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Kevin Kelly, MD, Phd Acute Myeloid and Lymphoid Leukemias

Relevant financial relationships in the past twelve months by presenter or spouse/partner.

Speakers bureau: Novartis, Janssen, Gilead, Bayer

The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.

14th Annual California Cancer Conference Consortium

August 10-12, 2018

Agenda

Management of Younger Patients With AML

Management of Older Patients With AML

Management of Relapsed AML

Management of Newly Diagnosed ALL

Management of Relapsed ALL

RATIFY: First-line Chemotherapy ± Midostaurin in

FLT3-Mutated AML

Stone RM, et al. N Engl J Med. 2017;377:454-464.

Pts with ND FLT3-

positive AML, aged 18-

59 yrs, and stratified

according to FLT3

subtype (TKD or ITD

high or low)

(N = 717)

Randomized phase III study

Daunorubicin

60 mg/m2 IVP D1-3 +

Cytarabine

200 mg/m2/d IVCI D1-7 +

Midostaurin

50 mg PO BID D8-21

(n= 360)

Daunorubicin

60 mg/m2 IVP D1-3 +

Cytarabine

200 mg/m2/d IVCI D1-7+

Placebo

D8-21

(n = 357)

Cytarabine

3 g/m2 over 3h q12h

D1,3,5 +

Midostaurin

50 mg PO BID D8-21

(n = 231)

Cytarabine

3 g/m2 over 3h q12h

D1,3,5 +

Placebo

D8-21

(n = 210)

Midostaurin

50 mg PO BID D1-28

(n = 120)

Placebo

D1-28

(n = 85)

Stratified by

ITD/TKD

Induction*

(1-2 cycles)

Consolidation

(up to 4 cycles)

Maintenance

(12 cycles)

CR

CR

*Hydroxyurea allowed for ≤ 5 days prior to induction therapy.

RATIFY: Overall Survival

Stone RM, et al. N Engl J Med. 2017;377:454-464.

CR 59%

CR 54%

mOS, Mos (95% CI) 100 90 80 70 60 50 40 30

20 10

0 Pro

bab

ilit

y o

f S

urv

ival

(%)

0 24 12 48 36 72 60 90 84 Mos

Pts at Risk, n

Midostaurin

Placebo

360

357

269

221

208

163

181

147

151

129

97

80

37

30

1

1

Midostaurin

Placebo

74.7 (31.5-NR)

25.6 (18.6-42.9)

1-sided P = .009 by stratified log-rank test

Overall

ITD (high)

ITD (low)

TKD

717

214

341

162

0.78 (0.63-0.96)

0.80 (0.57-1.12)

0.81 (0.60-1.11)

0.65 (0.39-1.08)

.009 (1 sided)

.19 (2 sided)

.19 (2 sided)

.10 (2 sided)

Pts P Value HR (95% CI)

Midostaurin

Better

Placebo

Better

0.4 0.6 0.8 1.0 1.2

Standard of Care Induction Chemotherapy ±

Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin 3 mg/m2 on Days 1, 4, 7 of induction and Day 1 of each consolidation cycle

OS RFS

Castaigne S, et al. Lancet. 2012;379:1508-1516.

100

60

0

80

40 OS

(%

)

20

0 6 12 18 24 30 36 42 48

Pts at Risk, n

Control

Gemtuzumab

ozogamicin

139

139

117

118

82

98

45

66

26

43

16

25

6

16

0

4

0

0

Mos

Log-rank P = .0368

100

60

0

80

40

RF

S (

%)

20

0 6 12 18 24 30 36

Pts at Risk, n

Control

Gemtuzumab

ozogamicin

104

113

83

101

39

68

19

41 6

29

3

16

1

8

Mos

Log-rank P = .0003

AML15: Addition of Gemtuzumab Ozogamicin to

Cytarabine-Based Induction Therapies in AML

OS: Favorable Karyotype AML

Burnett AK, et al. J Clin Oncol. 2011;29:369-377.

No gemtuzumab ozogamicin

Gemtuzumab ozogamicin



100

50

0

75

25

OS

(%

)



1 2 3 4 5

Yrs

2P = .3

Pts, n

557

556

Events, n Obs.

315

297

Exp.

