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Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia. Definition. Clonal B cell malignancy. Progressive accumulation of long lived mature lymphocytes. Increase in anti-apoptotic protein bcl-2. Intermediate stage between pre-B and mature B-cell. . Epidemiology. Most common leukemia of Western world.

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Chronic Lymphocytic Leukemia

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  1. Chronic Lymphocytic Leukemia

  2. Definition • Clonal B cell malignancy. • Progressive accumulation of long lived mature lymphocytes. • Increase in anti-apoptotic protein bcl-2. • Intermediate stage between pre-B and mature B-cell.

  3. Epidemiology • Most common leukemia of Western world. • Less frequent in Asia and Latin America. • Male to female ratio is 2:1. • Median age at diagnosis is 65-70 years. • In US population incidence is similar in different races. Cancer statastics 2000; CA J Clin 2000; 50:7-33

  4. Etiology & Risk factors • High familial risk with two-fold to seven-fold higher risk. • No documented association with environmental factors. • No established viral etiology.

  5. Diagnostic Criteria • Defined by NCI & IWCLL. • Persistent lymphocytosis. • Absolute count more than 5000. • Mature appearing B-cells with <10% of prolymhocytes Blood 1996; 87: 4990

  6. Flow Cytometry • CD 19 and/or CD 20 are always co expressed with CD 5. • Weak expression of surface immunoglobulins (sIgM & sIgD). • CD 21, CD 23, CD 24 may be expressed.

  7. Bone Marrow • Not required for diagnosis. • Recommended to estimate the extent for prognostic implications. • Diffuse infiltration has poor prognosis.

  8. Cytogenetics • Deletions in chromosome 13 at q 14 • Chromosome 11 at q22 or q23. • Trisomy-12. • Less common are deletions in chromosome 17 & 6. J Mol Med 1999; 77:266

  9. Clinical Features • Disease of elderly with wide spectrum of clinical features. • 20% are asymptomatic. • Classic B symptoms. • Variable physical findings with normal to diffuse LAD , hepato/splenomegaly.

  10. Other Labs • Hypogammaglobulinemia seen >50%. • 5-10% have small monoclonal peak. • Positive Coombs’ test in 30% . • Autoimmune hemolytic anemia & thrombocytopenia in <10%

  11. The Rai Staging System Stage 0 Lymphocytosis only (> 15,000/mm3) Stage 1 Lymphocytosis and lymphadenopathy Stage 2 Lymphocytosis and splenomegaly with or without lymphadenopathy Stage 3 Lymphocytosis and anemia (Hgb <11 g/dL) with or without lymphadenopathy or hepatosplenomegaly Stage 4 Lymphocytosis and thrombocytopenia (Plt < 100,000/UL) with or without anemia, lymphadenopathy or hepatosplenomegaly

  12. Modified Rai Staging g. • Low-risk: stage 0, MS > 13 years. • Intermediate-risk: stage I & II with MS about 8 years. • High-risk: stages III & IV with MS about 3 years

  13. The Binet Staging System Stage A No anemia, no thrombocytopenia, <3 involved nodal areas Stage B No anemia, no thrombocytopenia, >=3 involved nodal areas Stage C Anemia (Hgb < 10 g/dL) and/or thrombocytopenia (Plt < 100,000/uL)

  14. Other Prognostic Features • Bone marrow pattern of lymphoid infiltration. • Lymphocyte doubling time. • Serum beta-2-microglobulin. • Mutational status of Ig V and CD 38 expression have recently been identified. Blood 94: 1848-1854, 1999

  15. Treatment • Nucleoside analogs like Fludarabine is the drug of choice. • More effective in higher CR & longer PFS compared to alkyalating agents. • No survival advantage. • Fludarabine in various combinations with Cytoxan & Rituxan are widely used. Blood 1996; 88 (suppl 1): 141a

  16. Monoclonal antibodies • Campath (anti-CD 52) is recently approved for refractory CLL. • Results in profound lympocytopenia, both B and T cells are destroyed. • Rituxan (anti CD 20) is widely used both as single agent and in combination. Blood 1999; 94 (suppl 1); 705a

  17. Bone marrow transplantation • Allogenic BMT is a viable option in younger patients. • Durable response rates seen in advanced, refractory disease. • Autologous BMT using purged marrow have been investigated in elderly. J Clin Oncol 16:2817-2724

  18. Transformation • Large- cell lymphoma/ Richter’s • Aggressive presentation • Extranodal involment • Sharp rise in LDH • CHOP is standard treatment. • Prolymphoctic leukemia. • > 55% increase in prolymphocytes • Progression of splenomegaly & cytopenias • Refractoriness to treatment.

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