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ACUTE MYELOID LEUKEMIA
1. Jeffrey Lancet, MD
Chair - Malignant Hematology
Sara Tinsley, PhD, ARNP, AOCN
Nurse Practitioner - Malignant Hematology
Game Changer: New Treatments in AML
2. Objectives
• Identify new strategies for management of AML
based on recent FDA approved agents
• Review mutations in AML that provide targets for
new therapies
• Discuss approaches for incorporating
immunotherapy in AML treatment algorithm
3. AML – A Major Therapeutic Challenge
100
80
60
40
20
0 1 2 3 4 5 6 7 8 9 10
Time (years)
Survival(%)
Age, years
< 50
50-64
65-74
≥ 75
0
5
10
15
20
25
<20 20-34 35-44 45-54 55-64 65-74 75-84 >84
PercentofNewCases
Age
Percent of New AML Cases by Age Group
5.3 6.0 5.7
10.1
16.9
23.0 22.6
10.4
1. Surveillance, Epidemiology, and End Results (SEER) Program Populations. AML (1988-2012). 2. Surveillance, Epidemiology, and End Results
(SEER) Program Populations AML (2009-2013).
4. Traditional and New Prognostic Factors in AML1,2
Pretreatment
Age
WBC at presentation
Comorbid conditions
Antecedent hematologic disorder
Cytogenetics
Molecular abnormalities
Prognostic Factors
in AML
1. Grimwade D, Hills RK. Hematology Am Soc Hematol Educ Program. 2009:385-395. 2. National Comprehensive Cancer Network (NCCN)
Clinical Practice Guidelines in Oncology. Acute myeloid leukemia. Version 1.2017.
5. Traditional and New Prognostic Factors in AML1,2
Pretreatment
Age
WBC at presentation
Comorbid conditions
Antecedent hematologic disorder
Molecular abnormalities
Favorable risk: Normal cytogenetics; NPM1 mutation or isolated CEBPA mutation in the absence
of FLT3
Intermediate risk: Core binding factor with KIT mutation
Poor risk: Normal cytogenetics with FLT3/ITD mutation; TP53 mutation
Favorable risk:
Core binding factor: inv(16) or t(16;16) or
t(8;21); t(15;17)
Intermediate risk:
Normal cytogenetics; +8 alone; t(9;11); Other
nondefined
Poor risk:
Complex (≥3 chromosomal abnormalities)
Monosomal karyotype
-5, 5q-, -7, 7q-; 11q23 [non-t(9;11)]
inv(3), t(3;3); t(6;9) (rare); t(9;22) (rare)
Prognostic Factors
in AML
1. Grimwade D, Hills RK. Hematology Am Soc Hematol Educ Program. 2009:385-395. 2. National Comprehensive
Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Acute myeloid leukemia. Version 1.2017.
Cytogenetics
6. European Leukemia Net (ELN) Guidelines:
AML Genetic-Cytogenetic Prognostic Subgroups
Genetic Risk Group Subset
Favorable
• t(8;21)(q22;q22); RUNX1-RUNX1T1
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
• Mutated NPM1 without FLT3-ITD (normal karyotype) or with FLT3-ITDlow
• Biallelic mutated CEBPA
Intermediate
• Mutated NPM1 and FLT3-ITDhigh
• Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse genetics)
• t(9;11)(p22;q23); MLLT3-KMT2A
• Cytogenetic abnormalities not classified as favorable or adverse
Adverse
• inv(3)(q21q26.2) or t(3;3)(q21;q26.2); GATA1,mECOM(EVI1)
• t(6;9)(p23;q34); DEK-NUP214
• t(v;11)(v;q23); KMT2A rearranged
• t(9;22)(q34.1;q11.2); BCR-ABL1
• -5 or del(5q); -7; -17/abn(17p)
• Complex karyotype, monosomal karyotype
• Wild type NPM1 and FLT3-ITDhigh
• Mutated RUNX1
• Mutated ASXL1
• Mutated TP53
Dohner, et al. Blood 2017; 129:424
7. European Leukemia Net (ELN) Guidelines:
AML Genetic-Cytogenetic Prognostic Subgroups
Age < 60 Age > 60
