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![Page 1: Olga Frankfurt, MD Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago, IL Acute Myeloid Leukemia - 2015.](https://reader036.fdocuments.in/reader036/viewer/2022062421/56649e0b5503460f94af287f/html5/thumbnails/1.jpg)
Olga Frankfurt, MDRobert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicago, IL
Acute Myeloid Leukemia - 2015
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Acute Myeloid Leukemia (AML) AML is a group of blood
cancers in which the bone marrow makes abnormal immature blood cells
These cells also prevent the normal blood cells from maturation
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Acute Myeloid Leukemia (AML)
New patients/deaths in 2014: 18,860/10,460 Median age: 66 -72 years Heterogeneity in genetics, clinical features and
outcome Outcome improved among age <60 with
intensive post-remission strategies and transplantation
Prognostic factors exist; many new, molecular Role of transplantation continues to be refined Myriad of new agents available
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AML Age-Specific Incidence Rates
NCI-SEER Program
02468
1012141618202224
0-4
5-910
-14
15-1
9
20-2
4
25-2
9
30-3
4
35-3
9
40-4
4
45-4
9
50-5
4
55-5
960
-64
65-6
9
70-7
4
75-7
9
80-8
485
+
Age (y)
Inci
denc
e/10
0,00
0
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Risk Factors for Developing AML
Previous exposure to radiation
Environmental factors : tobacco, benzene
Genetic factors Down’s syndrome Fanconi’s anemia, Bloom syndrome Ataxia telangectasia
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Risk Factors for Developing AML
Previous chemotherapy Alkylating agents
del 5 and del 7 5 - 10 years latency
Epipodophyllotoxins (etoposide, anthracyclines) Monocytic differentiation 11q23 1-3 years after exposure
Evolving from the prior antecedent hematologic disorder
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Clinical Features of AML
Constitutional symptoms
Infections
Abnormal blood counts
Complications related to the high WBC
Coagulation abnormalities
Metabolic abnormalities
Extramedullary tissue
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Morphology
peripheral blood smear
bone marrow core biopsy
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Evaluation of Patient with AML
History and Physical Examination CBC with differential and platelet, peripheral
smear, CMP, uric acid, DIC panel, pregnancy test Bone marrow aspirate and biopsy/ Flow
cytometry Cytogenetics Molecular studies:
FLT3, NPM1, c-kit, CEBPα, IDH1, IDH2, k-RAS, n- RAS Next generation sequencing
HLA typing and eligibility for stem cell transplant Serologies: hepatitis, HIV, CMV Study specific correlative laboratory studies
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Evolution of Prognostic Factors in AML
Prior to 1980s
Age, performance status, WBC, antecedent hematologic disorder
1980s – 1990s
CytogeneticsCytogenetics Favorable Intermediate Unfavorable
1990s – 2010s
Molecular genetics Molecular genetics (FLT3, MLL, NPM1, CEBPα, c-KIT, IDH1,2, TET2) and growing
2010- 2015 Next Generation Next Generation SequencingSequencing
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Cytogenetic Risk Groups
Favorable inv(16); t(15;17) with any abn; t(8;21) lacking del(9q) or complex karyotype
Intermediate Normal or +8 or +21 or others
Unfavorable -5/del(5q), -7/del(7q), inv(3q), abn of 11q, 20q, 21q, 17p, del(9q), t(6;9), t(9;22), complex karyotypes with 3 abn Slovak ML, et al. Blood. 2000;96(13):4015-4083.
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Overall Survival by Cytogenetic Group
Years After Entering Study
0
20
40
60
80
100
0 2
Cum
ulati
ve P
erce
ntag
e
84 6
Favorable 121 53 55% Intermediate 278 168 38% Unfavorable 184 162 11%
Estimate At Risk Deaths at 5 Years
Heterogeneity of 3 Groups: P < 0.0001
Favorable
Intermediate
Unfavorable
Slovak ML, et al. Blood. 2000;96(13):4015-4083.
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Therapy for AML- Principles
Without therapy AML is fatal – days-months
The therapy for AML: Induction and Consolidation
Chemotherapy may cure selected patients and prolong survival in responding patients
Chemotherapy is toxic and can cause substantial morbidity and mortality
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Current AMLTherapy-2015 Younger Adults
Induction: dauno 60-90 mg/m2/d x 3d + ara-C 100/200 mg/m2/d x 7d CI.
Consolidation: high- or intermediate-dose ara-C (1-4 cycles)
Allogeneic HCT for intermediate- and high-risk Consider in CBF with c-KIT, FLT3 Not done in FLT3-/NPM1+ , CEBP+(double
mutation)
Paschka J Clin Oncol, 2006; Schlenk N Engl J Med, 2008; Green J Clin Oncol, 2010; Dohner Blood, 2010
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Current AMLTherapy-2015 Older Adults
Decision: chemotherapy vs. hypomethylating agent
Intensive Chemotherapy Induction: dauno 60-90 mg/m2/d x 3d + ara-C 100
mg/m2/d x 7d Consolidation: intermediate-dose ara-C (1-4 cycles);
no clear role in older adults
Low dose Chemotherapy
Hypomethylating agents: Dacogen:5 days course or 10 days course Vidaza : 7 days course
Reduced intensity HSCT
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Investigational Approaches AMLTherapy-2015
Autologous HSCT is not a standard of care; being studied
Maintenance is not a standard of care; being studied
Maintenance after allo HSCT is not a standard of care for AML; being studied; many use hypomethylating agents
Adding stem cells to expedite count recovery after the chemotherapy ; being studied
Adding agents that stimulate platelet recovery after chemotherapy is being studied
Altering the immune system to fight leukemia ( CAR-T cells)
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Selected Agents in Clinical Trials Chemotherapy - Clofarabine, CPX-351, Vosaroxin,
Elacytarabine Hypomethylating agents – Decitabine, Azacitidine FLT3 inhibitors – Sorafenib, Quizartinib, Crenolanib,
ASP2215 MLL inhibitors – EPZ-5676 IDH1 and IDH2 inhibitors, pan IDH inhibitor Glutaminase inhibitor CB-839 Exportin 1 inhibitor - Selinexor Polo-like kinase inhibitor - Volasertib C-kit inhibitors – Dasatinib mTOR inhibitors – Temsirolimus Histone deacetylase inhibitors – Vorinostat, Panobinostat Antibody conjugates Cycline-dependent kinase inhibitor – Flavoperidol Hedgehog inhibitors MEK1/2 inhibitors – Trametinib Aminopeptidase inhibitors – Tosedostat
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312 695-6180 Academic Office
312 695-0990 Cancer Center
Olga Frankfurt, MDCo-director - Leukemia Program
Director - Chronic Leukemia/MDS
Associate Director for Umbilical Cord Blood Transplantation
Robert H. Lurie Comprehensive Cancer Center, Northwestern Medicine