ACUTE LEUKEMIA

Dr. David Lee

DEFINITION
C Neoplasms of hematopoietic precursor cells, characterized by the
accumulation of excess blasts in the bone marrow.
SIGNIFICANCE OF ACUTE LEUKEMIA
Acute leukemia is, at the very least, a hematologic urgency, and it is
sometimes a true emergency (if they have leukostasis, sepsis, DIC).
Most adults who get acute myeloid leukemia (AML) or acute
lymphoblastic leukemia (ALL) will succumb to their disease or
treatment-related complications. Only a minority are cured (in contrast
to pediatric ALL).
A hematologist should be notified promptly if this diagnosis is
suspected, and the management (particularly chemotherapy) should be
overseen by a hematologist (or a medical oncologist with experience
treating acute leukemia).
HOW TO DISTINGUISH ACUTE FROM CHRONIC LEUKEMIA
This is important since the management and prognosis are different for
the two groups.
see figure 1 for an approach.
CLASSIFICATION OF ACUTE LEUKEMIAS
C lymphoid (ALL) vs. myeloid (AML)
see figure 2 for differences in incidence and age distribution
C ALL and AML can be further classified into subtypes
ALL

AML

more common in children

1st peak at 3-4 years
secondary peak in elderly
M>F
overall incidence of
1-2/100,000 per year
curable in about 70% of children
curable in minority of adults

much more common in adults

incidence increases with age

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M>F
$10/100,000 per year for age over 65
curable in minority of adults

PRINCIPLES OF LEUKEMOGENESIS
C The neoplastic cell is a hematopoietic pleuripotent stem cell, or a stem
cell that usually already has lymphoid or myeloid commitment.
C Leukemogenesis is characterized by dysregulation of cell growth and
differentiation, associated with genetic mutations. This causes
proliferation of the leukemic clone with differentiation blocked at an
early stage, which is recognized by the accumulation of blasts and the
clinical consequences.
C The TWO -HIT MODEL OF LEUKEMOGENESIS posits that acute leukemias
arise from two (or more) derangements of genes that regulate
hematopoietic differentiation and proliferation, but that neither mutation
alone is sufficient to generate the acute leukemia phenotype. This model
is not a new concept, but it is only in recent years that advances in
molecular biology have provided an increasing body of evidence to
support this model.

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CAUSES OF ACUTE LEUKEMIAS

NB. Most patients with acute leukemia do not have an identifiable cause
C Ionizing radiation
-latent period of years: peak at 5 years
-radiation increases risks of AML, ALL, CML but not CLL
C Chemicals/drugs
-benzene
-chemotherapeutic agents
-alkylating agents (eg. cyclophosphamide, melphalan, etc)
-epipodophyllotoxins (eg. etoposide)
C Viruses
-HTLV-1 - Human T cell Leukemia/Lymphoma Virus
can cause T-cell ALL but not AML
C Hereditary genetic associations
-Downs syndrome
-Fanconis anemia
-Blooms syndrome
-increased risk if sibling has acute leukemia
C Hematologic disorders predisposing to acute leukemia
-CML and other myeloproliferative disorders (PRV, ET, MF)
-myelodysplastic syndromes
-aplastic anemia
-multiple myeloma, Waldenstrms macroglobulinemia
-paroxysmal nocturnal hemoglobinuria (PNH)
acute leukemia arising out of hematologic disorders is more
frequently AML than ALL

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CLINICAL FEATURES OF ACUTE LEUKEMIA

