Oncology Conference

Leukemia
Dr. D.W. Daugherty

FAB (1976) Classification

M0 -- Undifferentiated AML
M1 -- AML without maturation
M2 -- AML with maturation
M3 -- Acute Promyelocytic Leukemia
M4 -- Acute Meylomonocytic Leukemia
M5 -- Acute Monocytic Leukemia
M6 -- Erythroleukemia (DiGuglielmos)
M7 -- Megakaryoblastic Leukemia

WHO Classification of AML

AML with recurrent cytogenic
translocations
AML with multi-lineage dysplasia
AML and myelodysplasia, therapy related
AML, not otherwise categorized

FAB vs WHO Classifications of

Hematologic Neoplasm
FAB criteria
Morphology
Cytochemistry

WHO criteria
Morphology
Immunophenotyping
Genetic features
Karyotyping
Molecular testing
Clinical features

FAB Classification of ALL

L1: Small homogeneous blasts; mostly in
children
L2: Large heterogeneous blasts; mostly in
adults
L3: Burkitt large basophilic B-cell blasts
with vacuoles

Acute Leukemia:
Essentials:
Short course of symptoms
Fatigue, fever, easy bruising, bleeding
Cytopenias - or pancytopenia
More than 20% blasts in bone marrow
Blasts in peripheral blood in 90% cases

Acute Myeloid Leukemia (AML):

Incidence:
2.3 per 100,000 people per year
Higher among men than women (2.9 vs 1.9)
Most common leukemia in adults (80% of cases)
Vast majority of patients 65 years or older

Acute Myeloid Leukemia (AML):

Etiology:
Genetic
Radiation
Toxic chemical exposure
Medication (Alkylating-agents, Topoisomerase-II
inibitors, Chloramphenicol, Phenylbutazone,
Chloroquine, and Methoxypsoralen)

Acute Myeloid Leukemia (AML):

Most Common Presenting Sx:
Fatigue (50%)
Anorexia (30-40%)
Weight loss (30-40%)
Fever without evident cause (10%)
Easy Bruising (5%)
Bleeding (5%)

Acute Myeloid Leukemia (AML):

Symptoms:
Nonspecific
Most related to anemia, leukocytosis, leukopenia,
leukocyte dysfunction, or thrombocytopenia
Symptoms usually present for 3 months or more
before diagnosis is made

Acute Myeloid Leukemia (AML):

Other Common Sx:
Bone pain
Lymphadenopathy
Non-specific cough
Headaches
Excessive diaphoresis
Symptoms secondary to mass lesions (granulocytic
sarcoma or chloroma)

Acute Myeloid Leukemia (AML):

Physical Findings:
Fever
Splenomegaly
Sternal tenderness
Multiple bruises
Bleeding (gingivae most common)
Unexplained infections
GI bleed
Pulmonary, intracranial, and retinal hemorrhage

Acute Myeloid Leukemia (AML):

Laboratory and Radiographic Work-up:
CBC with manual differential
Uric Acid level
Clotting studies (PT, PTT, D-dimer, fibrinogen)
Bone marrow aspirate and biopsy
Chest xray
Echocardiogram

Acute Myeloid Leukemia (AML):

Hematological Findings:
Anemia (normochromic, normocytic)
Leukocytosis (median = 15,000)
Thrombocytopenia (< 100,000)

Acute Myeloid Leukemia (AML):

Morphology and Cytology:
> 20% myeloblasts in blood and/or bone marrow
Auer Rods (cytoplasmic granules)
Positive myeloperoxidase reaction in > 3% blasts

AML Histology

AML Histology

Acute Myeloid Leukemia (AML):

Classification/Subtypes:
French-American-British Classification
eight major subtypes
based on morphology and cytochemistry

World Health Organization Classification

based on molecular, morphologic, and clinical features

Classification of AML
Subtype

FAB Type

Morphology

Cytogenetic Abnl

AML w/o maturation

M0

no azurophil granules

AML

M1

del(5); del(7); +8

AML w/ differentiation

M2

Acute Promyelocitic Leukemia

M3

few Aeur rods

maturation beyond
promyelocytes; Auer
rods
hypergranular
promyelocytes; Auer
rods
> 20% monocytes;
monocytoid cells in
blood

