olga frankfurt, md robert h. lurie comprehensive cancer center northwestern university chicago, il...
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Olga Frankfurt, MDRobert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicago, IL
Acute Myeloid Leukemia - 2015
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
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
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
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
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
Clinical Features of AML
Constitutional symptoms
Infections
Abnormal blood counts
Complications related to the high WBC
Coagulation abnormalities
Metabolic abnormalities
Extramedullary tissue
Morphology
peripheral blood smear
bone marrow core biopsy
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
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
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.
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.
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
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
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
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)
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
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