Chronic lymphocytic leukemia


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Chronic lymphocytic leukemia

  2. 2. DEFFINITION AND EPIDEMIOLOGY <ul><li>- Chronic Lymphocytic Leukemia (CLL) is a low-grade Non-Hodgkin lymphoma . It is main characteristic is proliferation of malignant clone of mature- appearing Ly in the bone marrow with leukemic component- absolute lymphocytosis in the peripheral blood. In 90% it is B-CLL </li></ul><ul><li>- B-cell chronic lymphocytic leukemia(CLL) -the most common lymphoproliferative disorder in Western countries- incidence- 5/100,000-for males and 2,5/100,000 for females </li></ul><ul><li>- Disease of older adults – median age-65-68 years </li></ul>
  3. 3. Clinical features <ul><li>- has a long course, could be asymptomatic, often is diagnosed accidentally , on a routine blood count </li></ul><ul><li>In symptomatic patients- widespread lymphadenopathy, splenomegaly-the lymph nodes are nontender, non matted or fixed to surrounding tissue. Even bulky lymph node enlargement does not usually result in compressive symptoms </li></ul><ul><li>Rarely- malaise, easy fatigability, weight loss, night sweats- these symptoms usually correlate with the overall tumor load </li></ul>
  4. 4. CLINICAL FEATURES <ul><li>Anemia, thrombocytopenia, neutropenia- due to disease progression within the bone marrow; autoimmune complication; hypersplenism or treatment side effects </li></ul><ul><li>Symptoms of immune defficiency-hypogammaglobulinemia – pulmonary bacterial infections; T-cell deficiency-more often result of treatment- high risk of viral and opportinistic infections </li></ul><ul><li>Autoimmune manifestations such as autoimmune thrombocytopenia, Coombs positive hemolytic anemia or pure red cell aplasia </li></ul>
  5. 5. LABORATORY STUDIES <ul><li>Increase in the number of mature-appearing lymphocytes in circulation to more than 5000/microL </li></ul><ul><li>In the advance stages – anemia, thrombocytopenia </li></ul><ul><li>In patients with very large tumor burden-elevated serum lactic dehydrogenase (LDH), beta2 –microglobulin and uric acid levels </li></ul><ul><li>In 5%- serum protein electrophoresis detects M-components(paraprotein) </li></ul><ul><li>Often- hyppogammaglobulinemia </li></ul><ul><li>Often- Coombs test is positive </li></ul>
  6. 6. LABORATORY STUDIES <ul><li>Bone marrow generally shows a diffuse infiltration of small, mature-appearing lymphocytes </li></ul><ul><li>Flow cytometric immunophenotyping of the B cells-in typical CLL CD 19 B-cells express CD5, CD20 and CD23 together with abnormally low surface amounts of monotypic s Ig ( usually IgM or IgD) and always only a single Ig light chain , either kappa or lambda </li></ul>
  7. 7. DIAGNOSIS <ul><li>- Absolute lymphocytosis- > 5000/ microL mature-appearing lymphocytes in circulation </li></ul><ul><li>Diffuse infiltration of bone marrow of small , mature –appearing lymphocytes </li></ul><ul><li>Typical immunophenotyping of B-cells-CD19+; CD5+; CD23+; CD20+; low amounts of sIg </li></ul>
  8. 8. CYTOGENETIC ANALYSIS AND FISH <ul><li>The most common chromosomal abnormalities: </li></ul><ul><li>-Del on 11q; 13p; 13q; 17p;17q; del17p has very poor prognostic value- involves loss of p53 gene, which is important in the tumor response to purine nucleoside analogues. </li></ul><ul><li>-trisomy12 </li></ul><ul><li>- balanced and unbalanced translocations </li></ul>
  9. 9. DIFFERENTIAL DIAGNOSIS <ul><li>Other Non-Hodgkin Lymphoma ( NHL) with leukemic component ( circulating lymphoma cells) – immunophenotyping of circulating Ly helps to differentiate CLL from NHLwith leukemization; when adenopathy is the prominent aspect of the clinical presentation , a node biopsy with immunohistochemistry may be required to rule out more aggressive form of lymphoma ; </li></ul><ul><li>Hairy cell leukemia- usually affects men; splenomegaly without adenopathy, pancytopenia, Ly with specific morphology in peripheral blood and bone marrow-Hairy cells with large nucleus and filamentous projections of cytoplasm, with specific phenotype- CD11c+CD103+; CD5,CD23-neg . Bone marrow biopsy with immunohistochemistry is often required for the diagnosis . </li></ul>
