Striking Back at ALL: Achieving Lasting Benefits with Bispecific Antibodies & MRD-Guided Strategies Across Disease Settings

Chair, Nicholas J. Short, MD, discusses acute lymphoblastic leukemia in this CME/NCPD/CPE/AAPA/IPCE activity titled “Striking Back at ALL: Achieving Lasting Benefits with Bispecific Antibodies & MRD-Guided Strategies Across Disease Settings.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/42QsTDT. CME/NCPD/CPE/AAPA/IPCE credit will be available until May 22, 2025.

1. Striking Back at ALL
Achieving Lasting Benefits With Bispecific
Antibodies & MRD-Guided Strategies Across
Disease Settings

Nicholas J. Short, MD

Associate Professor, Department of Leukemia

The University of Texas MD Anderson Cancer Center
Houston, Texas

2. PeerView.com/XKA827

Our Goals for Today

Increase your understanding of the prognostic and clinical relevance of MRD
assessment in ALL

Augment your knowledge of evidence supporting bispecific antibody platforms in
different ALL treatment settings

Sharpen your skills for developing personalized treatment plans that leverage
MRD assessment and antibody-based treatment in ND and R/R ALL

Enhance your ability to address practical considerations when using bispecific
antibody platforms in ALL, including dosing and safety management

3. Test Your Knowledge and Earn Credit as You Go!

Answer
the baseline
question

for each module
to evaluate
your knowledge
and skills

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Review
the supporting
evidence
and get expert
insights within
the module

Answer the
question again
to demonstrate

what you
have learned

Each correct
answer counts
towards your
post-test
completion

D

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4. Current Placement of Antibody
Platforms in Current Guidelines

Nicholas J. Short, MD

Associate Professor, Department of Leukemia

The University of Texas MD Anderson Cancer Center
Houston, Texas

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

Copyright © 2000-2024, Peerview

5. A Wave of Innovation for Adults With B-ALL'

ember 2021
uly 2017 Sel
July 2014 _ rr,
November 2011 ane. FDA approval in MincHGVD-INO-
MiniHCVD-INO TOWER tal RRALL Bina
:
June 2010 October 2012 October 2020
= oros December 2015 february 2008 ogee rue
cozogamicin (NO) | INOVATE Mar Bina A

March 2011
INO weekly

January 2012
Blinatumomab (Bina) PL
RRALL
Tisagenlecteucel FDA
‘approval in RIR B-

ALL (aged <26 y)

1.Jabbour E etal. J Homato! Oncol. 2023:16:22.

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November 2018
INO

‘adults (218 years) with
RRALL

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6. Despite Progress, More Work Needs to Be Done

Incorporating newer therapeutics into
ALL has improved outcomes in more
i a 4
recent eras for adults with Ph ae = In an NCI study of real-world
FOVAD NO, bine, Of) 2011202 u 40 NR treatment patterns in adult

HOVAD (etuximab), 2000-2011 CR 75

HCVAD, 1992-2000, CC 4 B-ALL based on chart reviews,?

VAD, 1989-1992 g 4 2 25

HCVAD (INO, Blina, Ofa)

08

06

of Survival

+ Over a 2-year period, nearly
50% of patients did not receive
drug therapy for ALL

HCVAD (mean age: 47.8 years)

HCVAD (Rituximab)

+ Substantial heterogeneity in
treatment decisions

0 12 3 4 5 6.7 8 9 1011 12 13 14 15
Time, y

1. Jabbour E ot a. J Homato! Oncol 2028:16:22. 2. Shah $ ot al, ASCO 2019. Abstract 018517.

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7. Antibody Platforms Were First Used in the
Management of R/R B-ALL!

