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• The group of clonal diseases characterized by proliferation and accumulation of small, mature lymphocytes in blood, bone marrow and lymphoid tissues (lymph nodes, spleen)
• Neoplastic lymphocytes belong most often to B-cell lines and they have the special for B-cell antigenes on their surface; exceptionally neoplastic lymphocytes belong to T-cell lines or NK-cell
• According to REAL (Revised European-American Lymphoma)/ /WHO classification CLLs belong to the group of: – lymphoproliferative diseases– lymphomas
The Chronic Lymphocytic Leukemias (1)
Lymphoproliferative diseases
• Primary lymphatic system (central)– bone marrow– thymus
• Secondary lymphatic system (peripheral ) – spleen– lymph nodes– MALT (The mucosa-
associated lymphoid tissue = also called mucosa-associated lymphatic tissue)
I II III IV
Clinical stages of lymphomas according to Ann Arbor’s classification
A: no general symptomsB: general symptoms such as fever, night sweats, weight loss
Lister T, et al. J Clin Oncol 1989; 7:1630
• Ann Arbor’s classification is specific for all lymphomas
• CLL is classified according to
Rai and Binet classification
B-Cell neoplasms- Precursor B-cell neoplasm:
B-lymphoblastic leukemia/lymphoma- Mature (peripheral) B-cell neoplasms:
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemiaLympfioplasmacytic lymphomaSplenic marginal zone B-cell lymphoma
(+ /- villous lymphocytes)Hairy cell leukemiaPlasma cell myeloma/plasmacytomaExtranodal marginal zone B-cell
lymphoma of MALT typeNodal marginal zone B-cell lymphoma
(+/— monocytoid B cells)Follicular lymphomaMantle-cell lymphomaDiffuse large B-cell lymphoma
Mediastinal large B-cell lymphoma Primary effusion lymphoma
Burkitts lymphoma/Burkitt cell leukemia
B-Cell neoplasms- Precursor B-cell neoplasm:
B-lymphoblastic leukemia/lymphoma- Mature (peripheral) B-cell neoplasms:
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemiaLympfioplasmacytic lymphomaSplenic marginal zone B-cell lymphoma
(+ /- villous lymphocytes)Hairy cell leukemiaPlasma cell myeloma/plasmacytomaExtranodal marginal zone B-cell
lymphoma of MALT typeNodal marginal zone B-cell lymphoma
(+/— monocytoid B cells)Follicular lymphomaMantle-cell lymphomaDiffuse large B-cell lymphoma
Mediastinal large B-cell lymphoma Primary effusion lymphoma
Burkitts lymphoma/Burkitt cell leukemia
WHO classification
T-cell and NK-cell neoplasms- Precursor T-cell neoplasm: T-lymphoblastic lymphoma/leukemia - Mature (peripheral) T-cell neoplasms:
T-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaAggressive NK-cell leukemiaAdult T-cell lymphoma/leukemia (HTLV1 +)
Extranodal NK/T-cell lymphoma, nasal typeEnteropathy-type T-cell lymphomaHepatosplenic gamma-delta T-cell lymphomaSubcutaneous panniculitis-like T-cell lymphomaMycosis fungoides/Sezary syndromeAnaplastic large-cell lymphoma, T/null cell, primary cutaneous typePeripheral T-cell lymphoma, not otherwise characterizedAngioimmunoblastic T-cell lymphomaAnaplastic large-cell lymphoma, T/null cell, primary systemic type
T-cell and NK-cell neoplasms- Precursor T-cell neoplasm: T-lymphoblastic lymphoma/leukemia - Mature (peripheral) T-cell neoplasms:
T-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaAggressive NK-cell leukemiaAdult T-cell lymphoma/leukemia (HTLV1 +)
Extranodal NK/T-cell lymphoma, nasal typeEnteropathy-type T-cell lymphomaHepatosplenic gamma-delta T-cell lymphomaSubcutaneous panniculitis-like T-cell lymphomaMycosis fungoides/Sezary syndromeAnaplastic large-cell lymphoma, T/null cell, primary cutaneous typePeripheral T-cell lymphoma, not otherwise characterizedAngioimmunoblastic T-cell lymphomaAnaplastic large-cell lymphoma, T/null cell, primary systemic type
• Chronic lymphocytic leukemias are derived from:
• B-cell line– B-cell chronic lymphocytic leukemia – B-cell chronic prolymphocytic leukemia – Hairy cell leukemia – Splenic marginal zone B-cell lymphoma ( + /- villous
lymphocytes)
• T-cell line– T-cell chronic lymphocytic leukemia – T-cell chronic prolymphocytic leukemia – T-cell granular lymphocytic leukemia
• Chronic lymphocytic leukemias differ form each other in biology, morphology, antigen structure of the cell and in clinical course
The Chronic Lymphocytic Leukemia (1)
• B-CLL is a neoplastic disease characterized by proliferation and accumulation of small, mature, long-living lymphocytes in blood, marrow and lymphoid tissues (lymph nodes, spleen)
• This lymphocytosis leads to specific clinical and laboratory symptoms of B-CLL
• The neoplastic lymphocytes have on their surface the special for B-cell line antigens – CD19, CD20 and also CD5, CD23, and a very weak expression of surface immunoglobulin
The B-CLL - definition
• Most common adult leukemia in Europe and North America (in USA incidence of about 3/100.000 population)
• predominantly, CLL is a disease of elderly (50-55 years)
• 40% of leukemias in patients over 60 years old
• Morbidity:
– Men 2,2-3,69 / 100 000 / year
– Women 0,9-1,59 / 100 000 / year
/men affect twice as often as women; 2:1 ratio of male to female /
• CLL morbidity rapidly increases with age (especially between 50 and 60 years of age)
• in 98% of patients the leukemic cells are a monoclonal population of mature B lymphocytes with low-density surface immunoglobulin
• death from infections, BM failure, high-grade transformation (Richter's syndrome), kachexia
B-CLL epidemiology
• the cause of CLL is unknown
