The Acute Leukemias Flashcards by Dumebi Okonta

What is ALL

Acute lymphoblastic leukemia
A clonal disorder of the lymphocytes(both b and t lymphocytes) in which there is an accumulation of lymphoblasts in the bm resulting in marrow failure and pancytopenia

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Epidemiology of ALL

Median age of incidence- 3-5yrs
75% of cases diagnosed before the age of 10yrs
All makes up 76% of leukemia in individuals <15years with the remaining 20% in adults
Male predilection

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Aetiology of ALL

Exact aetiology basis unknown, however
Ionising radiation, chemicals and infections(viral/bacterial) has been seen to play a role
Less than 5% of all has been said to be associated with inherited genetic abnormality like down syndrome, bloom syndrome, ataxia telengiectasia.
However, majority are said to be associated with acquired genetic abnormalities

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Acquired genetic abnormalities associated with ALL

Change in number of chromosomes;hyperploidy and hypoploidy
Intrachromsomal rearrangements
All with ETV6-RUNX1 rearrangement
TCF3-PBX1
BCR-ABL2
MLL gene

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Pathogenesis of ALL

Like most malignancies, ALL occurs following genetic alterations which results in an enhanced ability of self renewal,loss of ability to control proliferation, resistance to apoptosis etc
Also an acquired ability to resist killing by chemotherapy is seen and this particular clone are mostly involved in relapse.

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FAB Classification of ALL

French American British
Based on morphology

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ALL L1

Small monomorphic lymphoblasts
Regular nuclear shape
Absent or small nucleoli

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ALL L2

Large and heterogeneous lymphoblasts
Irregular nuclear shape
Large conspicuous nucleolus

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ALL L3

Large homogenous lymphoblasts with deep basophilic cytoplasm , cytoplasmic vacuolisation
Irregular nuclear shape
Multiple nucleoli
Burkitt cell type

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An important diagnostic marker for ALL

Terminal deoxynucleotidyl transferase (tdt)

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WHO’S classification of ALL

B lymphoblastic leukemia/lymphoma otherwise not specified
~ with recurrent genetic abnormalities
T lymphoblastic leukemia /lymphoma

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Clinical features of ALL

L- Lymphadenopathy painless
Y
M- neutropenic fever
P
H- Hepatosplenomegaly
O- ocular swelling
B-Bone /joint pain
L
A- Anemic symptoms
S- scrotal enlargement in males
T- Thrombocytopenic bleeding
I- infection
C- CNS symptoms

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Investigations of ALL

Fbc…anemia, Thrombocytopenia, Leucocytosis
Pbf…pancytopenia with varying percentage of circulating lymohoblasts
Trephine decreased myelo, erythro, mgakaryopoeisis and
Increased lymphoblasts greater than 20%
Immunophenotyping CXR Lumbar puncture

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Differentials of ALL

ITP
Aplastic anemia
Viraemia
Juvenile rheumatoid arthritis

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Treatment for ALL

Could be supportive or definitive
Supportive including pain medications, treatment of infant,transfusion support etc

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Definitive treatment for ALL

Period of 2-3 years using drug combinations
-vincristine
-L-asparaginase
-Steroid
-Antracycline

Induction-To completely eradicate the tumor
Intensification/consolidation..following complete remission to further reduce tumor burden
Maintenance;to clear minimal residual disease
CNS directed therapy

Philadelphia positive ALL

Bad prognosis
Treated using allogeneic sct
Tyrosine kinase inhibitors like imatinib, dasatinib

Prognosis for ALL

Children have better prognosis than adults and children less than 1 yr
Male predilection T ALL is worser than B ALL
Presence of philadelphia chromosome
Presence of Cns disease

Acute myeloid leukemia..Definition

A clonal malignant disorder of the multipotent hc that results in the accumulation of myeloblasts predominantly in the marrow and also peripheral cytopenias

Epidemiology of AML

Commoner in older age groups with peak incidence around the 7th decade of life
Male predilection

Etiology of AML

Same as MDS
Alkylating agents like cyclophosphamide and topisomerase II Inhibitors like etoposide
Can also arise from several hsc diseases like cml pm pv most importantly mds
Or some inherited predisposition to Malignancy like fanconi’s anemia, dyskeratosis congenita

Pathogenesis of AML

Somatic mutations arising from translocation of chromosomal segments which disrupt several genes that code for proteins involved in control of cell cycle
This then results in an uncontrolled proliferation of cells with maturation arrest, resistance to apoptosis and accumulation of malignant myeloblasts in the BM

Consumption coagulopathy with bleeding occurs in

Acute promuelocytic leukemia

3 modes of classification of AML

FAB
WHO
Immunophenotyping

FAB Classification of AML

M0- M7 M0- AML undifferentiated M1- AML with minimal maturation M2-AML with maturation M3- Acute promyelocytic leukemia M4-Acute myelomonocytic leukemia M5-Acute monocytic/monoblastic leukemia M6-Acute erythroid leukemia M7-Acute megakaryoblastic leukemia

In immunophenotypic classification of Aml, what cluster of differentiation are typically affected

CD13 and CD33

Clinical features of AML

Tb, nf, as Some tissue infiltration mainly in monocytic variant -Gingival hyperplasia, granulocytic sarcoma -bleeding due to coagulopathy in premyelocytic leukemia

Investigations of AML

Sane as ALL, However myeloblasts seen instead of lymphoblasts Myeloblasts- medium sized cells High n:c ratio Fairly abundant granules or a granular cytoplasm Nucleus composed of fine, open chromatin and has 3 or more nucleoli

Cut off for morphological diagnosis of aml

>20% myeloblasts in bm Immunopenotyping to detect cd13 and 33 Cytochemical stain which include positivity for sudan B black and myeloperoxidase Cytogenetics to detect t(5,17),t(8,21), inv 16 LFT, RFT, CXR ECG are also important

What differentiates aml from all

Cytochemical stain which shows positivity for Sudan B black and MYELOPEROXIDASE enzyme I.e myeloperoxidase staining in Aml Presence of Auer rods also

Treatment of AML

Supportive and definitive

Definitive treatment for aml

Remission induction- to achieve complete remission Doxorubicin, cytosinearabinoside with or without thioguanine Post remission therapy

Acute promyelocytic leukemia is treated with

Retinoic acid Arsenic trioxide

Targeted therapy for aml

Anti Cd33- Gemtuzumab Anti FLT3- midostarin Allogeneic sct to prevent relapse