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    Cml Cml Presentation Transcript

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