LEUKEMIASLEUKEMIAS

Dr.NazzalDr.Nazzal BsoulBsoulHematologistHematologist

Al Bashir HospitalAl Bashir Hospital

TerminologyTerminology

Leukos: WhiteLeukos: White

Aimia: BloodAimia: Blood

LeukLeukeemia--------Leukmia--------Leukaeaemia ?mia ?

HHeematology-----Hmatology-----Haeaematology ?matology ?

Leukemoid reaction:Leukemoid reaction:

DefinitionDefinition Leukemia:Leukemia: is a cancer of the blood or bone is a cancer of the blood or bone marrow characterized by abnormal proliferation marrow characterized by abnormal proliferation of blood cells,usually WBCs(Leukocytes).of blood cells,usually WBCs(Leukocytes).

Acute leukemiaAcute leukemia: rapid increase of : rapid increase of immature immature blood cells.blood cells.

Chronic leukemiaChronic leukemia: excessive build up of : excessive build up of relatively mature,relatively mature,but still abnormal blood cells.but still abnormal blood cells.

Leukemoid ReactionLeukemoid ReactionA leukemoid reaction describes a high A leukemoid reaction describes a high

WBC count with neutrophilia,usually inWBC count with neutrophilia,usually in

response to infection.response to infection.

The WBC count may be as high as 50,000The WBC count may be as high as 50,000

/microL and can easily mimic CML or/microL and can easily mimic CML or

AML.AML.

Features Suggesting Leukemoid Features Suggesting Leukemoid ReactionReaction

Toxic granulation.Toxic granulation.

High LAP score.High LAP score.

Presence of an obvious cause for the Presence of an obvious cause for the

neutrophilia.neutrophilia.

Signs and SymptomsSigns and SymptomsMost of the signs and symptoms are due to:Most of the signs and symptoms are due to:

1-Anemia.1-Anemia. 2-Leukopenia.2-Leukopenia. 3-Thrombocytopenia.3-Thrombocytopenia.

Bicytopenia,Pancytopenia.Bicytopenia,Pancytopenia.All symptoms associated with leukemia All symptoms associated with leukemia

can be attributed to other diseases,can be attributed to other diseases, consequently,leukemia is alwaysconsequently,leukemia is always diagnosed by laboratory investigations.diagnosed by laboratory investigations.

CausesCausesLeukemia,like other malignancies, resultsLeukemia,like other malignancies, results

from from somatic mutations in the DNA.somatic mutations in the DNA.Certain mutations produce leukemia byCertain mutations produce leukemia by

activating activating oncogenesoncogenes or deactivating or deactivating tumor suppressor genestumor suppressor genes..

These mutations may occur These mutations may occur spontaneouslyspontaneously or as a result of exposure to or as a result of exposure to radiationradiation or or carcinogenic substances,carcinogenic substances,and likelyand likely to be influenced by to be influenced by genetic factorsgenetic factors..

Causes-cont’dCauses-cont’dIonizing radiationIonizing radiation

Viruses: Human T-lymphotropic virus (HTLV-1)Viruses: Human T-lymphotropic virus (HTLV-1)

Chemicals: Benzene,chemotherapy.Chemicals: Benzene,chemotherapy.

Smoking: slight increase in leukemia Smoking: slight increase in leukemia

incidence.incidence.

Genetic predisposition toward developingGenetic predisposition toward developing

leukemia: Down syn.,Fanconi anemialeukemia: Down syn.,Fanconi anemia

Acute Myeloid LeukemiaAcute Myeloid Leukemia

DefinitionDefinitionAcute myeloid leukemia (AML): acuteAcute myeloid leukemia (AML): acute

myelogenous leukemia,acute non-myelogenous leukemia,acute non-

lymphocytic leukemia.lymphocytic leukemia.

AML consists of a group of relatively well-AML consists of a group of relatively well-

defined hematopoietic neoplasmsdefined hematopoietic neoplasms

involving precursor cells commitedinvolving precursor cells commited

to the myeloid line(WBCs,RBCs,PLTs)to the myeloid line(WBCs,RBCs,PLTs)

ChracteristicsChracteristicsAML is characterized by a AML is characterized by a clonal proli-clonal proli-

ferationferation of myeloid precursors with a of myeloid precursors with a reduced capacity to differentiatereduced capacity to differentiate into into mature cellular elements.mature cellular elements.