Treatment

a ii N

‘TKI: multiagent therapy or TKI corticosteroid

latón 1 GE
Ci oe =
(AVA & ad mutation ts Ironman ou (EN

Broxucabtagene autoleucel (lowing therapy that has included TK)

anale sans y and wi rainy nue o 2 nes
a es PS)

Molecular e
Ph- B-ALL characterization and Binatumomab (category 1) (Consider HOT}
(AYA & adult) MRD assessment, if not se Conekier HOT
a Intsuma roma
Broxucabtageno autoleucel

‘Tisageniecloucel (patients <26 y and wih refractory disease or 22 relapses)

Multiagent therapy

‘Clinical at
TALL + a
Relapsedireractory regimens
1.NCCN Clinical Practico Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 4 2023, ps tww.ncen org/professionals/physician_gls/plal pa. PeerView.com

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8. Antibody Platforms Are Now Included in
Current Guidelines As Part of 1L Management!

‘Treatment Induction
‘Clinical wal

Pediatric-inspired
regimens (preferred)

Multiagent therapy

Clinical ral
Multiagent therapy

Clinical wa

Multiagent therapy

Palliative
conicostaroid

Consolidation Therapy

E } —+{ O e er“

Consider
‘multiager

continuing
nt therapy,

Blinatumomab

Allogeneic HCT
(especially If highs
features)

1.NCCN Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 4.2023. hitpsutwww.ncen rg/proessionalsphysican optalipat Peer VieW.com

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9. Antibody Platforms Are Now Included in
Current Guidelines As Part of 1L Management!

Systemic Options in Ph- B-ALL
Adult Patients (<65 Years and Without Substantial Comorbidities)
Preferred Regimens

+ ECOG1910: daunorubicin, vincristine, prednisone, and PEG (induction phase
and cyclophosphamide, cytarabine, and 6-MP (induction phase 2) plus
blinatumomab; with rituximab for CD20-positive disease

Other Selective Recommended Regimens

+ Single-agent blinatumomab

+ Hyper-CVAD (with altemating with HD MTX and cytarabine) + blinatumomab; with
rituximab for CD20-positive disease

+ Inotuzumab ozogamicin + mini Hyper-CVAD (with alternating with HD MTX and
cytarabine) + blinatumomab

Maintenance Regimens

+ Weekly methotrexate plus daily 6-MP plus monthly vincristine/prednisone pulses
(duration based on regimen)
+ Blinatumomab* alternating with POMP

+ Binatumomab canbe considered for consoldation patents who are MRO-unavaiable after multogent therapy, or in patents fr whom muiagent thrapy 5
‘conandeated, and fo censoldaton in persatoniraing MRO. ñ
1. NCCN Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 4.2023. htps /www.nccn orgprofessionas/physican_gls/pdlal pat. PeerView.com

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10. Evidence on the Role of
MRD Assessment

Nicholas J. Short, MD

Associate Professor, Department of Leukemia

The University of Texas MD Anderson Cancer Center
Houston, Texas

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

t © 2000-2024, PeerView

11. Converging Roles of the Wider Care Team in ALL

Onboarding and care
coordination; drug
interactions; educating
patients; managing AEs

Assessing patients and

PORTE Hematologist-oncologist

Patient with
ND or R/R ALL

Educating patients and

managing AEs Molecular testing/

MRD assessment

Treatment selection

On-therapy management

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12. Why MRD Assessment Is Important in ALL!

10°.
o 101
=
E 102
More robust 8 MFC.
remissions with 3 an?
=
MRD- status $ a
§ ron |
E 105
2
A nes |
= 10%.
o
Time
—. >
MRD-based MRD-based post-remission monitoring
remission .
1. Short N eta. Am J Hematol 2019:94:257.265. treatment PeerView.com

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13. Recommendations on Current Assessment Techniques!

MRD Assessment Techniques
FDA-approved NGS-based assay
(preferred) The preferred
sample for MRD

| assessment is the

Flow cytometry assays

first small volume

(up to 3 mL) pull
Real-time quantitative PCR | of the bone

marrow aspirate,
if feasible

(RQ-PCR) assays

Reverse transcriptase quantitative PCR |

(RT-qPCR) assays

1.NCCN Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 4.2023. hitpsuiwww.ncen org/prolessioalsphysican ouptalpat Peer View.com

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14. MRD Assessment Techniques:
Weighing the Pros and Cons!

