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  1. 1. Chronic myeloid leukemia
  2. 2. <ul><li>The myeloproliferative diseases (MPDs) are clonal stem cell disorders characterised by leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercelularity </li></ul><ul><li>They are divided into polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia or myelofibrosis and chronic myelogenous leukemia (CML) </li></ul>
  3. 3. <ul><li>CML results from a somatic mutation in a pluripotential hematopoietic cell </li></ul><ul><li>CML is a MPD characterized by increased granulocytic cell line, associated often with platelet hyperplasia </li></ul><ul><li>The disease usually envolves into an accelerated phase that often terminates in acute phase </li></ul><ul><li>- chronic phase 3-5 years </li></ul><ul><li>- accelerated phase 6-9 months </li></ul><ul><li>- blastic phase 3-6 months </li></ul>
  4. 4. Etiology <ul><li>Exposure to high- dose ionizing radiation </li></ul><ul><li>Chemical agents have not been established as a c a use </li></ul>
  5. 5. Epidemiology <ul><li>CML accounts for approximately 15 percent of all cases of leukemia and approximately 3 percent of childhood leukemias </li></ul><ul><li>The median age of onset is 53 years </li></ul>
  6. 6. Pathogenesis <ul><li>Hematopoietic abnormality </li></ul><ul><li>Expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation – increased white cell count </li></ul><ul><li>Megakaryocytopoiesis is often expanded </li></ul><ul><li>Erythropoiesis is usually deficient </li></ul><ul><li>Function of the neutrophils and platelets is nearly normal </li></ul>
  7. 7. Pathogenesis <ul><li>Genetic abnormality </li></ul><ul><li>CML is the result of an acquired genetic abnormality </li></ul><ul><li>A translocation between chromosome 9 and 22 [t(9;22)] – the Philadelphia chromosome </li></ul><ul><li>The oncogene BC R -ABL encodes an enzyme – tyrosine phosphokinase (usually p210) </li></ul>
  8. 8. Translocation t(9;22)(q34;q11)
  9. 9. Translocation t(9;22)(q34;q11)
  10. 10. Philadelphia Chromosome <ul><li>More than 95% of patients with CML ha ve Philadelphia (Ph) chromosome </li></ul><ul><li>A subset of patients with CML lack a detectable Ph chromosome but have the fusion product for the bcr/abl translocation detectable by reverse transcriptase- polymerase chain reaction (RT-PCR) </li></ul>
  11. 11. The bcr/abl fusion protein <ul><li>Uncontrolled kinase activity </li></ul><ul><li>Deregulated cellular proliferation </li></ul><ul><li>Decreased adherence of leukemia cells to the bone marrow stroma </li></ul><ul><li>Leukemic cells are protected from normal programmed cell death (apoptosis) </li></ul>
  12. 12. Clinical features <ul><li>30 -50% of patients are asymptomatic at the time of diagnosis (90% are diagnosed in chronic phase) </li></ul><ul><li>Symptoms are gradual in onset: </li></ul><ul><ul><li>fatigue, malaise, anorexia, abdominal discomfort, weight loss, excessive sweating </li></ul></ul><ul><ul><li>Less frequent symptoms : </li></ul></ul><ul><ul><li>Night sweats, heat intolerance- mimicking hyperthyroidism, symptoms of leukostasis (tinnitus, stupor), splenic infarction (left upper-quadrant and left shoulder pain), urticaria (result of histamine release) </li></ul></ul><ul><ul><li>Physical signs : </li></ul></ul><ul><ul><li>Pallor, splenomegaly, sternal pain </li></ul></ul>
  13. 13. Laboratory features <ul><li>The hemoglobin concentration is decreased or normal </li></ul><ul><li>Nucleated red cells in blood film can be seen </li></ul><ul><li>The leukocyte count above 25000/ μl (often above 100000/μ l ), granulocytes are at all stages of development </li></ul><ul><li>Hypersegmentated neutrophils </li></ul><ul><li>The basophiles count is increased </li></ul><ul><li>The platelet count is normal or increased </li></ul><ul><li>Neutrophils alkaline phosphatase (GAF) activity is low or absent (90%) </li></ul>
  14. 15. Laboratory features (2) <ul><li>The marrow is hypercellular (granulocytic hyperplasia)- proportion >10:1 (blasts <10% in chronic phase) </li></ul><ul><li>Reticulin fibrosis </li></ul><ul><li>Hyperuricemia and hyperuricosuria </li></ul><ul><li>Serum vitamin B12-binding proteine and serum vitamin B12 levels are increased </li></ul><ul><li>Pseudohyperkalemia, and spurious hypoxemia and hypoglycemia </li></ul><ul><li>Cytogenetic test- presence of the Ph chromosome </li></ul><ul><li>Molecular test – presence of the BCR-ABL fusion gene </li></ul>
  15. 16. Diagnosis <ul><li>Diagnosis is based on blood counts (leukocytosis and frequently also thrombocytosis) and differential (immature granulocytes, from the metamyelocyte to the myeloblast, and basophilia). Splenomegaly is present in >50% of cases of CML in the initial chronic phase, but ₃50% of patients are asymptomatic. </li></ul><ul><li>Proof of diagnosis is attained by demonstration of the Philadelphia (Ph) chromosome (22q–) resulting from the balanced translocation t(9; 22) (q34;q11), and/or the BCR–ABL rearrangement in peripheral blood or bone marrow cells. </li></ul>