C range of symptoms summarized below
C symptoms onset over days to weeks typically
Pathophysiology of the clinical manifestations of acute leukemias
C marrow failure due to infiltration
-anemia
-fatigue, pallor,
-thrombocytopenia -bleeding, spontaneous bruising
-neutropenia
-infections, sepsis
C infiltration of other organs
-liver, spleen, lymph nodes (particularly in ALL)
-lymphadenopathy
-hepatosplenomegaly
-mediastinal masses (T-ALL)
-gums
- gum hypertrophy
(monocytic subtype of AML)
-bone pain, esp. in children with ALL
-any organ or tissue
-skin
-leukemia cutis
-soft tissue
-chloromas
-testis
-CNS
-solid organs
C leukostasis (only seen with WBC >> 50 x 109/L)
-CNS
-strokes
-lungs
-pulmonary infiltrates, hypoxemia
C constitutional symptoms
-fevers, sweats are common
-weight loss uncommon
C other
-exposure of substances that can initiate coagulation
can cause DIC

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LABORATORY FEATURES
Hematologic indices
C WBC usually elevated, but can be normal or low
C normocytic anemia
C thrombocytopenia
C blasts are usually seen in the peripheral blood
C coagulopathy/DIC sometimes seen, especially in the
AML subtype promyelocytic leukemia.
C Bone marrow - see below
Other
C increased uric acid
C increased LD
C hypercalcemia is uncommonly seen
DIAGNOSIS
Although blasts are often readily identifiable in the peripheral blood, the
key investigation to make the diagnosis of acute leukemia before
committing the patient to chemotherapy is the bone marrow investigation.
features of acute leukemia on bone marrow
C hypercellular marrow
C excess number of blasts (Acute Leukemia is diagnosed when
over 20% of nucleated cells in the bone marrow are blasts.)
Bone marrow is also helpful to
C subclassify acute leukemia
C obtain samples for cytogenetic analysis
C these have prognostic value in addition to diagnostic value
Distinction between ALL and AML
C light microscopy morphology
AML blasts: Auer rods, cytoplasmic granules helpful if
present. ALL blasts do not have Auer rods or granules.
C special stains (cytochemistry)
C flow cytometry
NATURAL HISTORY OF ACUTE LEUKEMIAS
Without definitive treatment, AML and ALL are fatal, with a median
survival of about 6 weeks, but there is a wide range of survival times.

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TREATMENT OF ACUTE LEUKEMIA

Choice of treatment for acute leukemias is influenced by:
C type of acute leukemia
-ALL vs AML
C age
-young vs. elderly
-treatment-related morbidity and mortality is high in the elderly
C intent of treatment:
-curative vs. palliative
GENERAL PRINCIPLES OF TREATMENT
C specific treatment
-combination chemotherapy is the mainstay of treatment
-if curative intent then the general strategy is to:
C first achieve a complete remission (CR)
C then follow with further chemotherapy to prevent
relapse
C supportive medical care
-transfusion of red cells and platelets
-infection
-nutrition
C psychosocial support
-patient and family

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SPECIFIC TREATMENT
ALL
Phases of treatment
(each consisting of combinations of chemotherapy drugs)
C Induction
C Intensification
C CNS prophylaxis (typically with cranial irradiation as
well)
C Maintenance (aka continuation phase)
treatment regimen typically lasts ~2 years
AML
Phases of treatment
C Induction
C Consolidation - usually 2 or more courses of combination
chemotherapy
- for young patients in remission, allogeneic bone marrow
or stem cell transplant may be appropriate.
The mainstay of treatment for both induction and consolidation in AML
has been cytarabine combined with an anthracycline (eg daunorubicin,
idarubicin, or mitoxantrone).
MORBIDITY AND MORTALITY DURING TREATMENT
C treatment-related
-chemotherapy for acute leukemias causes significant
myelosuppression
-infection due neutropenia (most important)
bacterial sepsis
fungal
-bleeding due to thrombocytopenia
-other (bleeding, mucositis, etc.)
C leukemia-related
-refractory disease
-relapse
BONE MARROW TRANSPLANTATION /PERIPHERAL BLOOD STEM CELL
TRANSPLANTATION

The benefit of BMT/PBSCT is based on two general principles:

