Chronic Myeloid Leukemia/ CML

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Chronic Myeloid Leukemia/ CML Powered By Docstoc
					Salwa Hassan Teama
M.D. Clinical Pathology and Oncology Laboratory Medicine
Ain Shams University/ Cairo/ Egypt
Types of Leukemia
There are four common types of leukemia:
Chronic lymphocytic leukemia (CLL): CLL affects lymphoid cells
and usually grows slowly. It accounts for more than 15,000 new cases
of leukemia each year. Most often, people diagnosed with the disease
are over age 55. It almost never affects children.
Chronic myeloid leukemia (CML): CML affects myeloid cells and
usually grows slowly at first. It mainly affects adults.
Acute lymphocytic (lymphoblastic) leukemia (ALL): ALL affects
lymphoid cells and grows quickly. It accounts for more than 5,000 new
cases of leukemia each year. ALL is the most common type of leukemia
in young children. It also affects adults.
Acute myeloid leukemia (AML): AML affects myeloid cells and
grows quickly. It accounts for more than 13,000 new cases of leukemia
each year. It occurs in both adults and children.
Source: Wikipedia
   Chronic Myeloid Leukemia (CMLs)
    (Chronic myelogenous leukemia, Chronic granulocytic leukemia)

 Clonal disease
 Chronic myeloproliferative disorders
 Result from an acquired genetic change in a
 pluripotent haemopoietic stem cell.
 Granulocytic hyperplasia in bone marrow with
  variable maturation defect.
        Chronic Myeloid Leukemia

Chronic Myeloid Leukemia characterized by:
 Anemia
 Extreme blood granulocytosis
 Granulocytic immaturity
 Basophilia
 Often thrombocytosis
 Splenomegaly
 Ph chromosome in all leukemic cells
Positive CML

    It accounts for nearly 5,000 new cases of leukemia
    each year.

   Occurs more often in men than in women (ratio 1.5 :1)

 Median age of onset of 50-60 years. Rare below the
    age of 20 years but occurs at all decades of life.


Exposure to very high dose of ionizing radiation can
increase the occurrence of CML above the expected
frequency in comparable population.
Clinically, CML is a biphasic or triphasic disease that is usually diagnosed in the »
initial chronic and then spontaneously evolves after some years into an advanced phase,
which can sometimes be subdivided into an earlier accelerated phase and a late acute or
blastic phase.
Clinical Features

 In the past, The majority of patients presented with
  symptoms due to; splenomegaly, hemorrhage or

 Recently, 50% of patients asymptomatic diagnosed
  during routine blood tests for pregnancy, before
  blood donation,……
Signs and Symptoms

Chronic Phase
   Easy fatigability
   Loss of sense of well-being
   Anorexia
   Abdominal discomfort
   Weight loss
   Excessive sweating
   Hemorrhage from various sites
   Spontaneous bruising or unexplained bleeding
    from gums, intestinal or urinary tract
   ………………….
   A physical examination may detect pallor and
Signs and Symptoms

Advanced disease: In addition
 Bone tenderness or
 signs of infection
In established blastic transformation:
 Splenomegaly
 Enlarged liver
 Fever
 Lymphadenopathy or
 Rarely lytic lesions of bone

 Morphologic evaluation of the peripheral smear and
  bone marrow aspirate.

 Identificationof    the    t(9;22) Philadelphia
  chromosome translocation by FISH technique,
  or BCR-ABL1 fusion gene by RT-PCR.

 Flowcytometry
Hematology/ Peripheral Blood

   The leucocyte count at diagnosis is usually 20-200 x10^9/L.
   On extreme occasion patients may present with leukocyte number in
    the range 200-800 x10^9/L
   The diagnosis of CML can be established in patients with persistent
    leukocytosis in the range 10-20 x10^9/L.
   The mean blast percentage is about 3% but can range from 0-10%.
   Full spectrum of cells in the granulocytic series: Mature neutrophils
    (Predominating), Blast forms,             Intermediate myelocytes,
    Hypersegmented neutrophils (common).
   Absolute lymphocytosis and absolute monocytosis .
   Basophilia
 The blood hemoglobin concentration is decreased but may be
  normal in early disease.

 Red cells usually are only slightly altered.
 The reticulocyte count is normal or slightly elevated.
 The platelet count areusually increases in the range of 300-
  600 x10^9/L, but may be normal or even decreased.
CML/ Peripheral Blood
• Examination of the bone marrow by aspiration or trephine biopsy is not
 necessary to confirm the diagnosis of CML, but is usually carried to assess the
 degree of marrow fibrosis, to perform cytogenetic analysis and to exclude incipient
Bone Marrow Examination

 Granulopoiesis is dominant, with a granulocytic to    erythroid
    ratio between 10: 1 and 30: 1 rather than the normal 2: 1 to 4: 1.
 Defective erythropoiesis
 The marrow aspirate may show multiple small hypercellular
   Blast cells in chronic phase number from 2% to 10%.
 Eosinophil and basophils are increased.
 Megakaryocytes are small, hypolobated and increased in
   Gaucher like cells may be present.
Molecular Biology

The Philadelphia chromosome is present in all myeloid
cell lineage, in some B cells and in very small
proportion of T cells.