302.4

309.6

43%

41%

100

50

0

75

25

OS

(%

)

1 2 3 4 5 0

Yrs

Pts, n

65

72

Events, n Obs.

30

13

Exp.

18.2

24.8

2P = .0003



79%

51%

0

OS: All Pts

CD33 Splicing Polymorphisms in Pediatric AML

Following Gemtuzumab Ozogamicin

Lamba JK, et al. J Clin Oncol. 2017;35:2674-2682.

1.00

0.50

0

0.75

0.25 RR

(P

rob

ab

ilit

y)

0 2 4 6 8

Yrs From End of Induction 1

rs12459419 = CC

P < .001

No-GO (n = 145)

GO (n = 154)

1.00

0.50

0

0.75

0.25 RR

(P

rob

ab

ilit

y)

0 2 4 6 8

Yrs From End of Induction 1

rs12459419 = CT

P < .975

No-GO (n = 101)

GO (n = 125)

Older Patients

Outcomes in Older Adults With AML

(Aged 65-93 Yrs)

Oran B, et al. Haematologica. 2012;97:1916-1924.

OS

Mos After Diagnosis

OS by Leukemia Therapy, Stratified by

Charlson Comorbidity Index (CCI) 1.0

0.6

0.2

0.8

0.4

0

0

Treated, CCI = 0

Treated, CCI = 2

Untreated, CCI = 1

Treated, CCI = 1

Untreated, CCI = 0

Untreated, CC1 = 2

6 12 18 24 30 36 42 48 54 60

Number of Driver Mutations Increase With Age in

Pts With AML

Metzeler KH, et al. Blood. 2016;128:686-698.

No. Mutated Genes

No. Mutated Genes per Pt, by Age Category

0 1 2 3 4 ≥ 5

1.0

0.8

0.6

0.4

0.2

0

< 40 Yrs 40-59 Yrs ≥ 60 Yrs

P < .001 P = .006

Mutations in Older Pts With AML

Tsai CH, et al. Leukemia. 2016;30:1485-1492.

Variables* Pts With Alteration, %

P Value All Older Younger

TET2 14.3 24.3 8.1 < .001

DNMT3A 15.2 20.9 11.6 .008

TP53 7.6 13.0 4.2 .001

Cohesin 10.0 9.6 10.2 > .999

Variables* Pts With Alteration, %

P Value All Older Younger

FLT3/ITD 22.5 22.6 22.5 > .999

FLT3/TKD 6.5 6.8 6.3 .848

NRAS 12.1 13.0 11.6 .662

KRAS 3.2 2.3 3.9 .426

PTPN11 3.9 6.2 2.5 .050

KIT 3.2 2.3 3.9 .426

JAK2 0.6 0.6 0.7 > .999

WTI 6.9 3.4 9.1 .023

NPM1 22.3 28.2 18.6 .021

CEBPA 14.3 10.2 16.8 .055

RUNX1 13.4 19.8 9.5 .002

MLL/PTD 5.8 6.8 5.3 .543

ASXL1 10.9 17.6 6.7 < .001

IDH1 5.8 6.8 5.3 .543

IDH2 11.9 14.7 10.2 .183

*For all variables except Cohesin, n = 462; for Cohesin, n = 411.

1.0

0.6

0

0.8

0.4

Pro

po

rtio

nal S

urv

ivin

g

0.2

0 50 100 150 200

OS (Mos)

P = .042

No adverse genetic alterations (n = 37)

At least 1 adverse genetic alteration (n = 32)

AML Ontogeny Can Be Mutationally Defined

Lindsley RC, et al. Blood. 2015;125:1367-1376.

