Acute Myelogenous Leukemia: Biology, Treatment, and Opportunities for

Novel Therapies

Gary J. Schiller, M.D., F.A.C.P.

Professor of Medicine

Director

Hematological Malignancies / Stem Cell Transplant Program

David Geffen School of Medicine at UCLA

A Static Therapeutic Landscape

• Statistical hazards in evaluating new

interventions in a molecularly diverse disease

• Limitations on the regulatory definition of

response and survival

• Limitations in the pathway toward approval of

novel agents

• Strategies to overcome limitations may require

new definitions of disease and response

AML Incidence Increases and Survival

Decreases With Age• Median patient age and age at diagnosis is 66 years, and incidence increases with age1,2

1. AML guide 2014. American Cancer Society website. http://www.cancer.org/cancer/leukemia-acutemyeloidaml/detailedguide/index. Accessed 05/05/14.

2. NCCN clinical practice guidelines in oncology: acute myeloid leukemia. National Comprehensive Cancer Network website. V.2.2014.

http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf. Accessed 05/05/14. 3. Facts: Spring 2014. Leukemia and Lymphoma Society website. 2014:10.

http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/

pdf/facts.pdf. Accessed 05/05/14. 4. Acute myeloid leukemia. Leukemia and Lymphoma Society website. 2011:28.

http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/leukemia/pdf/aml.pdf. Accessed 05/05/14.

0

2

4

6

8

10

12

14

16

18

20

22

24

<1 1-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Incid

en

ce P

er 1

00,0

00

Age-Specific Incidence Rates for AML, 2006-20103

Age, Years

1.60.9 0.4 0.7 0.9 1.0 1.1 1.3 1.6 1.8

2.53.3

4.3

6.6

10.0

14.6

20.0

23.323.5

0

10

20

30

40

50

60

<45 45-54 55-64 65-74 >75

AML 5-year survival rates (2001-2007)

Acute Myelogenous Leukemia

• A biologically distinct subset of disease

attributed to accumulated molecular drivers of

proliferation and survival

• A clinically distinct subset of patients

• A reproducible profile of cytogenetic,

molecular, and clinical features that can be used

to define risk and identify a pathway to drug

approval

What Defines High-Risk Acute

Myelogenous Leukemia?

• Clinical Variables

– Antecedent hematologic disturbance

– Advanced age at presentation

– Leukocytosis at presentation

– Male gender

– Elevated LDH at presentation

What Defines High-Risk Acute

Myelogenous Leukemia? cont’d…

• Biologic Variables

– Adverse Cytogenetics

• Monosomies

• Complex (≥ 3) abnormalities

• inv(3), t(3;3), t(6;9), t(6;11), t(9;22), 17p

– Less-certain adverse cytogenetic features

• 11q23

• Alterations in gene expression, splicesome variants, lnc

RNA

AML

Functional Types of Mutations Observed

in Acute Myeloid Leukemia

• Myeloid Transcription Factors– CEBPA, RUNX-1

• Fusion Genes– PML-RARA, MYH11-CBFB, RUNX1-RUNX1T1

• DNA Methylation– DNMT3A, TET2, IDH1/2

• Chromatic Modification– MLL, ASXL1, EZH2, PHF6, BCOR

AML

Functional Types of Mutations Observed

in Acute Myeloid Leukemia (continued)

• Cohesins– SUC1A, STAG1/2

• Spliceosome genes– SF3B1, SRSF2, U2AF1, RSR-2

• Signal Transduction Genes– FLT3, NRAS, c-KIT, CBL

• Tumor Suppressor Genes– TP53, WT1, PHF6, NPM1

These mutations are associated with clonal

proliferation and/or absence of differentiation

Mutational Profiling Improves

Risk-Stratification in AML• Particularly useful for patients whose disease is

characterized by intermediate-risk cytogenetics

– Favorable Mutation Profile

• NPM1 and IDH1/2 positive

• FLT3-ITD negative

– Unfavorable Mutation Profile

• TET2, MLL-PTD, ASXL1, PHF6 mutated

• FLT3-ITD positive and above

– Intermediate Mutation Profile• FLT3-ITD positive without MLL. TET2, DNMT3A, +8, CEBPA

AML

Common Mutations in AML

• FLT3 Mutations

– Internal Tandem Duplication,

– Tyrosine Kinase Domain

• NPM1 Mutations

– Often associated with FLT3-ITD, DNMT3A,

TET2 and IDH mutations.

