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Chronic Myeloid Leukemia

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Chronic Myeloid Leukemia Introduction Characteristics Transformation Biology Therapy – PowerPoint PPT presentation

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Title: Chronic Myeloid Leukemia


1
Chronic Myeloid Leukemia
  • Introduction
  • Characteristics
  • Transformation
  • Biology
  • Therapy

2
  • Chronic myelogenous leukemia (CML) is a
    myeloproliferative disorder characterized by
    increased proliferation of the granulocytic cell
    line without the loss of their capacity to
    differentiate. Consequently, the peripheral blood
    cell profile shows an increased number of
    granulocytes and their immature precursors,
    including occasional blast cells

3
Chronic myeloid leukaemia
  • Sex 1.41 (mf)
  • 40-60 yrs old
  • Aetiology?
  • Unknown
  • Atom bomb exposure Japan
  • Chemicals Benzene

4
Chronic myeloid leukaemia
  • Clinical features
  • Wt loss, lassitude anorexia night sweats
  • Splenomegaly
  • Anaemia pallor dyspnea tachycardia
  • Bruising epistaxis menorrhagia
  • Gout renal impairment
  • Incidental finding (CBC)

5
Chronic myeloid leukaemia
  • The patient , a 49yr old teacher, saw her
    physician because of fatigue for about six
    months.
  • Physical exam. Showed little except for pallour,
    normal temperature, massive splenomegaly
  • Blood tests were ordered to investigate possible
    anaemia

6
Chronic myeloid leukaemia
  • Laboratory results indicated a high white count
    consistent with Chronic Myeloid Leukaemia

7
Characteristics
  • 85 diagnosed in chronic phase
  • 50 asymptomatic at diagnosis
  • Fatigue, wt loss, abdominal fullness, bleeding,
    night sweats
  • Splenomegaly, purpura
  • Leukocytosis , anemia, thrombocytosis
  • Marrow asp/bx, cytogenetics, bcr-abl molecular
    studies if Ph1 negative

8
Phases of CML
  • A) Chronic phase
  • Most patients , characterized by splenomegaly
    and leukocytosis with generally few symptoms.
    This phase is easily controlled by medication.
    The major goal of treatment during this phase is
    to control symptoms and complications resulting
    from anemia, thrombocytopenia, leukocytosis, and
    splenomegaly. Newer forms of therapy aim at
    delaying the onset of the accelerated or blastic
    phase , duration3-4 years

9
  • Chronic phase Peripheral blood leucocytosis,
    reflected in a numerical increase in all stages
    of myeloid differentiation. Basophilia frequently
    pronounced. Bone marrow aspirates usually shows
    profound hypercellularity and increased
    myeloiderythroid ratio (gt251). Philadelphia
    chromosome present in all myeloid cells

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11
  • Accelerated and blastic phases Characterised by
    the emergence of a discrete blast cell population
    and left-shift compared to chronic phase.
    Definition of accelerated phase requires at least
    one of the following
  • rising leucocyte count during adequate treatment
  • platelet count lt100, or gt1000 x 109/l
  • haemoglobin lt8.0g/dl
  • gt10 blasts in peripheral blood
  • gt20 basophils and eosinophils in peripheral
    blood
  • After 3-5 years duration

12
CML in blastic transformation
  • Blasts of variable phenotype
  • myeloid
  • megakaryocytic
  • erythroid
  • lymphoid (early B cell)
  • Clonal evolution
  • Ph chromosome with additional mutations
  • (e.g., double Ph, trisomy 8, p53 alteration)

13
CML in blastic transformation
  • unstable disease
  • weight loss, fever, sweats, bone pain
  • worsening
  • splenomegaly
  • anemia
  • platelet counts
  • blast and promyelocyte counts
  • basophilia and eosinophilia
  • resistance to therapy
  • blastic crisis develops in most
  • Death in weeks or months

14
  • Blastic phase is defined as gt30 blasts and
    promyelocytes in peripheral blood or marrow.
    Normal marrow erythropoiesis and megakaryopoiesis
    reduced.

