transforming modern care in aml€¦ · transforming modern care in aml clinical solutions with...

Transforming

Modern Care in AML Clinical Solutions

With Novel Agents

for Diverse Patient

Populations

Faculty Disclosures

Chair & Presenter

Harry P. Erba, MD, PhD

Professor of Medicine

Director, Leukemia Program

Duke University Medical Center

Durham, North Carolina

Harry P. Erba, MD, PhD, has a financial interest/relationship or affiliation in the form of:

Consultant and/or Advisor for Amgen Inc.; Astellas Pharma US, Inc.; Celgene; Covance Inc. (AbbVie

Inc.); Daiichi-Sankyo Company, Limited; GlycoMimetics; ImmunoGen Inc.; Incyte; Jazz Pharmaceuticals,

Inc.; Macrogen, Inc.; Millennium Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Pfizer,

Inc.; Seattle Genetics, Inc.; and Takeda Pharmaceuticals U.S.A., Inc.

Speakers Bureau participant with Abbvie Inc.; Celgene;Daiichi-Sankyo Company, Limited; ImmunoGen

Inc.; Incyte; Jazz Pharmaceuticals, Inc.; MacroGenics, Inc.; and Novartis Pharmaceuticals Corporation.

update

slide

Faculty Disclosures

Presenter

Naval Daver, MD

Associate Professor

Department of Leukemia

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, Texas

Naval Daver, MD, has a financial interest/relationship or affiliation in the form of:

Consultant and/or Advisor for AbbVie Inc.; Amgen Inc.; Astellas; Bristol Myers Squibb Company; Daichi

Sankyo Company Limited; F. Hoffmann-La Roche Ltd; Forty Seven, Inc.; Genentech, Inc.; Gilead

Sciences, Inc.; ImmunoGen Inc.; Jazz Pharmaceuticals, Inc.; Kite Pharma; Novartis Pharmaceuticals

Corporation; Pfizer Inc.; Servier Pharmaceuticals LLC; Syndax; and Trillium Therapeutics Inc.

Grant/Research Support from AbbVie Inc.; Astellas; Bristol Myers Squibb Company; Daichi Sankyo

Company Limited; F. Hoffmann-La Roche Ltd; Fate Therapeutics; Forty Seven, Inc.; Genentech, Inc.;

Hanmi Pharm.Co.,Ltd; ImmunoGen Inc.; NovImmune SA; Pfizer Inc.; Servier Pharmaceuticals LLC; and

Trovagene, Inc.

update

slide

Faculty Disclosures

Presenter

Courtney D. DiNardo, MD, MSCE

Associate Professor of Medicine

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, Texas

Courtney D. DiNardo, MD, MSCE, has a financial interest/relationship or affiliation in the form of:

Consultant and/or Advisor for AbbVie; Agios Pharmaceuticals Inc.; Celgene; Daiichi Sankyo, Inc.;

Immune-Onc Therapeutics; Notable Labs; and Novartis Pharmaceuticals Corporation.

Grant/Research Support from Abbvie, Agios Pharmaceuticals Inc.; Calithera; Celgene; Clear Creek Bio;

and Daiichi Sankyo, Inc.

update

slide

Faculty Disclosures

Presenter

Gail Roboz, MD

Professor of Medicine

Director of the Clinical and Translational Leukemia Programs

Weill Medical College of Cornell University

New York Presbyterian Hospital

New York, New York

Gail Roboz, MD, has a financial interest/relationship or affiliation in the form of:

Consultant and/or Advisor for Abbvie Inc.; Actinium Pharmaceuticals, Inc.; Agios Pharmaceuticals Inc.; Amphivena Therapeutics;

Argenx; Array BioPharma; Astellas Pharma US, Inc.; AstraZeneca; Astex Therapeutics; Bayer; Celgene; Celltrion; Daiichi-Sankyo

Company, Limited; Eisai Inc.; Epizyme; Helsinn; F. Hoffmann-La Roche/Genentech; Janssen Pharmaceuticals, Inc.; Jasper

Therapeutics, Inc.; Jazz Pharmaceuticals, Inc.; MEI Pharma-IDMC Chair; Novartis Pharmaceuticals Corporation; Orsenix; Otsuka

America Pharmaceutical, Inc.; Pfizer Inc.; Sandoz; Takeda Pharmaceuticals U.S.A., Inc.; and Trovagene.

