ACUTE MYELOID LEUKEMIA

INCIDENCE
 The incidence of acute myeloid leukemia
(AML) is ~3.6 per 100,000 people per year,
and the age-adjusted incidence is higher in
men than in women (4.4 versus 3.0).

 AML incidence increases with age; it is 1.7 in

individuals <65 years and 16.2 in those
>65. A significant increase in AML incidence
has occurred over the past 10 years.
 ETIOLOGY
 Heredity, radiation, chemical and other occupational exposures,
and drugs have been implicated in the development of AML. No
direct evidence suggests a viral etiology.

 Heredity
Certain syndromes with somatic cell chromosome aneuploidy,
e.g., Down (chromosome 21 trisomy), Klinefelter (XXY and
variants), and Patau (chromosome 13 trisomy), are associated
with an increased incidence of AML.

Radiation
Survivors of the atomic bomb explosions in Japan had an
increased incidence of myeloid leukemias that peaked 5 to 7
years after exposure. Therapeutic radiation alone seems to add
little risk of AML but can increase the risk in people exposed to
alkylating agents.
 Chemical and Other Exposures
Exposure to benzene, which is used as a solvent in
the chemical, plastic, rubber, and pharmaceutical
industries, is associated with an increased incidence
of AML. Smoking and exposure to petroleum products,
paint, embalming fluids, ethylene oxide, herbicides,
and pesticides, have also been associated with an
increased risk of AML.

 Drugs
Anticancer drugs are the leading cause of
treatment-associated AML. Alkylating agent–
associated leukemias occur on average 4 to 6 years
after exposure, and affected individuals have
aberrations in chromosomes 5 and 7.
Chloramphenicol, phenylbutazone, and, less
commonly, chloroquine and methoxypsoralen
can result in bone marrow failure that may evolve into
AML.
 Acute Myeloid Leukemia (AML) Classification
Systems

 French-American-British (FAB) Classification

M0: Minimally differentiated leukemia

M1: Myeloblastic leukemia without maturation
M2: Myeloblastic leukemia with maturation
M3: Hypergranular promyelocytic leukemia
M4: Myelomonocytic leukemia
M4Eo: Variant: Increase in abnormal marrow
eosinophils
M5: Monocytic leukemia
M6: Erythroleukemia (DiGuglielmo's disease)
M7: Megakaryoblastic leukemia
 History

   Increasing fatigue or decreased exercise tolerance (anemia)

  Excess bleeding or bleeding from unusual sites (DIC,

thrombocytopenia)

  Fevers or recurrent infections (granulocytopenia)

  Headache, vision changes, nonfocal neurologic abnormalities

(CNS leukemia or bleed)

  Early satiety (splenomegaly)

  Family history of AML (Fanconi, Bloom, or Kostmann syndromes

or ataxia telangiectasia)

  History of cancer (exposure to alkylating agents, radiation,

topoisomerase II inhibitors)

  Occupational exposures (radiation, benzene, petroleum products,

paint, smoking, pesticides)
 Physical Examination
  Performance status (prognostic factor)
   Ecchymosis and oozing from IV sites (DIC, possible acute
promyelocytic leukemia)

  Fever and tachycardia (signs of infection)

  Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS

leukemia)

  Poor dentition, dental abscesses

  Gum hypertrophy (leukemic infiltration, most common in monocytic

leukemia)

  Skin infiltration or nodules (leukemia infiltration, most common in

monocytic leukemia)

  Lymphadenopathy, splenomegaly, hepatomegaly

  Back pain, lower extremity weakness [spinal granulocytic sarcoma,

most likely in t(8;21) patients]
 Laboratory and radiologic studies

   CBC with manual differential cell count

  Chemistry tests (electrolytes, creatinine, BUN,
calcium, phosphorus, uric acid, hepatic enzymes,
bilirubin, LDH, amylase, lipase)
  Clotting studies (prothrombin time, partial
thromboplastin time, fibrinogen, D-dimer)
  Viral serologies (CMV, HSV-1, varicella zoster)
  RBC type and screen
  HLA-typing of patient, siblings, and parents for
potential allogeneic SCT
  Bone marrow aspirate and biopsy (morphology,
cytochemistry, cytogenetics, flow cytometry,
molecular studies)
  Cryopreservation of viable leukemia cells
  Echocardiogram
  PA and lateral chest radiograph
 Symptoms
 Patients with AML most often present with
nonspecific symptoms that begin gradually or
abruptly and are the consequence of anemia,
leukocytosis, leukopenia or leukocyte
dysfunction, or thrombocytopenia.

