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Chapter 17Chapter 17

Chronic LeukemiasChronic Leukemias

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Chronic Chronic Lymphocytic Lymphocytic

LeukemiaLeukemia

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CLLCLL

►Chronic – mature cells, signs and Chronic – mature cells, signs and symptoms develop gradually, and often symptoms develop gradually, and often discovered accidentally; May not be discovered accidentally; May not be diagnosed for 10-15 years!diagnosed for 10-15 years!

►Lymphocytic – lymphoproliferative Lymphocytic – lymphoproliferative disorderdisorder

►Leukemia – replacement of normal bone Leukemia – replacement of normal bone marrow with neoplastic cells, causing marrow with neoplastic cells, causing anemia, thrombocytopenia, and anemia, thrombocytopenia, and neutropenianeutropenia

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CLLCLL

►Most common form of leukemia in older adultsMost common form of leukemia in older adults► Patients usually in their 50’s when diagnosedPatients usually in their 50’s when diagnosed► Average survival time is 5 years; May take an Average survival time is 5 years; May take an

aggressive course with only 1-2 years of survival aggressive course with only 1-2 years of survival timetime

►Many CLL patients die from infectionsMany CLL patients die from infections►No known specific etiologic agent or cause for No known specific etiologic agent or cause for

CLLCLL►Most frequently a neoplasm of B-lymphocytes Most frequently a neoplasm of B-lymphocytes

(rarely T cells)(rarely T cells)► Lymphocytes are small and have relatively Lymphocytes are small and have relatively

mature, well-differentiated appearancemature, well-differentiated appearance► Bare nuclei, called “smudge cells” frequently Bare nuclei, called “smudge cells” frequently

foundfound

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CLLCLL

►Will develop altered humoral immunity Will develop altered humoral immunity resulting from suppression of all classes of resulting from suppression of all classes of immunoglobulins, leading to immunoglobulins, leading to hypogammaglobulinemia; Subsequent hypogammaglobulinemia; Subsequent increase in susceptibility to infectionsincrease in susceptibility to infections

►Many patients (15-35%) develop autoimmune Many patients (15-35%) develop autoimmune disorders and produce autoantibodies to disorders and produce autoantibodies to neutrophils, platelets (i.e. ITP), or RBCs (WAIHA)neutrophils, platelets (i.e. ITP), or RBCs (WAIHA)

► Have significantly impaired immunologic Have significantly impaired immunologic activityactivity

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CLLCLL

►Normal adult peripheral blood:Normal adult peripheral blood: B-cell lymphocytesB-cell lymphocytes 30%30%

with surface immunoglobulinswith surface immunoglobulins T-cell lymphocytesT-cell lymphocytes 70%70%

without surface immunoglobulinswithout surface immunoglobulins► Very important to differentiate which type of Very important to differentiate which type of

lymphocytes are involved in the CLL (B cells lymphocytes are involved in the CLL (B cells or T cells)or T cells)

►Diagnosis of CLL can be done Diagnosis of CLL can be done morphologically, but distinguishing between morphologically, but distinguishing between T-cell and B-cell CLL requires testing for T-cell and B-cell CLL requires testing for cluster differentiation (CD) antigenscluster differentiation (CD) antigens

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CLLCLL

►Malignant B cells of CLL do not progress to Malignant B cells of CLL do not progress to the final stages of development, the plasma the final stages of development, the plasma cells; Appear to stop developmentally at cells; Appear to stop developmentally at earlier B-lymphocyte stage of developmentearlier B-lymphocyte stage of development

► CLL usually presents with elevated WBC CLL usually presents with elevated WBC count with many lymphocytescount with many lymphocytes

►Not usually curable with available therapyNot usually curable with available therapy► Treatments include bone marrow Treatments include bone marrow

transplants, radiation, chemotherapy, and transplants, radiation, chemotherapy, and intravenous gamma globulin to help prevent intravenous gamma globulin to help prevent bacterial infectionsbacterial infections

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CLL Laboratory ResultsCLL Laboratory Results

► Anemia is usually normochromic, normocytic with a Anemia is usually normochromic, normocytic with a normal to low reticulocyte countnormal to low reticulocyte count

► Autoimmune hemolytic anemia may develop Autoimmune hemolytic anemia may develop (positive DAT and elevated indirect bilirubin)(positive DAT and elevated indirect bilirubin)

► Often a decreased PLT count, due to bone marrow Often a decreased PLT count, due to bone marrow replacement of megakaryocytic precursors or replacement of megakaryocytic precursors or platelet antibodiesplatelet antibodies

► Lymphocytes may be morphologically identical to Lymphocytes may be morphologically identical to normal mature lymphocytes, or may have a normal mature lymphocytes, or may have a “soccer-ball” type of staining appearance“soccer-ball” type of staining appearance

