CHRONIC MYELOID LEUKEMIA

Dr.A.MEENAKSHI

PROF.S.TITO’S UNIT.

M4

Definition• Chronic myelogenous leukemia is a pluripotent

stem cell disease characterized by anaemia,extreme blood granulocytosis with immaturity ,basophilia,thrombocytosis and splenomegaly.

• The haemtopoietic cell contain a reciprocal translocation between chromosome 9 and 22 .known as the philadelphia chromosome.

• Occurs more often in men.• Disease of firsts.• High doses of ionising radiation can increase the

occurrence of CML.

Pathophysiology• Genetic hallmark of CML is the presence of

BCR-ABLfusion gene product.• The fusion protein is a result of reciprocal

translocation between the abelson oncogene on chromosome 9 and break point cluster region on chromosome 22.

• Fusion genes are generated that encode 190,210,or 230 kda forms of the BCR-ABL tyrosine kinase.

Other genetic abnormalities• Trisomy 8,p53 loss.• Interleukin 1 b involved in the progression of

CML to the blastic phase.

Clinical presentation Symptoms• Fatigue,malaise• Weight loss• Early satiety • Left upper quadrant pain or mass• Easy bruising ,bleeding• FeverUncommon presentation• Acute gouty arthritis,priapism,myocardial

infarction,venous thrombosis,visual disturbances,sweet syndrome..

Signs• pallor

• Splenomegaly

• Sternal tenderness

• Lymhadenopathy

• Hepatomegaly

• Purpura

• Retinal haemorrhage

Diagnostic approach to CMLPeripheral blood• Granulocytic leukocytosis>50*10p9/l• Predominance of neutrophils and increased %of

myelocytes.• Absolute basophilia.• Platelets are normal or increased in number.Bone marrow• Marrow is hypercellular with granulocytic

predominance.• Megakaryocytes are increased in number with

abnormal morphology.• Increase in reticulin fibrosis.• Blasts less than 5%.

PERIPHERAL SMEAR PICTURE

Band forms

Band forms

promyelocyte

myelocyte

metamyelocyte

BONE MARROW PICTURE

megakaryocyte

diagnosis of accelarated phase• Blasts 10-20% in peripheral blood and or

bone marrow.

• Basophils >20% in peripheral blood.

• Persistent thrombocytopenia.

• Increasing spleen size and white blood count despite therapy.

• Cytogenetic evidence of clonal evolution.

ACCELERATED PHASE

MYELOBLAST

Blast crisis phase• Blast > 20%

• Extramedullary blast proliferation.

• Large aggregates or clusters of blast in bone marrow.

BLAST CRISIS PHASE

MYELOBLAST

Other abnormalities

There is increase in

• uric acid level

• vitamin B12 level.

• lactate dehydrogenase.

• Increase in the level of angiogenic factors.

• Decrease level of leukocyte alkaline phosphatase.

• Increase in histamine levels.

• Identification of philadelphia chromosome• Can be done by conventional cytogenetic

karyotyping,FISH,RT-PCR.Conventional cytogenetics• Entire chromosomal complement is

evaluated to identify philadelphia chromosome and other abnormalities.

• Can be done on both peripheral blood and bone marrow.

Disadvantage• Presence of cryptic or submicroscopic

BCR-ABL arrangement cannot be identified

Fluorescent insitu hybridisation

Advantage

• Fast results,greater sensitivity than conventional cytogenetics.

• Submicroscopic or cryptic molecular alteration can be detected.

Reverse transciptase-PCR

• Detects different length products corresponding to chimeric BCR-ABL proteins of 190,210 and 230 kda.

• So helps in distinguishing CML from ALL.

Fluorescent insitu hybridisation

Prognostic factorsSokal index• Percentage of circulating blast,spleen

size,platelet count,age and cytogenetic clonal evolution.

• Was developed based on chemotherapy treated patients.

Hassford system• Developed on interferon alpha treated patients.• Includes% of circulating blast,spleen

size,platelet count,age,% of eosinophils and basophils.

Treatment • Drugs • Stem cell transplant.• Leukaphresis and splenectomy.

drugs• Imatinib mesylate,dasatinib,nilotinib• Hydroxyurea• busulphan• Interferon-alpha• Homoharringtonine• Anagrelide.• Cytarabin.