 Nearly half have had symptoms for ≥3

months before the leukemia was diagnosed.
 Physical Findings
 Fever, splenomegaly, hepatomegaly,
lymphadenopathy, sternal tenderness,
and evidence of infection and hemorrhage
are often found at diagnosis.

 Significant gastrointestinal bleeding,

intrapulmonary hemorrhage, or
intracranial hemorrhage occur most often
in acute promyelocytic leukemia (APL
 Hematologic Findings
 Anemia is usually present at diagnosis and can
be severe. The degree varies considerably
irrespective of other hematologic findings,
splenomegaly, or the duration of symptoms. The
anemia is usually normochromic normocytic.

 The median presenting leukocyte count is about

15,000/µl. Between 25 and 40% of patients
have counts <5000/µl, and 20% have counts
>100,000/µl.

 Platelet counts <100,000/µl are found at

diagnosis in ~75% of patients, and about 25%
have counts <25,000/µl.
 PROGNOSTIC FACTORS

 Many factors influence the likelihood of

entering CR, the length of CR, and the
curability of AML. CR is defined after
examination of both blood and bone marrow.
The blood neutrophil count must be ≥1500/µl
and the platelet count ≥100,000/µl.
 TREATMENT
 Treatment of the newly diagnosed patient with
AML is usually divided into two phases,
induction and postremission management .

 The initial goal is to quickly induce CR. Once CR

is obtained, further therapy must be used to
prolong survival and achieve cure.

 The initial induction treatment and subsequent

consolidation therapy are often chosen based
upon the patient's age.The influence of
intensifying therapy with traditional
chemotherapy agents such as cytarabine and
 anthracyclines in younger patients (<60
years) appears to increase the cure rate of
AML.

 In older patients, the benefit of intensive

therapy has been more difficult to document
and therefore pursuit of novel therapies as
consolidation for these patients has recently
been actively pursued.
 Induction Chemotherapy
 The most commonly used CR induction regimens
(for patients other than those with APL) consist of
combination chemotherapy with cytarabine
(cytosine arabinoside) and an anthracycline.

 Cytarabine is a cell cycle S-phase-specific

antimetabolite that becomes phosphorylated
intracellularly to an active triphosphate form that
interferes with DNA synthesis. Anthracyclines are
DNA intercalaters. Their primary mode of action is
thought to be inhibition of topoisomerase II,
leading to DNA breaks.
 Cytarabine is usually administered as a
continuous intravenous infusion at 100 to 200
mg/m2 per day for 7 days. Anthracycline
therapy generally consists of daunorubicin, 45
to 60 mg/m2, intravenously on days 1, 2, and 3
(the 7 and 3 regimen).

 Treatment with idarubicin at 12 or 13 mg/m2

per day for 3 days in conjunction with
cytarabine by 7-day continuous infusion is at
least as effective and may be superior to
daunorubicin in younger patients. The addition
of etoposide does not increase the CR rate but
may improve the CR duration.
 After induction chemotherapy, the bone marrow is
examined to determine if the leukemia has been
eliminated.

 If >5% blasts exist with ≥20% cellularity, the patient

has traditionally been retreated with cytarabine and an
anthracycline in doses similar to those given initially,
but for 5 and 2 days, respectively.

 Our recommendation, however, is to change therapy in

this setting. Patients who fail to attain CR after two
induction courses should immediately proceed to an
allogeneic stem cell transplant (SCT) if an appropriate
donor exists.
 Treatment of Promyelocytic Leukemia
 Tretinoin is an oral drug that induces the
differentiation of leukemic cells bearing the
t(15;17); it is not effective in other forms of
AML. APL is responsive to cytarabine and
daunorubicin, but about 10% of patients treated
with these drugs die from DIC induced by the
release of granule components by dying tumor
cells.
 Postremission Therapy
 Induction of a durable first CR is critical to
long-term disease-free survival in AML.
However, without further therapy virtually
all patients experience relapse. Once
relapse has occurred, AML is generally
curable only by SCT
 ALL
 Treatement:
 Induction
Vincristine
Prednisolone
L-asparaginase
Daunorubicin
Methotrexate
 Maintenance
Prednisolone
Vincristine
Mercaptopurine
Methotrexate