Acute Myelomonocytic Leukemia

M4

Acute Monocytic Leukemia

M5

Acute Erythroleukemia

M6

monoblastic;
promonocytic
predominance of
erythroblasts;
dyserythropoiesis

M7

dry' aspirate; biopsy

dysplastic with blasts

Acute Megakaryocytic Leukemia

t(8:21) t(6:9)

t(15:17)
inv(16) del(16) t(16:16)
t(4:11)

t(9:11) t(10:11)

Acute Myeloid Leukemia (AML):

Prognostic Factors:
Age at diagnosis
Comorbidities (acute vs chronic)
Chromosomal findings
Symptomatic interval preceding diagnosis
Presenting Leukocyte count
Circulating myeloblast count
FAB classification
Morphologic characteristics of the leukemic cell

Acute Lymphoid Leukemia (ALL):

Incidence:
Approximately 3,000 new cases per year
Mostly affects children,
children accounts for 2/3 of
childhood leukemia (peak age 4 years)
years
Comprises less than 20% of leukemia in young
adults
May be B-cell, T-cell, or null-type (non-B, non-T
cell)

Acute Lymphoid Leukemia (ALL):

Etiology:
Uncertain, but several proposed linkages:
Genetic - Philadelphia chromosome
Viral infection (EBV, HIV)
Exposure to high energy radiation (T-cell ALL)
Toxic chemical exposure
Smoking

Acute Lymphoid Leukemia (ALL):

Common Sx:
Pallor
Fatigue
Shortness of breath
Easy bruising
Petechiae
Weight loss / failure to thrive
Bone and/or joint pain

Acute Lymphoid Leukemia (ALL):

Physical Findings:
Fever
Splenomegaly and/or hepatomegaly
Lymphadenopathy
Multiple bruises
Petechiae
Unexplained infections

Acute Lymphoid Leukemia (ALL):

Laboratory and Radiographic Work-up:
CBC with manual differential
Chemistry studies to check for organ dysfunction
Bone marrow aspirate and biopsy
Genetic/Immunological studies
Lumbar puncture

Acute Lymphoid Leukemia (ALL):

Hematological Findings:
Anemia (normochromic, normocytic)
WBC < 5,000 (or > 25,000)
Leukocytosis (median = 15,000)
Thrombocytopenia (< 50,000)

ALL Histology

ALL Histology

Classification of ALL
Immunologic Subtype

FAB Type % of Cases

Cytogenetic Abnl

Pre-B cell ALL

L1, L2

75

t(9:22) t(4:11) t(1:19)

T-cell ALL

L1, L2

20

14q11 or 7q34

B-cell ALL

L3

t(8:14) t(8:22) t(2:8)

L1 - 85% of childhood ALL

L2 - Majority of adult ALL
L3 - Includes Burkitts. < 5% of ALL

Acute Lymphoid Leukemia (ALL):

Prognostic Factors:
Adult vs Childhood type
Morphology (FAB class)
Chromosomal findings
WBC > 50,000
B-cell type worse than T-cell type
Lymphadenopathy
Hepatosplenomegaly

Acute Leukemia Treatment:

Two phases of treatment
induction
post-remission

Initial goal is to quickly induce complete

remission.
Combination chemotherapy
Continued low-dose post-remission therapy must
be used to ensure prolonged survival. Otherwise
recurrence rates can be as high as 90%

Acute Leukemia:
After Induction Chemotherapy:
Bone marrow biopsy is obtained
If >5% of blasts with >20% cellularity, then
retreatment necessary.
Stem cell transplant may be necessary if
retreatment fails.