Mrozek, et al. J Clin Oncol 2012; 30:4515
8. AML is a Complex Biological Disease
Dohner, et al. Blood 2017; 129:424
9. Marker % Prognosis
FLT3/ITD mutation 30 Worse
NPM1 mutation ~35 Better
IDH1/2 mutations 18-20 Worse or neutral
c-KIT mutation (CBF) 15 Worse
Bcl-2 Majority Worse
MLL PTD 7 Worse
DNMT3A mutation 22 Worse
ASXL1;TET2 10 Worse; epigenetic modulation
p53 mutation 5-20 Very poor
EVI1 expression 10 Very poor
A Closer Look at Mutations
of Prognostic Relevance in AML
10. Case Study: De Novo FLT3-Mutant AML
• 30 year old female presented with WBC of 120,00,
hemoglobin of 6.2g/dL, and platelets of 20,000
• BMBX performed and revealed hypercellular marrow with
60% blasts, normal cytogenetics, and FLT3 ITD mutation,
NPM1 negative
• No comorbidities
• No routine medications
11. Question 1: What therapeutic plan should be
undertaken at this time?
A. Add midostaurin 50 mg/day on Days 8-21 to induction
B. Induction chemotherapy with Daunorubicin and Cytarabine
C. Add gemtuzumab ozogamicin 3 mg/m2
D. Repeat BMBx at Day 14-21, and if continued positivity for
FLT3-ITD, add midostaurin during consolidation Cycle 1
E. Daunorubicin,Cytarabine, and midostaurin 50mg days 8-21
12. Activating FLT3 Mutations in AML
Litzow MR. Blood. 2005;106:3331-3332; Stone R et al. Poster at 2011
ASCO Annual Meeting. Abstract TPS199.
Characterized by
high relapse rate,
poor prognosis
Immunoglobulin-like
loops
Extracellular
Transmembrane
domain
Juxtamembrane
domain
Kinase 1 domain
Kinase 2 domain
C-terminus
TK Domain
5% to 10%
IT Duplication
25% to 30%
14. Overall Survival
Median OS (months): Midostaurin 74.7 (31.7-NE); Placebo 25.6 (18.6-42.9)
Arm 4-Year Survival
Midostaurin 51.4% (95%CI: 46, 57)
Placebo 44.2% (95%CI: 39, 50)
+ Censor
Hazard Ratio: 0.77
1-sided log-rank P value*: 0.0074
Stone RM, et al. N Engl J Med 2017; 377:454.
15. Key Points
• Midostaurin improves survival and response rates in FLT3-
mutated AML
– Effect is independent of FLT3 mutation allelic burden
• Administration
– 50 mg/day on days 8-21
– Continue during consolidation
– Role in maintenance is unclear
• Likely induces disease-modifying effect independent of
transplant
• Most common side effects include GI, cytopenias.
• Combination with Gemtuzumab is not studied
16. Selective, Potent FLT3 Inhibitors
Drug
Half-life
(Dosing)
D835
Activity
Single
Agent
Frontline CT
Combinations
Post-HSCT
Maintenance
Quizartinib
(AC220)
Long;
once daily
No
Phase 3
open
Phase 3 ongoing
Pilot study
completed, included
in phase 3
Crenolanib
Short;
TID
Yes
Phase 2
completed
Phase 2 ongoing Phase 2 ongoing
Gilteritinib
(ASP2215)
Long;
once daily
Yes
Phase 3
open
Phase 1/2 ongoing
Pilot study
completed,
phase 3 planned
17. Case Study: AML with MDS changes
• 70-yr-old man with history of MDS, diagnosed 2015
– WHO subtype: RAEB-1
– Cytogenetics: 46 XY
– R-IPSS: intermediate
– Supportive care only
• March 2017 – change in blood counts
– WBC 1.4 x 103/µL, Hb 7.7 g/dL, Plts 17 x 103/µL
– Differential with 22% neutrophils, 12% blasts, 63%
lymphocytes
– ECOG PS 0; swims 1/2 mile per day
– No significant comorbidities except for osteoarthritis
18. Case Study: AML with MDS changes
• Bone marrow aspirate/biopsy
– 90% cellularity, trilineal dysplasia
– 31% blasts
– Cytogenetics: del 7q (12/20 metaphases)
