CML

INTRODUCTION:
  • CML results from a somatic mutation in a pluripotential hematopoietic cell
  • CML is a MPD characterized by increased granulocytic cell line, associated often with platelet hyperplasia
  • The disease usually envolves into an accelerated phase that often terminates in acute phase
  1. Chronic phase 3-5 years
  2. Accelerated phase 6-9 months
  3. Blastic phase 3-6 months
ETIOLOGY:
  • Exposure to high- dose ionizing radiation
  • Chemical agents have not been established as a cause
PATHOGENESIS:
  • Hematopoietic abnormality

  1. Expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation – increased white cell count
  2. Megakaryocytopoiesis is often expanded
  3. Erythropoiesis is usually deficient
  4. Function of the neutrophils and platelets is nearly normal
  • Genetic abnormality
  1. CML is the result of an acquired genetic abnormality
  2. A translocation between chromosome 9 and 22 [t(9;22)] – the Philadelphia chromosome
  3. The oncogene BCR-ABL encodes an enzyme – tyrosine phosphokinase (usually p210)
DIAGNOSIS:
  • More than 95% of patients with CML have Philadelphia (Ph) chromosome
  • A subset of patients with CML lack a detectable Ph chromosome but have the fusion product for the bcr/abl translocation detectable by reverse transcriptase- polymerase chain reaction (RT-PCR)
  • The hemoglobin concentration is decreased or normal
  • Nucleated red cells in blood film can be seen
  • The leukocyte count above 25000/μl (often above 100000/μl), granulocytes are at all stages of development
  • Hypersegmentated neutrophils
  • The basophiles count is increased
  • The platelet count is normal or increased
  • Neutrophils alkaline phosphatase (GAF) activity is low or absent (90%)
  • The marrow is hypercellular (granulocytic hyperplasia)- proportion >10:1 (blasts
  • Reticulin fibrosis
  • Hyperuricemia and hyperuricosuria
  • Serum vitamin B12-binding proteine and serum vitamin B12 levels are increased
  • Pseudohyperkalemia, and spurious hypoxemia and hypoglycemia
  • Cytogenetic test- presence of the Ph chromosome
  • Molecular test – presence of the BCR-ABL fusion gene
  • The bcr/abl fusion protein

  1. Uncontrolled kinase activity
  2. Deregulated cellular proliferation
  3. Decreased adherence of leukemia cells to the bone marrow stroma
  4. Leukemic cells are protected from normal programmed cell death (apoptosis)
CLINICAL FEATURES:

  • 30 -50% of patients are asymptomatic at the time of diagnosis (90% are diagnosed in chronic phase)
  • Thrombocytopenia, Lymphadenopathy & High HbF are the features of juvenile CML
Symptoms are gradual in onset:

  • fatigue, malaise, anorexia, abdominal discomfort, weight loss, excessive sweating
Less frequent symptoms:
  • Night sweats, heat intolerance- mimicking hyperthyroidism, symptoms of leukostasis (tinnitus, stupor), splenic infarction (left upper-quadrant and left shoulder pain), urticaria (result of histamine release)
Physical signs:

  • Pallor, splenomegaly, sternal pain
TREATMENT:
  • Imatinib mesylate (Glivec) or other TKI-the current standard approach
  • Imatinib used in CML acts by Competitive inhibition of ATP binding site of Abl kinase
  • Interferon alfa
  • Oral chemotherapeutic agents (hydroxyurea, busulfan)
  • Allo- SCT:The only curative treatment for CML is Allogenic stem cell Transpintation
PROGNOSIS:
Sokal score = (11x age + 35x spleen + 89x blasts + 0,4x platelet – 550)/1000
Euro scale = (0,666x age /0 when age / + 0,0420x spleen + 0,0584x blasts + 0,0413x eosinophils + 0,2039x basophils /0 when basophils3%/ + 1,0956x platelet /0 when platelet <15000g 1="" l="" when="">/) x 1000
RISK SOKAL EURO
LOW <0,8 <780
MODERATE 0,8-1,2 780-1479
HIGH >1,2 >1480
Exam Question

  • Imatinib is the drug of choice for CML
  • BCR ABL gene mutation is seen in CML
  • Chromosomal translocation seen in CML is 9:22
  • Imatinib used in CML acts by Competitive inhibition of ATP binding site of Abl kinase
  • Phildalphia chromosome is mostly seen in CML
  • Decrease in "Alkaline phosphatase" is seen in CML
  • Thrombocytopenia, Lymphadenopathy & High HbF are the features of juvenile CML
  • Size of splenomegaly indicates prognosis in CML
  • Basophillic leucocytosis occurs in CML
  • CML in children is associated with Down's syndrome
  • Best Rx for CML is Allogenic stem cell Transpintation
Don't Forget to Solve all the previous Year Question asked on CML