Imatinib• It is an ABL specific tyrosine kinase

inhibitor.• Imatinib induces apoptosis in cells

expressing BCR/ABL.• Dose is 400mg/day.• It should achieve cytogenetic remission

by 6months and molecular remission by 18 months.

• Side effects-edema,pleural and pericardial effusion,nausea,vomiting,diarrhoea,muscle cramps,skin rash,bone pain and arthralgia.myelosuppression.

Criteria for Extent of Imatinib Treatment Hematologic response -White cell count

<10x109(platelet count <450 x 109/L, no immature myeloid cells in the blood, and disappearance of all signs and symptoms related to leukemia (including palpable splenomegaly) lasting for at least 4 weeks.

• Major cytogenetic response-Less than 35% of cells containing the Ph chromosome by cytogenetic analysis of marrow cells.

• Complete cytogenetic response-No cells containing the Ph chromosome by cytogenetic analysis of marrow cells.

• Major molecular response-Blood cell BCR-ABL ratio <0.05% (3-log reduction in PCR signal from mean pretreatment baseline value)

• .Complete molecular response-Blood cell BCR-ABL levels undetectable (usually by nested RT-PCR method).

Guidelines for response to imatinib treatment

Time of observation

unsatisfactory

Suboptimal response

Optimal response

3 NoHR pHR CHR

6 No mcyR mcyR McyR

12 noMCYR McyR CcyR

18 noCcyR CcyR MMR

Newer tyrosine kinase inhibitorsDasatinib• Structurally unrelated to imatinib binds to

the ABL kinase domain.• Side effect-myelosuppression,pleural

effusion,prolongation of QT interval.Nilotinib• Structural derivative of imatinib binds to

ABL kinase domain.• Side effects-rashes,transient elevation of

indirect bilirubin levels and myelosuppression.

Hydroxy urea

• Inhibitor of ribonucleotide reductase.

• Lower the blood counts in 1-2 days.

• Dose is 500-3000 mg/day.

• Side effect-nausea and skin rash.

• Given for patients intolerant to imatinib.

Busulphan

• Gradually lowers the blood counts.

• Dose-6-10 mg/day.

• Should not be used in patients expected to undergo bonemarrow transplantation.

Interferon alpha

• Causes complete haemotologic response in >70% of patients.

• Dose is 5 million units daily by subcutaneous administration.

• Hasford score was developed to predict the survival of patients treated with interferon alpha.

Homoharringtonine

• it is a plant alkaloid causes cytogenetic response in patients in late chronic phase.

Anagrelide

• It is used for treating elevated platelet count in CML.especially in presence of thrombosis and bleeding

Leukapheresis

• Control CMLonly temporarily.

• Used in hyperleucocytic patients where rapid cytoreduction can reverse the symptoms.

• Pregnant patient with CML can be controlled by leukaphresis.

Allogenic stem cell transplant• Outcome depends on patients age,phaseof

disease,type of donor,preparative regimen,graft vs host disease,post transplantation treatment.

• Patients age should be less than 70 years.transplantation from donor should be HLA matched.

• Peripheral blood can be used a source of haemotopoietic progenitor cells.preoperative regimen like cyclophosphamideplus total body irradiationis used.

• Complications-graft vs host disease.

Differential diagnosis

• Chronic myelomonocytic leukemia

• Juvenile myelomonocytic leukemia

• Chronic neutophilic leukemia

• Atypical CML

• Diseases associated with hypereosinophilia.

Chronic myelomonocytic leukemia• Anemia, monocytosis >1000/l; blood blasts <10%;

increased plasma and urine lysozyme; BCR rearrangement absent; uncommon cases with PDGFR- mutation respond to imatinib.

• Chronic eosinophilic leukemia• Blood eosinophil count >1500/l; cardiac and neurologic

manifestations common; a proportion of cases have PDGFR- mutations and are responsive to imatinib mesylate.

Chronic monocytic leukemia• Proportion of monocytes elevated; very rare form of

leukemia.Juvenile myelomonocytic leukemia• Infants and children <4 years; eczematoid or

maculopapular rash; anemia and thrombocytopenia; increased HgF in 70% of cases; neurofibromatosis in 10% of cases; BCR rearrangement absent .