Grant/Research Support from Cellectics.

Data Safety Monitoring Board for Abbvie Inc.; Actinium Pharmaceuticals, Inc.; Agios Pharmaceuticals Inc.; Amphivena Therapeutics;

Argenx; Array BioPharma; Astellas Pharma US, Inc.; AstraZeneca; Astex Therapeutics; Bayer; Celgene; Celltrion; Daiichi-Sankyo

Company, Limited; Eisai Inc.; Epizyme; Helsinn; F. Hoffmann-La Roche/Genentech; Janssen Pharmaceuticals, Inc.; Jasper

Therapeutics, Inc.; Jazz Pharmaceuticals, Inc.; MEI Pharma-IDMC Chair; Novartis Pharmaceuticals Corporation; Orsenix; Otsuka

America Pharmaceutical, Inc.; Pfizer Inc.; Sandoz; Takeda Pharmaceuticals U.S.A., Inc.; and Trovagene.

update

slide

Planning Committee Disclosures

The planners from Medical Learning Institute, Inc., the accredited provider, and PVI, PeerView Institute for

Medical Education, the joint provider, do not have any financial relationships with an ACCME-defined

commercial interest related to the content of this accredited activity during the past 12 months unless

listed below.

Content/Peer Reviewers Disclosures

The following Content/Peer Reviewers have nothing to disclose:

Stacy L. Sims, MSN, RN, CMCN

Natalie I. Vokes, MD

Disclosure of Unlabeled Use

This educational activity may contain discussions of published and/or investigational uses of

agents that are not indicated by the FDA. The planners of this activity do not recommend

the use of any agent outside of the labeled indications. The opinions expressed in the

educational activity are those of the faculty and do not necessarily represent the views of

the planners. Please refer to the official prescribing information for each product for

discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance

patient outcomes and their own professional development. The information presented in this

activity is not meant to serve as a guideline for patient management. Any procedures,

medications, or other courses of diagnosis or treatment discussed or suggested in this

activity should not be used by clinicians without evaluation of their patient's conditions and

possible contraindications and/or dangers in use, review of any applicable manufacturer's

product information, and comparison with recommendations of other authorities.

Today’s Agenda

• New developments in patients fit for

intensive therapy

• Options for older patients unfit for intensive treatment

• Targeting mutation-defined AML

Seminar and Tumor

Board Sessions

A Look at Traditional Approaches to AML Therapy1,2

1. Scheinberg DA et al. In: DeVita VT, Jr. et al, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, PA: Lippincott-Raven; 1997:2293-2321.

2. https://medlineplus.gov/acutemyeloidleukemia.html.

FIT for Intensive Chemotherapy

“7+3”

History/Genetics

Unfavorable Risk

Allogeneic HCT

Intermediate Risk ???

Chemotherapy vs Allogeneic HCT

Favorable Risk Chemotherapy

UNFIT for Intensive Chemotherapy

Clinical Trial

Hypomethylating Agents

Best Supportive Care

Hospice

Mapping Recent Approvals and the Emergence

of Novel Agent Classes in AML

FLT3-mutant AML

Midostaurin for newly diagnosed (with intensive chemo)

Gilteritinib for relapsed/refractory (single agent)

IDH-mutant AML

Ivosidenib (IDH1)

Enasidenib (IDH2)

CD33-positive AML

Gemtuzumab ozogamicin

Older/unfit patients

Venetoclax/HMA (or LDAC)

Glasdegib / LDAC

Blastic plasmacytoid dendritic cell neoplasm

Tagraxofusp

Secondary AML

CPX-351

Seminar and Tumor Board

New Directions and Treatment

Choices in Older Patients Fit

for Intensive Therapy

Tumor Board: A 74-Year-Old Man With sAML

• William is a 74-year-old man; absolute monocytosis for 2 years, mild thrombocytopenia

for 6 years

• He develops fatigue, night sweats, unintentional weight loss, and myalgias

• CBC: leukocytosis (WBC 30,000 with 45% monocytes atypical)

• BM biopsy: AML severe fibrosis; NGS: ASXL1, SRSF2, TET2, and CBL



for 6 years




For discussion: what are the options for William?

