1 Leukemia

2 Leukemia A group of malignant disorders affecting the blood and blood-forming tissues of A group of malignant disorders affecting the blood and blood-forming tissues of –Bone marrow –Lymph system –Spleen Occurs in all age groups Occurs in all age groups A group of malignant disorders affecting the blood and blood-forming tissues of A group of malignant disorders affecting the blood and blood-forming tissues of –Bone marrow –Lymph system –Spleen Occurs in all age groups Occurs in all age groups

:Epidemiology CML occurs in all age groups, but most commonly in the middle-aged and elderly. Its annual incidence is 1–2 per 100,000 people, and slightly more men than women are affected. CML represents about 15– 20% of all cases of adult leukemia in Western populations.The only well-described risk factor for CML is exposure to ionizing radiation; for example, increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki [16incidenceionizing radiationatomic bombings of Hiroshima and Nagasaki [16

4 Leukemia Results in an accumulation of dysfunctional cells because of a loss of regulation in cell division Results in an accumulation of dysfunctional cells because of a loss of regulation in cell division Fatal if untreated Fatal if untreated –Progressive Results in an accumulation of dysfunctional cells because of a loss of regulation in cell division Results in an accumulation of dysfunctional cells because of a loss of regulation in cell division Fatal if untreated Fatal if untreated –Progressive

5 Leukemia Often thought of as a childhood disease Often thought of as a childhood disease The number of adults affected with leukemia is 10 times that of children The number of adults affected with leukemia is 10 times that of children Often thought of as a childhood disease Often thought of as a childhood disease The number of adults affected with leukemia is 10 times that of children The number of adults affected with leukemia is 10 times that of children

6 Leukemia Etiology and Pathophysiology No single causative agent No single causative agent Most from a combination of factors Most from a combination of factors –Genetic and environmental influences No single causative agent No single causative agent Most from a combination of factors Most from a combination of factors –Genetic and environmental influences

7 Leukemia Etiology and Pathophysiology Associated with the development of leukemia Associated with the development of leukemia –Chemical agents –Chemotherapeutic agents –Viruses –Radiation –Immunologic deficiencies Associated with the development of leukemia Associated with the development of leukemia –Chemical agents –Chemotherapeutic agents –Viruses –Radiation –Immunologic deficiencies

8 Leukemia Classification Acute versus chronic Acute versus chronic –Cell maturity Acute:Acute: Chronic:Chronic: Acute versus chronic Acute versus chronic –Cell maturity Acute:Acute: Chronic:Chronic:

9 Acute leukemiaAcute leukemia is characterized by a rapid increase in the number of immature blood cells there are. Crowding due to such cells makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children.malignant cellsleukemia in children Chronic leukemiaChronic leukemia is characterized by the excessive build up of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal, resulting in many abnormal white blood cells. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group.

8/12/ Leukemia Classification Type of white blood cell (WBC) Type of white blood cell (WBC) –Acute lymphocytic leukemia (ALL) –Acute myelogenous leukemia (AML) Also called acute nonlymphoblastic leukemia (ANLL)Also called acute nonlymphoblastic leukemia (ANLL) –Chronic myelogenous leukemia (CML) –Chronic lymphocytic leukemia (CLL) Type of white blood cell (WBC) Type of white blood cell (WBC) –Acute lymphocytic leukemia (ALL) –Acute myelogenous leukemia (AML) Also called acute nonlymphoblastic leukemia (ANLL)Also called acute nonlymphoblastic leukemia (ANLL) –Chronic myelogenous leukemia (CML) –Chronic lymphocytic leukemia (CLL)

11 Myelogenous Leukemia Leukemia characterized by proliferation of myeloid tissue (as of the bone marrow and spleen) and an abnormal increase in the number of granulocytes, myelocytes, and myeloblasts in the circulating blood Leukemia characterized by proliferation of myeloid tissue (as of the bone marrow and spleen) and an abnormal increase in the number of granulocytes, myelocytes, and myeloblasts in the circulating blood