As a result,there is an As a result,there is an accumulation ofaccumulation of leukemic blastsleukemic blasts or other immature or other immature forms in the BM,peripheral blood,andforms in the BM,peripheral blood,and other tissues with a variable other tissues with a variable reduction inreduction in the production of normal RBCs,plateletsthe production of normal RBCs,platelets,, and mature granulocytesand mature granulocytes..

EpidemiologyEpidemiologyAML is the most common acute leukemiaAML is the most common acute leukemia

in adults (80%).in adults (80%).

In USA 3-5 cases per 100 000 population.In USA 3-5 cases per 100 000 population.

In contrast AML accounts for less than In contrast AML accounts for less than

10% of acute leukemia cases in 10% of acute leukemia cases in

children less than 10 years of age.children less than 10 years of age.

The M/F ratio is approximately 5:3.The M/F ratio is approximately 5:3.

Epidemiology-cont’dEpidemiology-cont’dAML has been associated with following:AML has been associated with following:

1-Environmental factors1-Environmental factors: chemicals,: chemicals, radiation,tobacco,and chemotherapy.radiation,tobacco,and chemotherapy. 2-Genetic abnormalities2-Genetic abnormalities: Down syndrome,: Down syndrome, Fanconi anemia.Fanconi anemia. 33-Other -Other benign hematological disordersbenign hematological disorders:: Paroxysmal nocturnal hemoglobinuriaParoxysmal nocturnal hemoglobinuria 4-Malignant hematological disorders:MDS,MPN4-Malignant hematological disorders:MDS,MPN

ClassificationClassificationMultiple classification systems.Multiple classification systems.

FAB classification:FAB classification:

French-American-British Classification.French-American-British Classification.

FAB Classification relies on FAB Classification relies on morphologic,morphologic,

cytochemicalcytochemical,and ,and immunophenotypingimmunophenotyping

criteria to define 8 major subtypescriteria to define 8 major subtypes

(M0-M7)(M0-M7)

Clinical PresentationClinical PresentationPatients with AML present usually withPatients with AML present usually with

symptoms related to pancytopenia:symptoms related to pancytopenia:

1-Anemia.1-Anemia.

2-Leukopenia with neutropenia.2-Leukopenia with neutropenia.

3-Thrombocytopenia.3-Thrombocytopenia.

Pathological FeaturesPathological FeaturesCBC and differential.CBC and differential.

Blood film (smear).Blood film (smear).

Bone marrow examination: BM aspirate Bone marrow examination: BM aspirate

and trephine biopsy.and trephine biopsy.

1-Morphology.1-Morphology.

2-Immunephenotyping.2-Immunephenotyping.

3-Cytogenetics and molecular biology.3-Cytogenetics and molecular biology.

WBC Count in AMLWBC Count in AMLWBC count in AML can be WBC count in AML can be highhigh,,normalnormal,or,or

lowlow..

Median WBC count in AML is 15 000/uL.Median WBC count in AML is 15 000/uL.

20% of patients have > 100 000/uL20% of patients have > 100 000/uL

25-40% of patients have <5000/uL25-40% of patients have <5000/uL

95% of patients have blast cells on blood95% of patients have blast cells on blood

film.film.

TreatmentTreatmentAML is usually treated with:AML is usually treated with:

1-Chemotherapeutic agents.1-Chemotherapeutic agents. 2-Bone marrow transplantation (BMT),2-Bone marrow transplantation (BMT), hematopoietic stem cell transplantationhematopoietic stem cell transplantation (HSCT).(HSCT). 3-Supportive treatment: blood transfusion,3-Supportive treatment: blood transfusion, PLT transfusion,Granulocyte colonyPLT transfusion,Granulocyte colony stimulating factor (G-CSF),i.v fluids,stimulating factor (G-CSF),i.v fluids, antibiotics.antibiotics.

PrognosisPrognosisThe response to treatment and overallThe response to treatment and overall

survival of patients with AML are survival of patients with AML are heterogenous.heterogenous.

Prognostic factors are related to patientPrognostic factors are related to patient and tumor characteristics:and tumor characteristics: 1-Age1-Age 2-Performance status2-Performance status 3- Karyotype3- Karyotype

Adverse Clinical PredictorsAdverse Clinical Predictors

Advanced age.Advanced age.

Poor performance status.Poor performance status.

History of exposure to cytostatic agents orHistory of exposure to cytostatic agents or

radiotherapy.(Therapy-related AML).radiotherapy.(Therapy-related AML).

History of MDS or other hematologicalHistory of MDS or other hematological

diseasesdiseases

Chronic Myeloid Leukemia Chronic Myeloid Leukemia (CML)(CML)

TerminologyTerminology

Chronic myeloid leukemia (CML).Chronic myeloid leukemia (CML).

