chronic myeloid leukemia

CHRONIC MYELOID

LEUKEMIA

K SRINIVAS,DEPT OF GEN

MED

Sunday,

February 1,

2015

1CHRONIC MYELOID LEUKEMIA

DEFINITION

CML is defined as clonal expansion of a hemotopoietic stemcell possessing a reciprocal translocation between chromosome 9 and 22.

Sunday, February 1, 2015

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CHRONIC MYELOID LEUKEMIA

This translocation results in head to tail fusion of the

breakpoint cluster region (BCR) gene on chr 22q11 with ABL1

gene located on chr 9q34


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Sunday, February 1, 2015CHRONIC MYELOID LEUKEMIA

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CML is myeloproliferative stem cell disorder resulting in

proliferation of all haemotopoetic lineages but manifesting

mostly in the granulocyte series

ETIOLOGY

Cigarette smoking acclerated the progression to blast crisis.

Atomic bomb survivors had increase evidence.


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INCIDENCE

I.5 per I00,000 population per year

Higher in men than in women(I.9 vs I.I)

Incidence gradually increases with age until in middle forties

when it starts to rise rapidly.


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PATHOPHYSIOLOGY

The product of fusion gene resulting from the t(9;22) plays a

central role in the development of CML.

This chimeric gene is transcribed in to hybrid BCR-ABLI m RNA

in which exon ABLI is replaced by variable numbers of 5’BCR

exons producing a fusion protein P210BCR ABLI .

A rare brealk point occuring in the region of 3’ exons results in

230kDa,p230 BCR ABLI .


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Attchments of BCR sequences to ABLI results in 3 functional changes

1. the ABL protein becomes constituviley active as tyrosine

kinase(TK)enzyme

2. The DNA protein binding capacity of ABL is attenuated.

3. The binding of ABL to cytoskeletal action microfilaments is

enhanced.


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NATURAL HISTORY


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HAS 3 PHASES

A CHRONIC PHASE in which the disease is responsive to treatment and easily controlled.

AN ACCELERATED PHASE in which the disease control becomes more difficult.

BLAST CRISIS in which the disease transforms in to acute leukemia myeloid (70%) and lymphoblastic(30%),which is relatively refractory to treatment

CLINICAL PRESENTATION

Some patients are diagnosed while asymptomatic, during health

screening tests.

Fatigue

Malaise and wt loss

Symptoms resulting from splenic enlargement .

Infections , thrombosis , bleeding


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CVA

MI,

venous thrombosis

priapism

visual disturbances

pulmonary in sufficiency


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PHYSICAL FINDINGS

Pallor

Minimal to moderate splenomegaly

Sternal tenderness

Retinal haemorrhages

Purpura

Lymphadenopathy and myeloid sarcomas are unusual except in the late

stages of the disease


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HEMATOLOGIC FINDINGS

PERIPHERAL SMEAR

elevated white blood cell count (>1,00,000)

The circulating cells are predominantly neutrophils,

metamyelocytes, myelocytes

Small portion of myeloblasts < 5%

Platelet count is elevated

Mild degree of normocytic normochromic anemia is seen


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BONE MARROW

Marrow cellularity is increased,with an increased myeloid to

erythroid ratio

Marrow blast percentage is normal or slightly elevated

Reticulin stain measured fibrosis is seen in half of the patients,

collagen fibrosis is unusualSunday, February 1, 2015

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DISEASE ACCLERATION

Increased degree of anemia

Blood or marrow blasts between 10 and 20%

Marrow basophils >20%

Platelet count lees than 1,00,000

BLAST CRISIS

Blood or marrow blasts >20%

Hyposegmented neutrophils may appear (pegler huet anomaly)


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Leukocyte alkaline phosphatase is low in CML

cells.

Histamine production is increased secondary to

basophilia causing pruritis, diarrhea and flushing.

