Acute myeloid leukemia

ACUTE MYELOID
LEUKEMIA
SHUMAYLA ASLAM, MD
1ST YEAR RESIDENCY
SOURSE: HARRISON’S INTERNAL MEDICINE 19TH EDITION CHAPTER 132
dr.shumaylaaslam@gmail.com

Acute myeloid leukemia (AML)
is a neoplastic disease characterized
by
- infiltration of the blood,
- bone marrow, and
- proliferative, clonal undifferentiated
cells of the hematopoietic system.

Incidence
• ~3.5 per 100,000 people per year
• higher in men than in women (4.5 vs 3.1)
• increases with age
• 1.7 in individuals age <65 years
• 15.9 in those age >65 years
• The median age at diagnosis is 67 years.

ETIOLOGY
• Heredity
– aneuploidy (trisomy 21 noted in Down syndrome,
– Inherited diseases with defective DNA repair (Fanconi
anemia, Bloom syndrome, and ataxiatelangiectasia)
– Congenital neutropenia (Kostmann syndrome)
– Germline mutations of CCAAT/enhancer-binding protein
α (CEBPA), runt-related transcription factor 1 (RUNX1),
and tumor protein p53 (TP53)

• Radiation
– High-dose radiation
• atomic bombs ; nuclear reactor accidents,
• increases the risk of myeloid leukemias that peaks 5–7 years
after exposure.
– Therapeutic radiation alone seems to add little risk
• Chemical and Other Exposures
– Exposure to benzene
• 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

• Drugs
– Anticancer drugs are the leading cause of therapy-
associated AML.
– Alkylating agent-associated leukemias occur on average
4–6 years after exposure
– Topoisomerase II inhibitor–associated leukemias occur 1–
3 years after exposure
– Newer agents for treatment of other hematopoietic
malignancies and solid tumors are also under scrutiny for
increased risk of AML.

CLASSIFICATION
The current categorization of AML uses the World Health Organization
(WHO) classification
• AML with certain genetic abnormalities
– AML with a translocation between chromosomes 8 and 21
– AML with a translocation or inversion in chromosome 16
– APL (M3) with a translocation between chromosomes 15
and 17
– AML with a translocation or inversion in chromosome 3
– AML (megakaryoblastic) with a translocation between
chromosomes 1 and 22

• AML with myelodysplasia-related changes
• AML related to previous chemotherapy or radiation
• AML not otherwise specified
– AML with minimal differentiation (M0)
– AML without maturation (M1)
– AML with maturation (M2)
– Acute myelomonocytic leukemia (M4)
– Acute monocytic leukemia (M5)
– Acute erythroid leukemia (M6)
– Acute megakaryoblastic leukemia (M7)
– Acute basophilic leukemia
– Acute panmyelosis with fibrosis
• Myeloid sarcoma
• Myeloid proliferations related to Down syndrome
• Undifferentiated and biphenotypic acute leukemias

• FAB subtype
– M0- Undifferentiated acute myeloblastic leukemia
– M1- Acute myeloblastic leukemia with minimal
maturation
– M2- Acute myeloblastic leukemia with maturation
– M3- Acute promyelocytic leukemia (APL)
– M4- Acute myelomonocytic leukemia
– M4 eos- Acute myelomonocytic leukemia with
eosinophilia
– M5- Acute monocytic leukemia
– M6- Acute erythroid leukemia
– M7- Acute megakaryoblastic leukemia

CLINICAL PRESENTATION
• SYMPTOMS
• Patients with AML often have several non-
specific (general) symptoms. These can include:
– Fatigue usually the first symptom
– Fever with or without an identifiable infection is the initial
symptom in approximately 10% of patients
– Night sweats
– Loss of appetite
– Weight loss
– Signs of abnormal hemostasis (bleeding, easy bruising)
are noted first in 5% of patients.
– On occasion, bone pain, lymphadenopathy, nonspecific
cough, headache, or diaphoresis are the presentingdr.shumaylaaslam@gmail.com

• Physical Findings
– splenomegaly,
– hepatomegaly,
– lymphadenopathy,
– sternal tenderness,
– evidence of infection and hemorrhage are
often found at diagnosis.

• Significant gastrointestinal bleeding,
intrapulmonary hemorrhage, or intracranial
hemorrhage occurs most often in APL.
• Bleeding associated with coagulopathy may
also occur in monocytic AML and with
extreme degrees of leukocytosis or
thrombocytopenia in other morphologic
subtypes.