Common Mutations in AML

• IDH1 + IDH2 Mutations

– More common in normal karyotype AML

– May adversely affect outcome in setting of

NPM1 mutations

– Some mutations (R172) much more adverse

– Present in 6-9% (IDH1) and 8-12% (IDH2)

of patients

Methods of Identifying Common

Mutations in Acute Myeloid Leukemia

• Polymerase Chain Reaction (PCR)

– Useful for FLT3, IDH1/2, NPM1

– Not useful for CEBPA, DNMT3A, KIT

• DNA Sequencing

– Requires time, defining a panel for profiling,

defining allelic burden

Routine Evaluation of AML for the

Purpose of Risk-Stratification• STANDARD: Morphology

Flow Cytometry / Immunohistochemistry

F.I.S.H. for common abnormalities:

t(8;21) RUNX1-RUNX1T1

inv(16) or t(16;16) CBFβ-MYH11

t(15:17) PML-RARα

t(9;11) MLLT3-MLL

inv(3) or t(3;3) RPN1-EVI 1

Karyotype

Molecular Studies for mutations in flt3, NPM-1, Kit, CEBPα

• USEFUL: Molecular studies for mutations in DNMT3a, TET2,

MLL, IDH1, IDH2, WT1, ASXL1 (marker of 2o

AML?),

• INVESTIGATIONAL: Molecular studies for mutations in PHF6,

BCOR, CEBPε

Cytogenetic and Molecular Findings Characteristic of

Newly-Diagnosed High-Risk AML

• Cytogenetic Classification

– Intermediate Risk

• Normal

• +8

– Unfavorable Risk

• -5/-7

• 11q23

• 20q-

• ≥ 3 abnormalities

– Favorable-Risk

• t(8;21)

• inv(16) or t(16;16)

• Mutation

– flt3 ITD

– Mutant TET2, MLL-PTD,

DNMT3a, ASXL1, PHF6

– Kit

– CEBPa

Further Clinical Features Associated with

High-Risk AML

• Impaired performance status

• Co-morbid medical conditions

• Disease refractory to conventional induction

• Disease refractory to HMA therapy

• Disease relapsed after

– allogeneic hematopoietic progenitor cell transplant

– recent completion of consolidation chemotherapy

Treatment Strategies for AML

• Dose-Intensification

• Re-packaging of Cytotoxic

Chemotherapy- Pharmacologic

Approaches

• Immune-based Therapy

– Allogeneic Transplantation

• Targeted Therapy

Treatment Strategies for the

Management of High-Risk AML

• Dose-intensified induction chemotherapy

Author Patient

Characteristics

Dose Follow-Up Rate of CR DFS OS

Fernandez,

et al.

n = 657

age = 17-

60

45DNR

vs. 90

DNR

23.7 vs.

15.7m

57.3%

70.6%

15.7m

23.7m

Lowenberg

et al.

Burnett

et al.

Luskin, et

al. (2016)

n = 813

age 60-83

N=1206

n= 657

45 DNR

vs. 90

DNR

60DNR vs.

90DNR

45 DNR

vs. 90

DNR

40m

80.1 m

54%

64%

84%

81%

26% at 2y

31% at 2y

50% at 2y

52% at 2y

16.6m vs. 25.4 m

HR 0.74

Dose-Intensified Induction Chemotherapy

for AML

• No significant survival benefit for AML with flt3 ITD or MLL-

PTD. Unclear whether 60 mg/sq.m. is equivalent to 90.

• Survival advantage originally in favor of higher-dose DNR

among those younger pts with intermediate- and favorable-risk

cytogenetics, not among those with unfavorable-risk karyotype

in ECOG study, although further follow-up showed benefit. Still

no benefit for older patients.

• Greatest benefit in the HOVON/AMLSG/SAKK for high-dose

DNR achieved in patients age of 60-65, and for patients with

CBF leukemia

• No benefit was seen in patients with AML characterized by

“very unfavorable” karyotype in the early iteration of ECOG

trial, but current update showed benefit on multivariate analysis

Other Dose-Intensification Strategies

• Cytarabine

• Mitoxantrone and Etoposide

• Autologous transplantation

• Other ways to deliver chemotherapy

– Liposomal particles

– Novel cytotoxic chemotherapy

Analysis of Efficacy by Age for Patients Aged 60–75

With Untreated Secondary Acute Myeloid Leukemia

(AML) Treated With CPX-351 Liposome Injection

Versus Conventional Cytarabine and Daunorubicin

in a Phase III Trial

Bruno C. Medeiros,1 Jeffrey E. Lancet,2 Jorge E. Cortes,3 Laura F. Newell,4 Tara

L. Lin,5 Ellen K. Ritchie,6 Robert K. Stuart,7 Stephen A. Strickland,8 Donna

Hogge,9

Scott R. Solomon,10 Richard M. Stone,11 Dale L. Bixby,12 Jonathan E. Kolitz,13

Gary J. Schiller,14 Matthew J. Wieduwilt,15 Daniel H. Ryan,16 Antje Hoering,17

Michael Chiarella,18 Arthur C. Louie,18 Geoffrey L. Uy19

1Stanford University School of Medicine, Stanford, CA; 2H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 3MD Anderson Cancer Center, Houston, TX; 4Oregon Health & Science University, Portland, OR; 5University of Kansas Medical Center, Kansas City, KS; 6Weill Cornell Medical College of Cornell University, New

