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