Chronic myelocytic leukemia.Chronic myelocytic leukemia.

Chronic myelogenous leukemia.Chronic myelogenous leukemia.

Chronic granulocytic leukemia (CGL).Chronic granulocytic leukemia (CGL).

DefinitionDefinitionCML is a myeloproliferative neoplasm CML is a myeloproliferative neoplasm

characterized by the dysregulated production characterized by the dysregulated production and uncontrolled proliferation of and uncontrolled proliferation of maturemature and and maturing granulocytes maturing granulocytes with fairlywith fairly normal differentiation.normal differentiation.

CML is associated with the fusion of genes:CML is associated with the fusion of genes: BCR(on chromosome 22)and ABL1(onBCR(on chromosome 22)and ABL1(on chromosome 9), resulting in the chromosome 9), resulting in the BCR/ABL1BCR/ABL1 fusion gene.fusion gene.

This abnormal fusion gene (protein) This abnormal fusion gene (protein)

typically results from a typically results from a reciprocal reciprocal

translocation between chromosometranslocation between chromosome

9 and 22,t(9;229 and 22,t(9;22).(Philadelphia ).(Philadelphia

chromosome)chromosome)

EpidemiologyEpidemiology

CML accounts for 15-20 % of leukemias inCML accounts for 15-20 % of leukemias in

adults.adults.

Annual Annual incidenceincidence of 1-2 cases per 100,000 of 1-2 cases per 100,000

Median age at presentation is 60 years.Median age at presentation is 60 years.

Exposure to ionizing radiation is the onlyExposure to ionizing radiation is the only

known risk factor.known risk factor.

The The prevalenceprevalence of CML is steadily of CML is steadily

increasing due to ?.increasing due to ?.

Clinical manifestationClinical manifestation

CML has a triphasic or biphasic course:-CML has a triphasic or biphasic course:-

1-1-Chronic phaseChronic phase: 85% of pts.at dg.: 85% of pts.at dg.

2-2-Accelerated phaseAccelerated phase: WBC count is: WBC count is

more difficult to control.more difficult to control.

3-3-Blast crisisBlast crisis: a condition resembling: a condition resembling

acute leukemia (AML,ALL).acute leukemia (AML,ALL).

Clinical findingsClinical findings

Clinical findings at dg. vary among Clinical findings at dg. vary among

reported series and also dependreported series and also depend

upon the stage of the disease at dg.upon the stage of the disease at dg.

20-50% of patients are asymptomatic.20-50% of patients are asymptomatic.

50-80% of patients are symptomatic:50-80% of patients are symptomatic:

Systemic symptoms(fatique,w.loss,Systemic symptoms(fatique,w.loss,

excessive sweating,bleeding due toexcessive sweating,bleeding due to

PLT dysfunction).PLT dysfunction).

Clinical findings-cont’dClinical findings-cont’d

Abdominal symptomatology: Lt.UQ Abdominal symptomatology: Lt.UQ

pain,early satiety,nausea,vomiting.pain,early satiety,nausea,vomiting.

Tenderness over the lower sternum.Tenderness over the lower sternum.

Other frequent findings include:Other frequent findings include:

Splenomegaly: 48-76% of cases.Splenomegaly: 48-76% of cases.

Anemia: 45-62% of cases.Anemia: 45-62% of cases.

Leukocytosis: WBC count aboveLeukocytosis: WBC count above

100,000/microL.100,000/microL.

Thrombocytosis: 15-34% of cases.Thrombocytosis: 15-34% of cases.

Peripheral bloodPeripheral blood

Leukocytosis: median WBC count 100,000Leukocytosis: median WBC count 100,000

/microL(range 12-1000/microL)./microL(range 12-1000/microL).

Anemia: 45-60%.Normochromic,normocyt.Anemia: 45-60%.Normochromic,normocyt.

Thrombocytosis: above 600,000(15-30%)Thrombocytosis: above 600,000(15-30%)

Blood film:all stages of maturation.Blood film:all stages of maturation.

LAP score: Low (Leukemoid reaction high LAP score: Low (Leukemoid reaction high

or N)or N)

Absolute basophilia,eosinophilia,Absolute basophilia,eosinophilia,

monocytosis.monocytosis.

Bone marrowBone marrow

Bone marrow aspirate and biopsy:Bone marrow aspirate and biopsy:

1-Granulocytic hyperplasia.1-Granulocytic hyperplasia.

2- Increase in reticulin fibrosis and2- Increase in reticulin fibrosis and

vascularity.vascularity.