Method Specimen Sensitivity Advantages

Fast
Relatively inexpensive

Potential to detect phenotypic shifts

Does not require access to pretreatment specimens

Flow cytometry
for “difference Fresh viable cells ~104
from normal”

RQ-PCR for IGH + Sensitive
TCR gene DNA ~104to 105 + Well standardized with consensus guidelines
rearrangements + Requires access to pretreatment specimens
RO Tee ter + Sensitive
A04to 105
ESTE RNA 10*to 10° Uses standard primers utilized for diagnostic purposes
fusions
+ Very sensitive
+ Fast (uses consensus primers)
108
Nes DNA Ag + Requires access to pretreatment specimens
+ Potential to track small subclones and clonal evolution
1. Shor N et al. Am J Hematol, 2019,94:257-266. PeerView.com

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15. MRD Assessment Techniques:
Weighing the Pros and Cons!

Method Specimen Disadvantages

* Confounders: increased benign B-cell precursors during
Fk 7 & de
Fons eee OS an marrow recovery; potential phenotypic shifts

+ Requires significant technical expertise

from normal” + Limited standardization (though attempts are in progress)

+ Time-consuming and labor-intensive

RQ-PCR for IGH + Requires significant technical expertise
TCR gene DNA ~104to 105 + May not detect small subclones at diagnosis, thus may
rearrangements miss clonal evolution
+ Expensive
RQ-PCR for
+ Applicable to <50% of ALL cases
A040 105
ESE IO RNA 10*to 10%. Limited standardization
fusions
+ Requires complex bioinformatics
Ns DNA -108 + Minimal clinical validation
+ Expensive
1. Shor N et al. Am J Hematol, 2019,94:257-266. PeerView.com

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16. MRD Monitoring Principles Include Assessments
After Induction and Post-Consolidation!

ming of MRD Assessment in AL u ds
TIE increased in patients with
molecular relapse or
——j Upon completion of initial induction persistent low-level
disease burden

End of consolidation | w For some techniques, a

baseline sample (ie, prior
to treatment) is needed to
characterize the leukemic
clone for subsequent MRD
assessment

Additional time points should be guided
by the regimen used and risk features

1. NCCN Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia, Version 4.2023. htps/www.necn orgprofessionals/physican_ols/pdtal pd. PeerView.com

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17. Illustrating Timepoints for MRD Assessment in Ph- B-ALL!

Treatment Induction

‘Clinical wal
Pedlatric-inspired
regimens (preferred)

Multiagent therapy

Clinical ral

Mutagen therapy

‘Clinical wal
Multiagent therapy

Persistent
rising MRO.

Consolidation Therapy +
}—{sinstumonst HL “sten

Repeat

‘MRD
assessment

Consider allgene HET
(especialy ini
teatro)

‘multiagent therapy,

Allogeneic HCT
(especially If high-k
features)

Patatve
conicosteroid
1.NCCN Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 4 2023. hitpstwww.ncen org/professionals/physician_gls/plal pa. PeerView.com

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18. Choosing Next Steps Based on
Rising MRD Status Post-Remission

Nicholas J. Short, MD

Associate Professor, Department of Leukemia

The University of Texas MD Anderson Cancer Center
Houston, Texas

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

Copyright © 2000-2024, PeerView

19. A Patient With B-ALL and Persistent MRD+ Disease

Robert, a 55-year-old male, presents with Ph- B-ALL and PS of 1

Treatment History

Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin,
and dexamethasone, alternating with HD MTX and cytarabine)
After 4 cycles of therapy, NGS MRD shows 0.2% and 2,000 residual

sequences per million

« What are the options for Robert? No additional treatment?
+ Is treatment recommended based on MRD status?

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20. Antibody Platforms Are Included in
Current Guidelines for the Management of Ph- B-ALL1

Consolidation Therapy

‘Treatment Induction

‘Clinical war

Pediatric-inspired
rogimens preferred)

Multiagent therapy

Clinical ral

Mutagen therapy

‘Clinical wal

Multiagent therapy

Palliative
coricosteroid

1.NCCN Clinical Pracice Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 4 2023. hitpsitww.ncen org/professionals/physician_gls/plal pa. PeerView.com

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21. BLAST: Assessed Blinatumomab in MRD+ ALL!

