Resetting Standards in MDS: New Principles for Integrating Innovative Therapy Into Risk-Adapted Care

Co-Chairs, Guillermo Garcia-Manero, MD, and Amy E. DeZern, MD, MHS, discuss myelodysplastic syndromes in this CME/MOC/NCPD/CPE activity titled “Resetting Standards in MDS: New Principles for Integrating Innovative Therapy Into Risk-Adapted Care.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/CPE information, and to apply for credit, please visit us at https://bit.ly/3WH74oW. CME/MOC/NCPD/CPE credit will be available until October 5, 2025.

1. Resetting Standards in MDS

New Principles for Integrating Innovative Therapy
Into Risk-Adapted Care

Guillermo Garcia-Manero, MD Amy E. DeZern, MD, MHS

McCredie Professor of Medicine Vice Chair for Hematologic Malignancies

Chief, Section of MDS Professor of Oncology

Vice Chair, Department of Leukemia Division of Hematologic Malignancies

The University of Texas MD Anderson Sidney Kimmel Comprehensive Cancer Center
Cancer Center The Johns Hopkins University School of Medicine
Houston, Texas Baltimore, Maryland

Go online to access full CME/MOC/NCPD/CPE information, including faculty disclosures.

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2. C

s Are Changing M

How Recent Developm

1L luspatercept FDA approved
Ivosidenib m/DH1 MDS FDA approved®

>

Since 2020,
+ Multiple regulatory approvals Decitabine + codazuridine?
(4 unique agents) FDA approval: 2020
+ Validation of newer

classifications and „ee
a approval:
prognostic tools il IPSS-M
What are the next steps? BCL2? XPO1? 2020 ae, > Pe A
Novel combination strategies? of MDS imetelstat
classifications (ESA refractory)
{no aocenedta dag docpseter 202078 1138023000
man E eta MEM oe. 20221 ape um casa oa powers. lat 262876114800 pe PeerV
ra ie eerView

5. hts ww accessdata ida govidrugsatda_docs/applater/2023/2111920gts01 ti pt.
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3. Criteria and Differential Diagnosis of MDS

Cytopenia(s) EXCLUDE Other Causes of Cytopenias
+ Hb <11 g/dL or and Morphologic Changes
+ ANC <1,500/mcL or Vitamin B12/folate deficiency
Platelets <100 x 10%L HIV or other viral infection
Copper deficiency
Alcohol use
Medications (especially methotrexate,
MDS “Decisive” Criteria azathioprine, recent chemotherapy)
>10% dysplastic cells in + Autoimmune conditions (eg, ITP, Felty
21 lineage or syndrome, SLE)
5%-19% blasts or Congenital syndromes (eg, Fanconi anemia)
Abnormal karyotype Other hematologic disorders (eg, aplastic
typical for MDS or anemia, LGL disorders, MPN)
Evidence of clonality

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4. New Resources Include the 2022 WHO and ICC Classification

How Do These Tools Compare?

Nomenclature
Lineage
Morphologically defined
<5% BM and <2% PB
5%-9% BM or 2%-4% PB
10%-19% BM or 5%-19% PB
5%-19% BM; 2%-19% PB
Genetically defined
SF3B1
Del(Sa)
TP53
Additional
Deleted subgroup
Added subgroup

1. Stan M et a. Blood Rev. 2023:62:101128,

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Myelodysplastic neoplasms. Myelodysplastic syndrome

MDS NOS-SLD, MDS NOS-MLD

Number of dysplastic lineages removed

MDS-LB, MDS-h -
MDS IB1, MDS IB2 MDS EB, MDS/AML

MDS-f -

MDS with low blasts and SF387 mutation
or MDS with low blasts and RS

MDS with low blasts and isolated del(5q)

MDS with SF381 mutation
or MDS NOS (with RS but SF3B1 WT)
MDS with del(5q)
‘MDS with TP53 mutation including MDS, MDS/AML

MOSBITRSS (for MDS, it must be multihit-mutated 7P53)

MDS NOS removed MDS unclassifiable removed
MDS NOS without dysplasia with -7, del(7q), or

complex karyotype

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5. MDS Risk Calculat
Is a Simple, Easy-to-Use Tool!

Input relevant patient data ... ae
1 Aid!

FR

Calculate Risk

mds-risk-model.com

SE
El

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1. Bernard E et al. NEUM Evid 20221.

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6. Can Newer Therapies Help Achieve the Goal of Transfusion

Independence in LR MDS?

