Module Blood and Lymph Module Blood and Lymph 2011/20122011/2012

UKMMCUKMMC

LEUKAEMIA I & IILEUKAEMIA I & II

LEUKAEMIASLEUKAEMIAS

A heterogeneous group of malignant A heterogeneous group of malignant blood disorders - blood disorders - MalignantMalignant haemopoietic progenitor/stem cell.haemopoietic progenitor/stem cell.

Uncontrolled clonal proliferation of Uncontrolled clonal proliferation of malignant cells of haematopoietic malignant cells of haematopoietic origin.origin.

LeukaemiasLeukaemias Proliferation of abnormal / malignant Proliferation of abnormal / malignant

cloneclone

Replacement of normal haemopoietic Replacement of normal haemopoietic

cells in the bone marrowcells in the bone marrow

Bone marrow failureBone marrow failure

Infiltrate other organs and proliferatesInfiltrate other organs and proliferates

(organomegaly, CNS, skin infiltration)(organomegaly, CNS, skin infiltration)

Leukaemias - EtiologyLeukaemias - Etiology

Majority of leukaemias - unknown.Majority of leukaemias - unknown.

Increase incidence of leukaemia Increase incidence of leukaemia

in relation to certain factors.in relation to certain factors.

Evolution of leukaemia - is a Evolution of leukaemia - is a multistep process.multistep process.

Leukaemias Leukaemias

* * Ionizing radiation Ionizing radiation (quantity: large doses)(quantity: large doses)* Chemicals * Chemicals * Genetic abnormalities * Genetic abnormalities (& oncogenes)(& oncogenes)

* Viruses : eg: * Viruses : eg: HTLV I HTLV I T cell leukaemia/lymphoma T cell leukaemia/lymphoma (first described in (first described in

Japan)Japan) HTLV II HTLV II Hairy cell leukaemia Hairy cell leukaemia

* Others - ?* Others - ?

Ionizing RadiationIonizing Radiation First identifiable agent associated First identifiable agent associated

with induction of leukaemias:with induction of leukaemias:

AML, CMLAML, CML Irradiation therapy for other Irradiation therapy for other

malignancies malignancies myelodysplasia myelodysplasia acute leukaemia (eg: AML)acute leukaemia (eg: AML)

ChemicalsChemicals Benzene, petroleum derivatives and Benzene, petroleum derivatives and

alkylating agents; bulsulphan, alkylating agents; bulsulphan, chlorambucil, chloramphenicol etc etc chlorambucil, chloramphenicol etc etc

Genetic abnormalitiesGenetic abnormalities

Examples:Examples: Translocation t(9:22) Translocation t(9:22) in chronic in chronic

myeloid leukaemiamyeloid leukaemia

t ( 15,17) t ( 15,17) in acute promyelocytic in acute promyelocytic leukaemialeukaemia

Some genetic disorders – associated Some genetic disorders – associated with increased incidence of leukaemia:with increased incidence of leukaemia:

Down’s Syndrome, Fanconi’s anaemia Down’s Syndrome, Fanconi’s anaemia

Leukaemia - ClassificationLeukaemia - Classification

LEUKAEMIA: LEUKAEMIA:

AcuteAcute ChronicChronic LymphoidLymphoid

MyeloidMyeloid

On the basis of the degree of cell On the basis of the degree of cell differentiation, onset and clinical course.differentiation, onset and clinical course.

Acute Leukaemias:Acute Leukaemias:eg:eg:Acute Lymphocytic Leukaemia (ALL)Acute Lymphocytic Leukaemia (ALL)Acute Myeloblastic Leukaemia (AML)Acute Myeloblastic Leukaemia (AML)

Chronic leukaemias:Chronic leukaemias:eg:eg:Chronic Myeloid Leukaemias (CML)Chronic Myeloid Leukaemias (CML)Chronic Lymphocytic leukaemias Chronic Lymphocytic leukaemias (CLL)(CLL)OthersOthers

ACUTE LEUKAEMIASACUTE LEUKAEMIAS

Malignant disorderMalignant disorder Increase - immature haemopoietic Increase - immature haemopoietic

cellscells

BlastsBlasts

Arise de novoArise de novo A terminal event of pre-existing A terminal event of pre-existing

blood disorders - PRV, MDSblood disorders - PRV, MDS..