116 patients with ALL in

CR but MRD 20.1% after Aragon

23 intensive courses; 15 mcg/m?/d x 4 weeks
35% in 2CRD2 every 6 weeks x 4

+ Primary endpoint: complete MRD response status after 1 cycle of blinatumomab

Among adults with MRD+ ALL in hematologic remission after
chemotherapy, 78% achieved a complete MRD response with blinatumomab
(evaluable N = 113)

1. GokbugetN et al. Blood. 2018.131:1522-1591. PeerView.com

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22. BLAST: Overall Survival!

MRD Complete Responder at C; MRD Nonresponder at Cycle 1
(n= 85) (n= 22)

Median OS: 38.9 mo (95% Cl, 33.7-NR) Median OS: 12.5 mo (95% Cl, 3.2-NR)
HR = 2.63 (95% Cl, 1.40-4.96); P = .002

10

08
Hil Hr:

==, __ MRD complete responder at cycle 1

06
Io

04

2
3
3
2
a
Q
°

02 MRD nonresponder at cycle 1

0 3 6 8 12 15 18 A ZA 2 HR 36 39 42 4 4 Si 5
Study Month (Landmark Analysis Beginning at Study Day 45)

8 82 78 74 69 66 43 41 31 3 2 20 0 8 3 3 3 1 0

MRO nonresponder
pepa 27 4 2 1 0 6 6 6 6 4 4 1 1 1 1 «0 0 0

Complete MRD response after blinatumomab treatment was associated with
significantly improved OS

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1. GokbugetN ot al. Blood. 201

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23. BLAST: Final Analysis Suggests Complete MRD
Response During Blinatumomab Treatment Can Be Curative’

All Patients All Patients by MRD Response
“ 10
09 >
Eo Z os No (n=23)
207 =. NR (29.5-NR) 14.4 mo (3832.3)
3 307
2% © 06
& 05 © 05 ves
zo Boa
-2 03 À Median survival 36.5 mo (95% Cl, 22.0-NR) Z 03
& 02 À Median follow-up for survival was 59.8 mo (5 y) 802
Y) 0.1 4 Estimated 5-y survival: 43% overall (95% Cl, 34-52) a 01
o 0
O 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66
Time, mo Time, mo
ans ye ome wo SO Si 4 4 4 4 1 0
oe on ee ew ow wo Ye M FS ® mM te 4% 4 4 1 0
Estimated 5-y survival for complete MRD responders:
50% (95% Cl, 39-60); P= .002
1. GokbugetN etal. Louk Lymphoma, 2020,61:2665-2673. PeerView.com

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24. BLAST: While Post-Blinatumomab HCT May Be Beneficial,
Long-Term Survival Without HCT Is Possible!

400 All Patients

ge MHCT in CCR (N=74) — "No HOT in CCR (n =36)

5 80 722
32
£2 60
35
3% w = 35
SE 194 2
gu 20
as Ea

of
Alive Without Relapse Died Without Relapse Relapsed
05 Complete MRD Responders

8% MHCT in CCR (n=61) — "No HCT in CCR (n =23)

5 8
E 009
£2 60
32 459
25 40 204 328
sE 20 213
2a $
as .

of
Alive Without Relapse Died Without Relapse Relapsed
1. GokbugetN eta, Leuk Lymphoma, 2020.61:2665-2673. PeerView.com

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25. Choosing Consolidation Therapy
Based on MRD Status

Nicholas J. Short, MD

Associate Professor, Department of Leukemia

The University of Texas MD Anderson Cancer Center
Houston, Texas

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

t © 2000-2024, PeerView

26. A Patient With B-ALL and MRD- Status After
Upfront Therapy

Robert, a 55-year-old male, presents with Ph- B-ALL and PS of 1

Treatment history

+ Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin,
and dexamethasone, alternating with HD MTX and cytarabine)

+ After 4 cycles of therapy, assessment by flow cytometry shows MRD- status
(<0.01%)

+ What are the options for Robert? No additional treatment?