Still reasonable to pursue 7+3?

CPX-351?

Venetoclax + HMA

Subsequent transplant or no?

update slide

CPX-351 Versus 7+3:

Improvement in OS, OS From HCT, and Remission Rate1

1. Lancet JE et al. J Clin Oncol. 2018;36:2684-2692.

Overall remission rate was also significantly higher with CPX-351 vs 7+3:

47.7% vs 33.3%

Landmark analysis showing significant OS

improvement with CPX-351 from time of HCT

CPX-351 Versus 7+3 in High-Risk AML

5-Year Follow-Up Results1

OS improvement maintained, showing that CPX-351 has the ability to produce or contribute to long-

term remission and survival in older patients with newly diagnosed high-risk/secondary AML

1. Lancet JE et al. American Society of Clinical Oncology 2020 Annual Meeting (ASCO 2020). Abstract 7510.

Survival Landmarked From Time of HCT

3-y KM-Estimated

Survival Rate, %

5-y KM-Estimated

Survival Rate, %

CPX-351 21 18

7+3 9 8

Events/N Median OS (95% CI) HR (95% CI)

CPX-351 124/153 9.33 (6.37-11.86) 0.70 (0.55-0.91)

7+3 145/156 5.95 (4.99-7.75)

CPX-351 153 122 92 79 62 52 49 45 40 35 33 31 30 29 29 29 29 28 28 26 22 6 2 1 0

7+3 156 110 77 56 43 35 28 25 20 19 17 14 14 13 13 12 12 12 12 11 5 1 0 0 0

0

20

40

60

80

100

0 3 6 9 121518212427303336394245485154576063666972

Su

rviv

al,

%

Time From Randomization, mo

Su

rviv

al,

%

CPX-351 53 48 42 37 35 35 32 32 31 29 28 28 28 27 27 26 24 24 21 15 6 2 0 0 0

7+3 39 31 27 20 18 14 12 12 12 9 9 9 9 9 9 9 9 9 8 2 0 0 0 0 0

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72

3-y KM-Estimated

Survival Rate, %

5-y KM-Estimated

Survival Rate, %

CPX-351 56 52

7+3 23 Not estimable

Events/N Median OS (95% CI) HR (95% CI)

CPX-351 25/53 Not reached 0.51 (0.28-0.90)

7+3 30/39 10.25 (6.21-16.69)

Time From HCT, mo

update

slide

CPX-351: Managing Count Recovery and Outpatient Use1


Less Early Mortality With CPX-351 vs 7+3

Patients, %

CPX-351 7+3

Grades 1 and 2

Grades 3 to 5

75 50 25 0 25 50 75

Febrile neutropenia

Fatigue

Pneumonia

Hypoxia

Hypertension

Bacteremia

Sepsis

Respiratory failure

Ejection fraction decreased


Delayed count recovery with CPX-351

• ~6 days longer prolonged recovery

from neutropenia and

thrombocytopenia versus 7+3

MDACC approach

• Admit patient (preferred) or start

outpatient induction → close

monitoring after d 3-4; lab assessment

3 x/wk for outpatient

• Consider frequent blood and platelet

transfusions (eg, Hb thresholds

>8.5 g/dL; platelets >15,000/mcL)

CPX-351 7+3

Regimen Early Mortality

Day 30 Day 60

CPX-351 5.9% 13.7%

7+3 10.6% 21.2%

Two-sided P = .149 Two-sided P = . 097



for 6 years




Receives CPX-351 on 5/20/19 as outpatient

Culture negative for febrile neutropenia

06/28/19: BM CRp by 07/16/19

07/24/19: CPX-351 consolidation

as outpatient

08/28/19: BM CR (NGS panel is negative)

Proceeds to allogeneic HCT

10/18/19: preparative regimen

fludarabine/melphalan

10/23/19: haplo (son) alloHCT

Cyclophosphamide post cells

Last visit, 02/10/20: doing well

Older Patients Fit

for Intensive Therapy A Role for Maintenance in CR1?