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17
  • C) Accelerated phase occurs 3-6 months before the
    diagnosis of blast crisis. Clinical features in
    this phase are intermediate between the chronic
    phase and blast crisis

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19
  • Physical
  • Splenomegaly is the most common physical finding
    in patients with CML.
  • In more than half the patients with CML, the
    spleen extends more than 5 cm below the left
    costal margin at time of discovery.
  • The size of the spleen correlates with the
    peripheral blood granulocyte counts , with the
    biggest spleens being observed in patients with
    high WBC counts.
  • A very large spleen is usually a harbinger of the
    transformation into an acute blast crisis form of
    the disease

20
Wt 3kgs
Normal c200gms
SplenomegalyCML
21
Chronic myeloid leukaemia
  • CAT scan
  • Very large spleen

22
  • Physical findings of leukostasis and
    hyperviscosity can occur in some patients, with
    extraordinary elevation of their WBC counts,
    exceeding 300,000-600,000 cells/mL. Upon
    funduscopy, the retina may show papilledema,
    venous obstruction, and hemorrhages

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24
Biology of CML
  • First neoplastic process linked to a consistent
    acquired genetic abnormality
  • Ph chromosome shortened chromosome 22 (22q-)
    resulting from t(922)-(q34q11)
  • Translocation creates two new genes
  • BCR-ABL on 22q- (Ph chromosome)
  • ABL-BCR on 9q (transcriptionally active, no
    functional role)

25
Translocation of t(922) in CML
26
Biology of CML
  • Bcr-abl protein is a deregulated tyrosine kinase
    with increased activity
  • Bcr-abl protein leads to malignant transformation
    by interference with control of proliferation,
    adherence, and apoptosis

27
Signaling Pathways
28
Biology of CML
  • Disease progression associated with chromosomal
    changes in 50-80 cases
  • Karyotypic evolution may precede hematologic and
    clinical manifestations
  • Frequent changes are trisomy 8, isochromosome
    i(17q), trisomy 19, additional Ph chromosome
  • Alterations in tumor suppressor genes

29
Detection of BCR-ABL
  • Cytogenetic analysis
  • Gold standard
  • Time-consuming, 20-25 metaphases/sample

30
Chronic myeloid leukemia
  • Ph chromosome present in precursors of
  • granulocytes
  • monocytes/macrophages
  • basophils
  • eosinophils
  • erythrocytes
  • platelets
  • some B lymphocytes

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32
Chronic myeloid leukaemia
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34
Chronic myeloid leukaemia
  • Other studies
  • Flow cytometry
  • Myeloid markers
  • Maturity markers
  • Cytogenetics
  • Chromosome studies
  • FISH
  • RT-PCR

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37
CML - Chronic Phase treatment
  • Busulfan
  • controls hematologic variables, inexpensive
  • prolonged myelosuppression, marrow fibrosis
  • idiosyncratic lung reaction busulfan lung
  • Hydroxyurea
  • control of disease, but no cure
  • can treat with excessive doses and marrow
    recovers
  • mouth sores, rash
  • preferred drug for pts being considered for BMT

38
CML - Treatment
  • Hydroxyurea is superior to busulfan
  • _Median survival 56 vs 44 months
  • Median duration of CP 47 vs 37 months
  • Meta-analysis of 5 other trials supports a
    survival advantage for Hydrea over Busulfan

39
CML - Treatment
  • Conventional chemotherapy (Hydroxyurea and
    Busulfan)
  • 50-80 Complete Hematologic Response (CHR)
  • rare cytogenetic response (CGR)
  • no effect on disease progression

40
CML - Treatment
  • Interferon
  • Standard treatment in non-transplant candidates
  • Disease control gt 3 mo for CHR in many series
  • Cytogenetic response 12 months
  • Major cytogenetic response at 24 months better
    outcome
  • Side effects flu-like symptoms, diarrhea,
    abnormal LFT, depression

