2 CLL - incidence The most common type of leukemia. 30% of all adult leukemias are CLL.Median age at diagnosis:62- 63Med age is increasing (>70 in USA)Male /female ratio = 2/1
3 CLL - etiology Not fully understood. There are some familial cases. 5-10% of cases have a family historyThe 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.)
4 CLL- pathogenesis A “B-cell” clone is involved. Antigen experienced “B” cellsCLL 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.
5 MBL MBL diagnostic criteria: Low amount of clonal “B” cell population With an age related frequencyA CLL phenotype “B” cell population is seen in 3% of adult populationMBL diagnostic criteria:“B” cell population < 5000/mm3> 3 months durationAsymptomatic and not related to another reason
6 MBL LPD CLL/SLL Regression Other PersistentMBL Secondary Hit ? Risk Factors geneticEnvironmentalLPDCLL/SLLMBLRegressionOtherPersistentMBLSecondary Hit ?Microenvironmental reasons Antigenic stimulation
7 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-receptorsSigns of monoclonality:sIg heavy chain is mostly μ or μ+δlight chain is κ or λSpecial diagnostic charactersCD 5 + , mouse red cell receptor +
9 CLL- Clinical presentation Symptoms (2)Easy bruising - bleedingAugmented skin reactionsConstitutional symptoms indicate disease progression or transformation or infectionsSymptoms due to:AIHA , organ involvement, secondary malignancy
10 CLL- Clinical presentation Findings(1)At the time of diagnosis; %LymphadenomegalySplenomegalyHepatomegalyInfectionSternal tendernessBleeding
11 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.
12 Richter’s syndrome:Transformation to “large cell lymphoma”.10-15% frequency.Fever , progressive LAP’s and occurrence or increase in constitutional symptoms.
13 Diagnostic Criteria 1- B cell lymphocytosis ( > 5.000 / mm3 ), NCI supported CLL Working Group1- B cell lymphocytosis ( > / mm3 ),And atypical cell ratio < 55 %2-Typical immunophenotypic properties of CLL: CD5 + , Monoclonal “B”cells3-If a bone marrow biopsy is made there must be > 30 % lymphocyte infiltration(BM biopsy doesn’t have to be performed for diagnosis)
14 B cell Lymphocytosis : > 5000/mm3 CLL Lab -1( at the time of diagnosis)B cell Lymphocytosis : > 5000/mm3All casesAnemia :% of the cases have Hb < 11g/dlNormochrome-normocyticTrombocytopenia :10% of the cases have a Plt count < / mm3
18 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)
19 LAB -4Radiologic studiesFindings related to organ dysfunctionCytogenetics
22 A No anemia or thrombocytopenia 14 STAGING ( Binet/International )Stage Definition Survival(years)A No anemia or thrombocytopenia< 3 areas involved/enlargedB No anemia or thrombocytopenia≥ 3 areas involved/enlargedC Hb < 10 g/dl and/or ,5Plt < /mm3
23 Prognostic parameters(Other than stage) poorgoodBone marrow involvement typediffuse mixed interstitial nodularchromosome changesdel 17p del 11q trisomy normal del 13 qOlder Age and male genderRapid lymphocyte doubling (<12 mo)Presence of atypical cellsHigh LDH or beta-2 microglobulin levelsIgVh mutation statusNon mutant mutantCD38 expression levelHigh lowZAP 70 expressionP53 mutation
24 Poor Prognostic Factors IgVh status:Non mutantCD38 expression:HighZAP 70 expression:HighP53 mutation +chromosome changesdel 17pdel 11qtrisomy 12Advanced stageOlder age and male genderRapid lymphocyte doubling (<12 mo)Presence of atypical cellsHigh LDH or beta-2 MCGBone marrow involvement type: diffuse
25 Some immunologic changes in CLL: Hypogamaglobulinemia: commonHypergamaglobulinemia : infrequent ( % 5 )Autoimmune cytopenias :Autoimmune hemolytic anemia : %Autoimmune thrombocytopenia : less commonAutoimmune granulocytopenia : occasionalDefects in the complement systemT - cell subgroup disproportionsGranulocytopenia
26 Complications Infections Autoimmune cytopenias Pure red cell aplasia Secondary malignancyTransformations
27 Special situations: CLL/PL: Ratio of prolymphocytes; : 10- 55 % Prolymphocytic leukemiaRatio of prolymphocytes are > 55 % in prolymphocytic leukemiaRichter’s syndrome:Transformation to;High grade NHLHodgkin’s disease (rare)
29 CLL- Treatment-2 Specific treatment-1: C = Cyclophosphamide Alkyllator based treatmentsSingle agent alkyllator: Chlorambucil (Chl) , Cyclophosphamide( C )Multiagent chemotherapy: COP , Chl + P , CHOPC = CyclophosphamideO = VincristinP = PrednisoloneH = Adriamycine
30 Alkyllator based treatments Alkyllator based treatments induce only a low percent of response.Different treatment modalities of alkyllators do not result in different survival .Single agent alkyllator treatment is chosed for old / low performance status patients for palliation treatment.
31 CLL- Treatment-3 Specific treatment-2: Purin analogs : Fludarabine (70 % response, 30% CR )Cladribine ( > 50 % response, %CR)PentostatinMonoclonal antibodiesanti-CD52,anti-CD20Best response rate and response duration with combinations of Fludarabine1-Fludarabine + Cyclophosphamide2-Fludarabine + Cyclophosphamide+ Rituximab (anti-CD20)note: anti CD-20 is not approved in TURKEY for CLL first line treatmentStem cell transplantation(young cases with high risk features)Other : Splenectomy , radiotherapyInvestigational (gene therapy ,biologic agents etc )
32 CLL- treatment Supportive treatment: AIHA: Corticosteroids Infection treatment and prophylaxisIv Ig:frequent infection+low IgGTransfusion when indicated