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Daver 7 3 Thank you Jk Basic Facts Unbridled proliferation of hematopoietic stem cells myeloid linage resulting in marrow failure and patient death unless successfully

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Slide1

AML

Elizabeth Ellent

Some slides borrowed from Dr. Richard Stone and Dr. Naval

Daver

Slide2

7 + 3

Slide3

Thank you

Slide4

Jk

Slide5

Basic Facts

Unbridled proliferation of hematopoietic stem cells (myeloid linage) resulting in marrow failure and patient death unless successfully treated

20 K new US cases with 10 K death annually

Risk factors:

Age (median age 67)

Prior chemo for other cancers

Ionization radiation

Industrial solvents

Slide6

Age, Survival, and Treatment Era in AML

1

1. Kantarjian

H et al.

Cancer

. 2010;116:4896-4901.

%

%

Slide7

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Gene

Overall Frequency, %

FLT3

(ITD, TKD)

37 (30, 7)

NPM1

29

DNMT3A

23

NRAS

10

CEBP

α

9

TET2

8

WT1

8

IDH2

8IDH17KIT6RUNX15MLL-PTD5ASXL13PHF63KRAS2PTEN2TP532HRAS0EZH20

Prognostic Relevance of

Integrated

Genomic Profiling

1

1. Patel JP et al. N Engl J Med. 2012;366:1079-1089.

Slide12

New Therapies and Emerging Agents for AML

… For many populations, including those at high risk or defined by molecular abnormalities

Novel cytotoxics

(

CPX-351

, vosaroxin)

Emerging/next-generation HMAs

(

SGI-110

, CC-486,

ASTX727)

Targeted therapies

(

FLT3i

,

IDHi

,

Bcl-2

, SINE, HDAC)

Immune checkpoint

inhibitors on the horizon(nivolumab, pembrolizumab)Novel antibodies(gemtuzumab, IMGN 33 and 123, AMG-330, Xmab-CD33/CD123)AML with actionable mutations, molecular, or high-risk features (eg, age, secondary AML)Combination therapy with HMAs for older patients

Slide13

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General Treatment

Goal 1: induction therapy

Remove morphologic evidence of leukemic cells in blood, bone marrow,

extramedullary

sites

Goal 2: reduce 10

9

- 10

10

cells

Undetectable at CR to low enough level to achieve prolonged disease free survival

Slide15

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Targeted agents

Midostaurin

is a potent FLT3 inhibitor of both ITD and TKD. (also inhibits VEGFR, PKC, KIT, PDGFR)

Specifically inhibits growth of leukemic cell lines made factor independent by transfection of activating FLT3 mutation.

Slide23

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RATIFY: DFS

1

Using a landmark analysis from the end of maintenance, there was no difference in DFS between the 2 arms

(HR = 1.4

[95% CI, 0.63-3.3];

P

= .38)

DFS at 1-year from end of maintenance was 75% (

95

% CI,

62%-

84

%)

for

midostaurin

and 91%

(95

% CI,

77%-

96%) for placeboThere was no difference between the arms in OS from the time starting maintenance (HR = 0.96 for midostaurin [95% CI, 0.58-1.59]; P = .86)1. Larson RA et al. 59th American Society of Hematology Annual Meeting and Exposition (ASH 2017). Abstract 145.

Slide29

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1.

Hills RK et al.

Lancet

Oncol.

2014;15:986-996.

Gemtuzumab Ozogamicin

Meta-Analysis

of 5

AML Randomized

Trials

1

Addition of GO

No ↑ CR rate: OR, 0.91;

P

= .3

Did not increase mortality: OR, 1.13;

P

= .4

Improved survival: OR, 0.89;

P = .01Reduced relapse: OR, 0.81; P = .001Improved survival: OR, 0.90; P = .01Highly significant survival benefit for favorable risk (OR, 0.47; P = .006) and int risk (OR, 0.84; P = .005)5 randomized trials of 3,325 pts: SWOG, ALFA, UK-MRC AML15 and 16, GOELAMS

Slide34

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Primary R/R AML (N = 125)

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

38 (30.4%) [22.5-39.3]

Time to CR/CRh, median (range) mo

2.7 (0.9-5.6)

Duration of CR/CRh, median [95% CI] mo

8.2 [5.5-12.0]

CR rate, n (%)

[95% CI]

27 (21.6%)

[14.7-29.8]

Time to CR,

median (range) mo

2.8 (0.9-8.3)

Duration of CR,

median [95% CI] mo

9.3 [5.6, 18.3]

CRh rate, n (%)

11 (8.8%)

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

52 (41.6%) [32.9-50.8]Time to first response, median (range) mo1.9 (0.8-4.7)Duration of response, median [95% CI] mo6.5 [4.6-9.3]Best response, n (%) CR27 (21.6) CRi or CRp16 (12.8) MLFS9 (7.2) SD44 (35.2) PD

13 (10.4)

NA

16 (12.8)

a

Data cut-off: May 12, 2017.

b

CRh

:

6 patients with investigator-assessed responses of

CRi

/

CRp

and 5 with MLF.

1.

DiNardo

CD et al. ASH 2017. Abstract 725

.