Specificity

> 95% for sec. AML

> 95% for de novo AML

< 95% for sec. AML

< 95% for de novo AML

SRSF2

ZRSR2

SF3B1

ASXL1

BCOR

EZH2

U2AF1

STAG2

NF1

RUNX1

CBL

NRAS

TET2

GATA2

TP53

KRAS

PTPN11

IDH1

IDH2

SMC1A

RAD21

FLT3

DNMT3A

SMC3

CEBPA

NPM1

11q23-rearranged

CBF-rearranged

Secondary AML De Novo AML Mutated cases, n (%) P Value

19 (20)

7 (8)

10 (11)

30 (32)

7 (8)

8 (9)

15 (16)

13 (14)

6 (6)

29 (31)

5 (5)

21 (23)

19 (20)

2 (2)

14 (15)

7 (8)

5 (5)

10 (11)

10 (11)

3 (3)

2 (2)

18 (19)

18 (1)

2 (2)

3 (3)

5 (5)

0

0

1 (1)

0

1 (1)

5 (3)

2 (2)

3 (2)

8 (4)

3 (2)

7 (4)

19 (11)

3 (2)

15 (8)

17 (9)

2 (1)

16 (9)

8 (4)

9 (5)

20 (11)

19 (11)

7 (4)

5 (3)

50 (28)

51 (28)

7 (4)

13 (7)

54 (30)

11 (6)

19 (9)

.0001

.0005

.0001

< .0001

.035

.009

.002

.07

.005

< .0001

.13

.002

.014

.6

.15

.4

1

1

1

1

1

.14

.14

.7

.28

< .0001

.002

< .0001

Odds Ratio 0.001 0.01 0.1 1 10 100 1000

Gene Color

Differential Outcomes in Pts With de novo AML

Based on Mutational Profile

Lindsley RC, et al. Blood. 2015;125:1367-1376.

Pts

Ach

ievin

g C

R A

fter

Inte

nsiv

e

In

du

cti

on

CT

(%

)

Even

t-F

ree S

urv

ival

(%)

Clinically defined

de novo AML,

age ≥ 60 yrs

100

50

0

75

25

No CR

CR

Clinically defined de novo AML, age ≥ 60 yrs

De novo/pan-AML

Secondary-type

TP53 mutated

100

50

0 0 6 12 18

Mos

Older Age Remains Independent Prognostic

Factor in AML

Metzeler KH, et al. Blood. 2016;128:686-698. Slide credit: clinicaloptions.com

HR for Death (95% CI) P Value Variable

Age ≥ 60 yrs Female sex AML category De novo AML Secondary AML Therapy-related AML ECOG performance status 0-1 ≥ 2 WBC count (50,000/μL increase) MRC cytogenetic risk category Intermediate Favorable Adverse

2.14 (1.60-2.87)

0.82 (0.66-1.01) 1

1.21 (0.85-1.71)

2.24 (1.48-3.39) 1

1.38 (1.10-1.73)

1.10 (1.03-1.17) 1

0.41 (0.25-0.66)

1.65 (1.24-2.19)

< .001

.059

.29

< .001

.005

.004

< .001

< .001

http://www.clinicaloptions.com/oncology

CPX-351

100-nm bilamellar liposomes

5:1 molar ratio of cytarabine to daunorubicin

1 unit = 1.0-mg cytarabine plus 0.44-mg daunorubicin

Lancet JE, et al. ASCO 2016. Abstract 7000.

First-line CPX-351 in Newly Diagnosed Elderly

AML: Phase II Study 204

CPX-351: liposomal formulation[1]

– Cytarabine + daunorubicin in 5:1 fixed molar ratio

– Taken up by cells, with preference for bone marrow

Phase II study in elderly AML[2]

– Aged 60-75 yrs, “fit” for chemo

– 2:1 randomization to CPX-351 (100 U/m2 IV Days 1, 3, 5) vs “7 + 3”

– CR/CRi rate superior with CPX-351 (P = .07)

– CPX-351: 67%; 7 + 3: 51%

50

40

30

20

10

0

Pre

va

len

ce

of

Syn

erg

y

or

An

tag

on

ism

(% o

f C

ell S

cre

en

ed

)

70

60

Percent synergistic

Percent antagonistic

CYT:DN Molar Ratios

1:10 1:5 1:1 5:1 10:1

1. Tardi P, et al. Leuk Res. 2009;33:129-139. 2. Lancet JE, et al. Blood. 2014;123:3239-3246.

First-line CPX-351 in High-Risk AML: Phase III

Study Design

Primary endpoint: OS

Secondary endpoints: event-free survival, CR + CRi, 60-day mortality

CPX-351 Induction, 1-2 cycles

100 units/m2

C1: Days 1, 3, 5; C2: Days 1,3

(n = 153)