OS According to Transfusion Status (From 2007)" 2024 Analysis (136 Patients Across 6 Trials)?
+ RBC TI was strongly predictive of survival
+ 5-y survival was 66% for RBC-TI patients compared with 34%
(95% Cl, 26-44) among RBC-TD patients

212 Weeks of RBC TI in the First 24 Weeks Since
10) Treatment Initiation

a

o
ES

RBC TI

Cumulative Survival
o
a

OS Probability

RBC TI

3

HR (95% Cl) = 0.41 (0.30-0.57)
aHR (95% Cl) = 0.47 (0.33-0.68)

HR = 1.91; P< 001 RBC TD

O 20 40 60 80 100 120 140 160 180 0

12 24 36 48 60 72 84 96 108
Time, mo

Time, mo

1. Mao Leu Res. 2007:31(up 3) 52:52. Malova Let a. EHA 2024 art P782 PeerView

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7. ng the Modern Management Era

g to

(>42,000) reated during the modern era (2001- 01 6)!
+ In HR patients, the median OS was 11.6 mo
+ Median time to AML of 19.4 mo

1.Astanzen Herrera et Blood. 2021:138:051. PeerView

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8. Our Goals for Today

Improve your knowledge of clinical and molecular features of MDS
that can inform accurate diagnosis, prognostication, and treatment
planning

Sharpen your understanding of evidence supporting the use of
innovative therapies for the risk-adapted treatment of MDS

Enhance your skills for team-based treatment selection with modern
therapeutics

Equip you with the skills you need to navigate practical treatment
planning, dosing, and safety management considerations

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9. Guillermo Garcia-Manero, MD
‘McCredie Professor of Medicine
Chief, Section of MDS

Vice Chair, Department of Leukemia
The University of Texas MD Anderson
Cancer Center

Houston, Texas

New Standards, Durable Efficacy in
LR MDS

‘Amy E. DeZern, MD, MHS
Vice Chair for Hematologic Malignancies
Professor of Oncology

Division of Hematologic Malignancies
Sidney Kimmel Comprehensive Cancer
Center

The Johns Hopkins University School of
Medicine

Baltimore, Maryland

1000-2024, PeerView

10. cal Consu ael Is a 74-Year-Old Man Wi

Presentation Testing Confirms LR MDS Current Treatment
+ Presents with fatigue + 19% ring sideroblasts + RBC transfusion
and anemia + 3% BM blasts
(Hb: 7.4 g/dL) + SF3B1 mutation
+ Platelets: 250
+ ANC: 5,000
=
vor
„> ER À
Le > a
> e
= - >
=

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11. + Presents with fatigue

and anemia

Testing Confirms LR MDS

* 19% ring sideroblasts

+ 3% BM blasts

(Hb: 7.4 g/dL)
Platelets: 250
ANC: 5,000

SF3B1 mutation

Current Treatment
RBC transfusion

E
a YEN
e
E ii
> y Ye”
£

LR MDS
calculated

using IPSS-M „_..

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12. Consult Conti Change in Transfusion Requireme:

Presentation Testing Confirms LR MDS Current Treatment
+ Presents with fatigue + 19% ring sideroblasts + RBC transfusion
and anemia + 3% BM blasts
(Hb: 7.4 g/dL) + SF3B1 mutation Changes in transfusion
+ Platelets: 250 requirement
+ ANC: 5,000 .

Now 6 RBC units over
a 2-month period

Discussion

+ Is an intervention necessary with this transfusion requirement?

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13. Consult Co

Presentation Testing Confirms LR MDS Current Treatment
+ Presents with fatigue + 19% ring sideroblasts + RBC transfusion
and anemia + 3% BM blasts
(Hb: 7.4 g/dL) + SF3B1 mutation Changes in transfusion
+ Platelets: 250 requirement
+ ANC: 5,000 + Now 6 RBC units over

a 2-month period

Discussion
+ Does longer follow-up from COMMANDS still support 1L luspatercept?
+ Or should ESA therapy be initiated, with luspatercept held in reserve?

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14. Consult Conti Change in Transfusion Requireme

Presentation Testing Confirms LR MDS Current Treatment

+ Presents with fatigue + 19% ring sideroblasts + RBC transfusion
and anemia + 3% BM blasts
(Hb: 7.4 g/dL) + SF3B1 mutation

+ Platelets: 250

+ ANC: 5,000

Changes in transfusion
requirement

+ Now 6 RBC units over
a 2-month period

Discussion

+ What if this patient had RS-negative LR MDS, would you consider 1L
luspatercept?

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15. Centered on ESA Therapy and Transfusion

ESA Therapy
(part of MDS anemia treatment
guidelines, although not approved
in the US for MDS)

+ Larger doses may be necessary + Iron overload risk (iron chelation)

+ Loss of effect over time + Burden on patients and rare
infection risk

+ Transfusion dependency and
increased risk of AML
transformation

1. NCCN Clinical Practice Guideinesin Oncology. Myelodyaplaste Syndromes. Version 3.2024 ps nmw.nccn o professional pican, spas pa. PeerView

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16. ropoiesis to Alleviate Anemia‘?

