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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
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)..