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Chronic Myeloid Leukaemia


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Chronic Myeloid Leukaemia

  2. 2. <ul><li>Definition </li></ul><ul><li>Chronic myelogenous leukemia is a pluripotent stem cell disease characterized by anaemia,extreme blood granulocytosis with immaturity ,basophilia,thrombocytosis and splenomegaly . </li></ul><ul><li>The haemtopoietic cell contain a reciprocal translocation between chromosome 9 and 22 .known as the philadelphia chromosome. </li></ul><ul><li>Occurs more often in men. </li></ul><ul><li>Disease of firsts . </li></ul><ul><li>High doses of ionising radiation can increase the occurrence of CML. </li></ul>
  3. 4. <ul><li>Pathophysiology </li></ul><ul><li>Genetic hallmark of CML is the presence of BCR-ABLfusion gene product. </li></ul><ul><li>The fusion protein is a result of reciprocal translocation between the abelson oncogene on chromosome 9 and break point cluster region on chromosome 22. </li></ul><ul><li>Fusion genes are generated that encode 190,210,or 230 kda forms of the BCR-ABL tyrosine kinase. </li></ul><ul><li>Other genetic abnormalities </li></ul><ul><li>Trisomy 8,p53 loss . </li></ul><ul><li>Interleukin 1 b involved in the progression of CML to the blastic phase. </li></ul>
  4. 5. <ul><li>Clinical presentation </li></ul><ul><li>Symptoms </li></ul><ul><li>Fatigue,malaise </li></ul><ul><li>Weight loss </li></ul><ul><li>Early satiety </li></ul><ul><li>Left upper quadrant pain or mass </li></ul><ul><li>Easy bruising ,bleeding </li></ul><ul><li>Fever </li></ul><ul><li>Uncommon presentation </li></ul><ul><li>Acute gouty arthritis,priapism,myocardial infarction,venous thrombosis,visual disturbances,sweet syndrome. . </li></ul>
  5. 6. <ul><li>Signs </li></ul><ul><li>pallor </li></ul><ul><li>Splenomegaly </li></ul><ul><li>Sternal tenderness </li></ul><ul><li>Lymhadenopathy </li></ul><ul><li>Hepatomegaly </li></ul><ul><li>Purpura </li></ul><ul><li>Retinal haemorrhage </li></ul>
  6. 7. <ul><li>Diagnostic approach to CML </li></ul><ul><li>Peripheral blood </li></ul><ul><li>Granulocytic leukocytosis>50*10p9/l </li></ul><ul><li>Predominance of neutrophils and increased %of myelocytes. </li></ul><ul><li>Absolute basophilia . </li></ul><ul><li>Platelets are normal or increased in number. </li></ul><ul><li>Bone marrow </li></ul><ul><li>Marrow is hypercellular with granulocytic predominance. </li></ul><ul><li>Megakaryocytes are increased in number with abnormal morphology. </li></ul><ul><li>Increase in reticulin fibrosis. </li></ul><ul><li>Blasts less than 5%. </li></ul>
  8. 9. Band forms promyelocyte myelocyte metamyelocyte
  9. 10. BONE MARROW PICTURE megakaryocyte
  10. 11. <ul><li>diagnosis of accelarated phase </li></ul><ul><li>Blasts 10-20% in peripheral blood and or bone marrow. </li></ul><ul><li>Basophils >20% in peripheral blood . </li></ul><ul><li>Persistent thrombocytopenia. </li></ul><ul><li>Increasing spleen size and white blood count despite therapy. </li></ul><ul><li>Cytogenetic evidence of clonal evolution . </li></ul>
  12. 13. <ul><li>Blast crisis phase </li></ul><ul><li>Blast > 20% </li></ul><ul><li>Extramedullary blast proliferation. </li></ul><ul><li>Large aggregates or clusters of blast in bone marrow. </li></ul>