Enhan

Ligand + Luspatercept is a fusion protein
that consists of a modified

activin receptor (ActRIIB)—a

I, Astivin

receptor

RBC
iambrane member of the TGFB
1 A A superfamily—and the Fc of
uspatercept
Ligand i human 1gG1
Smad2 phosphorylation "2" (ligand trap)
Inhibits RBC maturation à + Inhibits Smad2/3 signaling and
> traps GDF8, GDF 11, and ActB
« Stimulates RBC production
Smad2 signaling inhibited
Promotes RBC maturation
1.Piga Act al. EHA 2018, Ans S344.2, Att Ket a. Am J Hematol 201489-766-770. 3. Suragan Reta. Na Med. 2014: 20408-416, PeerView

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17. COMMANDS: Improvements in RBC TI and Hb Levels Wi
spatercept Therapy

100

80 Primary endpoint (achievement
# a 637 of RBC TI in 212 weeks with a
El 42 concurrent mean Hb increase
2 40 21.5 g/dL) was achieved by 110
ES

56 (60.4%) patients versus 63
(34.8%) (P < .0001)!

o

Luspatercept (n = 147) Epoetin Alfa (n = 154)

+ Led to FDA approval in ESA-naive adult patients with very low- to int-risk MDS who may
require regular RBC transfusion

+ Now a category 1 NCCN recommendation for LR MDS anemia with no del(5q) + other
cytogenetic abnormalities with RS 215%?

1. Datla Porta MG eL al. Lancet Haomal. 2024-11:0646-658. 2. NCCN Cinical Practice Guidolnes in Oncology. Myolodysplasic Syndromes. Version 32024.
ps a cn or professionals ptysician_alspdfimds pdt

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18. Versus ESA Therapy!

Duration of RBC TI 212 Weeks for the ITT Population
Luspatercept _Epoetin Alfa

dá Median duration, wk 126.6 89.7
i (95% Cl) (99.0-NE) (61.9-123.9)
09 HR (95% Cl) 0.586 (0.380-0.904)

Luspatercept

Probability
=

Epoetin alfa

+ Censored

O 10 20 30 40 50 60 70 80 90 100110120130 140 150 160 170 180 190 200210220230
RBC TI Duration, wk

No. at Risk

Luspatercept 124124115100 86 76 67 59 50 46 40 35 28 20 18 10 9 5 5 4 3 1 0 0

Epoetin alfa 88 88 79 65 54 47 43 32 23 20 15 14 12 9 9 7 6 6 5 4 2 1 1 0
Ost cto date: September 28 202 R
arena Seo AGH 2023. Abt 100 PeerView

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19. COMMANDS: Consistent Benefit Wi
Across Subgroups

spatercep

Preplanned subgroup analysis of RBC TI 224 weeks (weeks 1-48) showed responses
were greater with luspatercept versus epoetin alfa regardless of baseline TB, sSEPO
category, or SF3B1 mutation status?

100 mLuspatercept (N = 182) = Epoetin alfa (N = 181)

90 P<.0001

80 72.9
63.7

iii

“4 UBwooks AUB weeks 290UL _>200%0<200 UL

Tp lation Baseline TB Baseline sEPO SF3B1 mutation RS status
status
Dat cuof dato: September 28, 2023. .
Dela Porta MG eta Lancet Hasmolo 2024:11:0046-058.2. Garcie-Maneco Got a ASH 2023. Abstract 193. PeerView

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20. Consult Continued: Michael Prepares for Therapy Wi
ispatercept—What Are the Practical Implications?

Presentation Testing Confirms LR MDS Current Treatment
+ Presents with fatigue * 19% ring sideroblasts + Transfusion
and anemia + 3% BM blasts requirement: 6 units
(Hb: 7.4 g/dL) + SF3B1 mutation over a 2-month period
+ Platelets: 250 + Luspatercept
+ ANC: 5,000 recommended

Discussion

+ What are the safety/dosing considerations (eg, starting dose, max dose)?

+ Is there a role for luspatercept combination therapy?

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21. COMMANDS: Safety Summary’?

