Acute Leukemia

17/9/2006
Definition:
Leukemias are clonal, neoplastic proliferation of immature cells of the
hematopiotic system, which are characterized by aberrant or arrested
differentiation.
Incidence:
Acute leukemias afflict 3-4 per 100,000 populations annually in USA.
(11000 new case per year).
Acute leukemia is the most common malignant disease of childhood.
80% of ALL cases occur in children and 90% of cases AML occur in
adults
Etiology:
1- Radiation. Less than 100 cGY are not leukemogenic. Radiation can
induce ALL, AML, CML but not CLL.
2- Viruses have not been associated with acute leukemia
EBV, HIV mainly with lymphoma; HTLV-1 associated with
Adult T-cell lymphoma
3- Chemicals
a- Benzene and toluene
b- Drugs; alkylating agent, topoisomerase inhibitor agents.
4- Heredity
a- Bloom syndrome; Autosomal recessive, short stature,
telengectasia, Jewish and cytogenetic abnormalities.
b- Fanconi aplasia [anemia]. Autosomal recessive, absence of
radii and hypoplasia of the thumbs, hypogonadism, small
stature and multiple chromosomal abnormalities.
c- Down syndrome; trisomy 21, risk of both ALL and AML.
5- Hematologic diseases:
a- CML.> 80% transform to acute leukemia.
b- MDS
6- Cigarettes smoke, as much as 20% of AML may be attributable to
smoking.
7- Not proven: mobile phone, electricity transformer, pesticides.
Diagnosis:
a- Symptoms
Fatigue and weakness are the most common
1

b-

c-

def-

gh-

Bruising, fever and weight loss are frequent

CNS; headaches, nausea, vomiting, blurred vision and
cranial nerve palsy
Bone pain, ALL>AML
Abdominal fullness, ALL>AML
Oliguria: dehydration, uric acid nephropathy or DIC.
Physical findings
Pallor, petechia and purpura most frequent
Sternal tenderness, lymphadenopathy and
hepatospleenomegaly ALL>AML
Miningismus may indicate CNS involvement. CNS
leukemia is most common in ALL, less common in M4 and
M5 and rare in the other type.
Optic fundus infilteration with leukemic cells appear as Roth
like spots with flame hemorrhage
Gingival enlargement is seen in ALL, and M5 AML.
Bleeding out of proportion of thrombocytopenia suggest the
presence of DIC in type M3
Signs of infection
Organs involvement at the time of diagnosis: kidneys 25%,
lung, joints and GIT 5% and heart 2%.
Lab
Normochromic normocytic anemia present in90% of
patients. Macrocytosis reflects megaloblastoid maturation.
Leukocyte. WBC elevated in 60%, normal in 15% and
decreased in 25%. Circulating blasts are demonstrable in
virtually every case of acute leukemia. Blasts account for
most of the circulating cells in patients with elevated WBC.
Biochemical tests
Uric acid, CA, MG, PO, RFT, LFT, PT, PTT.
Lysozyme serum concentration in M4 and M5 of AML.
Radiologic studies
Chest X-ray for leukemic infiltrate or infection. X-ray of any
tender bone looking for periosteal elevation or bony
destruction.
Cerebrospinal fluid [CSF] examination in-patient with
meningismus or CNS abnormalities.
Septic work up.

i- Bone marrow findings. The diagnosis of acute leukemia is

established by bone marrow examination. Blasts must
account for more than 30% of the nucleated cells.
j- Cytogenetic abnormalities
M0: with lymphoid markers: t (9; 22)
M2: t (8; 22)
M3: t (15; 17) this translocation uniquely disrupts the gene
encoding for the retinoic acid receptor on chromosome
17q21
M4 with eosinophilia: del 16 or inv 16
M5: 11qM6: del 7q and or del 5q
M7 frequent in children with trisomy 21
Differential Diagnosis:
1- Lymphoma
2- Myelodysplastic disorder
3- Multiple myeloma
4- Aplastic anemia
5- Megaloplastic anemia
6- Infectious mononucleosis
7- Tuberculosis
8- Myelophthesis
Acute Leukemia [AML or ALL]
AML is the diagnosis when:
-3% of the leukemic blasts are MPO or SBB positive by light
microscopy.
-Auer rods are needle like collections of primary (MPO+)
granules and prominent in M2, M3 and M5 AML subtype.
-M5 always NSE positive
-M7 confirmatory test is platelet peroxidase
ALL is the diagnosis when:
-PAS positive and MPO and SBB are negative
Table 1. French-American-British [FAB] classification of acute myeloid
leukemia
FAB
M0
M1
M2