+ Another course of chemotherapy? Add blinatumomab?

+ In this case, adding blinatumomab is supported by recent evidence (E1910)
and other trials adding blinatumomab to hyper-CVAD

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27. E1910: Randomized Phase 3 Trial Combining Blinatumomab
With Chemotherapy in Adult Frontline ALL!

Blood/marrow transplant

I MRD+

Blinatumomab
yl

Induction ith a

Register

chemotherapy
2 cytes, flowed by Consolidation tx Maint
i 3 laintenance
Swkrestpered | | intensification en,

chemotherapy
1 cycle

Register

Discontinue intensification tx
study ifno CR

or CRi

Consolidation tx
4 cycles chemotherapy

Randomize

Blood/marrow transplant
Hf suitable donor and

recommended

+» Accrual = 488

+ US intergroup study

+ n= 265/360 (509) patients
+ USA, Canada, Israel

1. hitpsficinicatrials goviet2/showNCT02003222. PeerView.com

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28. E1910: Improvement in OS With the Addition of
Blinatumomab to Consolidation Chemotherapy!

OS Comparison: MRD- Patients

Blina +
Chemo HR
ean (m=113 ec) P

10

09 Log-ranked P = 003

Blina + chemo Median Smo NR
3 + 3.6-y 0S, % 83 65 0.42 003
2 os + Deaths, n 17 39 (0.24-0.75) *
E + CNSR 95 73
= 05
204 0.46
= Median RFS, mo NR 224 (0.27-0.78) 004
503
3

02

01

0

0 10 2 30 0 So 60 70 80 So
Time From Step 3 Randomization, mo

+ Pena 2n= 8 secondary to ALL, n= 9NRM. ‘n= 20 seco = 7 NRM, n= 2 unknown '
AD tar ASH 2022 ÓN “ PeerView.com

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29. E1910: Blinatumomab Also Demonstrated
Benefit in MRD+ Patients!

OS Comparison: MRD+ Patients Blina+ — chemo HR
Chemo = Y 2
(red) (M=22) (95%C)
10 Median OS, mo NR a
pa a [at

08
07
06
05
04
03
02
04

¿ Tr A re +++ Blina + chemo

Chemo

Survival Probability

o 10 20 30 40 50 60 70 80 90

Time From Step 3 Randomization, mo
2 6 ALL. n= 1 NRM n = 3 Unknown. n = 7 ALL. n= 6 NR. ñ
1. Lizow Met al. ASH 2022. Abstract LBA PeerView.com

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30. E1910: Receiving 4 Cycles of Blinatumomab
Improved OS Outcomes!

10

10
09 08 rag
208 208
5 Biinatumomab = Blnatumomab
3 tor2oyces 3 07 1 or 2 cycles
Bos 308
Los Control & os
304 304
Bos Total Fall CNSR Mediano Spy Total Fall CNSR Mediano
Bina torzeyden 40 10 El - 2 Bmetorzoces 40 10 30 -
02 À conta 103 E 6 > 02 7 pines cycios ss 5 se -
04 04
HR 0.72, 95% C10.35-1.45; P=.36 HR: 0.29, 95% CI, 0.10-0.86; P = .017
0 o
0 10 20 30 40 50 60 70 8 90 0 10 20 30 40 50 60 70 80 90
Time From 9-Month Post-Step 3 Randomization, mo Time From 9-Month Post-Step 3 Randomization, mo
1 Luger Seta ASH 2023, Abstract 2877. PeerView.com

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31. Combination of Hyper-CVAD + Blinatumomab
Has Been Assessed in Patients With Ph- ALL’

Intensive Phase Blinatumomab Phase

I I I (| | I | I “After 2 cycles of chemo for MRD+, Ho-Tr, Ph-like, TP53, t(4;11)

4wk = 2wk
Maintenance Phase

ES Hyper-cvan EN ofatumumab or rituximab [EJ Biinatumomab

MTX + Ara-C BEE ty mix ra-c x8 POMP

1. Short NJ e a. EHA 2023. Abstract POSS. PeerView.com

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32. Encouraging Long-Term Survival
With Hyper-CVAD + Blinatumomab Combination!