Luspatercept Epoetin Alfa TEAES of any grade
(n=178) (n= 176) + 164 (92.1%) luspatercept
+ 150 (85.2%) epoetin alfa

Patients, n (%)

Median treatment duration
+ 41.6 (range, 0-165) weeks of luspatercept

TEAEs of interest + 27.0 (range, 0-171) weeks of epoetin alfa
Fatigue 26(14.6) 1(0.6) 12(68) 1(06)
Diarrhea 26 (14.6) 2(1.1) 20(11.4) 1(0.6) Progression 5(2.8) eee
ESTER to HR MOS 7140) = Epoctin Alfa
lema 23(129) 0 12 (6.8) 0
Asthenia 22 (12.4) 0 25(14.2) 1(06) Prosrescion
Nausea 21(118) 0 13 (7.4) 0
Dyspnea 21(118) 7(39) 13(7.4) 2(1.1) 32 (18)
Deaths"
TEE 8(45) 5(28) 5(28) 1(06) u
Hypertension? 23 (13) 15 (8) 12 (7) 8 (5) 0 40 20
ee Patients, n (%)
Kane O oto ASCO 2023 Absract 709.2. latzbocer U eta once 2028:402:379-985 PeerView

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22. Dosing Considerations‘?

+ Recommended starting dosage is 1 mg/kg SC once every 3 weeks in LR MDS
+ Prior to each dose, review the patient's Hb and transfusion record

+ Dose titration based on response is recommended; in COMMANDS, titration was up to
1.75 mg/kg"

+ Recommendation for HTN management: monitor BP prior to each administration

+ Manage new-onset HTN or exacerbations of pre-existing HTN using antihypertensives

1. Gare Manero G tal. ASCO 2023 Abstract 7009. 2 Rebloe (uspetercapt-sam) Presrbing Information. A
haps accossdata fa gowcrugsatda,eeesebe/20207611360"20 pal = PeerView

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23. te Luspatercept Dosing on RBC TI
Lessons From MEDALIST

Multiple Periods of RBC TI 28 Weeks During the Entire Treatment Period (n = 73)!

© REC transfusion event
[ES — RBC TI <8 weeks
— RC TI 2 8 weeks

73/153 luspatercept-treated

m patients achieved RBC TI
28 weeks during the entire
treatment period

51 (33.3%) had 22
separate response periods
28 (18.3%) had 23
separate response periods

A: iaa * 15 (0.8%) had 24 separate
Time, wk response periods

1. Fennaux Pet al. N Eng! J Med. 2020:562:140-151 PeerView

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24. Is There a Role for Luspatercept Earlier in the Disease Course?

ELEMENT-MDS
Screening period In patients not dependent on transfusion?
oa zen ON) Treatment pers

Endpoints,

Key Etgibilty Criteria Luspatercept
(n= 100) ney
+ 218 years of age 1.0-1.75 moi S End of treatment + Proportion of participants
+ NTD MDS (IWG 2018)" during weeks 1-96 who
+ IPSS-R very lon low, convert 10 TD (3 unta/16
or ntermedat-tck MOS. eek per ING 2018)
{thor trout RS) with Epoctin alfa! Posttreatment folow-up A ADO)
(ne -100 32-day safety follow-up Keeney gal
450-050 un long tem follow p> peste ieee

53.5% EM blasts
+ Endogenous SEPO <500 U/L.
wooks 1-48

+ HD S95 gat
+ Symptoms) of anemia ‘Additional secondary
EPS ne) Disease assessment twack 48 2 Timo TD (pe Mo 2018)
eo EE and week 96; discontinue + Transfusion-ree survival
ESA, iia ere perio © Durationtime to mH-E
+ FACT-An, EO-SD-SL

REG wanshaion stoy must bo aaa or 224 woos. "Zor (0) RBC uns ver 16 Wook pr 19 randomization: 1-2 RBC uns win the 18 wooks pro oler ar towed povided
‘rola wos creed tron 0.1 evn/Anes (o. sure procedo. Poca, moco e pesares el Comos, ond Lo De our o! La O wah or mio sympa)
‘tone «Sad by sein 1) PO vo 0-00 va 200.00, 2 satu (50% ca o RS negate). 9] PSS-R ely lw, on. va inmediato. Crossover Line Du reamen arms

e pm dang the sty rosment pres. "String dove 1.0 mg, dee est up 1.5 mpg o mann been 10-115 GL" String dase = 420 ung, dove escala 5
‘po 1.05 una (max 60. unas) mama Ho betwen 10.175801. 025 jours por 1 es 01073 yar tam a! Sono (whichever eur o) er AL progression, MOS PeerView
esinent, 08.

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25. Is There a Role for Combining Luspatercept With ESA Therapy?

N = 28 Consecutive Patients Treated With Real-Life Experience in 54 Patients With
Luspatercept and ESA Combination After No LR MDS Treated With Luspatercept + ESA?
Response or Loss of Initial Response to
Luspatercept Monotherapy!

