Chronic leukemia

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Chronic leukemia
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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.

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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.

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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.

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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

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Lab Studies

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

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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.

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Bone marrow
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Hairy-cell leukemia
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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.

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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.

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Rai system
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Binet system
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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.

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Treatment

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

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Chronic myelogenous leukemia (CML)

• a myeloproliferative disorder characterized by
  increased proliferation of the granulocytic cell
  line without the loss of their capacity to
  differentiate.

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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.

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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.

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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.

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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

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Clinical phases

• Initial chronic phase
• Accelerated phase
• Blast crisis.

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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

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Thrombocytosis
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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

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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.

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Blast crisis

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

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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)

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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).

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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).

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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

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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.

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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.

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CLINICAL FEATURES

• Splenic enlargement
• Hepatomegaly

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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.

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Myelofibrosis
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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.

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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.

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CLINICAL FEATURES

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

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CLINICAL FEATURES

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

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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.

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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).

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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.

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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.

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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.

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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.

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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.

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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.

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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

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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