York, NY; 7Hollings Cancer Center Medical University of South Carolina, Charleston, SC; 8Vanderbilt-Ingram Cancer Center, Nashville, TN; 9Gordon and Leslie Diamond Health Care Centre, Vancouver, BC, Canada; 10BMT Group of Georgia, Atlanta, GA; 11Dana-Farber Cancer Institute, Boston, MA; 12Comprehensive Cancer Center, University of Michigan, Grass Lake, MI; 13Monter Cancer Center, Northwell Health System, Lake Success, NY; 14David Geffen School of Medicine/UCLA, Los

Angeles, CA; 15University of California, San Diego, San Diego, CA; 16University of Rochester, Rochester, NY; 17Cancer Research and Biostatistics, Seattle, WA; 18Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc,

Ewing, NJ; 19Washington University School of Medicine, St Louis, MO

58th ASH Annual Meeting & Exposition; December 3–6, 2016; San Diego, CA

CPX-351 Phase III Study Design

• Randomized, open-label, parallel-arm, standard therapy–

controlled

– 1:1 randomization

Key Eligibility

• Previously

untreated

• Ages 60–75

• Able to tolerate

intensive therapy

• ECOG PS 0–2

Stratifications:

• Therapy-related AML

• AML with history of MDS

with and without prior

HMA therapy

• AML with history of CMML

• De novo AML with MDS karyotype

• 60–69 years

• 70–75 years

Induction(1–2 cycles)

Patients in

CR or CRi:

Consolidation(1–2 cycles)

Follow-up:

• Death

OR

• 5 years

CPX-351 (n=153)

7+3 (n=156)

AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; CR, complete response; CRi, CR with incomplete platelet/neutrophil recovery; ECOG

PS, Eastern Cooperative Oncology Group performance status; HMA, hypomethylating agents; MDS, myelodysplastic syndrome.

1. World Health Organization. WHO Classification of Tumours of Haematopoitic and Lymphoid Tissues. Swerdlow S et al (ed). Lyon, IRAC Press, 2008.24

CPX-351

• CPX-351 is a liposomal formulation of cytarabine and

daunorubicin

encapsulated at a 5:1 molar ratio

– Fixed molar ratio maintained in

human plasma for at least

24 hours after final dose1

– Drug exposure maintained for 7 days1

– Selective uptake by leukemic vs

normal cells in bone marrow of

leukemia-bearing mice2

1. Feldman EJ et al. J Clin Oncol. 2011;29(8):979–985; 2. Lim WS et al. Leuk Res. 2010;34(9):1245–1223.

Reprinted with permission. © 2011 American Society of Clinical Oncology. All rights reserved. Feldman EJ et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol. 2011;29(8):979–985.

25

Safety Profile

26

EventsMedDRA Preferred

Term

60–69 70–75

CPX-351n=96n (%)

7+3n=102n (%)

CPX-351n=57n (%)

7+3n=54n (%)

Any grade 3–4 AE 85 (89) 91 (93) 50 (88) 45 (85)

Any serious AE* 49 (51) 36 (37) 22 (39) 22 (42)

Febrile neutropenia 7 (7.3) 5 (5.1) 4 (7.0) 3 (5.7)

Sepsis 6 (6.3) 2 (2.0) 2 (3.5) 2 (3.8)

Respiratory failure 4 (4.2) 7 (7.1) 3 (5.3) 1 (1.9)

Acute respiratory failure 4 (4.2) 1 (1.0) 1 (1.8) 2 (3.8)

Ejection fraction decreased

3 (3.1) 5 (5.1) 3 (5.3) 1 (1.9)

Pneumonia 3 (3.1) 3 (3.1) 3 (5.3) 1 (1.9)

Disease progression 1 (1.0) 3 (3.1) 1 (1.8) 1 (1.9)

Hypoxia 1 (1.0) 3 (3.1) 1 (1.8) 0

Pulmonary edema 0 1 (1.0) 1 (1.8) 2 (3.8)

Any AE resulting in death 8 (8.3) 11 (11) 6 (11) 11 (21)*Specific serious AEs occurring in ≥2% of patients in either age group are listed. MedDRA, Medical Dictionary for Regulatory Activities.

• Grade 3–4 AEs and AEs resulting in death were generally similar between arms

– Differences in infection and bleeding events were associated with delayed recovery from myelosuppression in the CPX-351 arm

Improved Response with CPX-351• Improved overall response with CPX-351 in both age groups

• In the 70–75 age group, the allogeneic transplant rate was

significantly higher in the CPX-351 arm

27

Variable

CPX-351

n (%)

7+3

n (%)

Odds Ratio

(95% CI)

Age 60–69 n=96 n=102

CR+CRi 48 (50.0) 37 (36.3) 1.76 (1.00, 3.10)

CR 38 (39.6) 27 (26.5) 1.82 (1.00, 3.32)

CRi 10 (10.4) 10 (9.8) NC

No response 48 (50.0) 65 (63.7) NC

Allogeneic transplant rate 36 (37.5) 33* (32.4) 1.25 (0.70, 2.25)

Age 70–75 n=57 n=54

CR+CRi 25 (43.9) 15 (27.8) 2.03 (0.92, 4.49)

CR 19 (33.3) 13 (24.1) 1.58 (0.69, 3.62)

CRi 6 (10.5) 2 (3.7) NC

No response 32 (56.1) 39 (72.2) NC

Allogeneic transplant rate 16 (28.1) 6 (11.1) 3.12 (1.12, 8.72)*Intent-to-treat population. CR, complete response; CRi, CR with incomplete platelet/neutrophil recovery; NC, not calculable.