• Retinal hemorrhages are detected in 15%
of patients.
• Infiltration of the gingivae, skin, soft
tissues, or meninges with leukemic
blasts at diagnosis is characteristic of
the monocytic subtypes and those with
11q23 chromosomal abnormalities.

• Hematologic Findings
– Anemia is usually present at diagnosis and can be
severe.
• normocytic normochromic.
– Decreased erythropoiesis often results in a reduced
reticulocyte count, and red blood cell (RBC) survival
is decreased by accelerated destruction.
– Active blood loss also contributes to the anemia.
– leukocyte count is about 15,000/μL.
• Between 25 and 40% of patients have counts <5000/μL,
• 20% have counts >100,000/μL.
• Fewer than 5% have no detectable leukemic cells in the
blood.
– Platelet counts <100,000/μL are found at diagnosis
in ~75% of patients, and about 25% have counts
<25,000/μL.

Morphology
• In AML, the cytoplasm often contains primary
(nonspecific) granules, and the nucleus shows fine,
lacy chromatin with one or more nucleoli
characteristic of immature cells. Abnormal rod-shaped
granules called Auer rods are not uniformly present,
but when they are, myeloid lineage is virtually certain.
• Poor neutrophil function may be noted functionally by
impaired phagocytosis and migration and mor-
phologically by abnormal lobulation and deficient
granulation.
• Both morphologic and functional platelet
abnormalities can be observed, including large and
bizarre shapes with abnormal granulation and inability
of platelets to aggregate or adhere normally to onedr.shumaylaaslam@gmail.com

Diagnosis
• 20% or more
leukemic blasts in the
bone marrow
• Immunohistochemical
staining for
myeloperoxidase is
the best method for
determining which
cells are committed to
the myeloid lineage
• Immunohistochemical diagnosis of acute myeloid
leukemia (AML). (A) Bone marrow aspirate shows
increased blasts from a patient with AML with
inv(16) (Wright-Giemsa stain, 350). (B) Bone
marrow biopsy from the same patient shows 100%
cellularity with sheets of blasts (hematoxylin-eosin
stain, 340)

Diagnosis
the diagnostic work-up for AML :
• Complete blood count (CBC) with manual differential and
routine chemistry profile (including liver function tests,
serum creatinine, lactate dehydrogenase [LDH], and uric
acid)
• Coagulation profile – Prothrombin time (PT), partial
thromboplastin time (PTT), fibrinogen)
• Bone marrow aspiration and biopsy, including classical
cytogenetics, immunophenotyping, and molecular testing
for c-KIT, FLT3-ITD, NPM1, and CEBPA
• HLA typing of patient and family

• Imaging studies, including dental survey and
computed tomography (CT) scan of the chest and
abdomen, or chest x-ray and abdominal
ultrasound
• Sperm preservation in men (if desired by patient)
• Pregnancy test in women

Treatment
newly diagnosed patient with AML is usually
divided into two phases,
– induction
– postremission management
• The initial goal is to induce Complete
remission
• based on the patient’s age
– <60 years - Intensifying therapy with traditional
chemotherapy agents such as cytarabine and anthracyclines
in younger patients appears to increase the cure rate of AML.
– >60 years - the benefit of intensive therapy is controversial;

• INDUCTION CHEMOTHERAPY
• The most commonly used CR induction
regimens (for patients other than those with
APL) consist of combination chemotherapy with
cytarabine and an anthracycline (e.g.,
daunorubicin, idarubicin, mitoxantrone).

• <60 years-
– cytarabine is used either at standard dose
(100–200 mg/m2) administered as a
continuous intravenous infusion for 7 days
or higher dose (2 g/m2) administered
intravenously every 12 h for 6 days.
– anthracycline therapy generally consists
of daunorubicin (60–90 mg/m2) or
idarubicin (12 mg/m2) intravenously on
days 1, 2, and 3 (the 7 and 3 regimen).
– Other agents can be added (i.e., cladribine)
when 60 mg/m2 of daunorubicin is used.

