AML

Part 1
Learning Objectives
• Classification of Leukemia
• Definition of AML
• WHO classification of AML
• AML prognostic factors
• Classification of AML
• Signs & symptoms
• AML Diagnosis
• Recognize general principles of AML
treatment.
• Identify different treatment phases of
AML treatment.
Leukemia is a cancer of the early blood-forming cells
Acute Leukemia: A rapidly progressing cancer that starts in blood-forming
tissue such as the bone marrow, and causes large numbers of white
blood cells to be produced and enter the blood stream.

Classification of Leukemia
• Myeloid or Lymphoid (cell of origin)
• Acute or Chronic (severity)
1. Acute Myeloid Leukaemia (AML)
2. Chronic Myeloid Leukaemia (CML)
3. Acute Lymphoblastic Leukaemia (ALL)
4. Chronic Lymphocytic Leukaemia (CLL)
 How do we identify type of Leukemic cell??
Bone Marrow aspirate /core biopsy
- Morphology - Cytochemistry
-Immune phenotyping (IPT) by flowcytometry → CDs
◦ Takes advantage of the development of
monoclonal antibodies (MABs) to cell-surface
antigens that are differentially expressed during
hematopoietic differentiation.
◦ The antigens are referred to as cluster determinants (CDs) that define
cells at various stages of development and can easily separate ALL
from AML and T-cell from pre-B-cell ALL.
◦ Facilitated diagnosis and delivery of specific treatments for the major
subtypes of acute leukemia.
◦ The detailed information offered by flow cytometry and recognition of
several prognostic cytogenetic features has combined to more
narrowly predict prognosis and develop risk-directed therapies in ALL
and AML.

What is AML?
Acute myeloid leukemia (AML) is a heterogeneous hematologic
malignancy characterized by abnormal differentiation of cells of the
myeloid lineage, leading to clonal proliferation of leukemic blast cells in
the bone marrow, peripheral blood, and potentially extramedullary
tissue.This in turn leads to decreased production of normal hematopoietic
cells and associated complications related to ineffective hematopoiesis.

WHO Classification of AML and related neoplasms

1. AML with recurrent genetic abnormalities,
2. AML with myelodysplasia-related changes,
3. Therapy-related myeloid neoplasms,
4. AML not otherwise specified (NOS),
5. Blastic plasmacytoid dendritic cell neoplasm.

Diagnosis of AML
 • Peripheral blasts or bone marrow biopsy findings consistent with
AML should be present.
• Greater than or equal to 20% blasts (or blast equivalents) is required
for diagnosis of AML (WHO).
• Any percentage of blasts can be considered AML if they display any
of following karyotypes:
a. t(8;21)
b. Inversion (16) or t(16;16)
c. t(15;17)

AML prognostic Factors

“predictive biomarkers for treatment”
1. Patient-specific factors
A. Performance status & comorbidities
B. Total WBC at diagnosis
Age ≥ 60 years is associated with:
• decreased overall survival due to difficulty tolerating therapy
• higher likelihood of antecedent MDS
• Poor risk cytogenetics/ molecular characteristics

2. AML biology-specific factors

AML is a heterogeneous malignancy that is associated
with different outcomes depending on the biology of the
cancer clone.
A. karyotype
the strongest prognostic factor for response to induction therapy
and survival (favorable/intermediate/unfavorable)
a. Favorable; one (or more) of following chromosomal changes.
i. t(8;21) The presence of at least one (t(8;21) or inv (16) or
ii. inv(16) or t(16;16) t(16;16)) is called “Core-binding factor (CBF)”
iii t (15;17) “Acute Promyelocytic Leukemia; APL”
 b. Intermediate;
normal karyotyping, t(9;11) and trisomy 8.
c. Unfavorable, any of the following
karyotypes:
• deletion5, deletion5q, deletion7,
deletion7q, abnormalities of 11q23
(e.g. MLL gene) non t(9;11), inv3, t(3;3), t(6;9), t(9;22),
deletion 17p or abnormal (17p).
• Commonly, “complex karyotype” (≥ 3 chromosomal
aberrations).
• Monosomal karyotype.
B. Molecular mutations
1. F.LT3 (FMS – like tyrosine Kinase)
a. Plays a key role in proliferation, survival and differentiation of
early hematopoietic progenitor cells; all mutations lead to
uncontrolled proliferation of leukemic blasts
b. FLT3 mutation is both a prognostic and a predictive
biomarker.
c. Has an approved FDA companion diagnostic test.
d. FLT3-ITD (internal tandem duplication) responds well to
induction cth but associated with worse outcome due to
early relapse
e. FLT3-TKD (tyrosine kinase domain);better survival than FLT3-
ITD
2. NPM1 (Nucleophosmin); high sensitivity towards induction
chemotherapy
3. CEPBA (AKA “CEPB-alpha”) CCAAT enhancer binding protein alpha;
confers sensitivity towards HiDAC
4. IDH1 & IDH2 ( Iso citrate dehydrogenase)
5. DNMT3A ( DNA methyltransferase 3A)
6. KIT gene (CD117)
3.Response to treatment
The following is associated with Poor Prognosis:
• Lack of complete remission after first induction therapy
• Duration of remission < 6 months