Tumor Board:

An Older Patient With Intermediate-Risk AML

Bertrand is a fit 65-year-old man with pancytopenia due to normal karyotype

AML without FLT3 mutation

• NGS panel detects the following pathogenic mutations after therapy initiated:

EZH2, STAG2,TET2, DNMT3A

After initial consultation, standard 7+3 recommended

• Patient is in CR1 after standard 7+3 and one cycle intermediate-dose ARA-C

Discussion: Bertrand is uncertain/unwilling to consider HCT. Would NGS

have affected initial therapy? Is maintenance therapy an option?

• AZA maintenance after intensive chemotherapy improves DFS in older AML patients3

• CC-486 was recently assessed in the phase 3 QUAZAR study

• Primary endpoint: OS

a May also discontinue treatment based on investigator's decision.

1. https://clinicaltrials.gov/ct2/show/NCT01757535. 2. Roboz GJ et al. Future Oncol. 2016;12:293-302. 3. Huls G et al. Blood. 2019;133:1457-1464.

Phase 3 QUAZAR Study (CC-486-AML-001):

CC-486 as Maintenance Therapy in AML1,2

Maintain CR/CRi: Continue

treatment

Relapse with >5%-15% BM blasts:

Dose escalate to CC-486 300 mg or

placebo daily x 21 daysa

Relapse with ≥16% BM blasts:

Discontinue treatment

CC-486 maintenance

300 mg daily x 14 d

+ BSC 28-d cycles

Placebo maintenance

daily x 14 d

+ BSC 28-d cycles

N = 460

• AML with intermediate/

poor-risk cytogenetics

• Age ≥55 y

• Within 90 days of first

CR/CRi following

induction ±

consolidation

R 1:1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

Time After Randomization, mo

24.7 mo

14.8 mo

Stratified P = .0009

Stratified HR = 0.69 (95% Cl, 0.55-0.86)

CC-486

Placebo

QUAZAR: Efficacy Outcomes Summary1

1. Wei AH et al. 62nd American Society of Hematology Annual Meeting (ASH 2019). Abstract LBA3.

No. of Patients at Risk

CC-486 238 224 200 168 147 124 115 98 75 59 44 35 26 22 16 15 6 5 1 0

Placebo 234 206 164 127 103 92 82 70 52 34 28 23 19 16 14 11 8 6 1 0

Overall Survival

Median RFS was

10.2 mo with CC-486

versus 4.8 for placebo

• Stratified P = .0001

• Stratified HR = 0.65

1-year relapse rate was

53% in the CC-486 arm

and was 71% in the

placebo arm

Relapse-Free Survival

(From Randomization)

Su

rviv

al P

rob

ab

ilit

y

1.0


Beyond Conventional Care:

Options for Older Patients With

AML Unfit for Intensive Therapy

Tumor Board:

An Older Patient With Intermediate-Risk AML

George is a 72-year-old man with normal karyotype AML without FLT3

mutation

• WBC 3.0, ANC 0.5, Hb 7.5, platelets 35,000

• PMH: hypertension, diabetes mellitus

• Performance status 2

He receives azacitidine and venetoclax and achieves CRh after two cycles

• NGS available after cycle 1 shows NPM1, TET2, and DNMT3A mutations

Discussion: AlloHCT?