Outcomes by MRD Status

Survival Outcomes
With a median follow-up

10 ve
of 37 months, estimated 1 nié
2” 3-year RFS was 73%! #
go go
g E Total Events 94 RES, % (95% C
2] total Events 39RS % (95%) 25 | negara 25 4 mm
¿LR mes s0(15:8)
o
EE CE 5 2 EEE à ® À
Time Since Response, mo No. at Risk Time, mo
No ko. Censored Moe so 8 1 0
ONO 250 nun 909 209 om O
100
100 Negative
»
75 ®
® 807
go g toto 3928
25] total Even 305% 105% mien 253 were
se 81659) Posie 8 2 75626)
0 2 24 3% 4 6 72 u.
0 2 2, a © © nr
Time Since Start of Therapy, mo
ata mn = mo ee 3
SO RO 20 1009100 san 060 ne Zu Ze 1 5 à
1. Jabbour E et al. Lancot Hematol 2022:9:0878-0885. PeerView.com

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33. Updates on Antibody
Combination Platforms

Nicholas J. Short, MD

Associate Professor, Department of Leukemia

The University of Texas MD Anderson Cancer Center
Houston, Texas

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

t © 2000-2024, PeerView

34. Multiple Assessments of Newer Combinations
With Blina and/or INO in Older Adults With B-ALL

Median Age, 5 MRD ö
Reference (Regimen) N y [range] CRICRi, % Negativity, % OS, %
Advani A et al. 20221 37
(SWOG 1318: blina + Pomp) | 22 | 75 [66-84] | se 22 (3-year)
Gökbuget N et al. 20232 67
(GMALL-Bold: blina + chemo)| 5° | 66 [56-76] | 85 82 (3-year)
1. Advani A etal. J Cin Oncol. 2022:40:1874-1582. 2. Gökbuget N et al. Blood. 2023:142(auppl 1964. PeerView.com

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35. Multiple Assessments of Newer Combinations
With Blina and/or INO in Older Adults With B-ALL

A Median Age, 5 MRD
Reference (Regimen) N y [range] CR/Cri, % Negativity, % OS, %
Chevallier P et al. 20221 54
(EWALL-INO: INO + chemo) | 191 | 68 [55-84] 90) 81 (2-year)
Stelljes M et al. 20242 73
(INITIAL-1: INO +chemo) | 43 | 94 [56-80] 100 A (3-year)
Event-Free Survival® Overall Survival®

INO-based induction followed by
age-adapted chemotherapy was
— well tolerated and resulted in high —>
rates of remission and OS

EFS Probability

METTELLIIT)
Follow-Up Duration, mo

UEITELZIIT)

no sax FOUOW-Up Duration, mo a
Bonunaumosıo

Blue nos aro Kaplan Moir estimates and orange dashed ines ae 95% Ci eee ee A u
Chevalier tal 80d. 2021888112 tes Metal Cin Oncol 202442273282 PeerView.com

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36. Multiple Assessments of Newer Combinations
With Blina and/or INO in Older Adults With B-ALL

= Median Age, | CR/CRi, MRD
Reference (Regimen) N y [range] % Negativity, % OS, %
Jabbour E et al. 20231 46
(mini-hyper-CVD + INO + blina) | 8°} 68 [60-87] 99 94 (5-year)
Wieduwilt M et al. 20232 NR 84
(Alliance A041703: INO + blina) | 33 | 7 160-841 | 96 (1-year)
1. Jabbour E et al. Lancet Haematol, 2023;10:0433-0444. 2. Wieduwit M etal. Hemasphere. 2023. 7(Suppi}: 6088387. PeerView.com

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37. Dasatinib + Blinatumomab for Ph+ ALL in Adults!