Myeloid tissue is a biologic tissue with the ability to perform hematopoiesis. It is mainly found as the red bone marrow in bones, and is often synonymous with this. However, myeloid can also be present in the liver and spleen. Myeloid tissue is a biologic tissue with the ability to perform hematopoiesis. It is mainly found as the red bone marrow in bones, and is often synonymous with this. However, myeloid can also be present in the liver and spleen.biologic tissuehematopoiesisred bone marrowbonesliverspleenbiologic tissuehematopoiesisred bone marrowbonesliverspleen A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow, but not in circulating blood (except when caused by certain diseases). A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow, but not in circulating blood (except when caused by certain diseases).cellgranulocyticbone marrowbloodcellgranulocyticbone marrowblood Myeloid tissue is a biologic tissue with the ability to perform hematopoiesis. It is mainly found as the red bone marrow in bones, and is often synonymous with this. However, myeloid can also be present in the liver and spleen. Myeloid tissue is a biologic tissue with the ability to perform hematopoiesis. It is mainly found as the red bone marrow in bones, and is often synonymous with this. However, myeloid can also be present in the liver and spleen.biologic tissuehematopoiesisred bone marrowbonesliverspleenbiologic tissuehematopoiesisred bone marrowbonesliverspleen A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow, but not in circulating blood (except when caused by certain diseases). A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow, but not in circulating blood (except when caused by certain diseases).cellgranulocyticbone marrowbloodcellgranulocyticbone marrowblood 8/12/200912

Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. [1] They are also called polymorphonuclear leukocytes (PMN or PML) because of the varying shapes of the nucleus, which is usually lobed into three segments. Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. [1] They are also called polymorphonuclear leukocytes (PMN or PML) because of the varying shapes of the nucleus, which is usually lobed into three segments.white blood cellsgranulescytoplasm [1]nucleuswhite blood cellsgranulescytoplasm [1]nucleus The myeloblast is a unipotent stem cell, which will differentiate into one of the actors of the granular series. The myeloblast is a unipotent stem cell, which will differentiate into one of the actors of the granular series.granular Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. [1] They are also called polymorphonuclear leukocytes (PMN or PML) because of the varying shapes of the nucleus, which is usually lobed into three segments. Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. [1] They are also called polymorphonuclear leukocytes (PMN or PML) because of the varying shapes of the nucleus, which is usually lobed into three segments.white blood cellsgranulescytoplasm [1]nucleuswhite blood cellsgranulescytoplasm [1]nucleus The myeloblast is a unipotent stem cell, which will differentiate into one of the actors of the granular series. The myeloblast is a unipotent stem cell, which will differentiate into one of the actors of the granular series.granular 8/12/200913

8/12/ Acute Myelogenous Leukemia (AML) Leukemia characterized by proliferation of myeloid tissue (as of the bone marrow and spleen) and an abnormal increase in the number of granulocytes, myelocytes, and myeloblasts in the circulating blood Leukemia characterized by proliferation of myeloid tissue (as of the bone marrow and spleen) and an abnormal increase in the number of granulocytes, myelocytes, and myeloblasts in the circulating blood One fourth of all leukemias One fourth of all leukemias –85% of the acute leukemias in adults Abrupt, dramatic onset Abrupt, dramatic onset –Serious infections, abnormal bleeding Uncontrolled proliferation of myeloblasts Uncontrolled proliferation of myeloblasts –Hyperplasia of bone marrow and spleen Leukemia characterized by proliferation of myeloid tissue (as of the bone marrow and spleen) and an abnormal increase in the number of granulocytes, myelocytes, and myeloblasts in the circulating blood Leukemia characterized by proliferation of myeloid tissue (as of the bone marrow and spleen) and an abnormal increase in the number of granulocytes, myelocytes, and myeloblasts in the circulating blood One fourth of all leukemias One fourth of all leukemias –85% of the acute leukemias in adults Abrupt, dramatic onset Abrupt, dramatic onset –Serious infections, abnormal bleeding Uncontrolled proliferation of myeloblasts Uncontrolled proliferation of myeloblasts –Hyperplasia of bone marrow and spleen