  14. 15. <ul><li>Other abnormalities </li></ul><ul><li>There is increase in </li></ul><ul><li>uric acid level </li></ul><ul><li>vitamin B12 level. </li></ul><ul><li>lactate dehydrogenase . </li></ul><ul><li>Increase in the level of angiogenic factors. </li></ul><ul><li>Decrease level of leukocyte alkaline phosphatase. </li></ul><ul><li>Increase in histamine levels. </li></ul>
  15. 16. <ul><li>Identification of philadelphia chromosome </li></ul><ul><li>Can be done by conventional cytogenetic karyotyping,FISH,RT-PCR . </li></ul><ul><li>Conventional cytogenetics </li></ul><ul><li>Entire chromosomal complement is evaluated to identify philadelphia chromosome and other abnormalities. </li></ul><ul><li>Can be done on both peripheral blood and bone marrow. </li></ul><ul><li>Disadvantage </li></ul><ul><li>Presence of cryptic or submicroscopic BCR-ABL arrangement cannot be identified </li></ul>
  16. 17. <ul><li>Fluorescent insitu hybridisation </li></ul><ul><li>Advantage </li></ul><ul><li>Fast results,greater sensitivity than conventional cytogenetics. </li></ul><ul><li>Submicroscopic or cryptic molecular alteration can be detected . </li></ul><ul><li>Reverse transciptase-PCR </li></ul><ul><li>Detects different length products corresponding to chimeric BCR-ABL proteins of 190,210 and 230 kda. </li></ul><ul><li>So helps in distinguishing CML from ALL. </li></ul>
  17. 18. Fluorescent insitu hybridisation
  18. 19. <ul><li>Prognostic factors </li></ul><ul><li>Sokal index </li></ul><ul><li>Percentage of circulating blast,spleen size,platelet count,age and cytogenetic clonal evolution. </li></ul><ul><li>Was developed based on chemotherapy treated patients. </li></ul><ul><li>Hassford system </li></ul><ul><li>Developed on interferon alpha treated patients . </li></ul><ul><li>Includes% of circulating blast,spleen size,platelet count,age,% of eosinophils and basophils. </li></ul>
  19. 20. <ul><li>Treatment </li></ul><ul><li>Drugs </li></ul><ul><li>Stem cell transplant. </li></ul><ul><li>Leukaphresis and splenectomy . </li></ul><ul><li>drugs </li></ul><ul><li>Imatinib mesylate,dasatinib,nilotinib </li></ul><ul><li>Hydroxyurea </li></ul><ul><li>busulphan </li></ul><ul><li>Interferon-alpha </li></ul><ul><li>Homoharringtonine </li></ul><ul><li>Anagrelide. </li></ul><ul><li>Cytarabin. </li></ul>
  20. 21. <ul><li>Imatinib </li></ul><ul><li>It is an ABL specific tyrosine kinase inhibitor . </li></ul><ul><li>Imatinib induces apoptosis in cells expressing BCR/ABL. </li></ul><ul><li>Dose is 400mg/day. </li></ul><ul><li>It should achieve cytogenetic remission by 6months and molecular remission by 18 months. </li></ul><ul><li>Side effects-edema,pleural and pericardial effusion,nausea,vomiting,diarrhoea,muscle cramps,skin rash,bone pain and arthralgia.myelosuppression . </li></ul>
  21. 23. <ul><li>Criteria for Extent of Imatinib Treatment </li></ul><ul><li>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. </li></ul><ul><li>  Major cytogenetic response- Less than 35% of cells containing the Ph chromosome by cytogenetic analysis of marrow cells. </li></ul><ul><li>Complete cytogenetic response- No cells containing the Ph chromosome by cytogenetic analysis of marrow cells. </li></ul><ul><li>Major molecular response- Blood cell BCR-ABL ratio <0.05% (3-log reduction in PCR signal from mean pretreatment baseline value) </li></ul><ul><li>. Complete molecular response- Blood cell BCR-ABL levels undetectable (usually by nested RT-PCR method ). </li></ul>
  22. 24. 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