► Immune dysfunction and hypogammaglobulinemia Immune dysfunction and hypogammaglobulinemia is usually present, with proliferating B-cellsis usually present, with proliferating B-cells

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Chronic Chronic Myelocytic Myelocytic LeukemiaLeukemia

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CMLCML► Also known as Chronic Granulocytic Leukemia (CGL) Also known as Chronic Granulocytic Leukemia (CGL) ► A clonal myeloproliferative disorder of hematopoietic A clonal myeloproliferative disorder of hematopoietic

pluripotent cell transformation characterized by pluripotent cell transformation characterized by marked leukocytosis and excessive production of marked leukocytosis and excessive production of granulocytes at all stages of maturationgranulocytes at all stages of maturation

► Is associated with chromosomal abnormality called Is associated with chromosomal abnormality called Philadelphia Chromosome; 90-95% of patients with Philadelphia Chromosome; 90-95% of patients with CML carry Philadelphia Chromosome, which is the CML carry Philadelphia Chromosome, which is the joining of chromosomes 9 and 22joining of chromosomes 9 and 22

► Usually occurs between ages of 30-50 (“adult Usually occurs between ages of 30-50 (“adult leukemia”)leukemia”)

► CML accounts for 25% of all leukemia casesCML accounts for 25% of all leukemia cases► Often discovered accidentally during routine physicalOften discovered accidentally during routine physical► Mean survival is 3-4 years after diagnosisMean survival is 3-4 years after diagnosis► Most patients die from complications arising from Most patients die from complications arising from

blast cell crisisblast cell crisis► Only treatment is bone marrow transplantOnly treatment is bone marrow transplant

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CMLCML

►A clonal stem cell disorderA clonal stem cell disorder►Causative agents include exposure to Causative agents include exposure to

ionizing radiation, administration of ionizing radiation, administration of cytotoxic drugs, and exposure to virusescytotoxic drugs, and exposure to viruses

►Cause of CML is unknown in 95% of Cause of CML is unknown in 95% of casescases

►NotNot inherited; Appears to be acquired, inherited; Appears to be acquired, and the Philadelphia Chromosome is and the Philadelphia Chromosome is notnot present in non-hematopoietic tissuespresent in non-hematopoietic tissues

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Philadelphia Chromosome in Philadelphia Chromosome in CMLCML

► Philadelphia (Ph) chromosome found in neutrophil, Philadelphia (Ph) chromosome found in neutrophil, monocyte, erythrocyte, platelet, and basophil monocyte, erythrocyte, platelet, and basophil precursors from CML patient’s blood and bone marrowprecursors from CML patient’s blood and bone marrow

► Helps in defining translocation that produces Ph Helps in defining translocation that produces Ph chromosome as clonal abnormalitychromosome as clonal abnormality

► Specific notation is t(9;22)Specific notation is t(9;22)► Main portion of the long arm of chromosome 22 is Main portion of the long arm of chromosome 22 is

deleted and translocated to distal end of long arm of deleted and translocated to distal end of long arm of chromosome 9, and a small part of chromosome 9 chromosome 9, and a small part of chromosome 9 reciprocally translocates to the broken end of reciprocally translocates to the broken end of chromosome 22chromosome 22

► Provides subsequent progeny with growth advantage Provides subsequent progeny with growth advantage over normal cellsover normal cells

► Also, the expression of the anti-apoptosis gene, which Also, the expression of the anti-apoptosis gene, which is responsible for cell death, is alteredis responsible for cell death, is altered

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Laboratory Findings in CMLLaboratory Findings in CML

► Increased load of myeloid cells, often with WBC count Increased load of myeloid cells, often with WBC count over 100 x 10over 100 x 1099/L/L

► Will see all stages of maturation, from blasts to mature Will see all stages of maturation, from blasts to mature segs; However, segmented neutrophil and myelocyte segs; However, segmented neutrophil and myelocyte are the most numerous forms; Will see left shiftare the most numerous forms; Will see left shift

► Eosinophil, basophil and platelet numbers may be Eosinophil, basophil and platelet numbers may be increasedincreased

► Normochromic, normocytic anemia with Hgb usually < Normochromic, normocytic anemia with Hgb usually < 10 g/dL10 g/dL

► Bone marrow hypercellular with marked myeloid Bone marrow hypercellular with marked myeloid hyperplasia (M:E ratio of 10:1, instead of the normal hyperplasia (M:E ratio of 10:1, instead of the normal 3:1)3:1)

► Low to absent leukocyte alkaline phosphatase (LAP)Low to absent leukocyte alkaline phosphatase (LAP)