+ Phase 2 study of first- ner CNS —
line therapy in adults prophylaxis
with newly diagnosed Dasatinib + steroids
Ph+ ALL (no upper
age limit) Response evaluation (d 85)

“N u = | CHR+ CHR but = ER

+ Primary endpoint: CMR. no CMR
molecular response
(CMR + PNQ) after Blinatumomab 28 mcg for 2 cycles (max: 5 cycles) +
2 cycles of dasatinib

blinatumomab

Molecular response (CMR + PNQ)
after 2 cycles of blinatumomab

1. Foa Rot al. N Engl J Med. 2020,389:1613-1623. PeerView.com

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38. Dasatinib + Blinatumomab for Ph+ ALL in Adults!

Overall Survival

Efficacy Results!
CR in 98% of patients

MR of 29% at the end of dasatinib induction

(day 85); this increased to 60% after 2 cycles 5 la > a
of blinatumomab hom © © e »
After median follow-up of 18 months, OS was Dios Survival
95% and DFS was 88%

Lower DFS among patients with /KZF1
deletion plus additional genetic aberrations
(CDKN2A or CDKN2B, PAX5, or both)

3

Patients Who Were Alive
‘Without Disease, %
a 8

° y = ” 2
Time Since Complete Hematologic Response (Day 85)
Nash 62 ss ” 7

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1. Foa Rot al. N Engl J Med. 2020:383:1613-1623.

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39. Ponatinib + Blinatumomab for Ph+ ALL!

Induction Phase Consolidation Phase (C2-C5)
30 mg mg (if in CMR)
4 weeks 2 weeks

Maintenance Phase

|__| |_| || EJ

Ponatinib 30 mg Ponatinib 15 mg Blinatumomab IT MTX / Ara-C x 12

1. Short NJ et a. EHA 2023, Abstract 118 PeerView.com

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40. Ponatinib + Blinatumomab in Ph+ ALL:
Survival Outcomes’

Median follow-up: 16 months (range, 1-58+)
Event-Free Survival Overall Survival

EFS, %

» Total Events _ModianEFS 2yEFS,% Events __ Modan OS 2y05,%
60 7 NR 79 NR

No. at Risk
60

“es 7 7 0 8 7 3 4 0

Only 2 patients transplanted to date .
1. Shon NJ et al. EHA 2023. Abstract $118 PeerView.com

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41. Practical Aspects of Therapy With
Antibody Platforms in ALL

Nicholas J. Short, MD

Associate Professor, Department of Leukemia

The University of Texas MD Anderson Cancer Center
Houston, Texas

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

42. What Are the Practical Aspects of
Therapy With Antibody Platforms?

Blinatumomab Dosing by Weight and Schedule’

Dosing for consolidation cycles 2-4

Cych Patients Weighing 245 kg Patients Weighing <45 kg
ye (Fixed Dose) (BSA-Based Dose)
Dosing for induction cycle 1
15 mcg/m?/day
Days 1-28 28 meg/day (not to exceed 28 mcg/day)
Days 29-42 14-day treatment-free interval 14-day treatment-free interval

15 mcg/m?/day
Days 1-28 28 mog/day (not to exceed 28 mcg/day)
Days 29-42 14-day treatment-free interval 14-day treatment-free interval

Hospitalization is recommended for the first 9 days of cycle 1 and the first 2 days of cycle 2

+ Premedicate with dexamethasone

1. Binono (binatumomab) Preserbing information, ps angen com-media/Proje/Amgen’Repostoryip+amgen-comlneyiatincyto_pihep_engisheat. PeerView.com

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43. Adverse Events Reported
With Blinatumomab in Major Trials (TOWER)!