  23. 30. <ul><li>Newer tyrosine kinase inhibitors </li></ul><ul><li>Dasatinib </li></ul><ul><li>Structurally unrelated to imatinib binds to the ABL kinase domain. </li></ul><ul><li>Side effect-myelosuppression,pleural effusion,prolongation of QT interval . </li></ul><ul><li>Nilotinib </li></ul><ul><li>Structural derivative of imatinib binds to ABL kinase domain. </li></ul><ul><li>Side effects-rashes,transient elevation of indirect bilirubin levels and myelosuppression . </li></ul>
  24. 31. <ul><li>Hydroxy urea </li></ul><ul><li>Inhibitor of ribonucleotide reductase . </li></ul><ul><li>Lower the blood counts in 1-2 days. </li></ul><ul><li>Dose is 500-3000 mg/day. </li></ul><ul><li>Side effect-nausea and skin rash. </li></ul><ul><li>Given for patients intolerant to imatinib. </li></ul><ul><li>Busulphan </li></ul><ul><li>Gradually lowers the blood counts. </li></ul><ul><li>Dose-6-10 mg/day. </li></ul><ul><li>Should not be used in patients expected to undergo bonemarrow transplantation . </li></ul>
  25. 32. <ul><li>Interferon alpha </li></ul><ul><li>Causes complete haemotologic response in >70% of patients. </li></ul><ul><li>Dose is 5 million units daily by subcutaneous administration . </li></ul><ul><li>Hasford score was developed to predict the survival of patients treated with interferon alpha. </li></ul><ul><li>Homoharringtonine </li></ul><ul><li>it is a plant alkaloid causes cytogenetic response in patients in late chronic phase. </li></ul>
  26. 33. <ul><li>Anagrelide </li></ul><ul><li>It is used for treating elevated platelet count in CML.especially in presence of thrombosis and bleeding </li></ul><ul><li>Leukapheresis </li></ul><ul><li>Control CMLonly temporarily. </li></ul><ul><li>Used in hyperleucocytic patients where rapid cytoreduction can reverse the symptoms. </li></ul><ul><li>Pregnant patient with CML can be controlled by leukaphresis . </li></ul>
  27. 34. <ul><li>Allogenic stem cell transplant </li></ul><ul><li>Outcome depends on patients age,phaseof disease,type of donor,preparative regimen,graft vs host disease,post transplantation treatment. </li></ul><ul><li>Patients age should be less than 70 years.transplantation from donor should be HLA matched. </li></ul><ul><li>Peripheral blood can be used a source of haemotopoietic progenitor cells.preoperative regimen like cyclophosphamideplus total body irradiationis used. </li></ul><ul><li>Complications-graft vs host disease. </li></ul>
  28. 35. <ul><li>Differential diagnosis </li></ul><ul><li>Chronic myelomonocytic leukemia </li></ul><ul><li>Juvenile myelomonocytic leukemia </li></ul><ul><li>Chronic neutophilic leukemia </li></ul><ul><li>Atypical CML </li></ul><ul><li>Diseases associated with hypereosinophilia. </li></ul>
  29. 36. <ul><li>Chronic myelomonocytic leukemia </li></ul><ul><li>Anemia, monocytosis >1000/l; blood blasts <10%; increased plasma and urine lysozyme; BCR rearrangement absent; uncommon cases with PDGFR- mutation respond to imatinib. </li></ul><ul><li>Chronic eosinophilic leukemia </li></ul><ul><li>Blood eosinophil count >1500/l; cardiac and neurologic manifestations common; a proportion of cases have PDGFR- mutations and are responsive to imatinib mesylate. </li></ul><ul><li>Chronic monocytic leukemia </li></ul><ul><li>Proportion of monocytes elevated; very rare form of leukemia. </li></ul><ul><li>Juvenile myelomonocytic leukemia </li></ul><ul><li>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 . </li></ul>
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