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Chronic leukemia

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Blast crisis is defined as acute leukemia, with blood or marrow blasts 20%. Blast crisis Hyposegmented neutrophils may appear (Pelger-Huet anomaly). – PowerPoint PPT presentation

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Title: Chronic leukemia


1
Chronic leukemia
2
Chronic lymphocytic leukemia
  • is a monoclonal disorder characterized by a
    progressive accumulation of functionally
    incompetent lymphocytes.
  • Chronic lymphoid leukemia (CLL) is the most
    prevalent form of leukemia in western countries.
    It occurs most frequently in older adults and is
    exceedingly rare in children. In the US more than
    17,000 new cases are reported every year. CLL is
    more common in men than in women and more common
    in whites than in blacks. This is an uncommon
    malignancy in Asia. The etiologic factors for
    typical CLL are unknown.

3
IMMUNOLOGY
  • All lymphoid cells are derived from a common
    hematopoietic progenitor that gives rise to
    lymphoid, myeloid, erythroid, monocyte, and
    megakaryocyte lineages. Through the ordered and
    sequential activation of a series of
    transcription factors, the cell first becomes
    committed to the lymphoid lineage and then gives
    rise to B and T cells. A cell becomes committed
    to B cell development when it begins to rearrange
    its immunoglobulin genes. A cell becomes
    committed to T cell differentiation upon
    migration to the thymus and rearrangement of T
    cell antigen receptor genes.

4
IMMUNOLOGY
  • The cells of origin in the majority of patients
    with CLL are clonal B cells arrested in the
    B-cell differentiation pathway, intermediate
    between pre-B cells and mature B cells. B-CLL
    lymphocytes typically show B-cell surface
    antigens, as demonstrated by CD19, CD20, CD21,
    and CD24 monoclonal antibodies. B-CLL cells
    express extremely low levels of surface membrane.
    In addition, they express CD5. Because normal
    CD5 B cells are present in the mantle zone (MZ)
    of lymphoid follicles, B-cell CLL is most likely
    a malignancy of an MZ-based subpopulation of
    anergic self-reactive cells devoted to the
    production of polyreactive natural
    autoantibodies.

5
Clinical features
  • Localized or generalized lymphadenopathy
  • Splenomegaly (30-40 of cases)
  • Hepatomegaly (20 of cases)
  • Autoimmune hemolytic anemia or/and
    thrombocytopenia
  • Hemorrhagic syndrome
  • Signs of infection

6
Lab Studies
  • a complete blood count,
  • chemistry tests to measure major organ function,
  • serum protein electrophoresis,
  • a bone marrow biopsy,
  • imaging studies.

7
Lab Studies
  • Increased absolute number of circulating
    lymphocytes gt10109.
  • The peripheral blood smear shows many smudge or
    baske cells, nuclear remnants of cells damaged
    by the physical shear stress of making the blood
    smear.
  • Finding bone marrow infiltration by the same
    cells gt30.
  • Bone marrow aspiration and biopsy with flow
    cytometry.

8
Bone marrow
9
Hairy-cell leukemia
10
Lab Studies
  • Peripheral blood flow cytometry.
  • If cytogenetic studies are performed, trisomy 12
    is found in 25 to 30 of patients. Abnormalities
    in chromosome 13 are also seen.

11
Prognostic groups
  • Only blood and bone marrow involvement by
    leukemia but no lymphadenopathy, organomegaly, or
    signs of bone marrow failure - the best
    prognosis.
  • Lymphadenopathy and organomegaly - an
    intermediate prognosis,
  • Bone marrow failure, defined as hemoglobin lt100
    g/L or platelet count lt100,000/microL - the worst
    prognosis.

12
Rai system
13
Binet system
14
Indication for starting treatment
  • weight loss of more than 10,
  • extreme fatigue,
  • fever related to leukemia,
  • night sweats,
  • progressive marrow failure,
  • autoimmune anemia or thrombocytopenia not
    responding to prednisone,
  • progressive splenomegaly,
  • massive lymphadenopathy,
  • progressive lymphocytosis.

15
Treatment
  • Chlorambucil or fludarabine alone or in
    combination
  • Monoclonal antibodies - CAMPATH-1H, an antibody
    directed at CD52 Rituxan (rituximab)

16
Chronic myelogenous leukemia (CML)
  • a myeloproliferative disorder characterized by
    increased proliferation of the granulocytic cell
    line without the loss of their capacity to
    differentiate.

