CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

CLL - incidence The most common type of leukemia. 30% of all adult leukemias are CLL. Median age at diagnosis:62- 63 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 MBL diagnostic criteria: 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: “B” cell population < 5000/mm3 > 3 months duration Asymptomatic and not related to another reason

MBL LPD CLL/SLL Regression Other PersistentMBL Secondary Hit ? Risk Factors genetic Environmental LPD CLL/SLL MBL Regression Other PersistentMBL 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 : % 10- 40 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 50 - 75 Hepatomegaly 25 - 75 Infection 30 Sternal tenderness 10 - 15 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”. 10-15% frequency. Fever , progressive LAP’s and occurrence or increase in constitutional symptoms.

Diagnostic Criteria 1- B cell lymphocytosis ( > 5.000 / mm3 ), NCI supported CLL Working Group 1- B cell lymphocytosis ( > 5.000 / 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)

B cell Lymphocytosis : > 5000/mm3 CLL Lab -1 ( at the time of diagnosis) B cell Lymphocytosis : > 5000/mm3 All cases Anemia : 15 - 20% of the cases have Hb < 11g/dl Normochrome-normocytic Trombocytopenia : 10% of the cases have a Plt count < 100.000/ mm3

Smudge cell

Causes of anemia in CLL: Bone marrow infiltration Autoimmune hemolysis Splenomegaly Myelosupressive drugs Pure red cell aplasia Other: bleeding/chronic disease/nutritional

LAB -2 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

Differential diagnosis Infections ( Inf. Mononucleosis , Inf lymphocytosis, toksoplasmosis etc ) Prolymphocytic leukemia Hairy cell leukemia Lymphomas Sezary syndrome Macroglobulinemia Monoclonal “B” lymphocytosis ALL

STAGING ( Rai ) Stage Definition Survival months 0 Diagnostic lymphocytosis > 120 I + lymphadenomegaly 95 II Splenomegaly +/- LAP 72 III Anemia ( Hb < 11 g /dl ) 30 IV Trombocytopenia +/- anemia 30 ( < 100.000 / mm3 )

A No anemia or thrombocytopenia 14 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 < 100.000/mm3

Prognostic parameters(Other than stage) poor good 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 mutant mutant CD38 expression level High low ZAP 70 expression P53 mutation

Poor Prognostic Factors IgVh status:Non mutant CD38 expression:High ZAP 70 expression:High P53 mutation + chromosome changes del 17p del 11q trisomy 12 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

Some immunologic changes in CLL: Hypogamaglobulinemia: common Hypergamaglobulinemia : infrequent ( % 5 ) Autoimmune cytopenias : Autoimmune hemolytic anemia : % 10 -35 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; : 10- 55 % Prolymphocytic leukemia Ratio of prolymphocytes are > 55 % in prolymphocytic leukemia Richter’s syndrome: Transformation to; High grade NHL Hodgkin’s disease (rare)

CLL- Treatment Indications : Anemia (Hb < 11 g/dL) Thrombocytopenia (<100.000/mm3) Symptomatic, massive LAPs, massive organomegaly Transformation Rapidly progressive disease Immune cytopenia not responding to corticosteroids

CLL- Treatment-2 Specific treatment-1: C = Cyclophosphamide 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 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.

CLL- Treatment-3 Specific treatment-2: Purin analogs : Fludarabine (70 % response, 30% CR ) Cladribine ( > 50 % response, 10 -15 %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 (>100.000/mm3 ) Prominent splenomegaly Rapid course / resistant to treatment Treatment: Purin analogs MoAb (anti-CD52/anti-CD20) Multi-agent chemotherapy