chronic leukaemias

Chronic leukaemias

Chronic myelogenous leukaemiaChronic lymphocytic leukaemia

Chronic myelogenous leukaemia

A Myeloproliferative disorderA clonal disorder where 95% of patients

have a distinctive cytogenetic abnormality “the Philadelphia (Ph) chromosome”

Median age of ph+ CML is 67 yrs(30-80yrs)

Medial survival is 4-6 yrs, (range 1-10yrs)Curative only by BMT

Myeloproliferative disorders

Chronic myelogenous leukaemiaPolycythemia VeraMyelofibrosisEssential thrombocythemia

CML – Natural History Chronic phase:

Disease respond to treatment < 5% of blasts and promyelocytes in the peripheral

blood and bone marrow

Accelerated phase > 5% in either peripheral blood or bone marrow and <

20% in both peripheral blood and bone marrow. Blast crisis acute leukaemia

> 20% blasts are present in peripheral blood or bone marrow

70% AML 30% ALL

CML- SymptomsFatigueAbdominal fullness and discomfort Symptoms of anaemiaNight sweatingLow grade feverWhen WBC count is very high

“leukostasis”• Blurred vision• Respiratory distress• priapism

CML- SignsSplenomegaly ;

mild to gross, usually marked

10% have normal spleenSternal tendernessSigns of anaemia

Philadelphia chromosome A cytogenetic abnormality Due to reciprocal translocation

between the long arm of chromosomes 9(9q) and 22(22q) (9:22 translocation)

It is found in all haematopoietic precursors of CML patients.

This result in the transfer of the Abelson's (abl) oncogene to an area of chromosome 22 termed the break-point cluster region (bcr)

This results in a fused bcr-abl gene and production of an abnormal tyrosine kinase protein.

This protein causes disordered myelopoiesis in CML

CML- InvestigationsComplete blood countPeripheral blood film smearBone marrow aspirationPh chromosome analysisOthers

CML- InvestigationsComplete blood countPeripheral blood film smearBone marrow aspirationSouthern Blot analysisPh chromosome analysisNAP scoreOthers

Complete blood count

WBC countsIt may reach up to 500 x 109/lUsually around 150 x 109/l

AnaemiaPlatelets N or

CML- InvestigationsComplete blood countPeripheral blood film smearBone marrow aspirationPh chromosome analysisOthers

Peripheral blood film smear Shift to left of myeloid series with more myelocytes in PBF

than mature WBCs

Blast cells are < 5% Basophilia

PBF in CML

CML- InvestigationsComplete blood countPeripheral blood film smearBone marrow aspiration

Assess cellularityAssess fibrosisCytogenetic studies for Ph chromosome analysis

Others

CML - Bone marrow aspiration Hyper cellular bone marrow

Shift in the myeloid series to immature forms, this increase in number as patients progress to blastic phase of the disease.

Myeloblast count <5% of myeloid cells in chronic phase.

Elevated myeloid/ erythroid ratio in the marrow.

CML- Investigations Complete blood count Peripheral blood film smear Bone marrow aspiration

Assess cellularity Assess fibrosis Cytogenetic studies for Ph chromosome analysis

Others Vitamin B12 level due to secretion of

transcobolamin III Uric acid

Management of Chronic CMLGleevec® (Imatinib mesylate)

A tyrosine kinase inhibitorTyrosine kinase is required for transforming

functioin of the bcr-able fusion proteinIt induces hematological remission in almost

all patients with interferon resistent CMLCytogenetic response is seen in 50% of

patients.

Management of Chronic CMLAllogenic BMT

Is the only curative treatment available of CML so far

It should be considered in the first year of diagnosis if the patient is <40 yrs of age and has an HLA matched donor.

Interferon αUsed for patients who are not eligible for BMTMay induce a cytogenetic response in 20% of

patients.

Management of Chronic CML Hydroxurea

Uses: Initial treatment to lower WBC count prior to interferon

therapy. Palliative treatment of patients failing other treatment.

Splenectomy Hypersplenism discomfort

Accelerated phase of CMLFeatures

Bone painSpleenomegalyResistance to current treatmentProgressive anaemiaThrombocytopenia or thrombocytosisBlast cells >5% in either PB or BM and <30%

of both PB and BM.

Accelerated phase of CML

TreatmentImatinib mesylate

Bone marrow transplantation

High dose cytarabine

Blastic phase of CML

FeaturesFeverMalaiseProgressive splenomgalyBlast cells >20% in PB or BM

Blastic phase of CML

TreatmentImatinib mesylate

As in ALL (Vincrisitne and prednisolone + anthracycline)

Allogenic BMT

Chronic lymphocytic leukemia It is a disease of

morphologically mature but immunologically less mature lymphocytes.

Manifested by progressive accumulation of lymphocytes in the blood, bone marrow and lymphatic tissues.

CLLEpidemiology

The most common leukemia in adultmales >females> 45 yrsHere mature lymphocytes fail to respond to

Ag stimulation95% are B cell type5% are T cell type

The overall 5 year survival is 60%

CLLClinical presentation

Indolent lymphocytosis (asymptomatic)

Generalized lymphadenopathy

Hepato-splenomegaly

CLLClinical presentation

Pancytopenia Anaemia

Coombs positive hemolysis Hypoplastic

Bleeding Production thrombocytopenia Immune thrombocytopenia

Infection Depressed immunoglobulin levels

CLLinvestigations

CBCPBFBM aspiration Immunochemistry Total protein and Ig level

CBCPBFBM aspiration immunochemistryTotal protein and Ig level

CLLinvestigations

WBC: Increased counts Mainly lymphocytes Lymphocyte count >=10 x 109/l

Hb: Normal or low Hemolytic anaemia

Platelets: Normal or low

Complete blood counts


CLLinvestigations

Perioheral blood film Predominantly

lymphocytosis Normally looking Presence of smudge cells


CLLinvestigations

Not necessary for diagnosis

Infiltration of the bone marrow by lymphocytes.

Bone marrow aspiration

CBCPBFBM aspiration Immuno chemistryTotal protein and Ig level

CLLinvestigations

Immunoglobulin levelsLow immunoglobulin levels

Immuno-chemistry

•CD19 positive•CD20 positive•CD5 positive

CLL- staging

CLLwhom to treat?

Stage A No TreatmentObservation only

Stage B Treat if symptomaticObservation only for asymptomaticChemotherapy for symptomatic

lymphadenopathy

Stage C Treat AllShould be treated

CLLtreatment

Supportive treatment Treat infection

Herpes zoster Pseudomonas carinii

Proper hydration + allopurinol

Automimmune anaemia or thrombocytopenia corticosteroids Blood transfusion High dose immuneglobulin Cyclosporine Splenectomy Low dose radiation to the spleen

CLLTreatment options

Oral alkylating agents + corticosteroids Chlorambucil + prednisolone

Purine analogues: Fludrabine,

Combination chemotherapy: CVP or CHOP

Involved field radiotherapy: for lymph node areas

Splenic radiation for palliation of hypersplenism

chronic leukaemias

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