Exploratory Analysis by Age:

Overall Survival

28

• Age 60–69 years, hazard ratio of 0.68 (95% CI: 0.49, 0.95)

• Age 70–75 years, hazard ratio of 0.55 (95% CI: 0.36, 0.84)

Age 60–69 Age 70–75

Survival Following Allogeneic Hematopoietic Cell

Transplantation in Older High-Risk Acute Myeloid

Leukemia Patients Initially Treated With CPX-351

Liposome Injection Versus Standard Cytarabine and

Daunorubicin: Subgroup Analysis of a Large Phase III Trial

Jeffrey E. Lancet,1 Antje Hoering,2 Geoffrey L. Uy,3 Jorge E. Cortes,4

Laura F. Newell,5 Tara L. Lin,6 Ellen K. Ritchie,7 Robert K. Stuart,8

Stephen A. Strickland,9 Donna Hogge,10 Scott R. Solomon,11 Richard M. Stone,12

Dale L. Bixby,13 Jonathan E. Kolitz,14 Gary J. Schiller,15 Matthew J. Wieduwilt,16

Daniel H. Ryan,17 Michael Chiarella,18 Arthur C. Louie,18 Bruno C. Medeiros19

1H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 2Cancer Research and Biostatistics, Seattle, WA; 3Washington University School of Medicine, St Louis, MO; 4MD Anderson Cancer Center, Houston, TX; 5Oregon Health & Science University, Portland, OR; 6University of

Kansas Medical Center, Kansas City, KS; 7Weill Cornell Medical College of Cornell University, New York, NY; 8Hollings Cancer Center, Medical University of South Carolina, Charleston, SC; 9Vanderbilt-Ingram Cancer Center, Nashville, TN; 10Gordon and Leslie Diamond Health Care

Centre, Vancouver, BC, Canada; 11BMT Group of Georgia, Atlanta, GA; 12Dana-Farber Cancer Institute, Boston, MA; 13Comprehensive Cancer Center, University of Michigan, Grass Lake, MI; 14Monter Cancer Center, Northwell Health System, Lake Success, NY; 15David Geffen School of

Medicine/UCLA, Los Angeles, CA; 16University of California, San Diego, San Diego, CA; 17University of Rochester, Rochester, NY; 18Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc, Ewing, NJ; 19Stanford University School of Medicine, Stanford, CA

58th ASH Annual Meeting & Exposition; December 3–6, 2016; San Diego, CA

Survival Landmarked from Time of Transplant

30

• CPX-351 median OS not reached vs 10.25 months for 7+3

– HR of 0.46 favoring CPX-351 (P=0.0046)

– Cox proportional hazards HR, including transplant as a time-dependent covariate, was 0.51 (95% CI, 0.35–0.75; P=0.0007), favoring CPX-351

CI, confidence interval; HR, hazard ratio; OS, overall survival.

NonMyelosuppressive Options for High-

Risk AMLAuthor Agent Study Population Outcome

Im, et al. Epigenetic priming

with decitabine

followed by

cytarabine, 5 d

AML age >=70 (or

>60 ineligible for

chemo)

N=46, 36 eval.

CR/Cri=69% OS

12.4 m

Jakob, et al. Low-dose

Cytarabine after

Azacitidine x >4 cyc

Newly diagnosed

AML/MDS, age >

60 or R/R AML

15/31 rel. patients

treated, 4 HI and

OS incr. by 3 m.

Falantes, et al. Azacytidine as

frontline therapy

Retrospective AML,

71% poor risk

N=456, median OS

8.5 m; 1 y OS 64%,

51% and 36% by

risk

Jurcic, et al. Actinium-225-

Lintuzumab and

low-dose cytarabine

Newly diagnosed

AML age > 60 after

LDAC

N=18. Febrile

neutropenia.

Objective response

in 5 pts after 1 cyc

flt3 Tyrosine Kinase InhibitorsAuthor Agent Study Population Outcome

Ohanian, et al. Midostaurin Untreated flt3-mut.

AML age > 60

77% remission rate,

and duration 14.5m

for CR and OS

8.8m

Jilg, et al. Azacytidine and

ABT-199

MDS/sAML after

HMA failure

Synergistic in vitro

pro-apoptotic effect

Battipaglia, et al. Sorafenib after

allotransplant

flt3-mutated AML N=28. 1-year LFS:

91% and OS:89%

Abdelall, et al. Quizartinib and

azacitidine or low-

dose cytarabine

flt3-mutated AML

rel after HSCT or

ref to salvage

35/52 pts

responded; 3/8 who

had had prior flt3

inh.

