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TRANSCRIPT
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.
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8
10
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14
16
18
20
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<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