leukemia

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leukemia is a worldwide common disease, so everyone should have knowledge about this

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Oncology Conference Leukemia Dr. D.W. Daugherty

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Acute Leukemia: Essentials: Short course of symptoms Fatigue, fever, easy bruising, bleeding Cytopenias - or pancytopenia More than 20% blasts in bone marrow Blasts in peripheral blood in 90% cases

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Acute Myeloid Leukemia (AML): Incidence: 2.3 per 100,000 people per year Higher among men than women (2.9 vs 1.9) Most common leukemia in adults (80% of cases) Vast majority of patients 65 years or older

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Acute Myeloid Leukemia (AML): Etiology: Genetic Radiation Toxic chemical exposure Medication (Alkylating-agents, Topoisomerase-II inibitors, Chloramphenicol, Phenylbutazone, Chloroquine, and Methoxypsoralen)

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Acute Myeloid Leukemia (AML): Most Common Presenting Sx: Fatigue (50%) Anorexia (30-40%) Weight loss (30-40%) Fever without evident cause (10%) Easy Bruising (5%) Bleeding (5%)

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Acute Myeloid Leukemia (AML): Symptoms: Nonspecific Most related to anemia, leukocytosis, leukopenia, leukocyte dysfunction, or thrombocytopenia Symptoms usually present for 3 months or more before diagnosis is made

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Acute Myeloid Leukemia (AML): Other Common Sx: Bone pain Lymphadenopathy Non-specific cough Headaches Excessive diaphoresis Symptoms secondary to mass lesions (granulocytic sarcoma or chloroma)

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Acute Myeloid Leukemia (AML): Physical Findings: Fever Splenomegaly Sternal tenderness Multiple bruises Bleeding (gingivae most common) Unexplained infections GI bleed Pulmonary, intracranial, and retinal hemorrhage

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Acute Myeloid Leukemia (AML): Laboratory and Radiographic Work-up: CBC with manual differential Uric Acid level Clotting studies (PT, PTT, D-dimer, fibrinogen) Bone marrow aspirate and biopsy Chest xray Echocardiogram

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Acute Myeloid Leukemia (AML): Hematological Findings: Anemia (normochromic, normocytic) Leukocytosis (median = 15,000) Thrombocytopenia (< 100,000)

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Acute Myeloid Leukemia (AML): Morphology and Cytology: > 20% myeloblasts in blood and/or bone marrow Auer Rods (cytoplasmic granules) Positive myeloperoxidase reaction in > 3% blasts

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AML Histology

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AML Histology

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Acute Myeloid Leukemia (AML): Classification/Subtypes: French-American-British Classification eight major subtypes based on morphology and cytochemistry World Health Organization Classification based on molecular, morphologic, and clinical features

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Acute Myeloid Leukemia (AML): Prognostic Factors: Age at diagnosis Comorbidities (acute vs chronic) Chromosomal findings Symptomatic interval preceding diagnosis Presenting Leukocyte count Circulating myeloblast count FAB classification Morphologic characteristics of the leukemic cell

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Acute Lymphoid Leukemia (ALL): Incidence: Approximately 3,000 new cases per year Mostly affects children , accounts for 2/3 of childhood leukemia ( peak age 4 years ) Comprises less than 20% of leukemia in young adults May be B-cell, T-cell, or null-type (non-B, non-T cell)

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Acute Lymphoid Leukemia (ALL): Etiology: Uncertain, but several proposed linkages: Genetic - Philadelphia chromosome Viral infection (EBV, HIV) Exposure to high energy radiation (T-cell ALL) Toxic chemical exposure Smoking

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Acute Lymphoid Leukemia (ALL): Common Sx: Pallor Fatigue Shortness of breath Easy bruising Petechiae Weight loss / failure to thrive Bone and/or joint pain

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Acute Lymphoid Leukemia (ALL): Physical Findings: Fever Splenomegaly and/or hepatomegaly Lymphadenopathy Multiple bruises Petechiae Unexplained infections

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Acute Lymphoid Leukemia (ALL): Laboratory and Radiographic Work-up: CBC with manual differential Chemistry studies to check for organ dysfunction Bone marrow aspirate and biopsy Genetic/Immunological studies Lumbar puncture

