Transcript 7a78e3cd-45c1-4f6e-a2d0

LEUKEMIAS
Dr.Nazzal Bsoul
Hematologist
Al Bashir Hospital
Terminology
Leukos: White
Aimia: Blood
Leukemia--------Leukaemia ?
Hematology-----Haematology ?
Leukemoid reaction:
Definition
Leukemia: is a cancer of the blood or bone
marrow characterized by abnormal proliferation
of blood cells,usually WBCs(Leukocytes).
Acute leukemia: rapid increase of immature
blood cells.
Chronic leukemia: excessive build up of
relatively mature,but still abnormal blood cells.
Leukemoid Reaction
A leukemoid reaction describes a high
WBC count with neutrophilia,usually in
response to infection.
The WBC count may be as high as 50,000
/microL and can easily mimic CML or
AML.
Features Suggesting Leukemoid
Reaction
Toxic granulation.
High LAP score.
Presence of an obvious cause for the
neutrophilia.
Signs and Symptoms
Most of the signs and symptoms are due to:
1-Anemia.
2-Leukopenia.
3-Thrombocytopenia.
Bicytopenia,Pancytopenia.
All symptoms associated with leukemia
can be attributed to other diseases,
consequently,leukemia is always
diagnosed by laboratory investigations.
Causes
Leukemia,like other malignancies, results
from somatic mutations in the DNA.
Certain mutations produce leukemia by
activating oncogenes or deactivating
tumor suppressor genes.
These mutations may occur spontaneously
or as a result of exposure to radiation
or carcinogenic substances,and likely
to be influenced by genetic factors.
Causes-cont’d
Ionizing radiation
Viruses: Human T-lymphotropic virus (HTLV-1)
Chemicals: Benzene,chemotherapy.
Smoking: slight increase in leukemia
incidence.
Genetic predisposition toward developing
leukemia: Down syn.,Fanconi anemia
Acute Myeloid Leukemia
Definition
Acute myeloid leukemia (AML): acute
myelogenous leukemia,acute nonlymphocytic leukemia.
AML consists of a group of relatively welldefined hematopoietic neoplasms
involving precursor cells commited
to the myeloid line(WBCs,RBCs,PLTs)
Chracteristics
AML is characterized by a clonal proliferation of myeloid precursors with a
reduced capacity to differentiate into
mature cellular elements.
As a result,there is an accumulation of
leukemic blasts or other immature
forms in the BM,peripheral blood,and
other tissues with a variable reduction in
the production of normal RBCs,platelets,
and mature granulocytes.
Epidemiology
AML is the most common acute leukemia
in adults (80%).
In USA 3-5 cases per 100 000 population.
In contrast AML accounts for less than
10% of acute leukemia cases in
children less than 10 years of age.
The M/F ratio is approximately 5:3.
Epidemiology-cont’d
AML has been associated with following:
1-Environmental factors: chemicals,
radiation,tobacco,and chemotherapy.
2-Genetic abnormalities: Down syndrome,
Fanconi anemia.
3-Other benign hematological disorders:
Paroxysmal nocturnal hemoglobinuria
4-Malignant hematological disorders:MDS,MPN
Classification
Multiple classification systems.
FAB classification:
French-American-British Classification.
FAB Classification relies on morphologic,
cytochemical,and immunophenotyping
criteria to define 8 major subtypes
(M0-M7)
Clinical Presentation
Patients with AML present usually with
symptoms related to pancytopenia:
1-Anemia.
2-Leukopenia with neutropenia.
3-Thrombocytopenia.
Pathological Features
CBC and differential.
Blood film (smear).
Bone marrow examination: BM aspirate
and trephine biopsy.
1-Morphology.
2-Immunephenotyping.
3-Cytogenetics and molecular biology.
WBC Count in AML
WBC count in AML can be high,normal,or
low.
Median WBC count in AML is 15 000/uL.
20% of patients have > 100 000/uL
25-40% of patients have <5000/uL
95% of patients have blast cells on blood
film.
Treatment
AML is usually treated with:
1-Chemotherapeutic agents.
2-Bone marrow transplantation (BMT),
hematopoietic stem cell transplantation
(HSCT).
3-Supportive treatment: blood transfusion,
PLT transfusion,Granulocyte colony
stimulating factor (G-CSF),i.v fluids,
antibiotics.
Prognosis
The response to treatment and overall
survival of patients with AML are
heterogenous.
Prognostic factors are related to patient
and tumor characteristics:
1-Age
2-Performance status
3- Karyotype
Adverse Clinical Predictors
Advanced age.
Poor performance status.
History of exposure to cytostatic agents or
radiotherapy.(Therapy-related AML).
History of MDS or other hematological
diseases
Chronic Myeloid Leukemia
(CML)
Terminology
Chronic myeloid leukemia (CML).