7+3 Induction, 1-2 Cycles

Cytarabine: 100 mg/m2/day

Daunorubicin: 60 mg/m2

C1: Ara-C, 7 days; Daun, 3 days

C2: Ara-C, 5 days; Daun, 2 days

(n = 156)

Pts with

previously untreated

high-risk AML,*

60-75 yrs of age,

ECOG PS 0-2,

ability to tolerate

intensive therapy

(N = 309)

Until death or

5-yr follow-up

Consolidation† 1-2 cycles

in pts with CR or CRi

*Therapy-related AML; AML with history of MDS ± prior HMA therapy or CMML; de novo AML with

MDS karyotype. †CPX-351 arm: 65 units/m2, Days 1, 3; 7 + 3 arm: same dosing as reinduction (C2).

Stratified by age (60-69 yrs vs 70-75 yrs),

disease characteristics*


First-line CPX-351 in High-Risk AML: OS

100

80

60

40

20

0

Su

rviv

al

(%)

Mos From Randomization

0 3 6 9 12 15 18 21 24 27 30 33 36

ITT Analysis Population

Events, n/N

104/153

132/156

Median Survival,

Mos (95% CI)

9.56 (6.60-11.86)

5.95 (4.99-7.75)

CPX-351

7 + 3

HR: 0.69

P = .005


First-Line CPX-351: Survival Landmarked From

Time of Transplant

Lancet JE, et al. ASH 2016. Abstract 906.

Kaplan-Meier Curve for OS Landmarked at

Time of Stem Cell Transplant

OS

(%

)

mOS (95% CI)

Not reached

10.25 (6.21-16.69)

HR: 0.46; log-rank P = .0046

100

60

20

80

40

0

0 3 6 9 12 15 18 21 24 27 30 33 36

Mos From Stem Cell Transplant

CPX-351

7 + 3

Events, n/N

18/52

26/39

7 + 3

CPX-351

CPX-351

7 + 3

52

39

46

31

40

27

34

20

27

15

20

7

15

4

9

1

6

1

3

0

0

0

0

0

CPX-351: Toxicity Considerations


Grade 3-5

Nonhematologic AE,

n (%)

CPX-351

(n = 153)

7 + 3

(n = 151)

All Pts

(N = 304)

Febrile neutropenia 104 (68) 107 (71) 211 (69)

Pneumonia 30 (20) 22 (15) 52 (17)

Hypoxia 20 (13) 23 (15) 43 (14)

Sepsis 14 (9) 11 (7) 25 (8)

Hypertension 16 (10) 8 (5) 24 (8)

Respiratory failure 11 (7) 10 (7) 21 (7)

Fatigue 11 (7) 9 (6) 20 (7)

Bacteremia 15 (10) 3 (2) 18 (6)

Ejection fraction dec. 8 (5) 8 (5) 16 (5)

Complete

Recovery Counts

for Pts With

CR/CRi

ANC ≥ 500/µL Plts ≥ 50,000/µL

CPX-

351 7 + 3

CPX-

351 7 + 3

Pts receiving 1

induction, n

Median, days

58

35

34

29

58

36.5

34

29

Pts receiving 2

inductions, n

Median, days

15

35

18

28

15

35

18

24

Outcomes With Various Treatment Approaches

in Pts Aged > 70 Yrs With AML

Dhulipala VC, et al. ASH 2015. Abstract 2505. Slide credit: clinicaloptions.com

OS

1.0

0.6

0.2

0.8

0.4

0

0.7

0.3

0.9

0.5

0.1

0 6 12 18 24 30 36 42 48 54 60 Mos Pts at Risk, n

HMA

High intensity

Supportive care

Low intensity

110

238

187

67

90

140

47

32

39

54

13

11

56

93

29

19

12

27

4

7

8

17

4

6

3

15

2

3

19

37

6

8

2

9

2

1

2

8

2

1

1

4

2

1

HMA

High intensity

Supportive care

Low intensity

Censored


Survival Outcomes in Pts With TP53-Mutated AML

Papaemmanuil E, et al. N Engl J Med. 2016;374:2209-2221. Slide credit: clinicaloptions.com

Pro

bab

ilit

y o

f S

urv

ival

1.0

0.6

0.2

0.8

0.4

0 0 2 4 6 8 10

Yrs

TP53 wt; not complex karyotype

TP53 mut; not complex karyotype

TP53 wt; complex karyotype

TP53 mut; complex karyotype


Extended (10-Day) Decitabine in TP53-Mutated

AML

Welch JS, et al. N Engl J Med. 2016;375:2023-2036.