Altman, et al. ASP2215 R/R flt3-mutated

AML

N=215. High single-

agent response rate

(55%) in Phase I/II

trial; OS 39 w

Flt3 Tyrosine Kinase Inhibitor in

Induction Treatment

• Stone, et al. 126: 23 (Abs) 2015:

– N= 717 of 3279 previously untreated AML patients, age 18-60, in 225 sites

screened

– Induction consisted of Dauno (60) and Cytarabine (200)

– Randomized to midostaurin (50 mg po b.i.d, d8-22) vs. placebo, and stratified

by allelic fraction (high= >0.7, n=214 vs. low 0.05-0.7, n=341). TKD allowed

(n=162)

– Retreatment permitted after day 21

– Consolidation consisted of 4 cycles of HiDaC or Transplantation

– Median follow-up 57 months

– Similar adverse events, and similar rate of CR (59% vs. 54%)

– Similar rate of allo SCT at any time (58% vs. 54%)

– Superior overall survival in favor of midostaurin (50.8% vs. 43.1%) even with

censoring

– Superior EFS in favor of midostaurin (26.7% vs. 19.1%)

35

Final Results of the CHRYSALIS Trial: A First-in-Human Phase

1/2 Dose-Escalation, Dose-Expansion Study of Gilteritinib

(ASP2215) in Patients with Relapsed/Refractory Acute

Myeloid Leukemia (R/R AML)

Alexander E. Perl1; Jessica K. Altman2; Jorge Cortes3; Catherine Smith4; Mark Litzow5; Maria R.

Baer6; David Claxton7; Harry P. Erba8; Stan Gill9; Stuart Goldberg10; Joseph Jurcic11; Richard A.

Larson12; Charles Liu13; Ellen Ritchie14; Gary Schiller15; Alexander Spira16; Stephen A. Strickland17;

Raoul Tibes18; Celalettin Ustun19; Eunice S. Wang20; Robert Stuart21; Christoph Röllig22; Andreas

Neubauer23; Giovanni Martinelli24; Erkut Bahceci13; Mark Levis24

Abstract No. 321

1University of Pennsylvania-Abramson Comprehensive Cancer Center, Philadelphia, PA; 2Robert H. Lurie Cancer Center ofNorthwestern University, Chicago, IL; 3MD Anderson Cancer Center, Houston, TX; 4University of California-San Francisco,San Francisco, CA; 5Mayo Clinic, Rochester, MN; 6University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore, MD; 7Penn State Milton S. Hershey Medical Center, Hershey, PA; 8University of Alabama at Birmingham,Birmingham, AL; 9Astellas Pharma Global Development, Northbrook, IL; 10Hackensack University Medical Center,Hackensack, NJ; 11Columbia University Medical Center, New York, NY; 12University of Chicago, Chicago, IL; 13Weill CornellMedical College, New York, NY; 14University of California, Los Angeles Medical Center, Los Angeles, CA; 15Virginia CancerSpecialists, Fairfax, VA; 16Vanderbilt-Ingram Cancer Center, Nashville, TN; 17Mayo Clinic, Scottsdale, AZ; 18University ofMinnesota, Minneapolis, MN; 19Roswell Park Cancer Institute, Buffalo, NY; 20Medical University of South Carolina-HollingsCancer Center, Charleston, SC; 21Universitätsklinikum TU Dresden, Dresden, Germany; 22Universitätsklinikum Giessen undMarburg, Marburg, Germany; 23“Seragnoli” Institute of Hematology, Bologna, Italy. 24Johns Hopkins University, Baltimore,MD

36

Gilteritinib: A Highly Selective FLT3/AXL Inhibitor

• Activating mutations of FLT3 occur in ~30% of AML cases1

– Internal tandem duplications (ITD) in the juxtamembrane domain confer a poor prognosis1,2

– Point mutations (especially D835) in the tyrosine kinase domain induce resistance to FLT3 inhibitors3

• Gilteritinib (ASP2215) is a highly potent, selective FLT3/AXL inhibitor that has

demonstrated consistent and sustained inhibition of FLT3 in vitro4-6

• CHRYSALIS is a first-in-human, pharmacodynamic-driven, open-label Phase 1/2 trial

(NCT02014558) of once-daily oral gilteritinib in relapsed/refractory (R/R) AML

– Adults with R/R AML irrespective of FLT3 mutation status were enrolled from 28 sites across the US

and Europe

– Primary end points were safety, tolerability, and pharmacokinetic profile

– The key secondary end point was antileukemic activity; pharmacodynamic effects were an

exploratory end point

– Data locked June 2016

AML, acute myeloid leukemia; FLT3, fms-like tyrosine kinase 3.

1Levis M. Hematology Am Soc Hematol Educ Program. 2013;2013:220-226; 2Grunwald and Levis. Int J Hematol. 2013; 97(6):683-694. 3Smith CC, et al. Nature. 2012; 485(7397):260-263. 4Mori M, et al. J Clin Oncol. 2014;32(5s suppl): Abstract 7070. 5Perl, A et al. Haematologica. 2015;100(Suppl 1); 6Levis et al. J Clin Oncol. 2015;33(Suppl).