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Acute Lymphoid Leukemia (ALL): Hematological Findings: Anemia (normochromic, normocytic) WBC < 5,000 (or > 25,000) Leukocytosis (median = 15,000) Thrombocytopenia (< 50,000)

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ALL Histology

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ALL Histology

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L1 - 85% of childhood ALL L2 - Majority of adult ALL L3 - Includes Burkitt’s. < 5% of ALL

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Acute Lymphoid Leukemia (ALL): Prognostic Factors: Adult vs Childhood type Morphology (FAB class) Chromosomal findings WBC > 50,000 B-cell type worse than T-cell type Lymphadenopathy Hepatosplenomegaly

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Acute Leukemia Treatment: Two phases of treatment induction post-remission Initial goal is to quickly induce complete remission. Combination chemotherapy Continued low-dose post-remission therapy must be used to ensure prolonged survival. Otherwise recurrence rates can be as high as 90%

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Acute Leukemia: After Induction Chemotherapy: Bone marrow biopsy is obtained If >5% of blasts with >20% cellularity, then retreatment necessary. Stem cell transplant may be necessary if retreatment fails.

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Acute Leukemia: Post-remission Treatment: Stem cell transplant CNS prophylaxis (for ALL) Radiation therapy (for ALL) Prolonged low-dose chemotherapy for 1-3 years

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Acute Leukemia Treatment: Continued Supporative Care: Transfusions…. Platelets >20,000 Hgb >8 Empiric antibiotic treatment when fever present Allopurinol for increased uric acid levels

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Chronic Leukemia: Essentials: Most are asymptomatic at presentation Strikingly elevated WBC Marked left-shift Philadelphia chromosome Splenomegaly typical Lymphocytosis

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Chronic Myeloid Leukemia (CML): Incidence: 1.3 per 100,000 people per year Higher among men than women (1.7 vs 1.0) Vast majority of patients 40 years or older There is no clear etiology

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Chronic Myeloid Leukemia (CML): Pathophysiology: Philadelphia chromosome (9:22) in up to 95% BCR-ABL protein junction

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Chronic Myeloid Leukemia (CML): Common Sx: Note: approximately 70% of patients are asymptomatic at the time of diagnosis Lethargy Weight loss Increasing abdominal girth Easy bruising or bleeding Excessive diaphoresis

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Chronic Myeloid Leukemia (CML): Physical Findings: Fever Splenomegaly and hepatomegaly Bruising Bleeding (gingivae most common)

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Chronic Myeloid Leukemia (CML): Laboratory and Radiographic Work-up: CBC with manual differential Serum Vitamin B12 and B12 binding capacity Leukocyte alkaline phosphatase (decreased) Uric acid level Chromosomal testing - Philadelphia chromosome Bone marrow biopsy

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Chronic Myeloid Leukemia (CML): Hematological Findings: Anemia (normochromic, normocytic) Leukocytosis (median = 20,000) Basophilia Thrombocytopenia (< 100,000)

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CML Histology

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CML Histology

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Chronic Myeloid Leukemia (CML): Three Phases: Chronic phase : 3-5 years. Current treatment is with alpha-interferon. Young patients should undergo BMT. Accelerated phase : New nonrandom cytogenic abnormalities in up to 80% of patients. Difficult to control. Development of myelofibrosis. Elevated leukocyte counts. Lasts several months before becoming blastic. Blast phase : > 30% blasts in blood or marrow. Treatment with chemotherapy similar to acute leukemia. Some patients go into remission with treatment, but it is short lived.

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Chronic Myeloid Leukemia (CML): Prognostic Factors: Age at diagnosis Splenomegaly Blasts > 5% in blood or marrow at diagnosis Basophilia > 7% Platelets > 700,000

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Chronic Lymphoid Leukemia (CLL): Incidence: 2 new cases per 100,000 people per year Comprises 30% of all cases of leukemia Most common lymphoid leukemia Almost exclusively due to B-cell clonal expansion More common in men Most common in individuals < 50 years

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Chronic Lymphoid Leukemia (CLL): Etiology: Uncertain, several proposed linkages: Genetic Viral infection ( EBV , HIV) - Burkitt’s Exposure to high energy radiation (T-cell ALL) Toxic chemical exposure Smoking

