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Chronic Myeloid Leukaemia
 

Chronic Myeloid Leukaemia

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    Chronic Myeloid Leukaemia Chronic Myeloid Leukaemia Presentation Transcript

    • 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
      • Fever
      • Uncommon 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 CML
      • Peripheral 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 factors
      • Sokal 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 MMR CcyR noCcyR 18 CcyR McyR noMCYR 12 McyR mcyR No mcyR 6 CHR pHR NoHR 3 Optimal response Suboptimal response unsatisfactory Time of observation
    •  
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      • Newer tyrosine kinase inhibitors
      • Dasatinib
      • 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 .
    • THANK YOU