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C The infusion of stem cells obtained from bone marrow or

peripheral blood stem cell harvest allows the patient to receive
more intensive treatment (total body irradiation and chemo) that
would otherwise cause lethal toxicity. (ie. infuse stem cells to
rescue the patient.) Although once believed to be an important
component of transplant, this dose intensity effect is now
believed to play a smaller role in the curative potential of
transplant.
C allogeneic transplantation also has the advantage of a graftversus-leukemia effect. This is an important neoplastic effect in
certain types of leukemia.
-this is due to the ability of the allogeneic marrow to induce
an immunologically-mediated anti-leukemia effect.
-this effect is not seen in autologous transplant.
Problems associated with myeloablative treatment with BMT/PBSCT
C myelosuppression with the associated complications of infection,
bleeding
C graft-versus-host disease
Indications for allogeneic BMT/PBSCT with intent to cure.
In patients < age 55 with HLA-matched sibling donor
C for relapsed acute leukemia
C as consolidation treatment after CR has been achieved
PROGNOSIS
Adult AML
Outcome of AML
with chemotherapy

complete remission

long term disease-free

survival

age < 60

75%

30-40%

age > 60

50%

5-15%

-secondary AML (ie AML that evolved from a pre-existing hematologic

disorder, or chemotherapy-induced AML) has a poor prognosis, regardless
of age. It is not considered to be curable with conventional chemotherapy.
Adult ALL
comparable to, or worse outcome than adult AML.
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Acute leukemias: Vignette 1

Mr. S.T., a 45 year old man, presents with a 3 week history of fatigue, a 1
week history of fever, and a 2 day history of bleeding gums. He otherwise
has no active medical problems. His temperature is 38.5/C, HR 110, BP
100/60. He is pale and has petechiae, but there are no other remarkable
physical findings. You ask for a stat CBC and diff.
Comment: Even before the bloodwork results come back, I am really worried about this
patient. He appears ill and the petechiae and bleeding gums indicate severe
thrombocytopenia. This is not just the common cold. I suspect a primary hematologic
disorder, or could he have sepsis?

WBC
Hb
MCV
RDW
Platelets
Reticulocytes

20.4
77
87
15.1
14
23

(4 - 10)
(120-160)
(80-96)
(11.5-14.5)
(150-450)
(18-94)

x 109/L
g/L
fL

neutrophils
lymphocytes
monocytes
eosinophils
basophils

1.1
1.3
0.5
0.1
0

(2.0-7.5)
(1.5-4.0)
(0.2-0.8)
(0-0.7)
(0-0.1)

x 109/L
x 109/L
x 109/L

blasts

17.4

(0)

x 109/L
x 109/L

x 109/L
x 109/L
x 109/L

Comment: There is leukocytosis, thrombocytopenia, normocytic anemia without

reticulocytosis.
Blasts predominate the white blood cell differential; therefore, the patient has acute
leukemia until proven otherwise. This is in keeping with the 3 week history of his
symptoms with crescendoing severity over the past week. I do not know whether it is
AML or ALL at this point.
The patient now requires urgent admission for further management. Get on the phone
now, not later. The peripheral blood smear should be reviewed to make sure that the
blasts are not actually some sort of other cell (such as lymphoma cells, or lymphocytes,
etc.). A bone marrow aspirate and biopsy should be done to confirm that this is acute
leukemia and to determine the specific type of acute leukemia. Cytogenetic evaluation of
the marrow specimen will also be of prognostic value, but this info will not be
immediately available. The PT and PTT should be done to rule out a coagulopathy.
He is neutropenic and therefore he is at risk of bacterial infection. I dont know if his
fever is due to acute leukemia or infection. Because overwhelming gram negative sepsis
can develop very rapidly (ie. within hours) in neutropenic patients, he should be started
empirically on intravenous antibiotics (with gram negative coverage, and Pseudomonas
coverage in particular) right after cultures of blood and urine are taken. An intravenous
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should be started and intravenous fluids should be given to keep him hydrated.
Allopurinol should be started in anticipation of starting chemotherapy soon. This is to
prevent uric acid associated with hyperuricemia/ tumour lysis syndrome. When the type
of acute leukemia is known, then specific treatment can be offered.

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