Venetoclax Regimens in AML: Post-HCT Outcomes1

1. Pratz KW et al. Blood. 2019;134(suppl 1):264.

Pro

bab

ilit

y o

f N

o E

ve

nt,

%

12-mo OS rate

84% (95% Cl, 66-93)

No. of Patients at Risk

31 31 29 27 26 23 15 15 14 9 3 3 3 2 0

Time, mo

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54

0

10

20

30

40

50

60

70

80

90

100

Patients With SCT(N = 31)

Rate

of

CR

/CR

h,

%

CRh CR

19

52

71

• Planned primary analysis:

venetoclax reduced the

risk of death by 25% over

the LDAC-alone arm

(HR = 0.75; P = .11),

although it was not

statistically significant

• An unplanned analysis

with an additional

6 months of follow-up

demonstrated a median

OS of 8.4 months for the

venetoclax arm

(HR = 0.70; P = .04)

1. Wei AH et al. Blood. 2020 Mar 27 [Epub ahead of print]. 2. Wei AH et al. ASCO 2020. Abstract 7511.

VIALE-C: Primary Endpoint1,2

Median OS (95% CI), mo

VEN + LDAC 8.4 (5.9-10.1)

Placebo +

LDAC 4.1 (3.1-8.1)

VEN + LDAC 143 103 78 54 35 30 14 3

Placebo + LDAC 68 43 30 22 14 12 6 0

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24

Pati

en

ts, %

Time, mo

OS + 6-mo follow-up

• Modest increase in hematologic

AEs in the venetoclax arm

• Rate of AEs leading to treatment

discontinuation (24% vs 25%) and

the rate of serious AEs such as

pneumonia (13% vs 10%) or

sepsis (6% in each arm) was

nearly identical between arms

a AEs shown were reported in ≥20% of patients in either treatment arm.

1. Wei AH et al. Blood. 2020 Mar 27 [Epub ahead of print].

VIALE-C: Safety Summary1

Venetoclax + LDAC was well-tolerated and associated with manageable toxicity

Adverse Event, n (%) Venetoclax + LDAC

(n = 142)

Placebo + LDAC

(n = 68)

Hematologic AEs (grade ≥3)a

Thrombocytopenia 64 (45) 25 (37)

Neutropenia 66 (46) 11 (16)

Febrile neutropenia 45 (32) 20 (29)

Anemia 36 (25) 15 (22)

Nonhematologic AEs (any grade)a

Nausea 60 (42) 21 (31)

Hypokalemia 40 (28) 15 (22)

Diarrhea 40 (28) 11 (16)

Constipation 26 (18) 21 (31)

Vomiting 36 (25) 9 (13)

Pneumonia 29 (20) 11 (16)

Edema peripheral 19 (13) 14 (21)

1. DiNardo C et al. 25th European Hematology Association Annual Congress (EHA 2020). Abstract LB2601.

VIALE-A: Venetoclax Plus AZA

0

0.2

0.4

0.6

0.8

1

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

Pro

bab

ilit

y o

f N

o E

ven

t

Median OS, mo (95% CI)

AZA + VEN 14.7 (11.9-18.7)

AZA + placebo 9.6 (7.4-12.7)

No. at Risk

AZA +

VEN 286 219 198 168 143 117 101 54 23 5 3 0

AZA +

placebo 145 109 92 74 59 35 30 14 5 1 0 0

HR = 0.66 (95% CI, 0.52-0.85)

P < .001

Time, mo

1.0

• Among treatment-naïve,

predominantly elderly patients with

AML ineligible for intensive therapy,

AZA + VEN led to statistically

significant and clinically meaningful

improvement in response rates and

OS compared with AZA1

• Safety: Notable serious AEs

(grade ≥3) were febrile neutropenia

(30%/10%) and pneumonia

(16%/22%)

– Laboratory tumor lysis

syndrome was rare at 1%

Venetoclax regimens in AML

• Efficacy in different mutational subsets?

• Addition of other targeted agents to venetoclax backbone?

• Other considerations

– Inpatient versus outpatient?

– Antifungal prophylaxis: yes or no, and what to choose?

