1. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

2. 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

3. 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.)

4. 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.

5. 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

6. 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

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-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 +

8. CLL- Clinical presentation
Symptoms (1)
Asymptomatic : %
Lymphadenomegaly
Splenomegaly & - or hepatomegaly
Fatique,fever,weight loss
Infections

9. 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

10. CLL- Clinical presentation
Findings(1)
At the time of diagnosis; %
Lymphadenomegaly
Splenomegaly
Hepatomegaly
Infection
Sternal tenderness
Bleeding

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 Group
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)

14. B cell Lymphocytosis : > 5000/mm3
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

15. Smudge cell

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

17. LAB -2 Autoimmune hemolytic anemia ; Haptoglobin decreases,
LDH , indirect bilirubin, reticulocyte , urobilinojen increases and
Coombs test becomes +.
2. Hypogamaglobulinemia (common) or
monoclonal paraproteinemia (rare)

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 -4
Radiologic studies
Findings related to organ dysfunction
Cytogenetics

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

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

22. A No anemia or thrombocytopenia 14
STAGING ( Binet/International )
Stage Definition Survival(years)
A No anemia or thrombocytopenia
< 3 areas involved/enlarged
B No anemia or thrombocytopenia
≥ 3 areas involved/enlarged
C Hb < 10 g/dl and/or ,5
Plt < /mm3

23. Prognostic parameters(Other than stage)
poor
good
Bone marrow involvement type
diffuse mixed interstitial nodular
chromosome changes
del 17p del 11q trisomy 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

24. 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

25. 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

26. Complications Infections Autoimmune cytopenias Pure red cell aplasia
Secondary malignancy
Transformations

27. 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)

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

29. 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

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)
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 )

32. CLL- treatment Supportive treatment: AIHA: Corticosteroids
Infection treatment and prophylaxis
Iv Ig:frequent infection+low IgG
Transfusion when indicated

33. 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

34. Prolymphocytic Leukemia
Advanced age (50% >70 y)
High WBC counts (> /mm3 )
Prominent splenomegaly
Rapid course / resistant to treatment
Treatment:
Purin analogs
MoAb (anti-CD52/anti-CD20)
Multi-agent chemotherapy