17
INCIDENCE
  • The incidence of chronic myelogenous leukemia
    (CML) is 1.5 per 100,000 people per year, and the
    age-adjusted incidence is higher in men than in
    women (2.0 versus 1.2). The incidence of CML
    increases slowly with age until the middle
    forties, when it starts to rise rapidly. The
    median survival of patients using older forms of
    therapy was 3-5 years.

18
ETIOLOGY
  • No clear correlation with exposure to cytotoxic
    drugs, such as alkylating agents, has been found,
    and here is no direct evidence of a viral
    etiology.
  • Cigarete smoking has been shown to accelerate the
    progression to blast crisis and therefore has an
    adverse effect on survival in CML.
  • The effect of radiation was demonstrated in a
    study of the atomic bomb survivors.
  • No increase in CML incidence was found in the
    survivors of the Chernobyl accident, suggesting
    that only large doses of radiation can induce CML.

19
PATHOPHYZIOLOGY
  • The diagnosis of CML is established by
    identifying a clonal expansion of a hematopoietic
    stem cell possessing a reciprocal translocation
    between chromosomes 9 and 22 and subsequently
    termed the Philadelphia (Ph) chromosome after the
    city of discovery. This translocation results in
    the head-to-tail fusion of the breakpoint cluster
    region (BCR) gene on chromosome 22q with the ABL
    (named after the abelson murine leukemia virus)
    gene located on chromosome 9q34.

20
Physical Findings
  • Splenomegaly early satiety and decreased food
    intake left upper quadrant abdominal pain may
    occur from spleen infarction.
  • Hypermetabolic state fever, weight loss, and
    chronic fatigue.
  • Hepatomegaly

21
Clinical phases
  • Initial chronic phase
  • Accelerated phase
  • Blast crisis.

22
Hematologic Findings
  • Elevated white blood cell counts
  • Early myeloid cells such as myeloblasts,
    myelocytes, metamyelocytes, and nucleated red
    blood cells.
  • Leukostasis and hyperviscosity with extraordinary
    elevation of their WBC counts, exceeding
    300,000-600,000 cells/mL.
  • The platelet counts at diagnosis can be low,
    normal, or even increased
  • Mild degree of normochromic normocytic anemia

23
Thrombocytosis
24
Hematologic Findings
  • Mature neutrophils, or granulocytes, have
    decreased apoptosis (programmed cell death),
    resulting in accumulation of long-lived cells
    with low or absent enzymes, such as alkaline
    phosphatase.
  • Histamine production secondary to basophilia is
    increased in later stages, causing pruritus,
    diarrhea, and flushing.
  • Bone marrow cellularity, primarily of the myeloid
    and megakaryocytic lineages, with a greatly
    altered myeloid to erythroid ratio, is increased.
  • The marrow blast percentage is generally normal
    or slightly elevated. Marrow or blood basophilia,
    eosinophilia, and monocytosis

25
Accelerated phase
  • This phase is characterized by poor control of
    the blood counts with myelosuppressive medication
    and the appearance of peripheral blast cells
    (gt15), promyelocytes (gt30), basophils (gt20),
    and platelet counts less than 100,000 cells/mL
    unrelated to therapy.
  • Splenomegaly may not be controllable by
    medications, and anemia can worsen.
  • Bone pain and fever, as well as an increase in
    bone marrow fibrosis, are harbingers of the last
    phase.

26
Blast crisis
  • is defined as acute leukemia, with blood or
    marrow blasts gt20.

27
Blast crisis
  • Hyposegmented neutrophils may appear (Pelger-Huet
    anomaly).
  • Blast cells can be classified as myeloid,
    lymphoid, erythroid, or undifferentiated, based
    on morphologic, cytochemical, and immunologic
    features.
  • Skin or tissue infiltration
  • Cytogenetic evidence of another Ph-positive clone
    (double) or clonal evolution (other cytogenetic
    abnormalities such as trisomy 8, 9, 19, or 21,
    isochromosome 17, or deletion of Y chromosome)

28
Chromosomal Findings
  • The cytogenetic hallmark of CML, found in 90 to
    95 of patients, is the t(922).
  • Some patients may have complex translocations
    (designated as variant translocations) involving
    three, four, or five chromosomes (usually
    including chromosomes 9 and 22). However, the
    molecular consequences of these changes appear
    similar to those resulting from the typical
    t(922).