627 (22) E

Overall response 36 (10) 60.7 (31) 12
High increase >1.5 g/dL in NTD or Hb

increase >1.5 g/DL with RBC TlinRBCTD 19(5) 56.8 (29) 16
RBC TI without Hb 1.5 g/dL increase 14 (4) 49 (25) 24
>50% reduction in RBC TB 4(1) + In 41% (21) of patients, concomitant therapy

with ESA led to improved response, 16 of
whom reached TI

+ Luspatercept dose increases to 1.75 mg/kg
augmented response in poor responders

1. Kono Ret al tod Ar: 2023:7:9677-9679, 2. Jenasova A eta. EMA 2024, Abstract P1006, PeerView

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26. Consult Revisited: What if Michael Had Received Prior E
Therapy But Experienced Loss of Response?

Presentation Testing Confirms LR MDS Current Treatment

+ Presents with fatigue + 19% ring sideroblasts + RBC transfusion and
and anemia + 3% BM blasts ESA therapy
(Hb: 7.4 g/dL) + SF3B1 mutation + After 16 months,

+ Platelets: 250 transfusion

+ ANC: 5,000 requirement to

4 units/month

Discussion
+ Is this a clear case of ESA failure?
+ How do you monitor for response with ESAs?

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27. Consult Revisited: What if Michael Had Received Prior E
Therapy But Experienced Loss of Response?

Presentation Testing Confirms LR MDS Current Treatment
+ Presents with fatigue + 19% ring sideroblasts + RBC transfusion and
and anemia + 3% BM blasts ESA therapy
(Hb: 7.4 g/dL) + SF3B1 mutation + After 16 months,
+ Platelets: 250 transfusion
+ ANC: 5,000 requirement to

4 units/month

Discussion
+ What is the next step—switch to luspatercept?

+ Does IMerge support switching to imetelstat? If so, what are the dosing
and safety recommendations to consider?

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28. Consult Revisited: What if Michael Had Received Prior E
Therapy But Experienced Loss of Response?

Presentation Testing Confirms LR MDS Current Treatment
+ Presents with fatigue + 19% ring sideroblasts + RBC transfusion and
and anemia + 3% BM blasts ESA therapy
(Hb: 7.4 g/dL) + SF3B1 mutation + After 16 months,
+ Platelets: 250 transfusion
+ ANC: 5,000 requirement f to

4 units/month

Discussion

+ What if this patient had received 1L luspatercept—could imetelstat be considered
in the 2L?

+ What if an /DH7 mutation had been present—how would that change your
treatment decision for this patient?

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29. MEDALIST: Reduction in Transfusion With

Luspatercept vs Placebo
70
P<.001
= Luspatercept = Placebo
rss
P< 001
8
go sais
2
Ss Median
£ 30 follow-up of
26 months
20 hrs
576
10
o +

Overall, 250% Reduction Overall, 275% Reduction
1. Zeiten AM et al, Blood 2022:140:285-289. 2. Germing U eta. Ann Hematol, 2023:102:311-321.

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Initial Nonresponders From MEDALIST Who

Continued Treatment to 144 Weeks
(N = 68)?

+ 81% received the maximum dose of

luspatercept (1.75 mg/kg)

+ 16% achieved RBC TI for 28 weeks during

weeks 25-48

26% had reduced RBC transfusion burden
10% achieved an erythroid response

Hb levels increased an average of 1.3 g/dL
from baseline

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30. Imetelstat!

Imetelstat is a 13-mer oligonucleotide
+ Selectively targets malignant cells with continuously upregulated

telomerase, inducing their apoptosis (cell death) and enabling the a Co
potential recovery of normal hematopoiesis Malignant

FDA approved for adults with low- to intermediate 1-risk MDS with
transfusion-dependent anemia requiring 24 RBC units over 8 weeks
who have

+ Not responded to or

+ Have lost response to or

+ Are ineligible for ESAs

Recommended in NCCN guidelines?

+ Inpatients with LR MDS and anemia who are ineligible for ESA Malignant
+ For patients not responding to luspatercept (category 1) “cells

+ For patients not responding to ESAs (category 1)

4. Toor A eta. Blood Concor J.2018:11:0408. 2. NCCN Caica Practico Guidelines in Oncology. Myelodysplastic Syndromes. Version 8.2024,
se nccn orgiprofessionals/physician_gl/pdtinds pal.

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31. IMerge: Phase 3 Trials Showed Higher Rates of
RBC TI Observed in Imetelstat vs Placebo‘?

ng-Term

mlmetelstat (n = 118) = Placebo (n = 60)

8-wk TI 16wk TI
Transfusion Independence

24-wk TI

Patients With Response, n (% [95% CI)

Imetelstat 47 (39.8 [30.9-49.3))

37 (31.4 123:1-405)) 33 (28.0 (20.1-37.0)) 16 (136/8-21.1)
Placebo 9 (15 [7.1-26.6)) 4 (6.7 [1.9-16.2)) 2 (3.3 [0.4-11.5)) 1 (1.7 [0.0-8.9))
1. Zeiten A et a. ASCO 2023. Abstract 70042. latzbecker Ut al Lance. 2023 Dec 1 Epub ahead ol ri PeerView

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32. Imetelstat 8-Week RBC TI Responders Have Sig antly

ger Duration of Transfusion Independence vs Placebo!