37CR indicates complete remission; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; DLT, dose limiting

toxicity; FLT3, fms-like tyrosine kinase 3.

CHRYSALIS Study Design and Cohort Accrual

20 mgn=5*

No DLTex vivo FLT3 inhibition observed

CR/CRp/CRi

Expand (n=11)**

40 mg

80 mg

120 mg

200 mg

300 mg

450 mg

Do

se E

scal

atio

n

n=3No DLT

ex vivo FLT3 inhibition observed

CR/CRp/CRiExpand (n=21)

n=3No DLT

ex vivo FLT3 inhibition observed

CR/CRp/CRi

Expand (n=13)**

n=3No DLT

ex vivo FLT3 inhibition observed

CR/CRp/CRi

Expand including subjects with FLT3 mutations

(n=67)

n=3No DLT

ex vivo FLT3 inhibition observed

CR/CRp/CRi

Expand including subjects with FLT3 mutations

(n=100)

n=3No DLT

ex vivo FLT3 inhibition observed

CR/CRp/CRi

Expand (n=17)

n=3

* Three evaluable subjects

** Enrollment stopped early for low response rate

38

Demographics and Baseline Characteristics

Safety Population

(N=252)

Median age, years (range) 62 (21–90)

Sex, n (%)

Male 129 (51)

Female 123 (49)

FLT3 Mutation*, n (%) 191 (76)

FLT3-ITD only 162 (64)

FLT3-ITD and FLT3-D835 16 (6)

FLT3-D835 only 13 (5)

Prior AML lines of therapy, n (%)

1 75 (30)

2 66 (26)

≥3 111 (44)

Prior stem cell transplant, n (%)

0 179 (71)

1 67 (27)

≥2 6 (2)

Prior TKI therapy†, n (%) 63 (25)

Safety population is defined as any subject who received at least one dose of study drug.

*3 patients had mutations other than only FLT3-ITD, both FLT3-1TD and FLT3-D835, and only FLT3-D835 mutations.†Sorafenib was the most commonly used prior TKI (n=54).

D835, missense mutation at aspartic acid residue 835; FLT3, fms-like tyrosine kinase 3; ITD, internal tandem duplication; TKI, tyrosine kinase inhibitor.

39

Incidence of Adverse Events

(Safety Population; N=252)

Treatment-Emergent Adverse Events Occurring in ≥20% of Patients

All Grades, n (%) Grade ≥3, n (%)

Anemia 86 (34) 62 (25)

Febrile neutropenia 98 (39) 98 (39)

Constipation 57 (23) 0

Diarrhea 92 (37) 13 (5)

Nausea 54 (21) 5 (2)

Fatigue 83 (33) 15 (6)

Peripheral edema 67 (27) 3 (1)

Pyrexia 65 (26) 13 (5)

Elevated AST 66 (26) 15 (6)

Cough 54 (21) 0

Dyspnea 59 (23) 12 (5)

AST, aspartate aminotransferase.

• Maximum tolerated dose of gilteritinib was 300 mg/day; 2 of 3 patients in the 450 mg/day dose escalation cohort

experienced dose limiting toxicities (diarrhea and elevated AST)

• Most common treatment-related AEs: diarrhea, fatigue, elevated ALT and AST; most were generally <Grade 3

• Overall, 11 patients (4%) had a maximum post-baseline QTcF interval >500 ms

• Seven deaths were deemed possibly related to treatment (pulmonary embolism, respiratory failure, hemoptysis,

intracranial bleed, ventricular fibrillation, septic shock, neutropenia; n=1 each)

ALT, alanine aminotransferase.

40

0

10

20

30

40

50

60

70

80

90

100

Response in FLT3mut+ and FLT3WT

Patients (N=249)

PR

CRi

CRp

CR

n=10

300 mg

Pro

po

rtio

n o

f P

atie

nts

Ach

ievi

ng

Res

po

nse

(%

)

0

10

20

30

40

50

60

70

80

90

100

Response in FLT3mut+ Patients by Gilteritinib Dose (N=191)

CR

CRp

CRi

PR

n=12 n=56 n=89

80 mg 120 mg 200 mg

n=2

450 mg

n=8

40 mg

n=14

20 mg

ORR=67%

ORR=47%

ORR=60%ORR=55%

ORR=38%

ORR=14%

ORR=50%

CRc included patients who achieved complete remission, complete remission with incomplete hematologic recovery, and complete remission with incomplete platelet recovery

ORR included patients in CRc plus patients who achieved PR.

CR, complete remission; CRc, composite remission (CRc=CR+CRi+CRp;); CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet

recovery; ORR, overall response rate (ORR=CRc+PR); PR, partial remission.

