Chronic%20myeloid%20leukemia - PowerPoint PPT Presentation

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Chronic%20myeloid%20leukemia

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Title: Chronic%20myeloid%20leukemia


1
Chronic myeloid leukemia
2
  • 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)

3
  • CML results from a somatic mutation in a
    pluripotential lymphohematopoietic cell
  • CML is a MPD characterized by increased
    granulocytic cell line, associated with erythroid
    and platelet hyperplasia
  • The disease usually envolves into an accelerated
    phase that often terminates in acute phase
  • chronic phase 3-5 years
  • accelerated phase
  • blastic phase 3-6 months

4
Etiology
  • Exposure to high- dose ionizing radiation
  • Chemical agents have not been established as a
    cause

5
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

6
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 platelet is
    nearly normal

7
Pathogenesis
  • Genetic abnormality
  • CML is the result of an acquired genetic
    abnormality
  • A translocation between chromosome 9 and 22
    t(922) the Philadelphia
    chromosome
  • The oncogene BCR-ABL encodes an enzyme
    tyrosine phosphokinase (usually p210)

8
Translocation t(922)(q34q11)
9
Translocation t(922)(q34q11)
10
Philadelphia Chromosome
  • More than 95 of patients with CML has
    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)

11
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)

12
Clinical features
  • 30 percent of patient are asymptomatic at the
    time of diagnosis
  • Symptoms are gradual in onset
  • easy fatigability, malaise, anorexia, abdominal
    discomfort, weight loss, excessive sweating
  • Less frequent symptoms
  • Night sweats, heat intolerance- mimicking
    hyperthyroidism, gouty arthitis, symptoms of
    leukostasis (tinnitus, stupor), splenic infartion
    (left upper-quadrant and left shoulder pain),
    urticaria (result of histamine release)
  • Physical signs
  • Pallor, splenomegaly, sternal pain

13
Laboratory features
  • The hemoglobin concentration is decreased
  • Nucleated red cells in blood film
  • The leukocyte count above 25000/µl (often above
    100000/µl), granulocytes at all stages of
    development
  • Hypersegmentated neutrophils
  • The basophiles count is increased
  • The platelet count is normal or increased
  • Neutrophils alkaline phosphatase activity is low
    or absent (90)

14
Laboratory features (2)
  • The marrow is hypercellular (granulocytic
    hyperplasia)
  • 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

15
Differential diagnosis
  • Polycythemia vera
  • Myelofibrosis
  • Essential thrombocytemia
  • Extreme reactive leukocytosis

16
Treatment
  • New treatment options -
  • - individualisation of treatment decisions based
    on the risk category in which a patiens resides

17
Treatment Prognostic factors
  • Sokal score
  • (11x age 35x spleen 89x blasts 0,4x
    platelet 550)/1000
  • Euro scale
  • (0,666x age /0 when age lt50, 1 when gt/
    0,0420x spleen 0,0584x blasts 0,0413x
    eosinophils 0,2039x basophils /0 when basophils
    lt3, 1 when basophils gt3/ 1,0956x platelet /0
    when platelet lt15000G/l, 1 when gt/) x 1000

18
Treatment
  • Oral chemotherapeutic agents (hydroxyurea,
    busulfan)
  • Interferon alfa
  • Imatinib mesylate (Glivec, Gleevec)
  • Allo- SCT

19
Treatment Hydroxyurea
  • Often used initially for white cell count
    reduction
  • Dose 1-6g/d orally, depending on the hight of
    the white cell count
  • The dose should be decreased to 1-2g/d when the
    leukocyte count reaches 20000/µl
  • Drug should be stopped if the white count falls
    to 5000/µl
  • Side effects suppression of hematopoiesis, often
    with megaloblastic erythropoiesis
  • It does not alter long-term prognosis

20
Treatment Interferon-alfa
  • Patients with low risk (Sokal/Euro score) and
    high TRM, patient not eligible for alloSCT
  • Side effects are more intensive above 60 years of
    age
  • Dose 3million units/m² subcutaneously 3 days per
    week, and after 1 week 5 million u/m². Maximal
    dose 5 million u/m² per day. After maximal
    response (6-8 months) 3-5 million u/m² once or
    twice weekly
  • Dose should be reduced or teporarily discontinued
    if the white cell count less than 5000/µl or
    platelet count less than 50000/µl
  • The higher the dose tolerated the greater the
    cytogenetic response

21
Treatment Interferon alfa
  • Initial side effects of INFalfa fever, fatigue,
    sweats, anorexia, headache, muscle pain, nausea,
    and bone pain 50 of patients
  • Later effects apathy, insomnia, depression, bone
    and muscle pain, hepatic, renal and cardiac
    dysfunction, immunemediated anemia,
    thrombocytopenia, hypothyroidism,
    hypertriglyceridemia
  • A polyethylene glycol-conjugated interferon-alfa
    (PEG-interferon)- better toleration, treatment
    once per week
  • Prolong the chronic phase of CML more likely than
    hydroxyurea
  • Hematologic improvement 75 of patients,
    cytogenetic remission 10, molecular remission-
    2
  • If after 6 months no or poor responce Imatinib
    or alloSCT