8-Week TI

Sto [pin Imetelstat (n=47) — Placebo(n=9) HR (95% Cl) P
E nh Median duration of
3" = RECHTEN) 133(8249) 023(009057) 0007
5 06 ==,
ten.
8 04 iu
2 ee — imita
=
El
3
5
&
0 8 16 2 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144
No. at Risk TI Duration, wk
Imetlstat 7 47 37 33 27 26 20 16 4 1 HN CUS 3 3 41 1 o
Po 9 a 2 1 1 14 1 1 1 1 1 1 1 0 o o o o
29 À tal ASCO 2023. Absrct 008. 2, Ptzbecker Ue al. Lance. 2023 De 1 Epub aed of pt PeerView

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33. IMerge: With Longer Follow-Up, 83% of Imetelstat Responders
Had a Single Continuous RBC TI Period!
Pretreatment Median (95% Cl)

transfusions duration of RBC TI
Fe > m z———

Imetelstat (n = 47)

51.6 weeks
28-week RBC TI (26.9-80.4)
responders
Mz8-week RBC TI
ORBC transfusion
> Treatment ongoing
Placebo (n = 9)
13.3 weeks
(8.0-24.9)
45 0 15 30 45 60 75 90 105 120 135 180 165 180
1. Satin et a EHA 2024, Abstract S184, PeerView

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34. Among Imetelstat Responders, RBC TI

Was Durable and Sustained Over Time
P<.001 P<.001 P= .002*
50
40
= 30
g
S
5 20
10

Median TI duration
= 52 weeks

28-week RBC TI 224-week RBC TI 21-year RBC TI
mimetelstat = Placebo 7
+ Reported as descriptive P. n=118 n=60 PeerView

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35. Imetelstat Associated Wi
Manageable Safety Profile
Most common treatment-emergent grade 3-4 AEs included’
+ Neutropenia (80 [68%] patients who received imetelstat vs 2 [3%] for placebo) and
+ Thrombocytopenia (73 [62%] vs 5 [8%])
In IMerge, low rates of disease progression and progression to AML?

a Consistent a

Imetelstat Placebo
(n= 118) (n= 60)
PFS
PFS events, n (%) 29 (24.6) 14 (23.3)
Median (95% Cl), mo NE (29.2-NE) NE (16.7-NE)
HR (95% Cl) 0.85 (0.44-1.64)
P 631
Disease progression, n (%) 13 (11) 8 (13.3)
Progression to AML
n(%) 2(1.7) 2 (3.3)
Median (95% Cl), mo NE (NE-NE) NE (NE-NE)
HR (95% Cl) 0.45 (0.06-3.23)
[2 418
1. Patzbecker Vet ol. Loco. 2023 Dec 1 [Epub ahead of pn 2. Sant V tal EMA 2024. Absact 5104. PeerView

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36. sing and Safety Considerations With Imetelstat!

4, Download the
11 Practice Aid!

+ Recommended dose: 7.1 mg/kg IV over 2 hours every 4 weeks

+ Discontinue if no decrease in RBC transfusion burden after 24 weeks of treatment
(administration of 6 doses) or if unacceptable toxicity occurs

+ Premedication at least 30 minutes prior to dosing
— Diphenhydramine (or equivalent) 25 mg to 50 mg, IV or orally
— Hydrocortisone (or equivalent) 100 mg to 200 mg, IV or orally

Dose Modifications for Grade 3/4 AEs

Dose Reduction Dose Every 4 Weeks, mg/kg
First dose reduction 5.6
Second dose reduction 44

1. to (metesta)Prescrin Information. ps mw accessdata do ovidugsalse_docsfabel2028/2177 70008 pl. PeerView

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37. Time for Innovation in HR MDS: Recent
Developments With Targeted Agents

Guillermo Garcia-Manero, MD ‘Amy E. DeZern, MD, MHS.
McCredie Professor of Medicine Vice Chair for Hematologic Malignancies
Chief, Section of MDS Professor of Oncology

Department of Leukemia Division of Hematologic Malignancies

ty of Texas MD Anderson Sidney Kimmel Comprehensive Cancer Center
Cancer Center The Johns Hopkins University School of Medicine
Houston, Texas Baltimore, Maryland

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38. Christine Presents With HR MDS and Initiates HMA Therapy

Current Treatment

Presentation
+ Fatigue, pallor, and

SOB

» Hb: 9 g/dL

+ Platelets: 90,000/mcL

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y

Testing Confirms HR MDS

+ 12% blasts

+ Cytogenetics:
3 abnormalities

+ NGS testing shows an
IDH1 mutation

À Example of MDS with
excess blasts
4

+ Lack of donor for HCT
(for the moment)

