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