AML Classification

Risk status and survival with conventional chemotherapy based upon

cytogenetics and molecular mutations

• Favorable
• Intermediate
 • Unfavorable/Adverse

AML Signs & Symptoms

Ineffective Hematopoiesis (bone marrow failure)
• easy bruising and petechiae due to thrombocytopenia,
• frequent infections, fever due to neutropenia,
• fatigue, pallor related to anemia
• cardiovascular effects of profound anemia.
Infiltrating other organs
visual changes, mucosal bleeding, neurological symptoms,
cardiopulmonary symptoms
• Skin
• Renal
• CNS
The prevalence of CNS disease at diagnosis of AML is vey rare

Features associated with the risk of CNS leukemia include

◦ hyperleukocytosis, monocytic, or myelomonocytic leukemia (FAB M4 or M5), and
young age

Leukostasis
• due to hyperleukocytosis (white blood cell count > 100,000/μL)
• should be suspected if the patient has pulmonary, CNS, or
cardiovascular symptoms that cannot be explained by other
medical conditions: dyspnea, confusion, somnolence, headache,
impaired vision, tinnitus, chest pain (myocardial ischemia/
infarction), limb ischemia, thrombosis, and priapism
• It is considered as a medical emergency
 • Treatment options include hydration, leukemia-directed
chemotherapy, and leukapheresis.

Disseminated intravascular coagulation (DIC)

May occur with Hyperleukocytosis (30–40% of patients)
Decreased platelets,
decreased fibrinogen,
elevated D-dimers, prolonged prothrombin time (PT), and
activated partial thromboplastin time (aPTT).
Tumor lysis syndrome (TLS),
May occur with Hyperleukocytosis (10%)

Myeloid sarcoma
Rare presentation of AML, which is defined as a tumor mass consisting of
myeloid blasts in which tissue architecture is destroyed.
The most common sites are skin, lymph nodes, gastrointestinal
tract, bone, soft tissue, and testes.
The presentation is usually as a solitary mass.
Myeloid sarcoma may be the first, and sometimes the only, early
manifestation of AML

AML Diagnosis

1. Complete blood count (CBC):

• may show circulating blasts (few or numerous)
• other morphologic changes of marrow replacement by leukemia
• morphologic characteristics of myeloblasts on the Wright stained
peripheral blood smear include
immature chromatin (“ground-glass”),
Increased nuclear: cytoplasmic
ratio,
presence of Auer rods (needle-
shaped cytoplasmic inclusions), is
pathognomonic for myeloblasts.
In the absence of Auer rods, flow cytometry
must be performed to determine the lineage
of blasts.
 2. History & physical (H&P)
3. UA, LDH, metabolic panel
4. PT, PTT, fibrinogen
5. Cytogenetics (Karyotype + FISH)
6. Molecular Analysis (c-KIT, FLT3 (ITD&TKD), NPM1, CEBPA,
IDH1, IDH2, TP53,other mutations)
7. Comprehensive pathology report
8. HLA matching
9. Brain CT, brain MRI with contrast
10. PET/CT
11. Lumbar Puncture (LP)
12. Evaluation of myocardial function (Echo/MUGA)

AML Treatment
(General Principles)
1. Four important PREDICTORS OF OUTCOMES in adult AML patients:
1. Age
Due to worse performance status, decreased organ function,
higher prevalence of unfavorable cytogenetics, likelihood of
antecedent MDS
CR rates rarely exceed 50% in patients age ≥ 60 years
2. Performance status
3. Cytogenetics (favorable/intermediate/ adverse risk) (2ry AML is
unfavourable)
For unfavorable/high risk AML and relapsed/refractory AML, it is
generally accepted that allogeneic HCT is the only curable
treatment available
4. Duration of first CR
CR < 6 months is poor, while CR > 12 months is more favorable
2. Remission induction chemotherapy should begin soon after a
definitive diagnosis is made
3. Cytogenetic/biomarker/molecular information and patient history
(treatment-related AML or prior MDS) is necessary to determine
treatment in the remission induction setting.
4. For proliferative cancers, hydroxyurea should be started (and
consider leukopheresis) or one dose of intermediate dose cytarabine
(1-2 grams) may be considered prior to receiving these results.
5. Modify treatment based upon patient co-morbidities.
6. Cardiac dysfunction may either disqualify patient for intensive
remission induction therapy or require using non-anthracycline
containing regimen.
7. Obesity – treat with full-dose based upon actual body weight and
height.
8. Remission induction therapy may be considered intensive or low-
intensity, based upon patient characteristics
•Intensive chemotherapy may be defined as chemotherapy aimed at
achieving CR.
•Low-intensity chemotherapy defined as chemotherapy aimed at
altering the natural course of the disease.
9. Treat with curative intent (intensive remission induction) for most
patients, unless considered unfit
•Age >60-65 years
•Not a candidate for intensive remission induction
10. Patients with ECOG performance status of 3 or greater and/or
significant comorbidities may be considered for:
• low-intensity chemotherapy or
• best supportive care
a. Blood product transfusions as needed
b. Prophylactic antibacterial(s) and antifungal(s)
c. Hydroxyurea titrated to control leukocytosis
11. Employ appropriate supportive care therapies at appropriate times
during therapy

AML treatment Phases