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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– 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/mm32. > 3 months duration3. Asymptomatic and not related to
another reason
Risk Factors genetic
Environmental
MBL
Regression
PersistentMBL
LPD
CLL/SLL
Other
Secondary Hit ?Microenvironmental reasons Antigenic stimulation
Immunophenotypic properties of CLL
lymphocytesB -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+δ • light chain is κ or λSpecial 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 presentationFindings(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 ),
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 :
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 infiltrationAutoimmune hemolysisSplenomegalyMyelosupressive drugsPure red cell aplasiaOther: bleeding/chronic
disease/nutritional
LAB -2
1. Autoimmune hemolytic anemia ;Haptoglobin decreases,LDH , indirect bilirubin, reticulocyte ,
urobilinojen increases andCoombs 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 )
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 2,5Plt < 100.000/mm3
Prognostic parameters(Other than stage)
• Bone marrow involvement typediffuse- 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 statusNon mutant mutant• CD38 expression levelHigh low
• ZAP 70 expression• High low
• 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 : % 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- TreatmentIndications :• 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-2Specific treatment-1:Alkyllator based treatments • Single agent alkyllator: Chlorambucil (Chl) ,
Cyclophosphamide( C )
• Multiagent chemotherapy: COP , Chl + P , CHOP
C = CyclophosphamideO = VincristinP = PrednisoloneH = 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-3Specific 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