22
Criteria of cytogenetic response
Cytogenetic response of Ph in bone marrow
complete 0
maior 1-35
minor 36-95
lack of response gt95
23
Criteria of molecular response
Complete molecular response BCR/ABL transcript undetectable in PCR
Maior molecular response 3-log reduction of BCR/ABL transcript in RQ-PCR
24
Treatment Interferon with Cytarabine
  • Cytarabine (Ara-C, cytosine arabinoside) has
    activity against CML cells
  • Dose 20-40mg/m² subcutaneously over 10 days per
    month combined with interferon-alfa
  • Combined therapy can improve the results of
    treatment

25
Traetment Imatinib mesylate (Gleevec)
  • Inhibits activity of mutant tyrosine kinase by
    blocking ATP binding
  • Very useful in older patients or patients
    intolerant or resistance to interferon-alfa
  • Imatinib has less toxicity, is easier to
    administer , and induces higher hematologic (90
    percent vs. 75percent), cytogenetic (40 percent
    vs. 10 percent) and molecular (7 percent vs. 2
    percent) types of remission
  • Dose 400mg/d orally (maximal dose 600-800mg/d in
    two divided doses)
  • Usually after 3-9 months of treatment
    cytogenetic response

26
Treatment Imatinib mesylate
  • Side effects nausea, vomiting, edema, muscle
    cramps, diarrhea, headache, abdominal pain-
    usually low-grade
  • The drug can be used prior the alloSCT if
    eligible, or nonmyeloablative SCT for older
    patient

27
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28
Treatment Early alloSCT
  • The early mortality in younger patient (below 40
    years of age) 15 percent
  • 5-year survival can be achieved in 60 percent of
    patients in chronic phase (some can be cured)
  • There is 20 percent chance of relapse of CML in
    the years after succesful transplantation
  • Donor lymphocyte infusion (DLI) can produce
    remission in transplanted patiens who have
    relapse of their disease

29
Treatment Prognostic factors
  • Sokal score
  • (11x age 35x spleen 89x blasts 0,4x
    platelet 550)/1000
  • Euro scale
  • (0,666x age /0 when age lt50, 1 when gt/
    0,0420x spleen 0,0584x blasts 0,0413x
    eosinophils 0,2039x basophils /0 when basophils
    lt3, 1 when basophils gt3/ 1,0956x platelet /0
    when platelet lt15000G/l, 1 when gt/) x 1000

30
Treatment Risk of transplant-related mortality
(TRM)
31
Treatment Decision making in the imatinib area
  • How does one treat the younger CML patients with
    a possible allogeneic donor?
  • OPTION 1 give all patients an initial trial of
    imatinib
  • OPTION 2 Offer early allograft to selected
    patients and trial of imatinib to other patients

32
Treatment Algorithm for treating CML (Option 1)-
2004
33
Treatment Algorithm for treating CML (Option 2) -
2004
34
Treatment Option 2 Proposed indications for
early allo-SCT
  • CML-CP up to age 45 with sibling donor
  • CML-CP up to age 35 with molecularly matched
    unrelated donor

35
Treatment
  • Splenic radiation- useful in marked splenomegaly
    and splenic pain (marked splenomegaly usully
    asociated with acute transformation of the
    disease)
  • Splenectomy- 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

36
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-10-19
  • Basophilia 20
  • Thrombocytopenia lt100G/l
  • Thrombocytaemia gt1000G/l
  • Additional chromosomal aberrations
  • refractory splenomegaly or refractory
    leucocytosis

37
Blast phase (blast crisis) of CML
  • Criteria of blast phase
  • Blasts 20
  • extramedullary tumors
  • Phenotype of blasts
  • Mieloblasts - 50
  • Limphoblasts - 30
  • Megakarioblasts 10
  • Acute myelofibrosis

38
Treatment of patients with AML phenotype
  • Start with Imatinib 600mg/d, if tolerated can
    increase to 400mg twice a week.
  • If remission develops consider allogeneic stem
    cell transplant
  • If relapse on Imatinib therapy consider an AML
    drug protocol depending on patients age and
    condition

39
Treatment of patients with ALL phenotype
  • Start with Imatinib 600mg/d orally- maximal dose
    400mg twice a day. If remission develops consider
    allogeneic stem cell transplantation
  • If relapse after imatinib consider ALL drug
    protocol
  • Vincristine sulfate 1,4mg/m² iv once per week
  • prednisone 60mg/m² per day orally
  • one-third of patiens reenters the chronic phase,
    but remission lasts usually about 4 months
  • Allogeneic stem cell transplantation can prolong
    remission in blasts crisis
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