Mapping the Future of Venetoclax Regimens


Targeting FLT3

and IDH Mutation–Positive AML

Tumor Board:

A 65-Year-Old Woman With Newly Diagnosed AML

• Carol is a fit 65-year-old woman with fatigue, presyncopal symptoms, and night sweats

• CBC: WBC 75,000/mcL, Hb 7.6 g/dL, platelets 22,000/mcL

• Bone marrow: 85% blasts in 95% cellular marrow; karyotype: 46, XX [20]

• Additional testing: FLT3-ITD+ (allelic ratio, 0.8), NPM1+, and DNMT3A+

• Therapy: 7+3 plus midostaurin followed by intermediate dose ARA-C with midostaurin

For discussion: what are the options for Carol?

Does the allelic ratio affect your treatment decisions?

What are the toxicities associated with midostaurin use in this setting?

Maintenance midostaurin?

AlloHCT in first remission?

Tumor Board:

A 65-Year-Old Woman With Newly Diagnosed AML

• It has been 12 months since Carol has achieved CR1, and she is on midostaurin

maintenance

• She develops recurrent thrombocytopenia and relative monocytosis on surveillance blood

counts

• Bone marrow biopsy: 30% myeloid blasts with reduced trilineage hematopoiesis

For discussion: what next?

Role of repeat mutational analysis

Review ADMIRAL trial: gilteritinib versus chemotherapy

Combination of gilteritinib with chemotherapy?

AlloHCT?

Overall, results showed improved OS and response with gilteritinib vs chemotherapy

ADMIRAL Trial: Gilteritinib Versus

Salvage Chemotherapy in Relapsed AML1

1. Perl A et al. N Engl J Med. 2019;381:1728-1740.

Response,

n (%) Gilteritinib

Salvage

Chemotherapy

CR 52 (21) 13 (11)

CRc

(CR, CRi,

CRp)

134 (54) 27 (22)

CR/CRh 84 (34) 19 (15)

0

20

40

60

80

100

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

1. Perl A et al. N Engl J Med. 2019;381:1728-1740.

ADMIRAL Trial: OS in Patients

Restarting Versus Stopping Gilteritinib1

No. at Risk

Resumed gilteritinib 35 29 22 17 12 6 2 2 1 0 0 0 0

Stopped gilteritinib 16 9 7 6 5 2 1 0 0 0 0 0 0

HR = 0.387 (95% CI, 0.164-0.915)

P = .024

Su

rviv

al P

rob

ab

ilit

y, %

Time From 60 Days After HCT, mo

Median OS, mo (95% CI)

Resumed gilteritinib 16.2 (9.8-NE)

Stopped gilteritinib 8.4 (2.8-19.3)

Censored –

Tumor Board:

What If Carol Presented With an IDH1 Mutation?

• Carol is a 70-year-old woman experiencing fatigue, presyncopal symptoms, night sweats

• PMH: hyperlipidemia and hypertension; PS = 2

• CBC: WBC 2,000/mcL, Hb 7.6 g/dL, platelets 22,000/mcL

• BM aspirate: 60% myeloid blasts with multilineage dysplasia; karyotype: 46, XX [20]

• Additional testing: PCR for IDH1 R132+, PCR for FLT3-ITD, and TKD negative


HMA with venetoclax?

Ivosidenib alone or with azacitidine?

HMA, venetoclax + ivosidenib?

CPX-351 versus 7+3?

• Expected safety profile; longer treatment cycles required with

the “triplet” combination including azacitidine (cohort 3)

• Composite complete remission seen in 80% of enrolled

patients, including 63% of patients with R/R AML

Note: 7 of 8 patients in cohort 3 had received prior therapy, including 2 with relapsed MDS and 3 with secondary AML from MDS.

1. DiNardo CD et al. EHA 2020. Abstract S143.

Ivosidenib Plus Venetoclax ± Azacitidine1

Demographics All CR

(CR/CRh/CRi)

MRD Neg

(n = 8)

MRD Pos/Ind

(n = 8)

Cohort 1, N (%) 4/6 2 (50) 2 (50)

Cohort 2, N (%) 6/6 2 (33) 4 (67)

Cohort 3, N (%) 6/8 4 (67) 2 (33)

Disease subgroup

MDS 4 2 (50) 2 (50)

De novo AML 3 1 (33) 2 (67)

sAML/ts-AML 4 2 (50) 2 (50)

