transforming modern care in aml€¦ · transforming modern care in aml clinical solutions with...
TRANSCRIPT
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.
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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.
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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.
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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.
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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
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 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
1. Lancet JE et al. J Clin Oncol. 2018;36:2684-2692.
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
1. Lancet JE et al. J Clin Oncol. 2018;36:2684-2692.
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
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
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
Seminar and Tumor Board
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
Seminar and Tumor Board
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
For discussion: what are the options for Carol?
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
• BM aspirate: 60% myeloid blasts with multilineage dysplasia; karyotype: 46, XX [20]
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
• BM aspirate: 60% myeloid blasts with multilineage dysplasia; karyotype: 46, XX [20]
• Additional testing: PCR for IDH2 R140+, PCR for FLT3-ITD, and TKD negative
For discussion: what are the options for Carol?
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
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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