Acute Leukemia:
Post-remission Treatment:
Stem cell transplant
CNS prophylaxis (for ALL)
Radiation therapy (for ALL)
Prolonged low-dose chemotherapy for 1-3 years

Acute Leukemia Treatment:

Continued Supporative Care:
Transfusions.
Platelets >20,000
Hgb >8

Empiric antibiotic treatment when fever present

Allopurinol for increased uric acid levels

Chronic Leukemia:
Essentials:
Most are asymptomatic at presentation
Strikingly elevated WBC
Marked left-shift
Philadelphia chromosome
Splenomegaly typical
Lymphocytosis

Chronic Myeloid Leukemia (CML):

Incidence:
1.3 per 100,000 people per year
Higher among men than women (1.7 vs 1.0)
Vast majority of patients 40 years or older
There is no clear etiology

Chronic Myeloid Leukemia (CML):

Pathophysiology:
Philadelphia chromosome (9:22) in up to 95%
BCR-ABL protein junction

Chronic Myeloid Leukemia (CML):

Common Sx:
Note: approximately 70% of patients are asymptomatic at the
time of diagnosis

Lethargy
Weight loss
Increasing abdominal girth
Easy bruising or bleeding
Excessive diaphoresis

Chronic Myeloid Leukemia (CML):

Physical Findings:
Fever
Splenomegaly and hepatomegaly
Bruising
Bleeding (gingivae most common)

Chronic Myeloid Leukemia (CML):

Laboratory and Radiographic Work-up:
CBC with manual differential
Serum Vitamin B12 and B12 binding capacity
Leukocyte alkaline phosphatase (decreased)
Uric acid level
Chromosomal testing - Philadelphia chromosome
Bone marrow biopsy

Chronic Myeloid Leukemia (CML):

Hematological Findings:
Anemia (normochromic, normocytic)
Leukocytosis (median = 20,000)
Basophilia
Thrombocytopenia (< 100,000)

CML Histology

CML Histology

Chronic Myeloid Leukemia (CML):

Three Phases:
Chronic phase: 3-5 years. Current treatment is with
alpha-interferon. Young patients should undergo BMT.

Accelerated phase: New nonrandom cytogenic

abnormalities in up to 80% of patients. Difficult to control.
Development of myelofibrosis. Elevated leukocyte counts.
Lasts several months before becoming blastic.

Blast phase: > 30% blasts in blood or marrow. Treatment

with chemotherapy similar to acute leukemia. Some patients
go into remission with treatment, but it is short lived.

Chronic Myeloid Leukemia (CML):

Prognostic Factors:
Age at diagnosis
Splenomegaly
Blasts > 5% in blood or marrow at diagnosis
Basophilia > 7%
Platelets > 700,000

Chronic Lymphoid Leukemia (CLL):

Incidence:
2 new cases per 100,000 people per year
Comprises 30% of all cases of leukemia
Most common lymphoid leukemia
Almost exclusively due to B-cell clonal expansion
More common in men
Most common in individuals < 50 years

Chronic Lymphoid Leukemia (CLL):

Etiology:
Uncertain, several proposed linkages:
Genetic
Viral infection (EBV, HIV) - Burkitts
Exposure to high energy radiation (T-cell ALL)
Toxic chemical exposure
Smoking

Chronic Lymphoid Leukemia (CLL):

Common Sx:
Note: approximately 70% of patients are asymptomatic at
the time of diagnosis

Fever
Pallor
Fatigue
Shortness of breath
Easy bruising
Gingival bleeding
Weight loss
Frequent infections

Chronic Lymphoid Leukemia (CLL):

Physical Findings:
Fever
Splenomegaly and/or hepatomegaly
Lymphadenopathy
Multiple bruises
Bleeding gingivae
Unexplained infections

Chronic Lymphoid Leukemia (CLL):

Laboratory and Radiographic Work-up:
CBC with manual differential
Peripheral smear
Flow cytometry
Chemistry studies to check for organ dysfunction
Lymph node biopsy

Chronic Lymphoid Leukemia (CLL):