Clearance Rate of TP53 Mutations Survival After SCT, by TP53 Mutation Status V

ari

an

t A

lle

le F

req

uen

cy

100

60

0

80

40

20

Su

rviv

al

(%)

60

0

80

40

20

100

0 200 400 600 800 1000

Days

Pts at Risk, n

TP53 mutation

Wild-type TP53

7

24

7

24

4

16

3

10

2

5

P = .99

Transplantation

and TP53 mutation

Transplantation

and wild-type TP53

Ivosidenib (AG-120)

Somatic IDH1 and IDH2 mutations result in accumulation of oncometabolite 2-HG[1]

– Epigenetic changes, impaired cellular differentiation

mIDH identified in multiple solid and hematologic tumors[1,2]

Ivosidenib (AG-120): first-in-class, oral, potent, reversible, selective inhibitor of mIDH1 enzyme[3]

1. Mondesir J, et al. J Blood Med. 2016;7:171-180.

2. Medeiros BC, et al. Leukemia. 2017;31:272-281.

3. DiNardo CD, et al. ASH 2017. Abstract 725.

Mutation Frequency, % mIDH1 mIDH2

Pts With AML[2] 7-14 8-19

Ivosidenib (AG-120) vs Enasidenib (AG-221)

Efficacy/toxicity profile of mIDH1 and mIDH2 inhibitor appears similar

1. DiNardo CD, et al. ASH 2017. Abstract 725. 2. Stein EM, et al. Blood. 2017;130:722-731.

3. DiNardo CD, et al. ASH 2017. Abstract 639.

Testing of combination therapies ongoing

– DNA methyltransferase inhibitors: synergistic effect on release of differentiation block in mIDH/leukemia models in vitro[3]

Parameter mIDH1 Inhibitor: Ivosidenib[1]

(N = 258)

mIDH2 Inhibitor: Enasidenib[2]

(N = 239)

Disease(s) evaluated R/R AML, other hematologic

malignancies R/R AML, MDS

CR/CRh at RP2D, % 30.4 26.6

CR duration, mos 9.3 8.8

Differentiation syndrome, % 11.2 7.0

Venetoclax With Decitabine or Azacitidine for

AML: Background

AML diagnosed at median age of 68 yrs,[1] yet elderly patients often ineligible or refractory to intensive induction CT[2]

BCL-2: antiapoptotic protein expressed at high levels in AML, associated with poor outcomes and CT resistance[3]

Venetoclax: oral BCL-2 inhibitor associated with in vitro antileukemic activity synergistic with hypomethylating agents (ie, azacitidine)[4]

– Venetoclax may serve as efficacious, low-intensity treatment for AML in elderly patients ineligible for standard induction CT

Current report assessed safety, efficacy of venetoclax in combination with azacitidine or decitabine in elderly patients with previously untreated AML ineligible for standard induction chemotherapy[5]

Slide credit: clinicaloptions.com

1. NIH. Cancer stat facts: leukemia - acute myeloid leukemia (AML). 2. Kantarjian H, et al. Blood. 2010;116:4422-4429. 3. Pan R, et al. Blood. 2015;126:363-372. 4. Bogenberger JM, et al. Leuk Lymphoma. 2015;56:226-229. 5. DiNardo CD, et al. ASCO 2018. Abstract 7010.

http://www.clinicaloptions.com/


AML: Study Design

DiNardo CD, et al. ASCO 2018. Abstract 7010. Slide credit: clinicaloptions.com

Multicenter, open-label phase Ib dose-escalation and dose-expansion trial (data cutoff: July 7, 2017)

Venetoclax ramped up to 400, 800, or 1200 mg QD† +

Decitabine 20 mg/m2 on Days 1-5 or

Azacitidine 75 mg/m2 on Days 1-7 in 28-day cycles

Patients with untreated AML; aged ≥ 65 yrs; ineligible for standard

induction; ECOG PS 0-2; no prior HMA/CT for antecedent hematologic disorder,

CAR T-cell tx, other experimental tx; no favorable-risk cytogenetics*; no active CNS involvement; WBC count ≤ 25 x 109/L; no

HIV, HBV, HCV infection (N = 145)

*Core binding factor: inv(16), t(16;16), t(8;21), or t(15;17). †Venetoclax ramped up during cycle 1: Day 1, 100 mg; Day 2, 200 mg; Day 3, 400 mg; Day 4, 800 mg; Day 5, 1200 mg (11 patients). On reaching assigned dose level of 400, 800, or 1200 mg QD, that dose was continued for rest of cycle.

