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
CLL - characteristic
• Disease of elderly (50-60 years)
• 2:1 ratio of male to female
• Most common adult leukemia in Europe and USA (USA:
3/100.000 population)
• In 98% of cases leukemic cells are monoclonal
population of immature B lymphocytes with low-density
surface immunoglobulin
• Etiology unknown
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
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
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
CLL – clinical staging (1)
RAI CLINICAL STAGING SYSTEM
• Stage
Clinical Features at Diagnosis
Median Survival (m)
________________________________________________________________________
• Low risk
• 0
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 < 100.000/ul.)
> 19
CLL – Rai stages
CLL – clinical staging (2)
BINET CLINICAL STAGING SYSTEM
• Stage
Clinical Features at Diagnosis
Median Survival (m)
____________________________________________________________________
• 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 <100.000/uL)
• ___________________________________________________________________
An area: cervical, axillary, inguinal/femoral, spleen, liver
CLL – Binet stages
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
CLL : ZAP-70
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
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)