+ Initiates azacitidine

+ No response after
initial cycles of
therapy

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39. Christine Presents With HR MDS and Initiates HMA Therapy

Presentation Testing Confirms HR MDS Current Treatment

Fatigue, pallor, and 12% blasts
SOB + Cytogenetics:

+ Hb: 9 g/dL 3 abnormalities

i + NGS testing shows an
+ Platelets: 90,000/mcL IDH1 mutation

Lack of donor for HCT
(for the moment)

+ Initiates azacitidine

+ No response after

initial cycles of

therapy

Discussion

+ What is the utility of tools such as IPSS-M in HR settings?
+ Is NGS the most efficient tool for capturing mutations?

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40. Christine Presents With HR MDS and Initiates HMA Therapy

Current Treatment

Presentation

+ Fatigue, pallor, and
SOB

+ Hb: 9 g/dL
+ Platelets: 90,000/mcL

Testing Confirms HR MDS

+ 12% blasts + Lack of donor for HCT
+ Cytogenetics:

(for the moment)
3 abnormalities + Initiates azacitidine

+ NGS testing shows an + No response after

IDH1 mutation initial cycles of

therapy

Discussion

therapy)?

+ What is the next step for this patient? IDH1 targeting agents?
+ Is there a case to be made for 1L IDH inhibition (eg, instead of HVA

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41. NCCN Recommendations for HR MDS According to HC
Candidacy Include Use of HMAs and Targeted Agents!

ELIGIBLE for HCT INELIGIBLE for HCT
AlloHCT
or
Azacitidine (if no response, consider single-agent
ivosidenib if m/DH7) followed by alloHCT Clinical trial
or or
Decitabine (if no response, consider single-agent Azacitidine (category 1)
ivosidenib if mDH1) followed by alloHCT or
Decitabine
ine (if no response, (other recommended)
consider single-agent ivosidenib if m/DH1) followed by or
alloHCT Oral decitabine/cedazuridine

or (other recommended)
High-intensity chemotherapy (if no response, consider
single-agent ivosidenib if m/DH1) followed by alloHCT
or
Clinical trial followed by alloHCT

1. NCCN Cinical Practice Guiteines in Oncology. Myelodyspteste Syndromes. Version 3.2024. ps. nee 0r/pofessonaliphyaan_ gs cime od. PeerView

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42. for IDH1m

Phase 1 Study of Ivosidenib in 19 Patients With R/R /DH1m MDS‘

+ CR = 38.9%
* OR = 83.3%
as + + Median DOR was not reached

+ Median OS = ~36 months
Aberrant
=> 9 + ~75% of RBC- and platelet-transfusion—

O 0 A dependent patients achieved TI

1. DNardo G et al Biood Adv. 2028:8 4200-4220, PeerView

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43. Ivosidenib Is a New Op for IDH1m

Phase 1 Study of Ivosidenib in 19 Patients With R/R /DH1m MDS"

Safety Summary From the Early Clinical Experience

Grade 2
diferentaton (A) e

syndrome
(n=2,10.5%) ee

Grade 1 QTe
prolongation
(n= 1; 5.3%)

+ Dosing in MDS: 500 mg orally once daily with or without
food until disease progression or unacceptable toxicity

+ Avoid a high-fat meal

1. ONardo G et al Blood Ad 2028:8 4200-4220, PeerView

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44. Consult Revisited: What if Christine Presented
With TP53m MD:

Presentation Testing Confirms HR MDS Current Treatment
+ Fatigue, pallor, and + 10% blasts + Lack of donor for
SOB + Cytogenetics: HCT (for the

+ Hb: 9 g/dL. 3 abnormalities moment)

. + NGS testing shows a
Platelets: 90,000/mcL TP53 mutation

Discussion
+ Is HMA therapy the SOC for this patient?
+ Would you consider a clinical trial with a venetoclax platform?

+ How would options change if this were RARA overexpressing MDS?
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45. t if Christine Presented

With TP53m

Testing Confirms HR MDS Current Treatment

+ Fatigue, pallor, and + 10% blasts + Lack of donor for
SOB + Cytogenetics: HCT (for the
+ Hb: 9 g/dL. 3 abnormalities moment)

. + NGS testing shows a
Platelets: 90,000/mcL TP53 mutation

Discussion

+ What are the implications of TP53 status for outcomes?
+ Should we wait for a donor before proceeding?

PeerView.com/SZU827

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46. VALIDATE Sheds on TP53m

VALIDATE: Largest Database of MD:
TP53 M ions Treated

tients
ith HMA Therapy!

