Oncology Conference

Leukemia

Dr. D.W. Daugherty

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
Subtype FAB Type Morphology Cytogenetic Abnl
AML w/o maturation M0 no azurophil granules -
AML M1 few Aeur rods del(5); del(7); +8
AML w/ differentiation M2
maturation beyond
promyelocytes; Auer
rods t(8:21) t(6:9)
Acute Promyelocitic Leukemia M3
hypergranular
promyelocytes; Auer
rods t(15:17)
Acute Myelomonocytic Leukemia M4
> 20% monocytes;
monocytoid cells in
blood
inv(16) del(16) t(16:16)
t(4:11)
Acute Monocytic Leukemia M5
monoblastic;
promonocytic t(9:11) t(10:11)
Acute Erythroleukemia M6
predominance of
erythroblasts;
dyserythropoiesis -
Acute Megakaryocytic Leukemia M7
dry' aspirate; biopsy
dysplastic with blasts
-
Classification of AML
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, accounts for 2/3 of
childhood leukemia (peak age 4 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
L1 - 85% of childhood ALL
L2 - Majority of adult ALL
L3 - Includes Burkitts. < 5% 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
5 t(8:14) t(8:22) t(2:8)
Classification 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
Stage Risk Clinical/Morphological Features
0 Low Lymphocytosis alone
I Intermediate Lymphocytosis with lymphadenopathy
II Intermediate
Lymphocytosis with lymphadenopathy
and splenomegaly or hepatomegaly
III High Lymphocytosis with anemia
IV High
Lymphocytosis with anemia and
thrombocytopenia
RAI Classification of CLL
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 5-
6 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
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
CML Median survival 5-6 years
Stage O > 15 years
Stage I 9 years
Stage II 5 years
Stage III and IV 2 years
CLL
AML
ALL
Thank you...