Chronic myelocytic leukemia.
Chronic myelogenous leukemia.
Chronic granulocytic leukemia (CGL).
Definition
CML is a myeloproliferative neoplasm
characterized by the dysregulated production
and uncontrolled proliferation of mature
and maturing granulocytes with fairly
normal differentiation.
CML is associated with the fusion of genes:
BCR(on chromosome 22)and ABL1(on
chromosome 9), resulting in the BCR/ABL1
fusion gene.
This abnormal fusion gene (protein)
typically results from a reciprocal
translocation between chromosome
9 and 22,t(9;22).(Philadelphia
chromosome)
Epidemiology
CML accounts for 15-20 % of leukemias in
adults.
Annual incidence of 1-2 cases per 100,000
Median age at presentation is 60 years.
Exposure to ionizing radiation is the only
known risk factor.
The prevalence of CML is steadily
increasing due to ?.
Clinical manifestation
CML has a triphasic or biphasic course:1-Chronic phase: 85% of pts.at dg.
2-Accelerated phase: WBC count is
more difficult to control.
3-Blast crisis: a condition resembling
acute leukemia (AML,ALL).
Clinical findings
Clinical findings at dg. vary among
reported series and also depend
upon the stage of the disease at dg.
20-50% of patients are asymptomatic.
50-80% of patients are symptomatic:
Systemic symptoms(fatique,w.loss,
excessive sweating,bleeding due to
PLT dysfunction).
Clinical findings-cont’d
Abdominal symptomatology: Lt.UQ
pain,early satiety,nausea,vomiting.
Tenderness over the lower sternum.
Other frequent findings include:
Splenomegaly: 48-76% of cases.
Anemia: 45-62% of cases.
Leukocytosis: WBC count above
100,000/microL.
Thrombocytosis: 15-34% of cases.
Peripheral blood
Leukocytosis: median WBC count 100,000
/microL(range 12-1000/microL).
Anemia: 45-60%.Normochromic,normocyt.
Thrombocytosis: above 600,000(15-30%)
Blood film:all stages of maturation.
LAP score: Low (Leukemoid reaction high
or N)
Absolute basophilia,eosinophilia,
monocytosis.
Bone marrow
Bone marrow aspirate and biopsy:
1-Granulocytic hyperplasia.
2- Increase in reticulin fibrosis and
vascularity.
Genetics
Genetic testing for: t(9;22)(q32;q11,2)
Philadelphia chromosome.
BCR/ABL1 fusion gene
Fusion mRNA gene product
Conventional cytogenetic analysis (karyotyping)
Florescence in situ hybridization (FISH)
Reverse transcription PCR (RT-PCR).
Diagnosis
CML is suspected in a patient with some
of the findings mentioned above(syst.
complaints,early satiety,hepatosplenomegaly,leukocytosis….)
Morphologic features in the blood and
BM.
Confirmed by genetic studies.
Differential diagnosis
Leukemoid reaction.
Juvenile myelomonocytic leukemia(JMML)
Chronic myelomonocytic leukemia(CMML)
Atypical CML.
Chronic eosinophilic leukemia.
Chronic neutrophilic leukemia.
Other myeloproliferative neoplasms.
Other Ph chromosome-posit.Malignancies.
Prognosis
The stage of disease at dg.is the strongest
single predictor of outcome in patients
with CML.
Scoring systems: Sokal prognostic score:4
clinical variables:
1-Spleen size
2-Percent blasts.
3-Age
4-PLT count above 700,000/microL.
Treatment of CML
Available treatment options:
1-Allogeneic hematopoietic stem cell
transplantation (HSCT,BMT): curative
treatment option.
2-Disease control without cure using
tyrosine kinase inhibitors (TKIs).
3-Palliative therapy with cytotoxic agents
4-Investigational therapies: Farensyl
transferase inhibitors,dicitabine.
Choice of therapy
Factors influencing the choice of therapy:
1-Phase of the disease.
2-Availability of a donor for HSCT.
3-Patient age.
4-Presence of co-morbidities.
5-Response to treatment with TKIs.
Choice of therapy
Factors influencing the choice of therapy:
1-Phase of the disease.
2-Availability of a donor for HSCT.
3-Patient age.
4-Presence of co-morbidities.
5-Response to treatment with TKIs.
Tyrosine Kinase Inhibitors
(TKIs)
TKIs target the active tyrosine kinase
implicated in the pathogenesis of CML.
1-First-generation oral TKIs:
Imatinib (Glivec,Cemivil).
2-Second-generation TKIs:
Nilotinib (Tasigna),Dasatinib.
Although TKIs do not cure CML,these
agents are able to achieve long-term
control of the disease.
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