41
CML - Allogeneic BMT
  • Considered the optimal treatment for patients
    with a compatible donor
  • lt 50 of patients are in the appropriate age
    group
  • Of the younger patients, lt 30 have a suitable
    donor
  • Matched-unrelated BMT best results in lt 30, but
    is appropriate for up to 45-50 with results
    similar to matched-related BMT in same age group
    (modern methods of typing of both HLA class I and
    class II)

42
CML - Allogeneic BMT
  • Curative potential
  • Long-term survival in 50-80 of patients
  • DFS 30-70
  • Relapse in 15-30 of patients and plateau reached
    at 5 years post-transplantation

43
CML - Allogeneic BMT
  • Factors influencing outcome
  • Age
  • Disease phase Best result in chronic phase
  • Time from diagnosis to BMT First 1-2 years

44
CML - Allogeneic BMT
  • Salvage therapy for relapse after BMT
  • Second transplantation outcome depends on time
    between first transplantation and relapse
  • Interferon Long-lasting cytogenetic remission in
    20-40 of patients with cytogenetic relapse only
  • Donor Lymphocytes Iinfusion most effective
    salvage therapy
  • CGR and CHR 60-80
  • 3-year DFS 38-87
  • Infrequent responses in transformed phase
  • Side effects myelosuppression, GVHD

45
STI-571
  • Signal Transduction Inhibitor
  • Signal Transduction - Simplistic View
  • t(922) results in bcr-abl, producing deregulated
    form of ABL protein-tyrosine kinase
  • BCR-ABL tyrosine kinase implicated as pathogenic
    mechanism for deregulated cellular proliferation
    in CML
  • Tyrosine kinases function by binding ATP and
    transferring phosphate from ATP to tyrosine
    residues on various substrates

46
Mechanism of action of STI-571
47
STI-571
  • STI-571 (formerly CGP57148B) blocks binding of
    ATP to BCR-ABL tyrosine kinase, thus inhibiting
    the activity of the kinase
  • In preclinical studies, STI inhibits all Abl
    kinases (p210 bcr-abl,p190bcr-abl, v-Abl, c-Abl)
    and PDGFR and c-Kit tyrosine kinases
  • Inhibits proliferation of bcr-abl expressing
    cells
  • in vitro studies of colony growth of cells from
    patients with CML
  • tumor bearing animal models - potent anti-tumor
    activity

48
STI-571uses
  • Chronic Myeloid Leukemia
  • Chronic phase - ?-interferon intolerant/refractory
  • Accelerated phase
  • Blast crisis
  • Newly diagnosed Chronic Phase (recently closed)
  • Ph1 Acute lymphocytic leukemia
  • Brain tumors
  • Sarcomas - Gastrointestinal Stromal Tumors (GIST,
    GI-stromal tumors)

49
  • Mortality/Morbidity. The general course of the
    disease is characterized by an eventual evolution
    to a refractory form of acute myelogenous or,
    occasionally, lymphoblastic leukemia. The median
    survival of patients using older forms of therapy
    was 3-5 years.

50
  • Leukapheresis using a cell separator can lower
    WBC counts rapidly and safely in patients with
    WBC counts of higher than 300,000 cells/mL, and
    it can alleviate acute symptoms of leukostasis,
    hyperviscosity, and tissue infiltration.
    Leukapheresis usually reduces the WBC count only
    temporarily and is often combined with
    cytoreductive chemotherapy for more lasting
    effects

51
  • DDX
  • Leukemoid reactions from infections (chronic
    granulomatous, eg, tuberculosis) Myelodysplasia Tu
    mor necrosis Essential thrombocytosis/thrombocythe
    mia Chronic neutrophilic leukemia Chronic
    myelomonocytic leukemia Acute myeloid leukemia

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