  16. 17. Accelerated phase of CML <ul><li>Most patients eventually became resistant to therapy and the disease enters a more agressive phase </li></ul><ul><li>Criteria of accelerated phase </li></ul><ul><li>Blasts in blood or bone marrow-10- 2 9% </li></ul><ul><li>Basophilia ≥ 20% </li></ul><ul><li>Thrombocytopenia <100G/l </li></ul><ul><li>Thrombocytaemia >1000G/l </li></ul><ul><li>Additional chromosomal aberrations </li></ul><ul><li>R efractory splenomegaly or refractory leucocytosis </li></ul>
  17. 18. Blast phase (blast crisis) of CML <ul><li>Criteria of blast phase </li></ul><ul><li>Blasts ≥ 3 0% in PB or BM </li></ul><ul><li>extramedullary tumors </li></ul><ul><li>Phenotype of blasts </li></ul><ul><li>Mieloblasts - 50% </li></ul><ul><li>Limphoblasts - 30% </li></ul><ul><li>Megakarioblasts – 10% </li></ul><ul><li>Acute myelofibrosis </li></ul>
  18. 19. Differential diagnosis <ul><li>Polycythemia vera </li></ul><ul><li>M yelofibrosis </li></ul><ul><li>Essential thrombocytemia </li></ul><ul><li>Chronic myelomonocytic leukemia (Mo>1000/µl) </li></ul><ul><li>Extreme reactive leukocytosis (GAF is increased) </li></ul>
  19. 20. Prognostic factors <ul><li>Sokal score = </li></ul><ul><ul><li>= (11 x age + 35 x spleen + 89 x blasts + 0,4 x platelet – 550)/1000 </li></ul></ul><ul><li>Euro scale = </li></ul><ul><ul><li>= (0,666 x age /0 when age <50, 1 when >/ + 0,0420 x spleen + 0,0584 x blasts + 0,0413 x eosinophils + 0,2039 x basophils /0 when basophils <3%, 1 when basophils >3%/ + 1,0956 x platelet /0 when platelet <15000G/l, 1 when >/) x 1000 </li></ul></ul>
  20. 21. Treatment <ul><li>Imatinib mesylate (Glivec ) or other TKI-the current standard approach </li></ul><ul><li>Interferon alfa </li></ul><ul><li>Oral chemotherapeutic agents (hydroxyurea, busulfan) </li></ul><ul><li>Allo- SCT </li></ul>
  21. 22. Treatment Algorithm for treating CML DIAGNOSIS Imatinib for all Response to imatinib ‘ Failed” response to imatinib Continue Consider for other TKI or SCT
  22. 23. Treatment <ul><li>Hydroxyurea: </li></ul><ul><li>Often used initially for white cell count reduction </li></ul><ul><li>It does not alter long-term prognosi s </li></ul><ul><li>Interferon-alf a </li></ul><ul><li>Hematologic improvement – 75% of patients, cytogenetic remission – 10% </li></ul><ul><li>Prolong the chronic phase of CML more likely than hydroxyurea </li></ul><ul><li>Interferon with Cytarabine </li></ul><ul><li>Combined therapy can improve the results of treatment </li></ul>
  23. 24. Tr ea tment Imatinib mesylate (Gleevec) <ul><li>Inhibits activity of mutant tyrosine kinase by blocking ATP binding </li></ul><ul><li>Imatinib has less toxicity, is easier to administer , and induces higher hematologic , cytogenetic and molecular types of remission . </li></ul><ul><li>Dose: 400mg/d orally (maximal dose 600-800mg/d in two divided doses) </li></ul><ul><li>Usually after 3-9 months of treatment – cytog e netic response </li></ul>
  24. 26. Response evaluation No response loss Anytime ‡ MMolR 18 Months CCgR 12 Months ‡ PCgR 6 Months CHR 3 Months Optimal response: Time:
  25. 27. Criteria of cytogenetic response >95 lack of response 36-95 minor 1-35 maior 0 complete % of Ph in bone marrow Cytogenetic response
  26. 28. Criteria of molecular response Maior molecular response: ≥ 3-log reduction of BCR/ABL transcript in RQ-PCR Complete molecular response: BCR/ABL transcript undetectable in PCR
  27. 29. Aditional T reatment <ul><li>Splenic radiation- useful in marked splenomegaly and splenic pain (marked splenomegaly usully asociated with acute transformation of the disease) </li></ul><ul><li>Splenectomy- can be helpful in patient with thrombocytopenia and massive splenomegaly refractory to therapy (postoperative complications) </li></ul><ul><li>Radiotherapy for extramedullary granulocytic tumors </li></ul><ul><li>Leukapheresis – useful in patients in early pregnancy </li></ul>
  28. 30. Treatment of patients with blast crisis ( AML phenotype ) <ul><li>Start with Imatinib 600mg/d. </li></ul><ul><li>If remission develops consider allogeneic stem cell transplant </li></ul><ul><li>If relapse on Imatinib therapy consider an AML drug protocol depending on patient ´s age and condition </li></ul>
  29. 31. Treatment of patients with blast crisis ( ALL phenotype ) <ul><li>Start with Imatinib 600mg/d orally- maximal dose 400mg twice a day. If remission develops consider allogeneic SCT. </li></ul><ul><li>If relapse after I matinib consider ALL drug protoco l </li></ul><ul><li>1/3 of patiens reenter the chronic phase, but remission lasts usually about 4 months </li></ul><ul><li>Allogeneic stem cell transplantation can prolong remission in blasts crisis </li></ul>