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Chronic Myeloid Leukemia

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Disorder of the stem cells in bone marrow ... Confirmed with bone marrow biopsy and FISH and/or PCR that shows presence of ... Using bone marrow from a donor ... – PowerPoint PPT presentation

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Title: Chronic Myeloid Leukemia


1
Chronic Myeloid Leukemia
2
Leukemia
  • ALL, AML, CLL
  • Chronic Myelogenous Leukemia
  • Cancer of the granulocytes or monocytes, compared
    to leukocytes in lymphocytic leukemias
  • Comprises about 14 of all adult leukemias
  • Males slightly higher than females
  • One of the first cancers to have a specific
    genetic link to a chromosomal mutation identified
    for the disease
  • Philadelphia Chromosome

3
Pathophysiology
  • Disorder of the stem cells in bone marrow
  • General infection fighting cells are the most
    harmed gt granulocytes and monocytes (aka,
    neutrophils)
  • These immature cells take over the bodys mature
    neutrophils and hinder the bodys ability to
    fight infection properly
  • CML is caused by a genetic mutation with
    chromosomes 9 and 22 in the body
  • Abl on chromosome 9 is translocated to chromosome
    22 and fuses with Bcr
  • This ABL-BCR protein is an unregulated tyrosine
    kinase and thus, is the source of the
    reproduction of immature granulocytes
  • Other functions include upstream changes of DNA
    repair mechanisms, suppression of the bodys
    programmed cell death proteins, and changes in
    cytoskeletal structures

4
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5
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6
How you are diagnosed
  • Usually by accident!
  • ?
  • Routine WBC test shows elevated leukocytes
  • Confirmed with bone marrow biopsy and FISH and/or
    PCR that shows presence of Philadelphia
    Chromosome
  • Presence of myeloid cells in peripheral blood
    determines staging of disease
  • S/SX lethargy, pallor, night sweats, weight
    loss, anorexia, fever, lymphadenopathy,
    splenomegaly

7
STAGING OF CML
  • Three main stages, determined by percentage of
    blast cells in the blood
  • Chronic Phase
  • Patient usually diagnosed
  • Fewer than 10 of cells in blood and bone marrow
    are granulocytes
  • Prognosis (with imatinib) 5yr 70, 10yr
    30-40
  • Accelerated Phase
  • 10-19 of cells are granulocytes
  • Blastic Phase, aka blast crisis
  • Fulminant symptoms of disease, multiple organ
    involvement
  • 20-30 or more granulocytes in bone marrow and
    blood
  • Prognosis UNPROMISING, 2 months, may extend
    survival with newer drugs or chemotherapy

8
Treatment Options
  • Pharmacotherapy
  • Newer drugs are prolonging chronic phase and
    increasing the number of patients who enter into
    remission
  • They are easier on the body versus SCT
  • Old Standard hydroxyurea (no possible cytogenic
    response) or interferon alpha cytarabine
  • New Standard tyrosine kinase inhibitors
  • Imatinib, dasatanib, nilotonib
  • Stem Cell Transplant
  • Using bone marrow from a donor to resupply the
    patient
  • Can be the only curative measure, although many
    drawbacks
  • Must be good candidates for surgery
  • Must have a relatively short time from diagnosis
    to transplant
  • Matching donor
  • Possible relapse of CML
  • Rejection (GVHD)

9
How to measure treatment
  • Hematologic response
  • The response that reflects a decrease in white
    blood cell count and platelets
  • A hematological response in CML would be shown
    when a patient went from about a 10 granulocyte
    count to a 4 granulocyte count
  • Good prognostic sign
  • Cytogenic response
  • Reduction or elimination of Ph cells in bone
    marrow
  • Can be Complete, Major or Minor
  • 0, 1-34, 35-90 respectively in bone marrow
    cells
  • Done by FISH and/or PCR
  • Chronic phase patients who have cytogenic
    responses have a significant increase in survival
    and a deterrence to progression to accelerated or
    blast phases
  • Better prognostic sign