• Next generation sequencing
– SRSF2 mutation
– CBL mutation
19. Question: What is the optimal therapeutic plan?
A. Begin induction chemotherapy with daunorubicin + cytarabine
B. Begin azacitidine 75 mg/m2 x 7 days, every 4 weeks
C. Begin gemtuzumab ozogamicin + azacitidine
D. Begin CPX-351
E. Supportive care and immediate hospice consultation
20. 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
daunorubicin
cytarabine
Cu++
Feldman, et al. J Clin Oncol 2011;29:979
21. CPX-351 Phase III Study Design
• Randomized, open-label, parallel-arm, standard therapy–controlled
– 1:1 randomization, enrolled from December 2012 to November 2014
– Patients with complete response (CR) or CR with incomplete platelet or neutrophil
recovery (CRi) were to be considered for allogeneic HCT, based on institutional
criteria
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/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.
CPX-351 (n=73)
7+3 (n=52)
22. Randomized Phase 3 Trial of CPX-351 vs
7+3 in Older Patients With Secondary AML
Lancet JE et al. ASCO. 2016.
CR + CRi – 47%
CR + CRi – 33%
23. Survival Landmarked from Time of Transplant
23
• CPX-351 median OS not reached vs 10.25 months for 7+3
– HR of 0.46 favoring CPX-351 (P=0.0046)
Median follow-up:
- CPX-351 = 531 days (96-983)
- 7+3 = 442 days (316-650)
Lancet, et al. ASH 2016; abstract 906
25. Summary
• CPX-351 indicated for newly diagnosed secondary AML
(patients suitable for induction chemotherapy)
• Common side effects include delayed count recovery,
infection, rash
• May provide effective bridge to transplant
• Typically not reimbursable for inpatient administration currently
26. Case Study: IDH2 mutation
• 79-yr-old female - history of COPD, Type 2 DM
• Evaluated for 2-mo history of worsening fatigue, SOB with
exertion
– ECOG PS 2
• Laboratory: WBC of 2.8 x 103/µL, Hb 8.1 g/dL, Plts 46 x 103/µL
– Differential with 30% neutrophils, 4% bands, 57%
lymphocytes, 3% eosinophils, 5% monocytes, 1% blasts
– Chemistries: creatinine 0.9 g/dL, LFT normal
• Bone marrow biopsy/aspirate
– Hypercellular (95%), with increased blasts (42%)
– Cytogenetics – 46 XX
– NGS – mutations of SRSF2, IDH2
27. Asks About QOL—How Do You Answer?
1. Watch out for the “age bias”:
2. Given patient’s functional
status, she is unlikely to
benefit from intensive
treatment
1. Be prepared to discuss the
options and remember that
undertreatment is a concern
Intensive
chemo
patients
• Had a significant
improvement in
QOL scores at
one month
QOL
predictors
• Fatigue
• Comorbidity NOT
predictive
Remember, older
patients can
tolerate intensive
treatment …
… and have
improvements in
QOL
In one
recent
QOL study
in older
AML1
Non-intensive chemo
patients had stable QOL
at 1 month
1. Tinsley SM et al. ASH 2015. Abstract 2112.
28. Question: Which of the following treatments would
you recommend?