Hematological Findings:
Increased number of lymphocytes on smear
smudge cells

B-cells with CD 19 and CD 5 on flow cytometry

Small lymphocitic lymphoma present in histology
of nodal biopsy

CLL Histology

CLL Histology

RAI Classification of CLL

Stage

Risk

Clinical/Morphological Features

Low

Lymphocytosis alone

Intermediate

Lymphocytosis with lymphadenopathy

II

Intermediate

Lymphocytosis with lymphadenopathy

and splenomegaly or hepatomegaly

III

High

Lymphocytosis with anemia

High

Lymphocytosis with anemia and

thrombocytopenia

IV

Chronic Lymphoid Leukemia (CLL):

Prognostic Factors:
Based on RAI classification
Lymphocytosis
Lymphadenopathy
Splenomegaly or Hepatomegaly
Anemia
Thrombocytopenia

Chronic Leukemia Treatment:

CML therapy is based on phase
Chronic: PO chemoprophylaxis
alpha-interferon with concominant BMT
Accelerated: within months progresses to blast phase
treatment same as for AML, with combination
Chemotherapy
Blast: same as for AML, with combination
chemotherapy

Chronic Leukemia Treatment:

CLL therapy is based on RAI stage
stage 0: Often followed without specific treatment
stage I and II: Treatment if symptomatic. Single agent
treatment with fludarabine. Combination treatment with
CVP or CHOP regimens
stage III and IV: Fludarabine, CVP, or CHOP regimens
Young patients with this disease are also candidates for
bone marrow transplantation

Chronic Leukemia Treatment:

CVP Regimen:
Cyclophosphamide
Vincristine
Prednisone

Chronic Leukemia Treatment:

CHOP Regimen:
Cyclophosphamide
Doxorubicin
Vincristine
Prednisone

Chemotherapy Agents:
Antimetabolites:
Base analogs. Incorporates into DNA and prevents
transcription
Also interferes with DNA polymerase, thus
inhibiting DNA replication and repair
Cell cycle S-phase-specific
Cytarabine - pyrimidine analog
Fludarabine - adenine analog

Chemotherapy Agents:
Anthracyclines:
Primarily intercalates between DNA bases and
prevents transcription. Secondarily inhibitions
topoisomerase-II leading to DNA breaks
Doxorubicin (CLL)
Daunorubicin (AML, ALL and CML)
Idarubicin (AML, ALL and CML)

Chemotherapy Agents:
Vinka alkaloids:
Vincristine: acts as an anti-microtubule that blocks
mitosis
Cyclophosphamide: converted to a nitrate that
intercalates into the DNA and causes damage via
cross-linking
Cell cycle phase specific for M phase and S phase

Chemotherapy Agents:
Prednisone:
Gluccocorticoid analog
Converted by liver to active form, prednisolone
Acts as immunosuppressant

Acute Myeloid Leukemia (AML):

Remission:
Combination tx with cytarabine/daunorubicin
65-75% will achieve CR. Two-thirds achieve CR
after a single cycle. The other one-third after a
second course.
50% of those who do not achieve CR fail because
of a drug-resistant leukemia. The other 50% because
of fatal complications of bone marrow or stem cells.

Acute Lymphoid Leukemia (ALL):

Remission:
Combination tx with daunorubicin, vincristine,
prednisone, and asparaginase
Childhood ALL CR rate is approximately 90-95%
Adult ALL CR rate is approximately 70-80%

Chronic Myeloid Leukemia (CML):

Remission:
With concominant BMT and alpha-interferon
treatment, remission rates of 40-60% can be
achieved.
Relapse rate is high, and median survival is only 56 years.

Chronic Lymphoid Leukemia (CLL):

Remission:
Remission has not been achieved in CLL.
Treatment with chemotherapy (fludarabine, CHOP,
or CVP) increases median survival rates:
Stage 0-I: 10-15 years
Stage II-IV: approximately 2-5 years for 90% of
patients

Prognostic
Factor

Survival
5 year survival is 10-35% for all patients
with AML

AML

5-10% will survive more than 5 years

20-35% for young patients who undergo
chemotherapy and BMT
Children

60-70% 5-year disease free survival

Adults

25-35% 5-year survival

ALL

CML

CLL

Median survival 5-6 years

Stage O

> 15 years

Stage I

9 years

Stage II

5 years

Stage III and IV

2 years

Thank you...