• ≥60 years- outcome is poor likely due to a
higher induction treatment–related mortality
rate and frequency of resistant disease,
especially in patients with prior hematologic
disorders (MDS) or who have received
chemotherapy treatment for another
malignancy
• older patients can be also treated with the 7
and 3 regimen with standard-dose cytarabine
and idarubicin (12 mg/m2), daunorubicin (45–90
mg/m2)*, or mitoxantrone (12 mg/ m2).
*has not shown benefit due to the increaseddr.shumaylaaslam@gmail.com

• older patients may be considered for
single-agent therapies with clofarabine
or hypomethylating agents (i.e., 5-
azacitidine or decitabine)

• Toxicity with high-dose cytarabine also
includes pulmonary toxicity and
significant and occasionally
irreversible cerebellar toxicity.
• This toxicity occurs more commonly in
patients with renal impairment and in
those older than age 60 years.

• After one cycle of the 7 and 3 chemotherapy
induction regimen, if persistence of leukemia
is documented, the patient is usually re-
treated with the same agents (cytarabine and
the anthracycline) for 5 and 2 days,
respectively.

POSTREMISSION THERAPY
• without further therapy, virtually all patients
experience relapse.
• Thus, postremission therapy is designed to
eradicate residual leukemic cells to prevent
relapse and prolong survival.
• The type of postremission therapy in AML is
often based on age and cytogenetic and
molecular risk.

• In the postremission setting, high-dose
cytarabine for three to four cycles is more
effective than standard-dose cytarabine.
• For younger patients, most studies include
intensive chemotherapy and allogeneic or
autologous hematopoietic stem cell
transplantation (HSCT).
• Autologous HSCT preceded by one to two
cycles of high-dose cytarabine is also an
option for intensive consolidation therapy.

Relapsed or Refractory disease
• Response rates depend on duration of first remission
• Patients in complete remission (CR) longer than 2y have
a 60% chance of responding to front-line regimens
• Patients in CR 1-2y have a 40% chance of responding to
front-line regimens; clinical trials are preferred
• Patients in CR less than 1y are unlikely to respond to
front-line regimens and should be referred for clinical
trials
• The prognosis for patients beyond first salvage is very
poor

• Recommended chemotherapy regimens for
relapsed or refractory disease:
• Mitomycin, etoposide, and cytarabine (MEC) :
– Etoposide 80 mg/m 2 IV over 1h plus cytarabine 1
g/m 2 IV over 6h plus mitoxantrone 6 mg/m 2; all three
drugs should be given daily for 6d or
• CLAG-M (cladribine, cytarabine, mitoxantrone,
and filgrastim) :
– Cladribine 5 mg/m 2 IV over 2h daily for
5d plus cytarabine 2 mg/m 2 IV over 4h daily for 5d,
with each dose starting 2h after
cladribine plus mitoxantrone 10 mg/m 2 IV for
3d plus filgrastim 300 µg for 6d starting 24h prior to
chemotherapy ordr.shumaylaaslam@gmail.com

• FLAG-IDA (fludarabine, cytarabine,
idarubicin, and filgrastim) :
–Fludarabine 30 mg/m 2/day IV over
30min on days 1-5
–Cytarabine 2 g/m 2/day IV over 4h; 4h
after fludarabine on days 1-5
–Idarubicin 10 mg/m 2/day IV on days 1-3
–Filgrastim 5 µg/kg/day SC to begin on
day 6 until neutrophil recovery

SUPPORTIVE CARE
• Patients with AML should be treated in centers expert
in providing supportive measures.
• Multilumen right atrial catheters should be inserted
as soon as patients with newly diagnosed AML have
been stabilized.
• Platelet transfusions should be given as needed to
main- tain a platelet count ≥10,000/μL.
• RBC transfusions should be administered to keep the
hemoglobin level >80 g/L (8 g/dL) in the absence of
active bleeding, DIC, or congestive heart failure,
which require higher hemoglobin levels.
• Blood products leukodepleted by filtration should be
used to avert or delay alloimmunization as well as
febrile reactions.

PROGNOSTIC FACTORS
• Favorable
– Translocation between chromosomes 8 and 21
– Inversion of chromosome 16 or a translocation
between chromosome 16 and itself
• Intermediate-I
– Mutated NPM1 and FLT3-ITD
– Wild-type NPM1 and FLT3-ITD
– Wild-type NPM1 without FLT3-ITD
• Intermediate-II
– t(9;11)(p22;q23); MLLT3-MLL
– Cytogenetic abnormalities not classified as
favorable or adverse

• Adverse
– Deletion (loss) of part of chromosome 5 or 7 (no
specific AML type)
– Translocation or inversion of chromosome 3
– Abnormalities of chromosome 11 (at the spot
q23)
– Complex changes - those involving several
chromosomes (no specific AML type)

That’s All for today !

Acute myeloid leukemia

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