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Chronic leukemias

chronic leukemia, CML, CLL.

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Chronic leukemias

  1. 1. CHRONIC LEUKEMIAS Dr Vijay Shankar S
  2. 2.  Chronic leukemias  Types  Chronic myeloid leukemia  Philadelphia chromosome  Chronic lymphocytic leukemia  Lab diagnosis
  3. 3.  Leukemias are classified into 2 major groups Acute Onset is usually rapid, The disease is very aggressive, The cells involved are usually poorly differentiated with many blasts. Chronic Onset is insidious, The disease is usually less aggressive, The cells involved are usually more mature cells
  4. 4.  Comparison of acute and chronic leukemias: Acute Chronic Age all ages usually adults Clinical onset sudden insidious Course (untreated) 6 mo. or less 2-6 years Leukemic cells immature >20% blasts more mature ` cells Anemia prominent mild Thrombocytopenia prominent mild WBC count variable increased Lymphadenopathy mild present;often prominent Splenomegaly mild present;often prominent
  5. 5. Chronic Myeloid Leukemia  Middle age 40-60y  Philadelphia chromosome, t(9:22)  Anemia, Fever & Bleeding  Marked leucocytosis – >50,000 (abnormal)  Marked splenomegaly, Hepatomegaly
  6. 6.  CML results from a somatic mutation in a pluripotential lymphohematopoietic cell  CML is a MPD characterized by increased granulocytic cell line, associated with erythroid and platelet hyperplasia  The disease usually envolves into an accelerated phase that often terminates in acute phase chronic phase 3-5 years accelerated phase blastic phase 3-6 months
  7. 7. Etiology  Exposure to high- dose ionizing radiation  Chemical agents have not been established as a cause
  8. 8. Epidemiology  CML accounts for approximately 15 percent of all cases of leukemia and approximately 3 percent of childhood leukemias  The median age of onset is 53 years
  9. 9. Pathogenesis Hematopoietic abnormality  Expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation – increased white cell count  Megakaryocytopoiesis is often expanded  Erythropoiesis is usually deficient  Function of the neutrophils and platelet is nearly normal
  10. 10. Pathogenesis Genetic abnormality  CML is the result of an acquired genetic abnormality  A translocation between chromosome 9 and 22 [t(9;22)] – the Philadelphia chromosome  The oncogene BCR-ABL encodes an enzyme – tyrosine phosphokinase (usually p210)
  11. 11. Translocation t(9;22)(q34;q11)
  12. 12. Translocation t(9;22)(q34;q11)
  13. 13. Philadelphia Chromosome • More than 95% of patients with CML has 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)
  14. 14. The bcr/abl fusion protein  Uncontrolled kinase activity  that results in  Increased granulocyte-colony stimulating factor  Increased platlet derived growth factor  Suppression of apoptosis in hematopoietic cells
  15. 15. Clinical features  30 percent of patient are asymptomatic at the time of diagnosis  Symptoms are gradual in onset: easy fatigability, malaise, anorexia, abdominal discomfort, weight loss, excessive sweating ● Less frequent symptoms: Night sweats, heat intolerance- mimicking hyperthyroidism, gouty arthitis, symptoms of leukostasis (tinnitus, stupor), splenic infartion (left upper-quadrant and left shoulder pain), urticaria (result of histamine release) ● Physical signs: Pallor, splenomegaly, sternal pain
  16. 16. Accelerated phase of CML  Most patients eventually became resistant to therapy and the disease enters a more agressive phase  Criteria of accelerated phase 1. Blasts in blood or bone marrow-10-19% 2. Basophilia ≥ 20% 3. Thrombocytopenia 4. Thrombocytaemia 5. Additional chromosomal aberrations 6. refractory splenomegaly or refractory leucocytosis
  17. 17. Blast phase (blast crisis) of CML • Criteria of blast phase 1. Blasts ≥20% 2. extramedullary tumors • Phenotype of blasts 1. Mieloblasts - 50% 2. Limphoblasts - 30% 3. Megakarioblasts – 10% 4. Acute myelofibrosis
  18. 18. Lab findings  Blood picture  Bone marrow examination  Cytogenetics  Cytochemistry ( NAP)