29
Treatment
  • The goal of therapy in CML are
  • to achieve a hematologic remission (normal CBC
    count and physical examination, ie, no
    organomegaly),
  • to achieve cytogenetic remission (normal
    chromosome returns with 0 Ph-positive cells),
  • to achieve molecular remission (negative PCR
    result for the mutational bcr-abl m-RNA).

30
Treatment
  • Allogeneic SCT
  • Imatinib Mesylate (Gleevec) - competitive
    inhibition at the adenosine triphosphate (ATP)
    binding site of the Abl kinase, which leads to
    inhibition of tyrosine phosphorylation of
    proteins involved in Bcr/Abl signal transduction
    induces apoptosis in cells expressing Bcr/Abl

31
Treatment
  • Interferons
  • Chemotherapy Initial management of patients with
    chemotherapy is currently reserved for rapid
    lowering of white blood cell counts, reduction of
    symptoms, and reversal of symptomatic
    splenomegaly. Hydroxyurea, a ribonucleotide
    reductase inhibitor, induces rapid disease
    control. The initial dose is 1 to 4 g/d the dose
    should be halved with each 50 reduction of the
    leukocyte count. Unfortunately, cytogenetic
    remissions with hydroxyurea are uncommon.

32
CHRONIC IDIOPATHIC MYELOFIBROSIS
  • is a clonal disorder of a multipotent
    hematopoietic progenitor cell of unknown etiology
    characterized by marrow fibrosis, myeloid
    metaplasia with extramedullary hematopoiesis, and
    splenomegaly.

33
CLINICAL FEATURES
  • Splenic enlargement
  • Hepatomegaly

34
DIAGNOSIS
  • Anemia, usually mild initially, is the rule,
    while the leukocyte and platelet counts are
    either normal or increased but either can be
    depressed.
  • The presence myelocytes and promyelocytes
    establishes the presence of extramedullary
    hematopoiesis
  • The presence of leukocytosis, thrombocytosis with
    large and bizarre platelets, as well as
    circulating myeloblasts suggests the presence of
    a myeloproliferative disorder as opposed to a
    secondary form of myelofibrosis
  • Marrow is usually not aspirable due to increased
    marrow reticulin, but marrow biopsy will reveal a
    hypercellular marrow with trilineage hyperplasia
    and, in particular, increased megakaryocytes, and
    fibrosis.

35
Myelofibrosis
36
TREATMENT
  • Splenectomy
  • Allopurinol can control significant
    hyperuricemia,
  • Hydroxyurea has proved useful for controlling
    organomegaly.
  • The role of IFN-a is undefined, and its side
    effects are more pronounced in the older
    individuals who are affected with this disorder,
    but reversal of myelofibrosis has been observed.
  • Glucocorticoids are used to control autoimmune
    complications and may ameliorate anemia alone or
    in combination with thalidomide.
  • Allogeneic bone marrow transplantation should be
    considered in younger patients.

37
POLYCYTHEMIA VERA
  • is a clonal disorder involving a multipotent
    hematopoietic progenitor cell in which there is
    accumulation of phenotypically normal red cells,
    granulocytes, and platelets in the absence of a
    recognizable physiologic stimulus.

38
CLINICAL FEATURES
  • Plethora
  • Acrocyanosis
  • Splenomegaly
  • Neurologic symptoms such as vertigo, tinnitus,
    headache, and visual disturbances.
  • Systolic hypertension
  • Venous or arterial thrombosis

39
CLINICAL FEATURES
  • Erythromelalgia
  • Digital ischemia.
  • Easy bruising, epistaxis, or gastrointestinal
    hemorrhage
  • Hypermetabolic syndrome
  • Hyperuricemia with secondary gout, uric acid
    stones, and acid-peptic disease

40
Diagnosis
  • Because isolated erythrocytosis is a common
    initial presentation for polycythemia vera but no
    clonal marker is available for the disease, the
    first task of the physician is to distinguish
    this autonomous clonal form of erythrocytosis
    from the many other types of erythrocytosis, most
    of which are correctable.
  • Secondary polycytemia is defined as an absolute
    increase in red blood cell mass caused by
    enhanced stimulation of red blood cell
    production. In contrast, polycythemia vera is
    characterized by bone marrow with an inherent
    increased proliferative activity.

41
Secondary polycythemia
  • Generalized inadequate tissue oxygenation or
    hypoxia can be due to the following
  • Decreased ambient oxygen concentration, as occurs
    in people living at high altitudes, can result in
    compensatory erythrocytosis as a physiologic
    response to tissue hypoxia.
  • Chronic obstructive pulmonary disease is commonly
    due to a large amount of ventilation in poor gas
    exchange units (high ventilation-to-perfusion
    ratios).
  • Alveolar hypoventilation can result from periodic
    breathing and oxygen desaturation (sleep apnea)
    or morbid obesity (pickwickian syndrome).