Antileukemic Activity of Gilteritinib

Gilteritinib ≥80 mg/day ORR=52%

Pro

po

rtio

n o

f P

atie

nts

Ach

ievi

ng

Res

po

nse

(%

)

FLT3mut+

(N=191)FLT3WT

(N=58)

ORR=12%

CRc=9%

ORR=49%

CRc=37%

CRc=42%

CRc=39%

CRc=30%CRc=46%

CRc=0

CRc=7%

CRc=0

41

Overall Survival in FLT3mut+ Patients Treated

With Gilteritinib (N=191)*

OS, overall survival.

Gilteritinib ≥80 mg/day in FLT3mut+ Patients

Median OS: 31 weeks (range: 1.7–61 weeks)

Median Duration of Response: 20 weeks (range: 1.1–55 weeks)

Median Time to Best Response: 7.2 weeks (range: 3.7– 52 weeks)

IDH2 mutant enzyme Inhibitors

Author Agent Study Population Outcome

Stein, et al. ( in

MDS: Abs 637;

2016)

AG-221

(Enasidenib)

IDH2 mutation-

positive heme

malignancies

N=198 accrued to

parallel bid and qd

cohorts, 181

evaluable.

Responses in 74

duration about 6 m;

in MDS, HI 4/15

DiNardo, et al. (Abs

1073, 2016)

IDH305 N=21 AML w/

R132 mut.-response

in 7

Reduction of tumor

burden in other

cancers

Matre et al. Inhibition of

glutaminase

Panel of AML cell

lines

Induction of

apoptosis, decr in

metabolites

Herold, et al. Analysis of MLL-

PTD by whole

exome sequencing

Most prevalent

mutations in ATM,

DNMT3b, TET1

Enasidenib in Patients With IDH2

Mutations: Responses

43

ParameterRelapsed or Refractory AML

Enasidenib 100 mg/d (n = 109) All Doses (N = 176)

ORR, % [n/N] 95% CI 38.5% (42/109) [29.4-48.3] 40.3% (71/176) [33.0-48.0]

Best response

CR, n (%) [95% CI] 22 (20.2) [13.1-28.9] 34 (19.3) [13.8-25.9]

CRi or CRp, n (%) 7 (6.4) 12 (6.8)

PR, n (%) 3 (2.8) 11 (6.3)

MLFS, n (%) 10 (9.2) 14 (8.0)

SD, n (%) 58 (53.2) 85 (48.3)

PD, n (%) 5 (4.6) 9 (5.1)

NE, n (%) 2 (1.8) 3 (1. 7)

Time to first response (mo), median

(range)1.9 (0.5-9.4) 1.9 (0.5-9.4)

Duration of response (mo), median

[95%CI]5.6 [3.8-9.7] 5.8 [3.9-7.4]

Time to CR (mo), median (range) 3.7 (0.7-11.2) 3.8 (0.5-11.2)

Duration of CR (mo), median [95%CI] 8.8 [5.3, NR] 8.8 [6.4, NR]

Stein EM et al. Blood. 2017;130:722-731.

Ivosidenib in R/R IDH1m AML: Response

44

CRh = 9 patients with investigator-assessed responses of CRi/CRp and 5 with MLFS

R/R AML 500 mg

(n=179)

CR+CRh rate, n (%) [95% CI] 57 (31.8) [25.1,

39.2]

Time to CR/CRh, median (range)

months

2.0 (0.9, 5.6)

Duration of CR/CRh, median [95%

CI] months

8.2 [5.6, 12.0]

CR rate, n (%) [95% CI] 43 (24.0) [18.0,

31.0]

Time to CR, median (range) months 2.8 (0.9, 8.3)

Duration of CR, median [95% CI]

months

10.1 [6.5, 22.2]

CRh rate, n (%) 14 (7.8)

Duration of CRh, median [95% CI]

months

3.6 [1.0, 5.5]

R/R AML 500 mg

(n=179)

Overall Response Rate, n (%) [95% CI] 75 (41.9) [34.6,

49.5]

Time to first response, median

(range) months

1.9 (0.8, 4.7)

Duration of response, median [95%

CI] months

6.5 [5.5, 10.1]

Best response, n (%)

CR 43 (24.0)

CRi or CRp 21 (11.7)

MLFS 11 (6.1)

SD 68 (38.0)

PD 15 (8.4)

NA 21 (11.7)

Among the 179 patients with R/R AML, 5 from dose escalation and 1 from dose expansion were not positive for mIDH1 by the companion diagnostic test and

none of these 6 patients achieved a CR or CRh

CR+CRh was consistent across baseline age groups, including patients who were > 65 years of age

Overall response rate includes CR, CRi/CRp, MLFS and PR

Ivosidenib in R/R IDH1m AML: OS by

Best Response

45

Non-CR/CRh responders include CRi, CRp, and MLFS who are not CRh

Non-responders = all others including those with best responses of SD, PD, or not evaluable

Months

Overall survival, median [95% CI]

CR+CRh 18.8 [14.2, NE]

Non-CR/CRh

responders9.2 [6.7, 10.8]

Non-responders 4.7 [3.7, 5.7]

All 9.0 [7.1, 10.0]

Overall follow-up,

median (range)

15.3 (0.2–

39.5)