  10. 10. DIFFERENTIAL DIAGNOSIS <ul><li>Prolymphocytic leukemia-splenomegaly, bulky adenopathy, very high Leu count; aggressive course; >55% of Ly are proLy-larger than typical small Ly with prominent nucleolus; IFT- CD23-neg ;CD 5+-; FCM7 + and strong expression of sIg </li></ul><ul><li>Mantle cell lymphoma-CD5+, CD23-neg;70%- t(11,14 ) wich results in overexpression of cyclin D1; aggressive course </li></ul><ul><li>Small-cell lymphocytic lymphoma- Ly has the same IFT, in SCLL the adenopathy is prominent and Leu count is not so eleveted , the difference is largely semantic since the treatment is identical. Both disorders should be considered varying manifestation of the same disease. </li></ul>
  11. 11. DIFFERENTIAL DIAGNOSIS <ul><li>Other non-hematologic disease- </li></ul><ul><li>viral infections with reactive lymphocytosis- </li></ul><ul><li>- infectious mononucleosis- affects younger patients- < 35 years; sore throat, fever, lymphadenopathy, hepatosplenomegaly, hepatitis, absolute lymphocytosis with polimorphism of Ly, usually without anemia and thrombocytopenia; the diagnosis is confirmed serologically </li></ul><ul><li>- CMV </li></ul>
  12. 12. Staging <ul><li>. Rai staging system: </li></ul><ul><li>Stage 0- lymphocytosis whithout clinical symptoms </li></ul><ul><li>Stage 1- lymphocytosis with lymphadenopathy </li></ul><ul><li>Stage 2 – lymphocytosis with splenomegaly </li></ul><ul><li>Stage 3- anemia with Hb< 100g/l whatever the oter signs </li></ul><ul><li>Stage 4- thrombocytopenia< 100 000/ microL whatever the other signs </li></ul>
  13. 13. Staging <ul><li>Binet staging system: </li></ul><ul><li>A- with Hb> 100g/L , Plt> 100, 000/ microL and limited lymphadenopathy and/or splenomegaly </li></ul><ul><li>B - Hb>100g/L, Plt>100, 000/microL, extensive lymphadenopathy and splenomegaly </li></ul><ul><li>C- Hb< 100g/l or Plt< 100,000/ microL </li></ul>
  14. 14. TREATMENT AND PROGNOSIS <ul><li>Prognostic factors : </li></ul><ul><li>-advanced stage- stage 3-4 according to Rai or 3 according to Binet </li></ul><ul><li>-lymphocyte doubling time < 6 months </li></ul><ul><li>-cytogenetic abnormalities , esp. del 17 </li></ul><ul><li>-expression of CD38 and ZAP-70 </li></ul><ul><li>- elevated LDH and beta 2 -microglobulin </li></ul>
  15. 15. Treatment and Prognosis <ul><li>The treatment of CLL with chemotherapy with or without transplantation is never curative.When patients are asymptotic, without large tumor burden and unfavorable prognostic factors it is better option to delay treatment till progression of the disease happens. </li></ul><ul><li>1. Chlorambucil – oral alkylating agent- response is obtained in 60-70% but is usually partial and last less 20 months. </li></ul><ul><li>2. Fludarabine- purine analog . The overall response rate is 75% with a mean duration 25 months. It could be administated alone( complete response-20%) or in combination with Cyclophosphamide ( complete response- 40%) </li></ul>
  16. 16. Treatment and Prognosis <ul><li>3.Alemtuzumab- recombinant CD 52 –antibody which is shared by CLL-B cells and normal T cells. It is the first-line option for CLL with del 17. Side effects- “ first dose effect”- rigors, fever, hypotension and respiratory distress; severe immunosupression, reactivation of CMV </li></ul><ul><li>4. Combination Fludarabine with Cyclophosphamide, Mitoxantrone and/or Rituximab- results in higher response rate including complete ( 60%) and sometimes molecular remissions and longer event-free survival. Side effects and toxity are more severe </li></ul>
  17. 17. Treatment and prognosis <ul><li>5. Intensive therapy-in younger patient with adverse prognostic factors- intensification with autologous stem cell rescue. However this procedure is not curative. Allogenic stem cell transplantation could be potentially curative, but its application is limited because of patient’s age and tolerance. It is currantly considered the therapy of choice for younger patients with refractory disease esp. 17p mutation </li></ul>
  18. 18. Complications <ul><li>1. Autoimmune disease: </li></ul><ul><li>- Hemolytic anemia and thrombocytopenia. The treatment include corticosteroids. </li></ul><ul><li>- Pure red cell aplasia- usually responds to cyclosporin </li></ul><ul><li>2.Severe infections-viral or bacterial due to severe hypogammaglobulinemia and suppressed T-Ly function ( therapy-related)- antibiotics, antiviral agents, sometimes administration of i.v.gamma globulin </li></ul><ul><li>3.Richter syndrome- transformation to diffuse large cell lymphoma or prolymphocytic leukemia- it is suspectet when the disease’s coure changes abruptly. </li></ul>