Acute Leukaemias: ClassificationAcute Leukaemias: Classification

1) French-American-British (FAB) Classification - 1) French-American-British (FAB) Classification - 19761976(based on morphology and cytochemistry)(based on morphology and cytochemistry)

ALL - L1, L2, L3ALL - L1, L2, L3 AML- M0 - M7AML- M0 - M7 Old ClassificationOld Classification

2) 2) WHO Classification WHO Classification - recent/new- recent/new

- more comprehensive- more comprehensive

- molecular, cytogenetic - molecular, cytogenetic markersmarkers

2) WHO classification

Clinical FeaturesClinical Features

Effects due to:Effects due to:

1) Bone marrow infiltration by leukaemic 1) Bone marrow infiltration by leukaemic blasts blasts anaemia, leucopenia, anaemia, leucopenia, thrombocytopenia.thrombocytopenia.

(and its complications).(and its complications).

2) Tissue (organ) infiltration 2) Tissue (organ) infiltration

Clinical featuresClinical features

Effects and complications:Effects and complications: AnaemiaAnaemia ThrombocytopeniaThrombocytopenia Neutropenia/leukopeniaNeutropenia/leukopenia Organ involvement/ failure Organ involvement/ failure

Particular subtypes of acute Particular subtypes of acute leukaemias:leukaemias:

EXAMPLES:EXAMPLES:

AAML-M3 (acute promyelocytic leukaemia)ML-M3 (acute promyelocytic leukaemia)

Increase incidence of disseminated Increase incidence of disseminated intravascular coagulation (DIC) & hemorrhage.intravascular coagulation (DIC) & hemorrhage.

ALL ALL CNS involvement > common in ALL than CNS involvement > common in ALL than in AMLin AML

Testicular involvement > common in Testicular involvement > common in ALL.ALL.

AML-M5 AML-M5 soft tissue infiltration: gums, skin, soft tissue infiltration: gums, skin, CNS.CNS.

T- ALL T- ALL Mediastinal mass Mediastinal mass

DiagnosisDiagnosis

ClinicalClinical Laboratory Laboratory

Laboratory InvestigationsLaboratory Investigations

* * Full blood picture: Full blood picture:

- anaemia- anaemia

- neutropenia, lymphopenia - neutropenia, lymphopenia

- thrombocytopenia- thrombocytopenia

(with or without presence of blasts)(with or without presence of blasts)

Investigation (cont)Investigation (cont)

BM aspiration/trephine biopsy :BM aspiration/trephine biopsy :

Reduced normal haemopoietic cells Reduced normal haemopoietic cells

Predominant cells in marrow = blast Predominant cells in marrow = blast cellscells

Cytochemical analysis : Cytochemical analysis :

differentiates AML and ALLdifferentiates AML and ALL

Myeloperoxidase, Sudan black.Myeloperoxidase, Sudan black.

Peroxidase negative: ALL blasts

Peroxidase Positive:AML

Immunophenotyping: use Immunophenotyping: use monoclonal antibodies.monoclonal antibodies.

* Cytogenetic analysis * Cytogenetic analysis

* Electron Microscopy* Electron Microscopy

* Molecular analysis* Molecular analysis

ManagementManagement

General / supportive treatment.General / supportive treatment. Chemotherapy.Chemotherapy.

Radiation, CNS Radiation, CNS prophylaxis(ALL)prophylaxis(ALL)

Stem cell transplantationStem cell transplantation

AML-M3 (acute promyelocytic AML-M3 (acute promyelocytic leukaemia)leukaemia)

All-trans retinoic acid (ALTRA) to All-trans retinoic acid (ALTRA) to induce differentiationinduce differentiation

Chemotherapy / TransplantationChemotherapy / Transplantation

CHRONIC MYELOID LEUKAEMIA (CML)CHRONIC MYELOID LEUKAEMIA (CML)

A clonal myeloproliferative disorder,A clonal myeloproliferative disorder,

rise from an acquired genetic rise from an acquired genetic change in change in pluripotential stem pluripotential stem cell.cell.