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 8 3 0 3 2 3 4 3 6 3 8 4 0

0 .0

0 .1

0 .2

0 .3

0 .4

0 .5

0 .6

0 .7

0 .8

0 .9

1 .0

O v e ra ll s u rv iv a l (m o n th s )

Su

rv

iva

l p

ro

ba

bil

ity

N u m b e r o f p a t ie n ts a t r is k :

N o n -re s p o n d e rs

57 50 32 16 45757 43 25 11 456 215 47 3

N o n -C R /C R h re s p o n d e rs

C R + C R h

C R + C R h

N o n -C R /C R h re s p o n d e rs

N o n -re s p o n d e rs

O ve ra ll

12 1

18 10 3 11517 6 214 0

1 0 4 29 9 35577 15 6 038 2

C e n s o re d

Immunotherapeutic Approaches of High-

Risk AML

• Tumor Antigens

• Immunomodulatory Agents

• Induction of autologous anti-leukemia reactivity

• Allogeneic hematopoietic stem-cell

transplantation

Allogeneic Hematopoietic Stem-Cell

Transplantation in High-Risk AML

Author Study Population Preparative Regimen Outcome

Duval, et al. n = 1673

AML relapsed or

primary induction

failure, retrospective

registry study

Multiple Survival at 3 years:

19%

Mortality at 100

days: 39%

Cause of Death:

AML in 42%

Koreth, et al. n = 6007,

AML-CR1 meta-

analysis donor vs. no

donor

Multiple Significant benefit

in survival for

poor-risk and

intermediate-risk

Brunet, et al. n = 206 AML in CR1

with known flt3 status

retrospective registry

study

Multiple 58% 2-year LFS

for flt3-mutated vs.

71% for

nonmutated. HR

for relapsed = 3.4

Novel Agents

• Monoclonal Antibodies and Vaccine

– Antibody-drug Conjugates

• Pollard et al. Gemtuzumab induced more CR in children with

11q23/MLL+ AML and reduced relapse after HSCT

• Swords, et al. n=25. Pevonedistat and aza- potential synergy

• Is there a bifunctional monoclonal antibody for AML CD123?

- Novel Vaccines- WT1, DC loaded with leukemia-Ag

Novel Drugs or Old Drugs given in Novel ways

– Drugs added to 7&3 or in lieu of 7&3

• Wierzbowska, et al. n= 125. Cladribine added to Dauno/cyt- no

efficacy seen in AML-MK

• Griffiths, et al. n=51. Lenalidomide with intermediate-dose cyt. Poor

response, skin toxicity

• Foran et al. Phase III Clofarabine v. DA- similar CR & IM, inferior

OS

• Muppidi, et al. CLAG+ M for 2o or R/R: 67% response & 107d OS

Agent Study Patient Population Treatment Key Study Endpoints

Additional agents and combinations

CXCR4

inhibitor

(Abraham et al.

ABS 767)

In

progress

AML Cell lines and human

primary AML samples

miR-15 up-

regulation with

donw-reg. of

bcl2, mcl1,

cyclin D1

Induction of apoptosis

Venetoclax

plus low-dose

cytarabine

(Wei et al. abs

102; 2016)

Australian

centre for

blood

diseases

and

others

Pts s/ AML unfit for intensive

chemotherapy, no organ

dysfunction or CNS disease

Phase ½ study

VC po daily +

LDAC daily x

10

15/20 pts had CR+Cri+PR.

16/19 had blasts reduced

beelow 5% and the 12-

month OS was 74.7%

BVD-523 Phase 1/2

Study of

the

ERK1/2

Inhibitor

BVD-523

in Patients

With AML

or MDS

Pts ≥ 18years with

relapsed/refractory AML who

are ineligible for intensive

induction chemotherapy,

particularly for RAS-mutated

disease

Oral Rates of CR and Cri, OS,

EFS, RFS

Selinexor Random

Phase 2

Pts > 60 years with R/R AML

after one prior therapy only

Single oral

agent vs. 1of3

Rates of CR, EFS

Questions Based on Today’s Presentation

• Which of the following elements would lead to a

change in therapeutic approach in a patient with

acute myeloid leukemia?

– History of type II diabetes, no medical management

– Family history of other malignancy

– Findings on sequencing panel in the leukemia blasts

– Availability of allogeneic transplantation at the treating

center

Questions Based on Today’s Presentation

• For which of the following would one consider

allogeneic transplantation in first remission AML? Yu

may choose one, or more than one.

– History of antecedent hematologic disturbance

– Multiple cytogenetic abnormalities in the leukemia blasts at

presentation

– Presence of high-risk molecular abnormalities in the

leukemia cells

– Presence of co-morbid medical condition

Challenges for the Community of Physicians

who treat high-risk AML- Summary

• Treatment has been developed on the basis of clinical

features more often than on biological features, but

this is changing with several drugs recently approved

• Complete remission has generally been a secondary

endpoint of clinical trials

• Allogeneic transplant as the post-remission strategy has

a significant impact on the use of survival as a primary

endpoint