A. CPX-351
B. Standard-dose daunorubicin + cytarabine
C. Decitabine 20 mg/m2 x 5 d, every 4 weeks
D. Decitabine 20 mg/m2 x 10 d, every 4 weeks
E. Low-dose cytarabine, 20 mg BID x 10 days
F. Enasidenib (AG-221)
G. Comfort care only/hospice
34. Key points
• Enasidenib indicated for IDH2-mutated relapsed/refractory AML
• Significant single-agent response activity
• Responses may be delayed – reports of time to response up to
6 months
• Differentiation syndrome is a rare, but potentially fatal adverse
event
– Characterized by fever, hypoxia, pulmonary infiltrates
– Manage by discontinuation of Enasidenib and oral steroid
therapy until symptoms resolved
• Variable rate of mutation clearance amongst responders
35. Gemutuzumab Ozogamicin
- Approved initially in 2001 for relapsed AML, CD33+, age > 60
- Withdrawn from commercial market in 2010 amidst concerns for toxicity
and lack of proven benefit in randomized studies
36. Gemtuzumab in newly diagnosed AML
Hills RK, et al. Lancet Oncol 2014; 15:986
37. Addition of Gemtuzumab Ozogamicin to
Induction Chemotherapy
• Gemtuzumab ozogamicin 3 mg/m2 on Days 1, 4, 7 of Induction and Day 1 of each
Consolidation cycle
Overall survival Relapse-free survival
Castaigne S, et al. Lancet. 2012;379:1508-1516.
38. Summary – Gemtuzumab Ozogamicin
• Indicated in newly diagnosed AML, age 18-70, CD33+, with
intermediate or favorable karyotype
• Single dose of 3 mg/m2 on day 1 is equivalent to 6 mg/m2 on
days 1, 4, 7 – in combination with “7+3” induction
– Reduced risk of VOD and 30/60 day mortality
• Role in FLT3-mutated AML, in setting of Midostaurin, is unknown
Burnett, et al. Haematologica 2016; 101:724
39. Addition of Gemtuzumab Ozogamicin to Induction
Chemotherapy
• 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. Slide credit: clinicaloptions.com
40. Addition of Gemtuzumab Ozogamicin to
Induction in AML – AML15 Trial
Favorable Karyotype AML
Burnett AK, et al. J Clin Oncol. 2011;29:368-377. Slide credit: clinicaloptions.com
Gemtuzumab ozogamicin
No gemtuzumab ozogamicin
Gemtuzumab ozogamicin
41. Phase III: Azacitidine vs CCR in Elderly AML With
Low Blast Count
• N = 113 older pts with 20% to 29% blasts (WHO-defined AML)
– Median age: 70 yrs; poor cytogenetics: 24%
– Azacitidine: n = 55; conventional care: n = 58
• Intensive chemotherapy: n = 11; LDAC: n = 20; BSC: n = 27
• Median follow-up: 20 mos; median cycles: 8 (range: 1-39)
Parameter AZA CCR P Value
CR, % 18.0 16.0 NS
Median OS, mos 24.5 16.0 .005
Hospitalization, PY 3.4 4.3 .05
Infection, PY 0.6 1.1 .003
Fenaux P, et al. J Clin Oncol. 2010;28:562-569.
