Presentation on theme: "CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). CLL - incidence The most common type of leukemia. 30% of all adult leukemias are CLL. Median age at diagnosis:62-"— Presentation transcript:
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
CLL - incidence The most common type of leukemia. 30% of all adult leukemias are CLL. Median age at diagnosis: –Med age is increasing (>70 in USA) Male /female ratio = 2/1
CLL - etiology Not fully understood. There are some familial cases. –5-10% of cases have a family history –The risk is 2-7 times higher in the first degree relatives of a CLL case (Capalbo S, Trerotoli P, Ciancio A, et al. Eur J Haematol 2000; 65(2):114–117.)
CLL- pathogenesis A “B-cell” clone is involved. –Antigen experienced “B” cells CLL lymphocytes have a long life span (failure of apoptosis). These are mature appearing cells which accumulate in blood, lymph nodes, bone marrow, spleen and liver.
MBL –Low amount of clonal “B” cell population –With an age related frequency –A CLL phenotype “B” cell population is seen in 3% of adult population MBL diagnostic criteria: 1.“B” cell population < 5000/mm3 2.> 3 months duration 3.Asymptomatic and not related to another reason
Risk Factors genetic Environmental MBL Regression Persistent MBL LPD CLL/SLL Other Secondary Hit ? Microenvironmental reasons Antigenic stimulation
Immunophenotypic properties of CLL lymphocytes B -cell characteristics: Presence of surface Ig (sIg)( pale ) CD 19, CD 20, CD21, CD23, CD 24 + HLA-DR antigen + Fc and C-receptors Signs of monoclonality: sIg heavy chain is mostly μ or μ+δ light chain is κ or λ Special diagnostic characters CD 5 +, mouse red cell receptor +
CLL- Clinical presentation Symptoms (1) Asymptomatic : % Lymphadenomegaly Splenomegaly & - or hepatomegaly Fatique,fever,weight loss Infections
CLL- Clinical presentation Symptoms (2) Easy bruising - bleeding Augmented skin reactions Constitutional symptoms indicate disease progression or transformation or infections Symptoms due to:AIHA, organ involvement, secondary malignancy
CLL- Clinical presentation Findings(1) At the time of diagnosis; % Lymphadenomegaly 80 Splenomegaly Hepatomegaly Infection 30 Sternal tenderness Bleeding 8
CLL- Clinical presentation Findings(2) Lymphatic obstruction and lymphedema or stasis, hemolysis or cholestasis may cause icterus, Signs due to secondary malignancy, Signs related to diseases other than CLL.
Richter’s syndrome: Transformation to “large cell lymphoma” % frequency. Fever, progressive LAP’s and occurrence or increase in constitutional symptoms.
Diagnostic Criteria 1- B cell lymphocytosis ( > / mm3 ), And atypical cell ratio < 55 % 2-Typical immunophenotypic properties of CLL: CD5 +, Monoclonal “B”cells 3-If a bone marrow biopsy is made there must be > 30 % lymphocyte infiltration (BM biopsy doesn’t have to be performed for diagnosis) NCI supported CLL Working Group
CLL Lab -1 ( at the time of diagnosis) B cell Lymphocytosis : > 5000/mm3 All cases Anemia : % of the cases have Hb < 11g/dl Normochrome-normocytic Trombocytopenia : 10% of the cases have a Plt count < / mm3
Causes of anemia in CLL: Bone marrow infiltration Autoimmune hemolysis Splenomegaly Myelosupressive drugs Pure red cell aplasia Other: bleeding/chronic disease/nutritional
LAB -2 1.Autoimmune hemolytic anemia ; Haptoglobin decreases, LDH, indirect bilirubin, reticulocyte, urobilinojen increases and Coombs test becomes +. 2.Hypogamaglobulinemia (common) or monoclonal paraproteinemia (rare)
