinib

Sequenced to alternative JAKi after 2 years due to loss of response
Increasing splenomegaly (now 11 cm)

Discussion

Would you consider another JAKi? Or is she JAKi-refractory?

# lfso, what are her options—would you counsel the patient on referral to a clinical trial?

Y What has been the safety experience to date with agents like imetelstat in treatment-refractory MF?
What add-on options might have been beneficial earlier for this patient?

Y What is the safety experience to date with add-on therapy?

PeerView.com

PeerView.com/AQJ827 Copyright © 2000-2024, Peerview

59. Take-Homes: A Patient With High-Risk MF
With Loss of Response to JAKi Therapy

Sarah, a 71-year-old woman with HR MF (not eligible for HCT) who is treatment-

refractory after 2 lines of JAKi therapy with increasing splenomegaly (now 11 cm)

Recommendations
Y Using another JAKi in this setting in unlikely to be beneficial
¥ Clinical trial enrollment is a feasible option, including pursuit of a different MOA
4 Imetelstat has shown efficacy in JAKi-refractory patients

v Add-on therapy could also have been considered (via a clinical trial) after this patient's
initial experience of a suboptimal response

PeerView.com

Peerview.com/AQU827 Copyright O 2000-2024, Peerview

60. Audience Q&A O ,

Copyright © 2000-2024, PeerView