Venetoclax ramped up to 400 or 800 QD† +

Decitabine 20 mg/m2 on Days 1-5 or

Azacitidine 75 mg/m2 on Days 1-7 in 28-day cycles

Dose Escalation Dose Expansion

Primary endpoint: safety

Secondary endpoints: CR, CRi, DoR, OS

Exploratory endpoint: MRD (< 10-3 leukemic cells at any measurement as detected by multicolor flow cytometry)



AML: Baseline Characteristics

Median follow-up of 15.6 mos


Characteristic, n (%) All Patients

(N = 145)

Median age, yrs (range) ≥ 75 yrs, n (%)

74 (65-86) 62 (43)

Male 81 (56)

ECOG PS 0 1 2

32 (22) 90 (62) 23 (16)

BL bone marrow blasts ≤ 30% 31% to 50% > 50%

44 (30) 48 (33) 53 (37)

Median mos on study (range) 8.9 (0.2-31.7)

Characteristic, n (%) All Patients

(N = 145)

BL hydroxyurea use 14 (10)

Cytogenetics Intermediate risk Favorable

74 (51) 71 (49)

Secondary AML 36 (25)

DiNardo CD, et al. ASCO 2018. Abstract 7010.



AML: Response and Survival

CR/CRi rates in subgroups: intermediate-risk cytogenetics, 74%; poor-risk cytogenetics, 59%; de novo AML, 67%; secondary AML, 67%; aged < 75 yrs, 69%; aged ≥ 75 yrs, 64%


Outcome All Patients*

(N = 145)

Venetoclax 400 mg Venetoclax 800 mg

Azacitidine (n = 29) Decitabine (n = 31) Azacitidine (n = 37) Decitabine (n = 37)

CR + CRi, % CR CRi

67 37 30

76 38 38

71 45 26

57 30 27

73 38 35

MRD negativity in patients with CR/CRi, n/N (%)

28/97 (29) 10/22 (45) 7/22 (32) 7/21 (33) 3/27 (11)

Median DoR in patients with CR/CRi, mos (95% CI) Intermediate risk Poor risk de novo AML Secondary AML

--

12.9 (11.0-NR) 6.7 (4.1-9.4)

9.4 (7.2-11.7) NR (12.5-NR)

NR (5.6-NR)

-- -- -- --

12.5 (5.1-NR)

-- -- -- --

11.7 (4.6-12.9)

-- -- -- --

9.2 (5.9-NR)

-- -- -- --

Median OS, mos (95% CI) 17.5 (12.3-NR) NR (11.0-NR) 17.5 (10.3-NR)

DiNardo CD, et al. ASCO 2018. Abstract 7010.

*Including 11 patients who received venetoclax at 1200 mg.



AML: Conclusions

In this phase Ib dose-escalation and dose-expansion trial, venetoclax plus decitabine or azacitidine was well tolerated with deep, durable responses in elderly patients with previously untreated AML

– CR/CRi rate in all patients: 67%

– Promising CR/CRi rates observed in high-risk subgroups: poor-risk cytogenetics (59%), secondary AML (67%), and ≥ 75 yrs of age (64%)

After median follow-up of 15.6 mos, median OS was 17.5 mos in all patients (1-yr survival rate ~ 50%)

MRD negativity observed in 45% of patients who received venetoclax 400 mg + azacitidine

Investigators suggested that venetoclax at 400 mg QD in combination with decitabine or azacitidine offers optimal risk–benefit profile

Slide credit: clinicaloptions.com DiNardo CD, et al. ASCO 2018. Abstract 7010.


Acute Lymphoblastic Leukemia

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