2.  Myeloid Leukemias are heterogenous group of diseases characterized by infiltration of the blood, bone marrow, and other tissues by neoplastic cells of the hemopoietic system. Source: p. 683

3.  Clonal expansion possessing reciprocal translocation between chromosomes 9 and 22  Results into head-tail fusion of BCR gene on chr 22q11 with ABL located on 9q34.

4.  1.5 per 100,000 people per year.  Higher incidence in men than in women  Increases slowly with age until the mid 40’s  where it rises rapidly Source: p. 683

5.  Cigarette smoking accelerated the progression to blast crisis  adversely affected survival  No clear correlation with exposure to cytotoxic drugs, or viral infection.  Only large doses of radiation can induce CML. Source: p. 683

6. translocation between the long arms of chromosomes 22 and 9; t(9;22) Relocation of ABL oncogene from the long arm of chromosome 9 to the long arm of chromosome 22 in the BCR region BCR/ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. chronic myelogenous leukemia (CML) phenotype http://emedicine.medscape.com/article/199425-overview Pathophysiology

8. t(9;22) Bcr/Abl fusion protein, p210 BCR/ABL Hybrid BCR/ABL mRNA Bcr/Abl fusion protein, p230 BCR/ABL (rare) CHRONIC MYELOGENOUS LEUKEMIA Transform hematopoetic progenitor cells

9.  t(9:22)  Trisomy 8  17p-(p53 loss) *acquisition of these genetic and/or molecular abnormalities is critical to the phenotypic transformation. Source: p. 683

10.  Shorter survival times ◦ Associated with large deletions adjacent to the translocation breakpoint on the derivative 9 chromosome.  Disease progression ◦ Heterogenous structural alterations of p53 gene ◦ Structural alterations and lack of protein production of the retinoblastoma gene ◦ Catalytic component of telomerase Source: p. 683

11.  Blastic transformation ◦ Progressive de novo DNA methylation at the BCR/ABL locus ◦ Hypomethylation of the LINE-1 retrotransposon promoter ◦ Functional inactivation of the tumor suppressor protein phospholipase A2 ◦ Interleukin 1B Source: p. 683 - 684

12. CommonLess CommonOccasional Fatigue Malaise Weight Loss Splenic Enlargement: Early satiety, LUQ pain or mass Granulocyte dysfunction: Infections Platelet dysfunction: Bleeding, Thrombosis Severe leukocytosis Thrombosis: Vasooclusive dse, CVA, MI, venous thrombosis, priaprism, visual disturbance, pulmonary insufficiency Insidious Clinical Onset Asymptomatic Patients diagnosed during Health Screening Tests p230 BCR/ABL positive CML  more indolent course of disease Source: p. 684

13.  Presenting symptoms ◦ Gum bleeding ◦ Pallor ◦ Easy fatigability ◦ Malaise

14.  ROS ◦ Weightloss without anorexia ◦ Early satiety and abdominal fullness ◦ Occasional feelings of feverishness  Medical History ◦ LMP: 4 days, profuse flow, longer and stronger than the usual  Physical Exam ◦ PR 112 bpm ◦ Pale palpebral conjunctivae ◦ Palpable spleen 4cm from the left subcostal along MCL ◦ Petechiae over both lower extremities

15.  Laboratory exams ◦ CBC: Hb 72g/dl, Hct 0.20, WBC162x10 9 /L,

16. Progression of CML : Worsening Of Symptoms Unexplained fever Bleeding Significant weight lossThrombosis Bone and joint painInfections Increasing dose requirement of drugs controlling the disease Source: p. 684

17. Findings Minimal to Moderate Splenomegaly Most common Mild HepatomegalyOccasional Persistent Splenomegaly despite continued therapy Sign of disease acceleration Lymphadenopathy Myeloid Sarcomas Unusual, except late in the course of the disease Poor prognostic indicator Source: p. 684

18. Findings ↑ WBC: Majority - Myelocytes, Metamyelocytes, Band forms ↑Platelet Count * ↓ Leukocyte Alkaline Phosphatase in CML cells ↑ Serum vitamin B12 & vitamin B12-binding proteins ↑ Histamine Production 2° to Basophilia - Later stage Causes: Pruritus, Diarrhea, Flushing ↑ Bone Marrow Cellularity ↑ Myeloid:Erythroid N / ↑ Marrow Blast Percentage Marrow / Blood Basophilia, Eosinophilia, and Monocytosis Marrow Collagen Fibrosis Source: p. 684

19. Findings t(9:22)(q34:q11.2)Hallmark of CML Philadelphia chromosomePresence of a shortened chromosome 22(22q-) from the reciprocal t(9:22) Complex or Variant Translocations Involves 3 to 5 chromosomes Including chromosome 9 & 10 Molecular consequence same as typical t(9:22) Evidence of Translocation (molecularly, by cytogenetics, or FISH) Diagnosis of CML Source: p. 684

20. Clinical Onset of CML Disease Acceleration Blast Crisis (Acute Leukemia) Averaging 3 years6-12months

21. Unexplained fever Significant weight loss Increasing dose requirement of the drugs controlling the disease Bone and joint pain Bleeding Thrombosis Infections Source: p. 684 Disease Acceleration Blast Crisis (Acute Leukemia)