LAB -3 Bone marrow: > 30 % infiltration by lymphocytes Immunophenotypic findings: CD5 +, CD19+ (or some other B cell antigens) pale sIg + with kappa or lambda type light chain (restricted) Lymph node biopsy: Similar to small lymphocytic lymphoma (not necessary for diagnosis)
LAB -4 –Radiologic studies –Findings related to organ dysfunction –Cytogenetics
STAGING ( Binet/International ) Stage Definition Survival(years ) A No anemia or thrombocytopenia 14 < 3 areas involved/enlarged B No anemia or thrombocytopenia 5 ≥ 3 areas involved/enlarged C Hb < 10 g/dl and/or 2,5 Plt < /mm 3
Prognostic parameters (Other than stage) Bone marrow involvement type diffuse- mixed- interstitial- nodular chromosome changes del 17p del 11q trisomy 12 normal del 13 q Older Age and male gender Rapid lymphocyte doubling (<12 mo) Presence of atypical cells High LDH or beta-2 microglobulin levels IgVh mutation status Non mutantmutant CD38 expression level Highlow ZAP 70 expression Highlow P53 mutation goodpoor
Poor Prognostic Factors Advanced stage Older age and male gender Rapid lymphocyte doubling (<12 mo) Presence of atypical cells High LDH or beta-2 MCG Bone marrow involvement type: diffuse IgVh status:Non mutant CD38 expression:High ZAP 70 expression:High P53 mutation + chromosome changes del 17p del 11q trisomy 12
Some immunologic changes in CLL: Hypogamaglobulinemia: common Hypergamaglobulinemia : infrequent ( % 5 ) Autoimmune cytopenias : Autoimmune hemolytic anemia : % Autoimmune thrombocytopenia : less common Autoimmune granulocytopenia : occasional Defects in the complement system T - cell subgroup disproportions Granulocytopenia
Complications Infections Autoimmune cytopenias Pure red cell aplasia Secondary malignancy Transformations
Special situations: CLL/PL: Ratio of prolymphocytes; : % Prolymphocytic leukemia Ratio of prolymphocytes are > 55 % in prolymphocytic leukemia Richter’s syndrome: Transformation to; –High grade NHL –Hodgkin’s disease (rare)
CLL- Treatment-2 Specific treatment-1: Alkyllator based treatments Single agent alkyllator: Chlorambucil (Chl), Cyclophosphamide( C ) Multiagent chemotherapy: COP, Chl + P, CHOP C = Cyclophosphamide O = Vincristin P = Prednisolone H = Adriamycine
Alkyllator based treatments 1.Alkyllator based treatments induce only a low percent of response. 2.Different treatment modalities of alkyllators do not result in different survival. 3.Single agent alkyllator treatment is chosed for old / low performance status patients for palliation treatment.
CLL- Treatment-3 Specific treatment-2: Purin analogs : Fludarabine (70 % response, 30% CR ) Cladribine ( > 50 % response, %CR) Pentostatin Monoclonal antibodies anti-CD52,anti-CD20 Best response rate and response duration with combinations of Fludarabine 1-Fludarabine + Cyclophosphamide 2-Fludarabine + Cyclophosphamide+ Rituximab (anti-CD20) note: anti CD-20 is not approved in TURKEY for CLL first line treatment Stem cell transplantation (young cases with high risk features) Other : Splenectomy, radiotherapy Investigational (gene therapy,biologic agents etc )
CLL- treatment Supportive treatment: AIHA: Corticosteroids Infection treatment and prophylaxis Iv Ig:frequent infection+low IgG Transfusion when indicated
Hairy cell leukemia Median age: 55 Pancytopenia : % 50 Splenomegaly > LAP Myelofibrosis Opport.infections Otoimmune changes CD 25,CD11c, CD103+, CD 5 – TRAP + Treatment Purin analogs (>% 70 CR) 2CDA Pentostatin Splenectomy IFN
Prolymphocytic Leukemia Advanced age (50% >70 y) High WBC counts (> /mm 3 ) Prominent splenomegaly Rapid course / resistant to treatment Treatment: Purin analogs MoAb (anti-CD52/anti-CD20) Multi-agent chemotherapy