Slide credit: clinicaloptions.com
42. Outcomes With Various Treatment
Approaches in AML Age > 70 Yrs
Dhulipala VC, et al. ASH 2015. Abstract 2505. Slide credit: clinicaloptions.com
44. Extended (10-Day) Decitabine in TP53-
Mutated AML
Welch JS, et al. N Engl J Med. 2016;375:2023-2036. Slide credit: clinicaloptions.com
Clearance Rate of TP53 Mutations Survival After SCT, by TP53 Mutation Status
45. New Azanucleoside-Based Combinatorial
Approaches in Elderly AML
Slide credit: clinicaloptions.com
Approach Study Phase Status
Azacitidine + durvalumab NCT02775903 II Enrolling
Azacitidine + ensadienib or AG-120 NCT02677922 I/II Enrolling
Azacitidine ± venetoclax NCT02993523 III Enrolling
Low-dose cytarabine ± venetoclax NCT03069352 III Enrolling
Azacitidine + glasdegib NCT02367456 I Enrolling
46. Phase I/II Study of Venetoclax + LDAC in Untreated
AML Pts Aged ≥ 65 Yrs
• Endpoints: safety, PK, MTD, RP2D, response, DoR, OS, biomarkers
Welch JS, et al. N Engl J Med. 2016;375:2023-2036. Slide credit: clinicaloptions.com
Pts with untreated
AML, aged ≥ 65 yrs,
ECOG PS 0-2, not
eligible for standard
induction tx
Venetoclax 600 or 800 mg QD +
Cytarabine 20 mg/m2 SC on
Days 1-10 of 28-d cycles
(N = 18)
Venetoclax 600 mg QD +
Cytarabine 20 mg/m2 SC on
Days 1-10 of 28-d cycles
(N = 53)
Phase I (3 + 3) Phase II
47. Summary
• AML is complex and heterogeneous, with many potential targets
• Treatment appears superior to supportive care, even in more
frail, elderly patients
• Limited data to indicate benefits of lower- vs higher-intensity
approach in older patients with AML
– Retrospective data indicate similar efficacy
– Prospective trials or validation lacking
Slide credit: clinicaloptions.com
Editor's Notes
To the right are cytogenetic risk categories divided into favorable, intermediate, and poor risk.
Along the bottom, one can see how the incorporation of molecular abnormalities can move the risk category from favorable to intermediate for the core binding factor leukemias with inversion 16 and translocation 8:21 in the presents of cKit mutation.
In addition, you can see you the mutations can move a normal cytogenetic risk category from favorable to poor depending on the presence or absence of FLT3 ITD.
This is a closer look at mutations and their prognostic relevance for patients with AML, and also in the second column, you can see the percentage of cases affected. One thing I would like to mention, these mutations can emerge as you are treating patients, so when the marrow is repeated for suspected progression, it is important to recheck mutations.
At the bottom, the p53 and increased EVl1 expression are very poor. The way that we use these markers currently, is to help us plan the best treatment for each patient. Some of these are targetable with therapy, such as FLT3/ITD and IDH1/2, and others are not targetable with therapy, such as ASXL1 and TET2.
Answer: A. Add midostaurin 50 mg/day on days 8-21
Answer D. Begin CPX-351
Outcomes Question?: Yes
Aligned learning objective (if applicable): Summarize current evidence on the benefits of standard chemotherapy-based protocols and emerging therapies for the treatment of AML, including in elderly patients, those with relapsed/refractory disease, or patients with poor-risk cytogenetics
Optimal Answer(s): D. Begin CPX-351
Slide number(s) showing the “informing” content: Slide 34 (First-line CPX-351 in Newly Diagnosed Elderly AML: Phase II Study 204)
Answer explanation (why is the optimal answer correct, and the others are not): CPX-351 is approved for patients with therapy-related AML or a history of myelodysplastic syndromes. This patient has a history of MDS.. In a phase II study of elderly fit patients with newly diagnosed AML, patients treated with CPX-351 had a higher rate of CR/CRi vs those treated with standard daunorubicin/cytarabine therapy. Gemtuzumab ozogamicin shows greater efficacy in younger patients with favorable karyotype rather than older patients. As an active 70-year-old with a PS of 0, the patient is better served with aggressive treatment rather than supportive care alone.
Question context description (why is this question important to test on): With new treatment options for induction therapy in AML, it is essential for clinicians to be able to differentiate old and new treatment strategies to individualize patient care for optimal outcomes.
21
AML, acute myeloid leukemia; AZA, azacitidine; BSC, best supportive care; CCR, conventional care regimen; LDAC, low-dose cytarabine; PY, patient-year; WHO, World Health Organization.
Fenaux and colleagues[1] conducted the phase III AZA-001 study, which compared azacitidine with conventional care regimens for patients with higher-risk MDS. Approximately one third of patients in this trial had AML by the World Health Organization definition of 20% to 29% blasts.
Patients in the AML subgroup (n = 113) who received azacitidine had a median OS similar to the overall population treated with azacitidine, about 24 months, which was 8-9 months longer than with conventional regimens.
Reference:
1. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28:562-569.