CHROMOSOMAL FINDINGS

Hall mark of CML is the t(9:22)(q34<q11.2)

Recognised by a presence of shortened chromosome 22(22q)

designated as philadelphia chromosome.

Some patients may have complex translocations involving 3, 4,

5 chromosomes.Sunday, February 1, 2015

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PROGNOSTIC FACTORS

Clinical outcome in cml is variable

Death was expected in 10 % of the patients with in 2 years and

20% thereafter,the median survival time was 4 years

2 important staging systems

Sokal index

Hasford system


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The prognostic factors are

% of circulating blasts

Spleen size

Plateletcount

Age

Cytogenic clonal evaluation

Developed based on chemotherpy treated patients

The prognostic factors are

% of circulating blasts

Spleen size

Plateletcount

% of eosinophils and basophils

Developed based on IFNtreated patients

SOKAL INDEX HASFORD SYSTEM


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TREATMENT

IMATINIB MESYLATE

HSCT

CHEMOTHERAPY

INTERFERON

LEUKAPHERISIS

SPLENECTOMY

NEWER AGENTSSunday, February 1, 2015

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TREATMENT

The goal of CML therapy is to achieve prolonged

non durable

non neoplastic,

non clonal haemotopoesis


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IMATINIB MESYLATE

Acts through competitive inhibition of ATP binding site of

ABL kinase which leads to inhibition of tyrosine

phopsphorylation of proteins involved in BCR ABL signal

transduction

Induces apoptosis in cell expressing BCR ABL

The dosage is 400mg/day Sunday, February 1, 2015

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SIDE EFFECTS

Fluid retention

Nausea

muscle cramps

Diarrhea

Skin rashes

myelosuppression


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RESISTANCE TO IMATINIB

4 mechanisms of resistance to imatinib

1. Gene amplification

2. Mutations at the kinase site

3. Enhanced expression of multidrug exporter proteins

4. Alternative signalling pathways


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NOVAL TK INHIBITORS

1. Nilotinib

2. Dasatanib

In patients with resistance to imatinib due to mutation at

kinase domain

IFN ALPHA has been approved by FDA only used if all other

options failed.


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HSCT

Allogenic hemtopoetic stem cell trans plantation

Autologous hemtopoetic stem cell trans plantation


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ALLOGENIC HSCT

Outcome depends upon

I. The patients age and phase of the disease

II. The type of donar

III. The preparative regimen

IV. GVHD

V. Post trans plantation treatment

Imatinib

Immunosuppression

Donar leukocyte transfusion


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AUTOLOGUS HSCT

Could potentially cure if cells are collected at complete

molecular remission.

Ptnts with this degree of response never relapse, so this

treatment modality has been abandoned by many groups


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CHEMOTHERAPY

Currently reserved for rapid lowering of

1. Wbc

2. Reduction of sym

3. Reversal of sym splenomegaly

HYDROXY UREA

BUSULPHAN

Not recommended mainly because of fatal myelosupression,

pulmonary, cardial fibrosis and addison like wasting syndrome


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LEUKAPHERISIS

Intensive leukapherisis may control the blood counts in

chronic phase CML

Useful in emergencies such as pulmonary failure and

crebrovascular accidents

Expensive and cumbersomeSunday, February 1, 2015

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SPLENECTOMY

Symptomatic relief of painful splenomegaly.

Significant anemia or thrombocytopenia associated with

hypersplenism.

Splenic radiation is usually used to reduce the size of spleen


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NEW AGENTS

Several new agents are in development for CML for those patients who fail

with currently available TK inhibitors

OMACETAXINE

XL228

FTY720

AP24534

SARAFENIB


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TREATMENT OF BLAST

CRISIS


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Treatment with imatinib is generally ineffective.

Ptnts should be considered for allogenic HSCT.

Other approaches include induction of chemotherapy tailored

to the phenotype of blast cell ,followed by TK inhibitors with

additional chemotherapy and HSCT


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chronic myeloid leukemia

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