Chronic Lymphocytic Chronic Lymphocytic Leukemia (CLL)Leukemia (CLL)

DEFINITIONDEFINITIONCLL is a neoplastic disease CLL is a neoplastic disease characterized by proliferation characterized by proliferation andand accumulation accumulation ((blood, marrow and lymphoid blood, marrow and lymphoid organsorgans)) of of morphologically mature but immunologically dysfunctional morphologically mature but immunologically dysfunctional llymphocytesymphocytes

CLL - characteristicCLL - 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 featuresCLL – 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 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)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)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 stagesCLL – Rai stages

CLL – clinical staging (2)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 stagesCLL – Binet stages

CLL – prognostic factorsCLL – 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-70CLL : ZAP-70

CLL – treatment (1)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)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)