Description
AML without cytological maturation
AML with minimal maturation
AML with significant maturation
3

Percentage adults
5
20
30

M3
M4
M5
M6
M7
L1
L2
L3

Hyper granular promyelocytic leukemia

Acute mylomonocytic leukemia
Acute monocytic leukemia
Acute erythroleukemia
Acute megakaryocytic leukemia
Small cell with minimal cytoplasm
Larger cells with moderate cytoplasm, TDT
positive
Large round cells, sig positive

10
25
10
5
Very rare
30%
65%
5%

Adverse prognostic factors AML

a- Secondary AML; after cytotoxic drugs, benzene, irradiation.
b- AML after MDS, CML
c- Age > 55y
d- Cytogenetics: t (15; 17), t (8; 21) and inv (16) good prognostic
subgroup.
Abnormalities of chromosome 5, 7, trisomy8, t (9; 11) and t (9;
22) poor prognostic subgroup
Karyotypic analysis provide the single most important prognostic
information in AML
Adverse prognostic factors ALL
a- WBC count high
b- Mature B-cells
c- Age: older age
d- Positive Philadelphia chromosome
e- Time to complete response > 4 weeks
Treatment of Acute Myeloid Leukemia
Remission induction chemotherapy: AML 7+3
Cytarabine 100mg/m2 IV q 12 hours for 7 days
Daunorubicin 45 mg/m2 IV q d for 3 days
Post-remission therapy:
A- High dose chemotherapy
Cytarabine 3 gm/ m IV q 12 hours day 1,3,5 for six doses
q 4 weeks x4
B- Allogeneic BMT, treatment related mortality rate is higher
than autologous BMT and consolidation chemotherapy. Results
are best in children.
C- Autologous BMT. Post remission consolidation
chemotherapy and autologous BMT have similar outcome
Definition of remission (Freireich criteria for CR):
4

Bone marrow blasts < 5%

Polymorph >1000
Platelet > 100,000
Bone marrow aspiration and biopsy should be done on day 14 after the start
of treatment.
60% to 75% achieve CR.
Median duration of remission is only 10 to 12 months
Less than 20% of patients are cured.
50% to 70% relapse and die within 2 years
Supportive therapies:
a- Indwelling silastic right atrial catheter
b- Blood component therapy:
1- Platelet transfusion if < 20,000
2- PRBC transfusion
3- Granulocyte transfusion not recommended
4- G-CSF, GM-CSF
c- Infection treatment and prophylaxis of infection
d- Prevention of tumor lyses syndrome: hydration, allopurinol and
alkalinization.

Investigational therapies:
1- Intensification chemotherapy
2- Immunotherapy: Anti-CD antibody
3- BMT; results are disappointing for patients with resistant acute
leukemia but promising in patients with CR1 AML and CR2 ALL
4- Major limitations
< 25% of patients have compatible donors
The best survival rate are achieved in patients younger than 22
years, most AML are older
Complications of BMT are substantial
The results of investigational BMT are still preliminary.
Promyelocytic Leukemia M3
a- All-trans retinoic acid (ATRA), 45mg/m2 per day PO divided in to
two doses for up to 2 months.
b- Coagulopathy (DIC) occurred in more than 90%. Heparin [may be
replaced with epsilon aminocaproic acid], Platelet transfusion to
keep platelets>50,000, Cryoprecipitate or FFP to sustain fibrinogen
level>100mg/dl.
5

Review questions
T/F
AML
1-Children are most frequently affected and may be cured.
2-If patients are untreated or unresponsive to treatment, death usually
within 3 months.
3-Death usually result from infection and/or bleeding
4-Histochemical tests are useful in determining subtypes. Affected
cells are usually stain positively with MPO, SBB and NSE
5- Chromosomal abnormalities occur and are diagnostic
6- During treatment patients need intensive supportive care.
ALL good prognosis
1-Age less than 15 years
2- High WBC
3- hyper diploid genetics
4- T (8; 14), L3 type
5- presence of paraprotien
7- Presence of Philadelphian chromosome
Gingival enlargements is seen in
M5
ALL
Both
Neither
Cytogenetic abnormalities in AML
Correlate with morphology
Predict response to treatment
Resolve at remission
Predict clinical course
Dr. Ali M. Al-Amri, MD.