R/R (AML/MDS) 5 3 (60) 2 (40)

PD 6 (of 16) – 6 (100)

Median DOR,

mo (95% CI) 5.7 (1-23) NR 3.0 (1.5-4.6)

Overall Survival

Su

rviv

ing

, %

Time, mo

MRD neg (n = 8)

MRD pos/ind (n = 8)

• Undetectable MRD by flow in 50% of responding

patients was associated with excellent duration of

ongoing response

27 28 28 29

39.5

45

0

5

10

15

20

25

30

35

40

45

50

Cycle 1 Cycle 2

Days/C

ycle

, m

ed

ian

Cohort 1 Cohort 2 Cohort 3

N

6 6 8

N

6 6 6

update

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 2 4 6 8 10 12 14 16 18 20 22 24

Tumor Board:

Carol’s Case Reimagined

• Carol is a 70-year-old woman with MDS with ASXL1 mutation only

• Treated with azacitidine for the past 3 years with hematologic response

• PMH: coronary artery disease, grade 3A chronic renal failure, diabetes

• She develops progressive neutropenia and thrombocytopenia


What would you do next?

LDAC + venetoclax?

Decitabine + venetoclax?

Glasdegib + LDAC?

Tumor Board:

Carol’s Case Reimagined

• Carol is a 70-year-old woman with MDS with ASXL1 mutation only

• Treated with azacitidine for the past 3 years with hematologic response

• PMH: coronary artery disease, grade 3A chronic renal failure, diabetes

• She develops progressive neutropenia and thrombocytopenia


• Additional testing: PCR for IDH2 R140+, PCR for FLT3-ITD, and TKD negative


Enasidenib alone or with HMA?

HMA, venetoclax + enasidenib?

Enasidenib Plus AZA in Newly Diagnosed AML

Response Summary1

1. DiNardo C et al. ASCO 2020. Abstract 7501.

ORR and CR

substantially

higher with

combination

therapy

ENA + AZA (n = 68) AZA Only (n = 33)

Overall response (CR, CRi/CRp, PR, MLFS), n (%) 48 (71) 14 (42)

ORR (95% CI) (58-81) (26-61)

CR, n (%) 36 (53) 4 (12)

CR rate (95% CI) (41-65) (3-28)

CRi/CRp, n (%) 7 (10) 4 (12)

ENA + AZA

(n = 68)

AZA Only

(n = 32)

n (%)

Any grade 3 or 4 TEAE 50 (74) 20 (63)

Thrombocytopenia 25 (37) 6 (19)

Neutropenia 24 (35) 7 (22)

Anemia 13 (19) 7 (22)

Febrile neutropenia 10 (15) 5 (16)

IDH-DS 7 (10) 0

P = .0064

P = .0001

Enasidenib +

AZA generally

well-tolerated

with a safety

profile similar to

the monotherapy

experience with

these agents

Review Committee Amended Protocol

for IDH-DS Diagnosis and Management1

a Typical onset is between 7-10 days and 5 months from start of enasidenib treatment or reinitiation of enasidenib after prolonged treatment interruption. b Owing to the

long half-life of enasidenib, treatment may not immediately reverse symptoms of IDH-DS.

1. Fathi AT et al. JAMA Oncol. 2018 ;4:1106-1110.

Suspicion of IDH-DS

New onset or worsening

of characteristic

symptoms of

unexplained etiology,

including fever, rapid

weight gain or edema,

respiratory symptoms

with or without

infiltrates, pleural or

pericardial effusions,

hypotension, and acute

renal failurea

Initiate treatment with DEX,

10 mg twice daily, as

indicated

• Empiric therapy for other

possible causes (eg,

anti-infective agents)

• Hydroxyurea for

management of

co-occurring leukocytosis

• Hyperuricemia agents

for co-occurring tumor

lysis syndrome

Hospitalization indicated in setting of

rapidly progressing symptoms (especially

respiratory symptoms), development of

hypoxia, renal failure, rising WBC count, or

DIC

• Stop/interrupt enasidenib treatmentb

Improvement

of IDH-DS

signs/symptoms

Continue DEX until

significant improvement

or resolution of signs/

symptoms, then taper

per institutional

guidelines

Older Patients with AML: What Are the Current Guidelines?1

1. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. Version 3.2020. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf.

