Chronic Myelogenous Leukemia

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.

Definition

Source: p. 683

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.

Chronic Myelogenous Leukemia

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

Incidence

Source: p. 683

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.

Etiology

Source: p. 683

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

t(9:22) Trisomy 8 17p-(p53 loss)

*acquisition of these genetic and/or molecular abnormalities is critical to the phenotypic transformation.

Disease Progression

Source: p. 683

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

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

Common Less Common Occasional

FatigueMalaiseWeight 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

p230BCR/ABL positive CML more indolent course of disease

Clinical Features

Source: p. 684

Presenting symptoms◦ Gum bleeding◦ Pallor◦ Easy fatigability◦ Malaise

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

Laboratory exams◦ CBC: Hb 72g/dl, Hct 0.20, WBC162x109/L,

Findings

Minimal to Moderate Splenomegaly

Most common

Mild Hepatomegaly Occasional

Persistent Splenomegaly despite continued therapy

Sign of disease acceleration

LymphadenopathyMyeloid Sarcomas

Unusual , except late in the course of the diseasePoor prognostic indicator

Physical Findings

Source: p. 684

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 stageCauses: Pruritus, Diarrhea, Flushing

↑ Bone Marrow Cellularity↑ Myeloid:Erythroid N / ↑ Marrow Blast PercentageMarrow / Blood Basophilia, Eosinophilia, and Monocytosis Marrow Collagen Fibrosis

Hematologic Findings

Source: p. 684

Findings

t(9:22)(q34:q11.2) Hallmark of CML

Philadelphia chromosome Presence of a shortened chromosome 22(22q-) from the reciprocal t(9:22)

Complex or Variant Translocations

Involves 3 to 5 chromosomesIncluding chromosome 9 & 10Molecular consequence same as typical t(9:22)

Evidence of Translocation (molecularly, by cytogenetics, or FISH)

Diagnosis of CML

Chromosomal Findings

Source: p. 684

Clinical Onset of CML

Disease Acceleration

Blast Crisis (Acute

Leukemia)

Progression of CML

Averaging 3 years 6-12months

• Unexplained fever• Significant weight loss• Increasing dose requirement of the drugs

controlling the disease• Bone and joint pain• Bleeding• Thrombosis• Infections

Complications of CML

Source: p. 684

Disease Acceleration

Blast Crisis (Acute

Leukemia)

Treatment