42
Secondary polycythemia
  • Generalized inadequate tissue oxygenation or
    hypoxia can be due to the following
  • Cardiovascular diseases associated with a
    right-to-left shunt (arteriovenous malformations)
    can result in venous blood mixing in the arterial
    system and delivering low oxygen levels to
    tissues.
  • Hemoglobin abnormalities associated with high
    oxygen affinity and congenital defects can lead
    to oxidized or met-hemoglobin. These conditions
    are usually familial.
  • Exposure to carbon monoxide by smoking or working
    in automobile tunnels results in an acquired
    condition. Carboxyhemoglobin has a strong
    affinity for oxygen.

43
Secondary polycythemia
  • Generalized inadequate tissue oxygenation or
    hypoxia can be due to the following
  • Impaired perfusion of the kidneys, which may lead
    to stimulation of erythropoietin EPO
    production, is usually due to local renal hypoxia
    in the absence of systemic hypoxia. For example,
    malignant and benign tumors that secrete EPO have
    been observed in patients with renal carcinomas,
    cerebellar hemangioblastomas, adrenal carcinomas,
    adrenal adenomas, hepatomas, and uterine
    leiomyomas.

44
DIAGNOSIS
  • Increased hemoglobin and hematocrit values
  • Direct measurement of red blood cell mass
  • In primary polycythemia, the disorder results
    from a mutation expressed within the
    hematopoietic stem cell or progenitor cells,
    which drives the eventual accumulation of red
    blood cells.
  • The secondary polycythemic disorders may also be
    acquired or congenital however, they are driven
    by circulating factors independent of the
    function of hematopoietic stem cells.

45
DIAGNOSIS
  • Because the hemoglobin or hematocrit level is
    affected by the plasma volume, and hematocrit and
    red cell mass are not linearly related, a red
    cell mass determination must also be performed to
    distinguish absolute erythrocytosis from relative
    erythrocytosis due to a reduction in plasma
    volume alone.

46
DIAGNOSIS
  • The plasma erythropoietin level. An elevated
    plasma erythropoietin level suggests either an
    hypoxic cause for erythrocytosis or autonomous
    erythropoietin production, in which case
    assessment of pulmonary function and an abdominal
    computed tomography scan to evaluate renal and
    hepatic anatomy are appropriate. A normal
    erythropoietin level does not exclude an hypoxic
    cause for erythrocytosis.
  • In polycythemia vera, in contrast to hypoxic
    erythrocytosis, the arterial oxygen saturation is
    normal.

47
DIAGNOSIS
  • A bone marrow aspirate and biopsy will provide no
    specific diagnostic information, and unless there
    is a need to establish the presence of
    myelofibrosis or exclude some other disorder,
    these procedures need not be done.
  • Although the presence of a cytogenetic
    abnormality such as trisomy 8 or 9 or 20q- in the
    setting of an expanded red cell mass supports a
    clonal etiology, no specific cytogenetic
    abnormality is associated with polycythemia vera,
    and the absence of a cytogenetic marker does not
    exclude the diagnosis.

48
Diagnostic criteria
  • Category A
  • Total red blood cell mass - In males, greater
    than or equal to 36 mL/kg in females, greater
    than or equal to 32 mL/kg
  • Arterial oxygen saturation greater than or equal
    to 92
  • Splenomegaly
  • Category B
  • Thrombocytosis with platelet count greater than
    400,000/mL
  • Leukocytosis with a white blood cell count
    greater than 12,000/mL
  • Increased leukocyte alkaline phosphatase greater
    than 100 U/L
  • Serum vitamin B-12 concentration greater than 900
    pg/mL or binding capacity greater than 2200 pg/mL
  • Diagnosis is established with A1 plus A2 plus A3
    or A1 plus A2 plus any 2 criteria from category B

49
Treatment
  • Patients with hematocrit values of less than 70
    may be bled twice a week to reduce the hematocrit
    to the range of 40.
  • Allopurinol
  • Antihistamines
  • Hydroxyurea
  • interferon (IFN)-a
  • Psoralens with ultraviolet light in the A range
    (PUVA) therapy.
  • Anagrelide - a quinazolin derivative and platelet
    antiaggregant
  • Splenectomy
  • Allogeneic bone marrow transplantation
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