Gross overproduction of neutrophils Gross overproduction of neutrophils and its precursors.and its precursors.

CML CML

Hallmark of CML : Philadelphia Hallmark of CML : Philadelphia chromosomechromosome

- the (9,22)(q34,q11) translocation.- the (9,22)(q34,q11) translocation.

95% CML:(Ph’) positive.95% CML:(Ph’) positive.

The (9,22)(q34,q11) translocation:The (9,22)(q34,q11) translocation:

Fusion Fusion BCR-ABL genes BCR-ABL genes

has greater tyrosine kinase has greater tyrosine kinase activity: oncogenic growth factoractivity: oncogenic growth factor

CMLCML Clinical Phase:Clinical Phase:

1) Chronic 1) Chronic

2) Blast crisis 2) Blast crisis (transform (transform acute leukaemia, mostly AML) acute leukaemia, mostly AML)

CML : CML : chronic phasechronic phase

Adults (40-60)Adults (40-60) anaemiaanaemia splenomegaly (massive)splenomegaly (massive) hepatomegalyhepatomegaly gout gout (hyperuricaemia)(hyperuricaemia) hyperviscosity syndrome hyperviscosity syndrome (due to leucocytosis)(due to leucocytosis) neutropenia, thrombocytopenia (not common)neutropenia, thrombocytopenia (not common) others…..others…..

CML CML (chronic phase)(chronic phase) - - InvestigationsInvestigations

FBP :FBP : Leucocytosis (Leucocytosis (WBC)WBC)

usually > 100 x 10 usually > 100 x 10 99/l/l

Morphology : myeloid cells at all stages Morphology : myeloid cells at all stages of of differentiation differentiation

Lab. Investigations:

Bone marrow :Bone marrow :

HypercellularHypercellular

Myelopoiesis is increased. Myelopoiesis is increased.

(increase myeloid series)(increase myeloid series)

((with few blasts which is less with few blasts which is less than 5% than 5% blasts)blasts)

Investigations :Investigations :

Neutrophil alkaline phosphatase (NAP) - Neutrophil alkaline phosphatase (NAP) - score : reducedscore : reduced

Cytogenetic analysis : Ph-chromosomeCytogenetic analysis : Ph-chromosome

Molecular analysis (bcr-abl fusion gene)Molecular analysis (bcr-abl fusion gene)

CML - TREATMENTCML - TREATMENT

Chronic phase:Chronic phase:

hydroxyurea, Glivec/Imatinibhydroxyurea, Glivec/Imatinib

- Transplantation - Transplantation

(Bone Marrow / Peripheral blood (Bone Marrow / Peripheral blood stem cell transplant)stem cell transplant)

Chronic Lymphocytic Leukaemia Chronic Lymphocytic Leukaemia (CLL)(CLL)

Proliferation and accumulation of a monoclonal Proliferation and accumulation of a monoclonal population of abnormal lymphocytes.population of abnormal lymphocytes.

Common : WestCommon : West Majority elderly >50 yearsMajority elderly >50 years Male preponderanceMale preponderance Majority : B-cell type (95%)Majority : B-cell type (95%)

--

CLL - Clinical FeaturesCLL - Clinical Features Common:Common:

anaemiaanaemia

lymphadenopathylymphadenopathy

infections - persistent / severeinfections - persistent / severe

splenomegaly splenomegaly

autoimmune haemolytic anaemia - autoimmune haemolytic anaemia - 10%10%

immune thrombocytopenia (ITP) - immune thrombocytopenia (ITP) - 5%5%

haemorrhagic manifestationshaemorrhagic manifestations

Diagnosis :Diagnosis : Clinical & LaboratoryClinical & Laboratory

Investigations:Investigations: Full blood picture:Full blood picture:

lymphocytosis. lymphocytosis. Bone marrow biopsy: Bone marrow biopsy: lymphocytes lymphocytes Clonality study : Clonality study :

- immunological study - immunological study (immunotyping)(immunotyping)

- molecular analysis - molecular analysis (eg: IgG /TCR gene rearrangement (eg: IgG /TCR gene rearrangement

studies)studies)..