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Chronic Lymphoid Leukemia (CLL): Common Sx: Note: approximately 70% of patients are asymptomatic at the time of diagnosis Fever Pallor Fatigue Shortness of breath Easy bruising Gingival bleeding Weight loss Frequent infections

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Chronic Lymphoid Leukemia (CLL): Physical Findings: Fever Splenomegaly and/or hepatomegaly Lymphadenopathy Multiple bruises Bleeding gingivae Unexplained infections

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Chronic Lymphoid Leukemia (CLL): Laboratory and Radiographic Work-up: CBC with manual differential Peripheral smear Flow cytometry Chemistry studies to check for organ dysfunction Lymph node biopsy

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Chronic Lymphoid Leukemia (CLL): Hematological Findings: Increased number of lymphocytes on smear smudge cells B-cells with CD 19 and CD 5 on flow cytometry Small lymphocitic lymphoma present in histology of nodal biopsy

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CLL Histology

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CLL Histology

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Chronic Lymphoid Leukemia (CLL): Prognostic Factors: Based on RAI classification Lymphocytosis Lymphadenopathy Splenomegaly or Hepatomegaly Anemia Thrombocytopenia

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Chronic Leukemia Treatment: CML therapy is based on phase Chronic : PO chemoprophylaxis alpha-interferon with concominant BMT Accelerated : within months progresses to blast phase treatment same as for AML, with combination Chemotherapy Blast : same as for AML, with combination chemotherapy

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Chronic Leukemia Treatment: CLL therapy is based on RAI stage stage 0 : Often followed without specific treatment stage I and II : Treatment if symptomatic. Single agent treatment with fludarabine. Combination treatment with CVP or CHOP regimens stage III and IV : Fludarabine, CVP, or CHOP regimens Young patients with this disease are also candidates for bone marrow transplantation

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Chronic Leukemia Treatment: CVP Regimen: Cyclophosphamide Vincristine Prednisone

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Chronic Leukemia Treatment: CHOP Regimen: Cyclophosphamide Doxorubicin Vincristine Prednisone

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Chemotherapy Agents: Antimetabolites: Base analogs. Incorporates into DNA and prevents transcription Also interferes with DNA polymerase, thus inhibiting DNA replication and repair Cell cycle S-phase-specific Cytarabine - pyrimidine analog Fludarabine - adenine analog

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Chemotherapy Agents: Anthracyclines: Primarily intercalates between DNA bases and prevents transcription. Secondarily inhibitions topoisomerase-II leading to DNA breaks Doxorubicin (CLL) Daunorubicin (AML, ALL and CML) Idarubicin (AML, ALL and CML)

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Chemotherapy Agents: Vinka alkaloids: Vincristine: acts as an anti-microtubule that blocks mitosis Cyclophosphamide: converted to a nitrate that intercalates into the DNA and causes damage via cross-linking Cell cycle phase specific for M phase and S phase

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Chemotherapy Agents: Prednisone: Gluccocorticoid analog Converted by liver to active form, prednisolone Acts as immunosuppressant

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Acute Myeloid Leukemia (AML): Remission: Combination tx with cytarabine/daunorubicin 65-75% will achieve CR. Two-thirds achieve CR after a single cycle. The other one-third after a second course. 50% of those who do not achieve CR fail because of a drug-resistant leukemia. The other 50% because of fatal complications of bone marrow or stem cells.

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Acute Lymphoid Leukemia (ALL): Remission: Combination tx with daunorubicin, vincristine, prednisone, and asparaginase Childhood ALL CR rate is approximately 90-95% Adult ALL CR rate is approximately 70-80%

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Chronic Myeloid Leukemia (CML): Remission: With concominant BMT and alpha-interferon treatment, remission rates of 40-60% can be achieved. Relapse rate is high, and median survival is only 5-6 years.

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Chronic Lymphoid Leukemia (CLL): Remission: Remission has not been achieved in CLL. Treatment with chemotherapy (fludarabine, CHOP, or CVP) increases median survival rates: Stage 0-I : 10-15 years Stage II-IV : approximately 2-5 years for 90% of patients

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