1. Chronic Lymphocytic Leukemia (CLL) DEFINITION CLL is a neoplastic disease characterized by proliferation and accumulation (blood, marrow and lymphoid organs) of morphologically mature but immunologically dysfunctional lymphocytes

2. CLL - characteristic Disease of elderly (50-60 years)
2:1 ratio of male to female
Most common adult leukemia in Europe and USA (USA: 3/ population)
In 98% of cases leukemic cells are monoclonal population of immature B lymphocytes with low-density surface immunoglobulin
Etiology unknown

3. CLL – clinical features
Most of patients: fatigue, reduced exercises tolerance, weight loss, fever, recurrent infections, sweats, bleeding
25% of patients: asymptomatic
80% of patients : nontender lymphadenopaty
50% of patients: splenomegaly
Hepatomegaly

4. CLL - diagnostic features
a) Blood test lymphocytosis ≥ 5G/l (4 weeks)
b) Morphology monoconal population of small mature lymphocyte
c) B-cell CLL phenotype clonal CD5+/CD19+ population
of lymphocyte
d) Markers of clonality κ/λ light chain restriction; cytogenetical abnormalities
e) Bone marrow infiltrate > 30% of nuceated cells on aspirate
f) Lymph node diffuse infiltrate of small lymphocye

5. CLL – diagnosis (2) Blood test
anaemia
trombocytopenia
smudge cells in peripheral blood film
Lymh node histology: diffuse infiltrate of small lymphocyte
Bone marrow histology
interstitial infiltration (30% - good prognosis)
diffuse involvement (25% - poor prognosis)
nodular involvement
Hypogammaglobulinemia
Cytogenetic abnormalities (FISH – 90%)
13q-; 11q-; +12q; 17p-; 6q-
Molecular abnormalities
p53; bcl2

6. CLL – clinical staging (1)
RAI CLINICAL STAGING SYSTEM
Stage Clinical Features at Diagnosis Median Survival (m)
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Low risk
Blood (> 5.000/ul. monoclonal lymphocytes) >150
and marrow (>30%) lymphocytosis
Intermediate risk
I Lymphocytosis and enlarged lymph nodes > 101
II Lymphocytosis and enlarged spleen and/or liver > 71
High risk
III Lymphocytosis and anemia (Hgb < 11g/dL) > 19
IV Lymphocytosis and thrombocytopenia (Plt < /ul.) > 19

7. CLL – Rai stages

8. CLL – clinical staging (2)
BINET CLINICAL STAGING SYSTEM
Stage Clinical Features at Diagnosis Median Survival (m)
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A Blood (> 5.000/ul. monoclonal lymphocytes) > 84
and marrow (>30%) lymphocytosis and less
than 3 areas of palpable lymphoid-tissue enlargement
B Lymphocytosis and 3 and more areas of palpable < 60
lymphoid-tissue enlargement
C Lymphocytosis with anemia (Hgb <11g/dL; < 24
women <10g/dL)
or thrombocytopenia (Plt < /uL)
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An area: cervical, axillary, inguinal/femoral, spleen, liver

9. CLL – Binet stages

10. CLL – prognostic factors
clinical stage
marrow histology (diffuse marrow involvement - poor prognosis)
leukemia cell doubling time
CD38 expression
IgVH mutational status
ZAP-70 expression
FISH cytogenetic
low-risk: normal kariotype; isolated del(13q)
high-risk: del(17p0, del(11q), trisomy 12
serum markers: 2-microglobulin; thymidine- kinase, sCD23

11. CLL : ZAP-70

12. CLL – treatment (1) Watch and wait Monotherapy
glucocorticoids
alkylating agents (Chlorambucil, Cyclophosphamide)
purine analogues (Fludarabine, Cladribine, Pentostatin)
Combination chemotherapy
Chlorambucil/ Cyclophosphamide + Prednisone
Fludarabine + Cyclophosphamide +/- Mitoxantrone
CVP, CHOP
Monoclonal antibodies (monotherapy and in combination)
Alemtuzumab (anti-CD52)
Rituximab (anti-CD20)
Splenectomy
Radiotherapy

13. CLL – treatment (2) Hematopoietic stem cell transplantation
allogeneic with reduced intesity conditioning
autologous
New and novel agents
Oblimersen – bcl2-directed antisense oligonucleotide
Lenalidomide
Flavopiridol
Anti-CD23
Anti-CD40
Vaccine strategies
Supportive therapy (allopurinol, G-CSF, blood and platelet transfusion, immunoglobulins, antibiotics)