Candidate

for Intensive

Therapy? Yes No

• Lower intensity therapy (HMAs or LDAC; HMAs +

sorafenib for FLT3-mutated AML)

• Venetoclax + azacitidine or decitabine or LDAC

• Glasdegib + LDAC

• Gemtuzumab ozogamicin (CD33-positive)

• Enasidenib (IDH2-mutated AML) or ivosidenib

(IDH1-mutated AML)

• BSC

• Standard-dose cytarabine + idarubicin or daunorubicin or mitoxantrone

• Standard-dose cytarabine + daunorubicin and gemtuzumab ozogamicin (CD33-positive) (also

recommended for intermediate-risk AML)

• Lower intensity therapy (HMAs)

• Venetoclax + decitabine or azacitidine or LDAC

• Standard-dose cytarabine + idarubicin or daunorubicin or mitoxantrone

• CPX-351 for therapy-related AML other than CBF/APL, or patients with antecedent MDS/CMML, or

AML-MRC (category 1)

Assess

Prognostic

Features

Unfavorable

Prognostic

Features

Favorable Risk

Induction Therapy, Patients Aged ≥60 Years

Subsequent reduced-intensity

HCT an option

• Standard-dose cytarabine + daunorubicin + midostaurin FLT3-Mutated

Visit us at: PeerView.com/AML-Live

• Download slides and Practice Aids

• Watch the uncut version of this event

• Request a live meeting at your institution

• Join the conversation on Twitter @PeerView

Thank you and good evening.

Please remember to complete and submit your Post-Test

and Evaluation for CME/MOC credit.

Missed anything?

update

alloHCT: allogeneic hematopoietic stem cell transplant

AML: acute myeloid leukemia

ANC: absolute neutrophil count

ARA-C: cytosine arabinoside

ASXL1: additional sex combs–like transcriptional regulator 1

AZA: azacitidine

BM: bone marrow

CBL: Cbl proto-oncogene

CD: cluster of differentiation

CMML: chronic myelomonocytic leukemia

CPX-351: liposomal cytarabine-daunorubicin

CR: complete response

CR1: first complete response

CRc: complete composite remission

CRh: complete remission with partial hematologic recovery

CRi: complete remission with incomplete hematologic

CRp: complete remission with incomplete platelet recovery

DEX: dexamethasone

DFS: disease-free survival

DIC: disseminated intravascular coagulation

DNMT3A: DNA methyltransferase 3 alpha

DOR: duration of response

EFS: event-free survival

ENA: enasidenib

EZH2: enhancer of zeste homolog 2

FLT3: FMS-like tyrosine kinase 3

HCT: hematopoietic stem cell transplant

HMA: hypomethylating agent

IDH: isocitrate dehydrogenase

IDH-DS: isocitrate dehydrogenase differentiation syndrome

ind: indeterminate

LDAC: low-dose cytarabine

MDACC: MD Anderson Cancer Center

MDS: myelodysplastic syndrome

Abbreviations

MLFS: morphologic leukemia-free state

MRC: myelodysplasia-related changes

MRD: minimal residual disease

NE: not evaluable

NF1: neurofibromin 1

NGS: next-generation sequencing

NPM1: nucleophosmin 1

ORR: overall response rate

PD: progressive disease

PMH: past medical history

pos: positive

PR: partial response

PS: performance status

R/R: relapsed/refractory

RFS: relapse-free survival

sAML: secondary acute myeloid leukemia

SCT: stem cell transplantation

SRSF2: serine/arginine-rich splicing factor 2

STAG2: stromal antigen 2

TEAE: treatment-emergent adverse event

TET2: ten-eleven translocation 2

TKD: tyrosine kinase domain

TP53: tumor protein 53

VEN: venetoclax

Abbreviations

transforming modern care in aml€¦ · transforming modern care in aml clinical solutions with...

Documents