Ivosidenib

Monotherapy

:

Response

1,a,b

Slide37

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At a median time on study of 8.9

mo

(range, 0.2-31.6), the median

OS

in all treated patients

was 17.5

mo

(95

% CI, 12.3-NR)

Estimated

1-y

and

2-y

OS rates were 59% and 46

%, respectively

Response Rates by Cohorts

1

Cohort

NComposite Response Rate, CR/CRi, n (%)Overall Response Rate (CR + CRi + PR + MLFS), n (%)All patients14597 (67)120 (83)VEN 400 mg6044 (73)49 (82)VEN 400 mg + AZA2922 (76)24 (83)VEN 400 mg + DEC3122 (71)25 (81)VEN 800 mg7448 (65)63 (85)VEN 800 mg + AZA3721 (57)31 (84)VEN 800 mg + DEC3727 (73)32 (86)VEN 1,200 mg115 (45)8 (73)1. DiNardo CD et al. Lancet Oncol. 2018;19:216-228.

Slide41

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Immune-Based Approaches to AML/MDS

1

1.

Boddu

P et al.

Am J

Hematol

Oncol

. 2017;13:4-15.

Slide45

Best

Response/Outcome

n (%)/Median [Range]

Evaluable

70

ORR

24

(

35)

CR/CRi/PR

16

(24)

HI

+ 50% blast reduction (

6 mo

+)

7

(10)

50% reduction in blast

17 (24)

Progression/stable dz (6 mo+)26 (37) [21/5]8-wk mortality8 (11)Median cycles to response2 [1-13]Median follow-up13.3 mo [8.2-25.5]AZA + NIVO in Relapsed AML: Response (N = 70)1,2Expected response rate with HMA alone in salvage: ORR = 20%-22%; CR/CRi = 16% 1. Daver N et al. EHA 2017. Abstract S474. 2. Stahl M et al. ASH 2018. Abstract 148.

Slide46

Entity

Management

% Cure/Comments

APL

AIDA;

ATRA + ATO

95+

CBF

FLAG

+ gemtuzumab

80+ >> 90%

Younger AML

FLAG-

ida

,

CLIA

, 7

+3; HD DA +

ara

-CFLT3+: Chemo + FLT3i (SOC)IDH1/2+: Chemo + IDHi (clinical trials)No mutation: Add gemtuzumab (SOC)4-50 >>> 70%-75%Older AML, not fit for intensive chemoLow-intensity chemo Rx: AZA + VEN, AZA + CPI, AZA + mAb (clinical trials)Secondary AML: AZA + VEN10-20 >>> 40%-45%Secondary AML, therapy-related or AHDConsider CPX-351 (especially in s-AML aged >60 y)15%-20% >>> 40%Always check CG, molecular (FLT3, NPM1, CEBPA, IDH1/2, CKIT, CBF)Prognosis; to determine need for alloSCT in CR1 or maintenance and targeted RxNot determinedMRD by FCMPrognosis; need for alloSCT in CR1 or maintenanceMRD eradication: PD-1, revlimid, monoclonalMost important after intensive chemoFinal Thoughts on AML: Approach at MDACC11. Slide courtesy of Naval Daver, MD.

Slide47

A 58 year old was recently dx with AML with inversion (16). He was started on standard 7+3 induction chemotherapy. A bone marrow biopsy is performed 21 days after induction is completed and shows hypoplasia. You await recovery and a repeat bone marrow

bx

reveals no leukemia and

cytogenetics

are negative for inversion 16. what do you offer for consolidation therapy

A. none

B. intermediate dose ARA C

C. high dose ARA C

D.Autologous

transplant

Allogenic

transplant

Slide48

A 58 year old was recently dx with AML with inversion (16). He was started on standard 7+3 induction chemotherapy. A bone marrow biopsy is performed 21 days after induction is completed and shows hypoplasia. You await recovery and a repeat bone marrow

bx

reveals no leukemia and

cytogenetics

are negative for inversion 16. what do you offer for consolidation therapy

A. none

B. intermediate dose ARA C

C. high dose ARA C

D.Autologous

transplant

Allogenic

transplant

Favorable karyotype consider HIDAC ( not

tx

)- CALG trial enrolled 285 pts with AML and assigned standard,

int

, or high dose ARA-C. CBF AML benefitted greatly from high dose

Slide49

A 52 year old male with AML undergoes induction chemotherapy with standard dose

cytarabine

200 mg/m2 x7 days along with

daunorubicin

90 mg/m2 x 3 days. BM

bx

done 7

dyas

after induction is completed and shows 18% cellularity and 1% residual blasts. What do you recommend next?

A. HIDAC 3 g/m2 every 12 hours x 5 days

B. standard dose

Cytarabine

with

Daunorubicin C. Await marrow recovery D. Gemtuzumab

E. Refer for allogeneic HSCT

Slide50

A 52 year old male with AML undergoes induction chemotherapy with standard dose

cytarabine

200 mg/m2 x7 days along with

daunorubicin

90 mg/m2 x 3 days. BM

bx

done 7

dyas

after induction is completed and shows 18% cellularity and 1% residual blasts. What do you recommend next?

A. HIDAC 3 g/m2 every 12 hours x 5 days

B. standard dose

Cytarabine

with

Daunorubicin C. Await marrow recovery D. Gemtuzumab

E. Refer for allogeneic HSCT

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