10
New Treatments Tyrosine Kinase Inhibitors
  • Enzyme that is able to transfer a phosphate group
    from ATP to a tyrosine residue in a protein
  • Main proponents of signal transduction of enzymes
    in body, in bone marrow, this is one of many
    proteins that plays a large role in hematopoeisis
  • In CML, the BRC-ABL gene is a tyrosine kinase
    that is constituently active, and thus produces
    unregulated granulocytes
  • A great advance in the treatment of CML was to
    develop a tyrosine kinase inhibitor, that turns
    off the active TK in the body, specific to the
    mutated gene, BRC-ABL
  • The first generation TK inhibitor for CML is
    imatinib mesylate

11
Imatinib mesylate
  • First generation TK inhibitor
  • Dosed in 400mg and 800mg tablets
  • Binds the closed form of the ATP binding site in
    BRC-ABL
  • IRIS study 97 pts in hematological remission
    and major cytogenic remission was 87 compared to
    interferon alpha cytarabine after 19 months
  • IRIS Follow-up five year study if patient shows
    a 3-log molecular response to imatanib, then
    probability of progression-free survival at 4
    years is 98 (Frame 2006)
  • Side Effects Fluid retention (76), diarrhea
    (30-60), nausea (43-73), fatigue, muscle
    cramps, bone pain, rash, neutropenia,
    thrombocytopenia (although might be signs of
    effectiveness)
  • Most can be alleviated with common medications
    and are not a cause of discontinuation
  • Resistance occurs

12
  • A small number of patients show some resistance
    to Imatanib
  • The BRC-ABL transcript has the ability to mutate
    and thus make imatinib ineffective
  • Imatinib binds to the closed conformation and
    BRC-ABL can mutate to the open conformation and
    thus makes imatanib ineffective
  • Two 2nd generation TKIs have proven to be more
    potent and are in trials to determine
    effectiveness against resistance to imatanib

13
2nd Generation TKIs
  • Dasatanib
  • aka Sprycel 300 times more potent than imatanib
  • Binds to multiple conformational states (open and
    closed), unlike imatanib
  • Very new drug, approved in July, 2006 for further
    clinical trials
  • Side Effects myelosuppression which can lead to
    bleeding, infection and fatigue, fluid retention,
    headache, skin rash, nausea
  • Can be used in patients who are resistant to
    imatanib
  • Nilotonib
  • Structurally similar to imatanib
  • 20 to 50 times more potent than imatanib
  • Binds in the closed conformation
  • Not FDA approved, still under scrutiny
  • COMBOS with dasatanib, nilotonib and imatinib
    have proven that they do not inhibit each other,
    and prove useful in pilot experiments with
    resistant cell clones

14
Treatment Algorithm
15
References
  • Faderl S, Kantarjian HM. Chronic Myelogenous
    Leukemia and Other Myeloproliferative Disorders.
    BOOK, check citing!. ACP Medicine. 2006.
    vol 2(2570-79)
  • Fausel C. Novel treatment strategies for chronic
    myeloid leukemia. Am J Health-Syst Pharm. 2006
    Dec 1 63(Suppl 8) S15-S20.
  • Grigg A, Hughes T. Role of Allogenic Stem Cell
    Transplantation for Chronic Myeloid Leukemia in
    the Imatinib Era. Biol Blood Marrow Transplant.
    2006 Mar 29 12795-807.
  • http//www.gleevec.com/info/page/safety_info
  • http//www.cmlmedicalmonitor.com/medical-monitor/e
    ducation/ayd_response.asp?trialshow
  • http//www.pharmcast.com/Patents/Yr2002/Mar2002/03
    2602/6362162_CML032602.htm
  • http//images.google.com/images?qPHILADELPHIACHR
    OMOSOMEimagehlensaXoiimagescttitle
  • http//commons.wikimedia.org/wiki/ImageBcr-abl_fu
    sion_gene.jpg
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