The Ph translocation results in juxtaposition of 5 ' -
sequences from the BCR gene with 3 ' - ABL sequence
derived from chromosome 9. It produce chimeric gene
designated BCR-ABL.
Source: Wikipedia
             Molecular Biology

   BCR-ABL is transcribed as an 8.5 kb mRNA and
    encodes a protein with a molecular weight of 210
    kDs. This p210 oncoprotein has far greater tyrosine
    kinase activity than normal ABL gene product.

   The majority of CML patients have a BCR-ABL
    fusion gene and for which mRNA transcript have a
    b3 (e14) a2 or b2 (e13) a2 fusion junction.
                FISH Technique

Biochemical Changes

The biochemical changes seen in CML are nonspecific:
Increased serum levels of:

 Serum B12 or B12 binding capacity

 Serum K

 Increased serum uric acid but the level is usually
 Serum alkaline phosphatase is normal or slightly
Management of chronic myeloid leukemia in
chronic phase


Imatinib functions by blocking the binding of ATP to the BCR-ABL tyrosine kinase, inhibiting its activity. In the
absence of tyrosine kinase activity, substrates required for BCR-ABL function cannot be phosphorylated, and
subsequent cellular events are abrogated.
Relationships between the putative number of leukemic cells, response,
and the level of BCR-ABL transcripts*

               Source: Blood 2006; 108: 1809-1820. © American Society of Hematology.
                  Accelerated Phase
One or more of the following:
 Marked increase in BCR-ABL expression.
 Blast 10%-19% of whit blood cells in          peripheral blood or
  nucleated bone marrow cells.

 Peripheral blood basophils > 20%.
 Persistent thrombocyopenia<100x10^9/L unrelated to therapy,
  or persistent thrombocytosis (>1000x10^9/L unresponsive to

 Increasing spleen size and increasing white blood cell count
  unresponsive to therapy.

 Megakaryocyte proliferation in sheets or clusters in association
  with marked reticulin or collagen fibrosis.
                   Blastic Phase
One or more of the following
  Blast >20% of peripheral leukocytes or of nucleated
    bone marrow cells.

  Extramedullary blast proliferation.
  Large foci clusters of blast in the bone marrow
                              Myeloid Blast Crisis

  Variants of
Chronic Myeloid
Variants of Chronic Myeloid Leukemia

 Ph Negative Chronic Myeloid Leukemia
 Chronic Myelomonocytic Leukemia
 Chronic Neutrophilic Leukemia and
 Chronic Eosinophilic Leukemia
 Juvenile Myelomonocytic Leukemia
 Ph Negative Chronic Myeloid Leukemia

About 6% of patients with hematological acceptable CML lack
Ph chromosome. The patients with no BCR-ABL gene shows:

 Lack basophilia
 Lack blast and myelocyte   peaks in leukocyte differential or
  show dysplastic features

 Monocytosis
 Poor response     to imatinib, INF or hydroxyurea and overall
  survival is inferior to Ph positive patients
    Chronic Myelomonocytic Leukemia

   Marrow cells lack a Ph chromosome

   Blood monocytosis is prominent and monocyte number may be as
    high as 50x 10^9/L

   Thrombocytopenia is common

   Basophilia and eosinophilia are absent

   Dysplatic changes are usually present in granulocyte and erythroid
    series. The disease is included in the FAB classification of the
    myelodysplastic syndromes.
Chronic Myelomonocytic Leukemia

       Chronic Neutrophilic Leukemia

 Rare disorder
 Diagnosed incidentally
 Increased white cell count is composed of mature neutrophil,
    without immature granulocyte in the blood and without
    basophilia or eosinophilia.
   Increased neutrophil alkaline phosphatase
    Hypercellular bone marrow but cytogenetic studies are
    usually normal
   Larger fusion protein (230kDa)
   Chronic Neutrophilic Leukemia

         Juvenile Myelomonocytic Lekaemia

 Rare  disease affecting children under the age of 12 year. It
  represent about 2% of all childhood leukemia.

 Increased   leukocyte number with variable numbers of blast
  cells in the peripheral blood.

 Increased   Hb F

 Hypercellular   bone marrow but usually lack chromosomal
  abnormalities, although monosomy 7 may be present.

 The  patients respond poorly to standard cytotoxic drug but
  patients may benefit from allogenic SCT.
              Juvenile Myelomonocytic Lekaemia

Morphology of JMML. Bone marrow smears were stained with May–Grünwald-Giemsa and shown at 1000-fold
magnification. Bd=band, Bl=myelomonoblast, Eb=erythroblast, Mc=myelocyte, Mo=monocyte,
Chronic Eosinophilic Leukemia
    References and Online Further Reading

 PA. Victor Hoffbrand , Daniel Catovsky,    Edward G. D. Tuddenham, Postgraduate Haematology, 5th
    Edition. 1076 page. ISBN:1-4051-0821-5

    Michael W. N. Deininger, John M. Goldman, and Junia V. Melo The molecular biology of chronic
     myeloid leukemia . Blood, 15 November 2000, Vol. 96, No. 10, pp. 3343-3356.

    National Comprehensive Cancer Network Practice Guidelines in Oncology. Chronic Myelogenous
     Leukemia. Version 1.2006. Available at: Accessed February 8, 2006.

    Kim Y-J, Kim D-W, Lee S, et al. Comprehensive comparison of FISH, RT-PCR, and RQ-PCR for
     monitoring the BCR-ABL gene after hematopoietic stem cell transplantation in CML. Eur J Haematol.

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