Blinatumomab Treated SOC Treated
(n = 267) 09)
Any AE, n (%) 263 (99) 108 (99)
Any grade 3 AE 98 (37) 33 (30)
Any grade 4 AE 82 (31) 48 (44)
Any grade 5/fatal AE 51 (19) 19 (17)
Grade 5 infection 30 (11) 13 (12)
Grade 23 AE of interest, n (%)
Neutropenia 101 (38) 63 (58)
Infection 91 (34) 57 (52)
Neurologic event 25 (9) 9 (8)
Cytokine release syndrome 13 (5) 0 (0)

+ Events occurred up to 30 days after last dose of protocol-specified therapy or before ASCT
1. antarian H et al. N Engl J Med. 2017:376:836-847. PeerView.com

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44. Principles for Managing Higher-Grade CRS for
Patients Treated With Blinatumomab

Management of grade 3 CRS is based on treatment holds and use of steroids

Patients Weighing 245 kg Patients Weighing <45 kg

+ Interrupt treatment

+ Administer dexamethasone 5 mg/m?
(max 8 mg) every 8 hours IV or orally
for up to 3 days

« Taper thereafter over 4 days

+ When CRS is resolved, restart at

5 mcg/m2/day, and escalate to

15 mcg/m?/day after 7 days if CRS

does not recur

+ Interrupt treatment

+ Administer dexamethasone 8 mg
every 8 hours IV or orally for up to
3 days

+ Taper thereafter over 4 days

+ When CRS is resolved, restart at

9 mcg/day, and escalate to

28 mcg/day after 7 days if CRS

does not recur

+ For grade 4 CRS, discontinue treatment and administer dexamethasone as
instructed for grade 3 CRS

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45. What Are the Practical Aspects of
Therapy With Antibody Platforms?

Inotuzumab Dosing for Cycle 1 and Subsequent Cycles (Response Based)!

Day 1 Day 8 Day 15
Dosing regimen for cycle 1

0.5 mg/m?

0.8 mg/m? 0.5 mg/m?

Cycle length 21 days"
Dosing regimen for subsequent cycles depending on response to treatment

Patients who have achieved a CR or CRi
Dose 0.5 mg/m? 0.5 mg/m? 0.5 mg/m?
Cycle length 28 days
Patients who have not achieved a CR
or CRi 2 2 2
Eire. 0.8 mg/m 0.5 mg/m 0.5 mg/m
Cycle length 28 days

* Premedicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions

1. Besponsa (inotuzumab ozogamicin) Prescribing Information. hips abeling pizer com Shot abelng aspxió=9503. PeerView.com

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46. Prevention of INO-Associated SOS/VOD'

» Proper selection of patients for INO
- Avoid INO in patients with severe underlying hepatic
dysfunction
« Limit INO to 2 cycles, when feasible
- Recommendation is based on standard dosing

(cumulative dose of 3.6 mg/m? after 2 cycles)
* Consider ursodiol prophylaxis (300 mg 3 x d) for all
patients while receiving INO
- Recommended by consensus guidelines but little
evidence-based data

1. Kebriae Petal. Bone Marrow Transplant. 2018:53:449-456. PeerView.com

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47. INO-Associated SOS/VOD12

* Occurs in 10%-15% of patients treated with INO
(20%-25% after HCT)
Early and rapid diagnosis is key to improving outcomes
Treatment (as with SOS/VOD from other causes)

- Discontinue INO
Diuretics
Hemodialysis (if indicated)
Defibrotide is the only approved agent in the US for
treatment of VOD/SOS

1. Kantarian H et al. N Eng J Med. 2016:375:740:753.2. Kantarjan H et el. Lancet Haematol. 2017.4:0387-398. PeerView.com

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48. Management of Other INO-Related Adverse Events!

* Cytopenias or neutropenic fever
- Dose reduction/interruptions as needed
- G-CSF if ANC <1K

+ Hepatotoxicity

- Dose reduction/interruptions as needed
- Rule out SOS/VOD
« Infusion reactions (rare)
- Prevent with corticosteroids, antipyretics, and
antihistamine

1.Kobraei P et a. Bone Morrow Transplant. 2018:53:449-456. PeerView.com

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49. Final Take-Homes

« Blinatumomab and inotuzumab ozogamicin are FDA
approved in R/R ALL and are being used widely across
disease settings

+ Understanding the toxicities associated with these two
agents is important to ensure prevention and
management of AEs

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