OS Based on TP53 Mutation and Allelic Status

+ Confirmation that TP53 mutations have a 10

significant negative effect on survival
(but not on response to HMA)

+ No OS differences between monoallelic and
biallelic TP53 mutations

+ Type of HMA monotherapy used does not
affect outcome of these patients TPS3 mutation

— Azacitidine vs decitabine; 0 20 40 60

No TP53 mutation

OS Probability
8 8

Monoallelic

HR for OS = 1.1 (0.9-1.4) N Time, mo
NoTPS?mutaion 358 zu vor 46
à 21 7 19 2
Monoatele 100 5 4 °
alero is 2 s 2
1.Kewan Tt ASH 2023. Abstract 1002. PeerView

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47. Venetoclax + HMA Combina

+ Phase 1b study of 105 patients
with treatment-naive HR MDS"

+ Venetoclax + azacitidine at
the RP2D

— 400 mg orally daily on d 1-14
of each 28-day cycle

+ 34 (31.8%) patients were
deemed eligible

+ Most patients enrolled with
HR MDS, 24% with TP53m

1. Garcia J etal ASH 2023, Abstract 319.

PeerView.com/SZU827

n Is Ac
Including Patients With TP53m Disease

Patients, %

e Against HR MDS.

>80% of Patients Who Received Ven + AZA Responded
100

90 19

MER + HI:

Responses

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48. Venetoclax + Azacitidine Is Associated
Profile in the MDS Setting!

+ SAEs in 73 (68.2%) patients

- Febrile neutropenia in 39 (36.4%) Any TEAE

- Infections in 43 (40.2%) Infections

+ 72 (67.3%) patients experienced atracan
21 TEAE leading to venetoclax "near opera
dose interruption Feb Neutropenia
Anemia

Hypokalemia
Nausea
Constipation
Diarrhea
Vomitng
Fatigue

1. Garcia Jet al. ASH 2023, Abstract 319.

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o

a Manageable Safety

Patients, %

20

40 60

80 100

"AI grades
= Grades 23

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49. The Ong

Venetoclax + Azaci

Venetoclax 400 mg QD (d 1-14/cycle) +

azacitidine 75 mg/m?
(7 d within = 9 calendar d/cycle)

500 patients newly
diagnosed with 1:1
higher-risk MDS

+ Stratification factors: IPSS-R, HCT transplant
eligible versus ineligible, and geographical region
+ Dual primary endpoints: CR and OS

1. Ms chicas govct/shownNCTOS4D1748. PeerView

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50. tal” Oral Therapy in MDS

in 39 Patients With Higher-Risk MDS or CMML*

+ Oral decitabine 35 mg plus
cedazuridine 100 mg on
days 1-5

+ Venetoclax (variable doses of
100-400 mg, days 1-14 ona
28-day cycle)

— ORR of 95%
- 49% of patients proceeded
to HCT
+ Most common grade 3/4 AES: RIIIE
thrombocytopenia (85%), Time Since Treatment, mo
neutropenia (74%), FN (21%) Phase 2 dose established: Oral decitabine 35 mg/cedazuridine
100 mg for 5 days; venetoclax 400 mg for 14 days
*.Bataler At Lancet Hacmato 202411: e186:95. PeerView

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51. Will Assess

Tamibarotene in ND HR MDS With RARA Overexpression‘

Double-blind, placebo-controlled study
90% power to detect a difference in CR rates between experimental and control arms

Study actively enrolling
Sites open/planned in United States, France, United Kingdom, Hungary, Poland, Czechia,
Canada, Israel, Mexico, Italy, Belgium, Germany, Spain, and Austria

Azacitidine IV or SC (days 1-7)

Newly diagnosed patients
with HR MDS with RARA pe =
on tamibarotene PO (days 8-28)
Stratified by IPSS-R risk

and geographic region Azacitidine IV o:

N=190 si
placebo

Primary endpoint: CR rate

Secondary endpoints: OS, ORR (CR, PR, marrow CR and HI, all per modified IWG for MDS), EFS (time to

AML transformation or death), TI, duration of CR, DOR, time to CR, time to initial response, and safety
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1. ps Tasse incauta govlet2/showNCTO4797780.

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52. ymposium Take-Home in LR and HR MDS

+ Molecular profiling has transformed the way we manage MDS

+ At the same time, significant progress has been made in the setting of LR MDS
with anemia

— COMMANDS and 1L approval of luspatercept (with further testing in non-TD
patients ongoing)

— Approval of imetelstat in ESA-failing or ESA-ineligible patients

— What's next—potential combinations? Options for thrombocytopenic patients?
+ HR MDS remains a challenge

— Awaiting results from VERONA

— Progress with HCT and the development of “total” oral therapy

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53. Ask Your =?)
Questions