  19. 19. CML vs Leukemoid Reaction Characteristic feature CML Leukemoid Reaction Age >40 yrs Any age Leukocytosis >100,000 30,000 – 50,000 Absolute Basophilia Present May not Splenomegaly Prominent May not Philadelphia Chromosome Present Absent LAP / NAP Very low / Absent High Transformation to Acute leukemia Yes No
  20. 20. Laboratory features  The hemoglobin concentration is decreased  Nucleated red cells in blood film  The leukocyte count above 25000/μl (often above 100000/μl), granulocytes at all stages of development  The basophil count is increased  The platelet count is normal or increased  Neutrophils alkaline phosphatase activity is low or absent (90%)
  21. 21. Laboratory features (2)  The marrow is hypercellular (granulocytic hyperplasia)  Reticulin fibrosis  Cytogenetic test- presence of the Ph chromosome  Molecular test – presence of the BCR-ABL fusion gene
  22. 22. Chronic Myeloid Leukemia:
  23. 23. basophil blast neutrophils and precursors promyelocyte CML
  24. 24. Blood smear shows a preponderance of mature neutrophilic granulocytes.Myelocyte at center, basophil at upper right
  25. 25. Blood smear showing a greater left shift. At center is a myeloblast
  26. 26. Two basophils in blood smear
  27. 27. Increased granulocytopoiesis in a bone marrow smear. Neutrophilic granulocytes,two basophils, and four eosinophils
  28. 28. Chronic Lymphocytic Leukemia  Elderly age  Anemia, fever & bleeding – slow over years.  Lymphocytosis & Lymphadenopathy  Spleen, & liver enlargement  Common B cell (CD5 +ve)
  29. 29. Chronic leukemias  Chronic lymphocytic leukemia  This is predominantly a disease of the elderly; > 90% are over 50 and 2/3 are over 60;  male:female is 2:1  Is characterized by peripheral and bone marrow lymphocytosis and a survival of a few years to > 10 years  This is a B cell abnormality  The lymphocytes appear normal, but are immunologically incompetent. However, some functionally normal B cells remain and there is a normal T cell pool
  30. 30. Chronic leukemias  Etiology  Genetic factors are important since it runs in families  Clinical course  The pace of the disease varies and is dependent on the rate of accumulation of abnormal lymphocytes  Median survival is 3-4 years, but 10-15% survive > 10years  There is no tendency for blast transformation, but complications of advanced disease result from progressive accumulation of long-lived, poorly functional lymphocytes.
  31. 31. Chronic leukemias  Signs and symptoms  Organomegaly and lymphadenopathy  Often discovered accidentally  Fatigue  Near the end – bruising, pallor, fever, and weight loss
  32. 32. Lab features  Absolute lymphocytosis of 10-150 x 109/L  Lymphocytes usually appear normal, but they are markedly fragile and smudge cells are seen on the peripheral smear  It is not necessary to do a bone marrow biopsy for diagnosis.  Anemia occurs late in the disease and may be due to decreased production secondary to marrow infiltration, hypersplenism, or autoimmune hemolytic anemia:  the same things may cause neutropenia or thrombocytopenia  Hypogammaglobulinemia as the disease progresses
  33. 33. CLL with smudge cells
  34. 34. lymphocytes ‘smudge’ cells CLL
  35. 35. CLL – Blood Film
  36. 36. Peripheral blood smears show predominantly mature lymphocytes, some with a clumped chromatin pattern
  37. 37. Peripheral blood smears show predominantly mature lymphocytes, some with a clumped chromatin pattern
  38. 38. Bone marrow smear in B-CLL, with diffuse infiltration of the bone marrow
  39. 39. Chronic leukemias  Prognosis is related to the extent and distribution of the disease – also called the stage:  Stage A – lymphocytosis without anemia or thrombocytopenia and < 3 areas of lymphoid involvement (lymph nodes, spleen, liver) – GOOD PROGNOSIS  Stage B – same as A, but > 3 areas of lymphoid involvement – INTERMEDIATE PROGNOSIS  Stage C – lymphocytosis with anemia, thrombocytopenia, or both – POOR PROGNOSIS
  40. 40. SUMMARY  Chronic leukemias  Types  Chronic myeloid leukemia  Philadelphia chromosome  Chronic lymphocytic leukemia  Lab diagnosis

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chronic leukemia, CML, CLL.

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