8/12/ Chronic Myelogenous Leukemia (CML) Excessive development of mature neoplastic granulocytes in the bone marrow Excessive development of mature neoplastic granulocytes in the bone marrow –Move into the peripheral blood in massive numbers –Ultimately infiltrate the liver and spleen Excessive development of mature neoplastic granulocytes in the bone marrow Excessive development of mature neoplastic granulocytes in the bone marrow –Move into the peripheral blood in massive numbers –Ultimately infiltrate the liver and spleen

16 Chronic Myelogenous Leukemia Philadelphia chromosome Philadelphia chromosome –The chromosome abnormality that causes chronic myeloid leukemia (CML) (9 &22) chromosomechronicmyeloidleukemiachromosomechronicmyeloidleukemia –Genetic marker Chronic, stable phase followed by acute, aggressive (blastic) phase Chronic, stable phase followed by acute, aggressive (blastic) phase Philadelphia chromosome Philadelphia chromosome –The chromosome abnormality that causes chronic myeloid leukemia (CML) (9 &22) chromosomechronicmyeloidleukemiachromosomechronicmyeloidleukemia –Genetic marker Chronic, stable phase followed by acute, aggressive (blastic) phase Chronic, stable phase followed by acute, aggressive (blastic) phase

8/12/ Leukemia Clinical Manifestations Relate to problems caused by Relate to problems caused by –Bone marrow failure Overcrowding by abnormal cellsOvercrowding by abnormal cells Inadequate production of normal marrow elementsInadequate production of normal marrow elements Anemia, thrombocytopenia, ↓ number and function of WBCsAnemia, thrombocytopenia, ↓ number and function of WBCs Relate to problems caused by Relate to problems caused by –Bone marrow failure Overcrowding by abnormal cellsOvercrowding by abnormal cells Inadequate production of normal marrow elementsInadequate production of normal marrow elements Anemia, thrombocytopenia, ↓ number and function of WBCsAnemia, thrombocytopenia, ↓ number and function of WBCs

8/12/ Leukemia Clinical Manifestations Relate to problems caused by Relate to problems caused by –Leukemic cells infiltrate patient’s organs SplenomegalySplenomegaly HepatomegalyHepatomegaly LymphadenopathyLymphadenopathy Bone pain, meningeal irritation, oral lesions (chloromas)Bone pain, meningeal irritation, oral lesions (chloromas) Relate to problems caused by Relate to problems caused by –Leukemic cells infiltrate patient’s organs SplenomegalySplenomegaly HepatomegalyHepatomegaly LymphadenopathyLymphadenopathy Bone pain, meningeal irritation, oral lesions (chloromas)Bone pain, meningeal irritation, oral lesions (chloromas)

It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosomemyeloproliferative diseasechromosomal translocation Philadelphia chromosome

CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. This chromosomal abnormality is so named because it was first discovered and described in 1960 by two scientists from Philadelphia,Pennsylvania:chromosomal translocation Philadelphia chromosome Philadelphia,Pennsylvania

This exchange brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the proto-oncogene ABL (Ableson leukemia virus) on chromosome 9. The resulting hybrid gene BCR-ABL codes for a fusion protein with tyrosine kinase activity, which activates signal transduction pathways, leading to uncontrolled cell growth.

The Philadelphia chromosome: T (9:22) translocation. The Ph chromosome is a shortened chromosome 22, which result from Reciprocal translocation between the long arms of chromosomes 9 & 22,The result is a hybrid bcr-abl gene (fusion protein) with increased tyrosine Kinase acm resulting in leukemic transformation.