1. Acute Myeloid Leukemia - 2015
Olga Frankfurt, MD
Robert H. Lurie Comprehensive Cancer Center
Northwestern University
Chicago, IL

2. 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

3. Normally, the bone marrow makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. A lymphoid stem cell becomes a white blood cell.
In AML, the myeloid stem cells usually become a type of immature white blood cell called myeloblasts (or myeloid blasts). The myeloblasts in AML are abnormal and do not become healthy white blood cells. Sometimes in AML, too many stem cells become abnormal red blood cells or platelets. These abnormal white blood cells, red blood cells, or platelets are also called leukemia cells or blasts. Leukemia cells can build up in the bone marrow and blood so there is less room for healthy white blood cells, red blood cells, and platelets. When this happens, infection, anemia, or easy bleeding may occur. The leukemia cells can spread outside the blood to other parts of the body, including the central nervous system (brain and spinal cord), skin, and gums.

4. Acute Myeloid Leukemia (AML)
New patients/deaths in 2014: 18,860/10,460
Median age: 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

5. AML Age-Specific Incidence Rates24
Incidence/100,000 22 20 18 16 14 12 10 8 6 4 2
0-4
5-9
85+
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
Age (y)
NCI-SEER Program

6. 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
Bnezene is the best-documented environmental leukemogens. Patients vary in their ability to metabolize benzene, suggesting that genetic and environmental factor predispose to the development of AML
TMPD; 20% AML
Primarily megakaryocytic (M7) associated with GATA1 mutation
GATA 1 zink finger transcription factor important for the erythro and thrombopoesis
Bloom syndrome also known as Bloom–Torre–Machacek syndrome is a rare autosomal recessive chromosomal disorder characterized by a high frequency of breaks and rearrangements in an affected person's chromosomes. The condition was discovered and first described by dermatologist Dr. David Bloom in 1954.

7. Risk Factors for Developing AML
Previous chemotherapy
Alkylating agents
del 5 and del 7
years latency
Epipodophyllotoxins (etoposide, anthracyclines)
Monocytic differentiation
11q23
1-3 years after exposure
Evolving from the prior antecedent hematologic disorder
Some alkylating agents are active under conditions present in cells; and the same mechanism that makes them toxic allows them to be used as anti-cancer drugs. They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically.
Nitrogen mustards[7]
Cyclophosphamide
Mechlorethamine or mustine (HN2)
Uramustine or uracil mustard
Melphalan
Chlorambucil
Ifosfamide
Nitrosoureas
Carmustine
Lomustine
Streptozocin
Alkyl sulfonates
Busulfan
Anthracycline has three mechanisms of action:
Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells.[6]
Inhibits topoiosomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication.
Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes

8. Molecular Pathogenesis of AML
Class I mutations – activating mutations
Class II mutations – inducing differentiation stop
confers proliferative and/or survival advantage
aberrant activation of signal transduction pathways
Ras, RTK KIT and FLT3, loss of function of NF-1, gain of function SHP-2
mutations in the transcription factors or transcriptional co-activators
CBF transcription complex [inv16/t(16;16) and t(8;21)], PML-RARα t(15;17)
AML, like other human cancers, is consequence of more than one mutation. Epidemiologic and genotypic data have shown that many AML cells have more than once recurring mutation, either as point mutation, gene rearrangements and/or chromosomal translocations. Data from animal models of leukemia strongly support a multistep pathogenesis of the disease.
It was demonstrated that different fusion transcript types that are specific for diverse AML subtypes cal already originate in utero. The AML-ETO, PML-RAR alpha, and MLL rearrangements were retrospectively detected in the blood from Guthrie cards that have been preserved from children who had developed the respective AMLe at young age. The long interval between birth and the clinical manifestation of leukemia ( up to 10 years) indicates that above fusion transcripts are not able to cause leukemia on their own but need a cooperation with additional secondary genetic alterations.
The concept that capillary blood, obtained from pricking the heel or finger and blotted onto filter paper, could be used to screen for metabolic diseases in large populations of neonates was introduced in Scotland by Robert Guthrie in Neonatal screening for phenylketonuria became nationwide in Since then, Guthrie card samples have been collected routinely from infants in over 20 countries to screen for phenylketonuria and more recently for congenital hypothyroidism, sickle cell disorders and HIV infection. The limitations of sensitivity and specificity when screening such small volumes of blood restricted the use of dried blood spots for many years. However, recent advances such as the production of monoclonal antibodies, expression of synthetic proteins, and the introduction of the polymerase chain reaction have overcome many of these problems.[1]
This type of blood testing is now available for use at home by consumers in the U.S. Available blood tests include Vitamin D, estrogen, testosterone, cortisol, TSH and lipids. New York is the only state that prohibits home blood spot testing.

9. Clinical Features of AML
Constitutional symptoms
Infections
Abnormal blood counts
Complications related to the high WBC
Coagulation abnormalities
Metabolic abnormalities
Extramedullary tissue
The clinical manifestations of AML reflect a maturation arrest of normal marrow precursors or their replacement by AML cells.

10. Morphology
peripheral blood smear
bone marrow core biopsy

11. 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

12. Evolution of Prognostic Factors in AML
Prior to 1980s
Age, performance status, WBC, antecedent hematologic disorder
1980s – 1990s
Cytogenetics
Favorable
Intermediate
Unfavorable
1990s – 2010s
Molecular genetics (FLT3, MLL, NPM1, CEBPα, c-KIT, IDH1,2, TET2) and growing
Next Generation Sequencing
Over the last decades, our understanding of the prognosis of AML has grown substantially.
Prior to the 1980s – age, WBC, and antecedent hematologic disorder were the only known prognostic factors with older age, higher WBC ct at dx, and antecedent hematologic disorder being negative.
From the 1980s-1990s – cytogenetics became prognostically relevant
And in the 1990s and early 2000s, the role of molecular genetics hit the forefront; predominantly to further characterize prognosis in those cases of normal karyotype; what we traditionally considered intermediate prognosis.
We now understand that there are interactions between genes. As new mutations are identified and their interactions are recognized, our understanding of their role in prognosis will be further refined.

13. 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):

14. Overall Survival by Cytogenetic Group
Years After Entering Study 20 40 60 80
100 2
Cumulative Percentage 8 4 6
Favorable %
Intermediate %
Unfavorable %
Estimate
At Risk Deaths at 5 Years
Heterogeneity of 3 Groups: P <
Favorable
Intermediate
Unfavorable
Slovak ML, et al. Blood. 2000;96(13):

15. 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

16. Current AMLTherapy-2015 Younger Adults
Induction: dauno 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

17. Current AMLTherapy-2015 Older Adults
Decision: chemotherapy vs. hypomethylating agent
Intensive Chemotherapy
Induction: dauno 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

18. 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)
Chimeric antigen receptor therapy

19. 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

20. 312 695-6180 Academic Office 312 695-0990 Cancer Center
Olga Frankfurt, MD
Co-director - Leukemia Program
Director - Chronic Leukemia/MDS
Associate Director for Umbilical Cord Blood Transplantation
Robert H. Lurie Comprehensive Cancer Center, Northwestern Medicine