GeneticsGenetics

Genetic testing for: t(9;22)(q32;q11,2)Genetic testing for: t(9;22)(q32;q11,2)

Philadelphia chromosome.Philadelphia chromosome.

BCR/ABL1 fusion geneBCR/ABL1 fusion gene

Fusion mRNA gene productFusion mRNA gene product

Conventional cytogenetic analysis (Conventional cytogenetic analysis (karyo-karyo-

typingtyping))

FFlorescence lorescence iin n ssitu itu hhybridization (ybridization (FISHFISH))

RReverse everse ttranscription ranscription PCRPCR ( (RT-PCRRT-PCR).).

DiagnosisDiagnosis

CML is suspected in a patient with some CML is suspected in a patient with some

of the findings mentioned above(syst.of the findings mentioned above(syst.

complaints,early satiety,hepatospleno-complaints,early satiety,hepatospleno-

megaly,leukocytosis….) megaly,leukocytosis….)

Morphologic features in the blood and Morphologic features in the blood and

BM.BM.

Confirmed by genetic studies.Confirmed by genetic studies.

Differential diagnosisDifferential diagnosis

Leukemoid reaction.Leukemoid reaction.

Juvenile myelomonocytic leukemia(JMML)Juvenile myelomonocytic leukemia(JMML)

Chronic myelomonocytic leukemia(CMML)Chronic myelomonocytic leukemia(CMML)

Atypical CML.Atypical CML.

Chronic eosinophilic leukemia.Chronic eosinophilic leukemia.

Chronic neutrophilic leukemia.Chronic neutrophilic leukemia.

Other myeloproliferative neoplasms.Other myeloproliferative neoplasms.

Other Ph chromosome-posit.Malignancies.Other Ph chromosome-posit.Malignancies.

PrognosisPrognosis

The stage of disease at dg.is the strongestThe stage of disease at dg.is the strongest

single predictor of outcome in patientssingle predictor of outcome in patients

with CML.with CML.

Scoring systems: Sokal prognostic score:4Scoring systems: Sokal prognostic score:4

clinical variables:clinical variables:

1-Spleen size1-Spleen size

2-Percent blasts.2-Percent blasts.

3-Age3-Age

4-PLT count above 700,000/microL. 4-PLT count above 700,000/microL.

Treatment of CMLTreatment of CMLAvailable treatment options:Available treatment options:

1-Allogeneic hematopoietic stem cell 1-Allogeneic hematopoietic stem cell

transplantation (HSCT,BMT): transplantation (HSCT,BMT): curativecurative

treatment option.treatment option.

2-Disease control 2-Disease control without cure without cure using using

tyrosine kinase inhibitors (TKIs).tyrosine kinase inhibitors (TKIs). 3-Palliative therapy with cytotoxic agents 3-Palliative therapy with cytotoxic agents

4-Investigational therapies: Farensyl 4-Investigational therapies: Farensyl

transferase inhibitors,dicitabine.transferase inhibitors,dicitabine.

Choice of therapyChoice of therapy

Factors influencing the choice of therapy:Factors influencing the choice of therapy:

1-Phase of the disease.1-Phase of the disease.

2-Availability of a donor for HSCT.2-Availability of a donor for HSCT.

3-Patient age.3-Patient age.

4-Presence of co-morbidities.4-Presence of co-morbidities.

5-Response to treatment with TKIs. 5-Response to treatment with TKIs.

Choice of therapyChoice of therapy

Factors influencing the choice of therapy:Factors influencing the choice of therapy:

1-Phase of the disease.1-Phase of the disease.

2-Availability of a donor for HSCT.2-Availability of a donor for HSCT.

3-Patient age.3-Patient age.

4-Presence of co-morbidities.4-Presence of co-morbidities.

5-Response to treatment with TKIs. 5-Response to treatment with TKIs.

Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitors(TKIs)(TKIs)

TKIs TKIs targettarget the active tyrosine kinase the active tyrosine kinase

implicated in the pathogenesis of CML.implicated in the pathogenesis of CML.

1-First-generation oral TKIs:1-First-generation oral TKIs:

Imatinib (Glivec,Cemivil).Imatinib (Glivec,Cemivil).

2-Second-generation TKIs:2-Second-generation TKIs:

Nilotinib (Tasigna),Dasatinib.Nilotinib (Tasigna),Dasatinib.

Although TKIs do not cure CML,these Although TKIs do not cure CML,these

agents are able to achieve long-term agents are able to achieve long-term

control of the disease. control of the disease.

THANK YOUTHANK YOU