• there is increased incidence in farmers, rubber manufacturing workers and tire repair workers
• genetics factors have been postulated to play a role in high incidence of CLL in some families
B-CLL etiology & pathogenesis (1)
• Cytogenetics - clonal chromosomal abnormalities are detected in approximately 50% of CLL patients
• Immunoglobulin genes - monoclonal surface immunoglobulin is expressed by over 90% of patients (60% kappa and 40% lambda light chains)– nearly half of all cases have leukemia cells that express mutated
immunoglobulin variable region genes (Ig VH genes) - associated with more indolent disease
• Immunologic abnormalities– autoimmune disease (hemolytic anemia and thrombocytopenia, pure
red cell aplasia)– hypogammaglobulinemia– cellular immune defects
B-CLL etiology & pathogenesis (2)
• often none! - 25% of patients are asymptomatic and the diagnosis is typically accidental
• unspecific: night sweats, fever, weakness (many patients have fatigue, reduced exercises tolerance or malaise, weight loss)
• recurrent infections (bacterial, viral – Herpes Zoster, fungal) – they are the most common cause of death
• bleeding and symptoms of anemia and thrombocytopenia• Lymphadenopathy (lymph node enlargement)
– at diagnosis - nontender in 80% of patients– later - may become very large
• splenomegaly - mild to moderate in 50% of patients• hepatomegaly• some organs infiltration (lungs, pleura, skin and soft tissue)
Blood lymphocytosis does not cause symptoms!
B-CLL clinical symptoms (1)
• Morphology: – Leucocytosis with monoclonal lymphocytosis of greater than
5.000/ul.– anemia
• Because of „displacement ”• and/or autoimmunohemolic (10-20% of patients have a positive
direct antiglobulin test; AIHA is commonly connected with the presence of warm auto- antibodies IgG class – rapidly increasing fatigue, skin getting yellow, anemia with enlarged reticulocytosis, higher level of bilirubin)
• pure red cell aplasia is very rare (selective aplasia of red cell line in bone marrow)
– thrombocytopenia • Because of „displacement ”• and/or immunologic (about 5% of B-CLL patients have anty-
platelet antibodies)• protein electrophoresis – Hipogammaglobulinemia, monoclonal protein
in 5% of patients
B-CLL laboratory features (1)
B-CLL laboratory features (2)• Peripheral blood smear:
– Lymphocytosis • small, mature, morphologically normal
– Smudge cells– Neutropenia
• Because of „displacement ”• and/or autoimmunologic
B-CLL laboratory features (3)
• Bone Marrow smear (cytological examination) – extensive replacement of marrow element by mature
lymphocytes (more than 30%)
• Bone Marrow Biopsy (histological examination): Lymphocyte infiltration
– nodular infiltration, – interstitial infiltration, – difussed infiltration– mixed infiltration
Difussed infiltration (unfavourable prognostic factor)
B-CLL laboratory features (4)
• lymph node finding (histopathological examination)
- diffuse infiltration of small lymphocytes identical to low-grade,
small lymphocytic lymphoma
B-CLL laboratory features (6)
• Immunophenotype:
– CD5+/CD19+/CD23+/CD20+,
– sometimes also CD38+,
– low expression of CD22;
– lack expression of CD 10-, CD 103-,
– 90% of the patient have a very weak expression of surface
immunoglobulin (kappa or lambda light chain, IgM, IgD)
B-CLL laboratory features (7)
• Radiological examinations (X-ray, ultrasonography, CT, ...)
• Serological examinations (direct and indirect antiglobulin tests)
• Biochemical examinations (lactate dehydrogenase, 2-microglobulin)
B-CLL features (8)
• Cytogenetic examinations - clonal chromosomal abnormalities are
detected in approximately 50% of CLL patients
– deletion 13 (13q14.3)
– trisomy 12
– structural abnormalities of chromosomes 11 (11q-), 14, 17
Genomic aberrations found in approximately 50% of CLL
B-CLL laboratory features (9)
Diagnosis of B-CLL
Blood test lymphocytosis ≥ 5G/l (6 weeks)
Morphology monoclonal population of small mature lymphocyte
B-cell CLL phenotype clonal CD5+/CD19+ population of lymphocyte
Markers of clonality κ/λ light chain restriction; cytogenetical abnormalities
Bone marrow infiltration > 30% of nucleated cells on aspirate
Lymph node diffuse infiltrate of small lymphocytes
RAI’s CLINICAL STAGING SYSTEMStage Clinical Features at Diagnosis Median
Survival (years)
0
Low risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
>12,5
I
Intermediate risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and enlarged lymph nodes
8
II
Intermediate risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and enlarged spleen and/or liver
6
III
High risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and anemia (Hb < 11g/dl)
1,5-2
IV
High risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and thrombocytopenia(< 100 000 /ul)
1,5-2
CLL – Rai stages
BINET’s CLINICAL STAGING SYSTEMStage Clinical Features at Diagnosis Median
Survival
(month)
A Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and less than 3 areas of palpable lymphoid-tissue enlargement
Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and thrombocytopenia
> 120 month
B Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and 3 and more areas of palpable lymphoid-tissue enlargement
Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and thrombocytopenia
60 month
C Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
with anemia (Hgb <10g/dL) or thrombocytopenia (Plt <100.000/uL)
24 month
An area: cervical, axillary left, axillary right, inquinofemoral left, inquinofemoral right lymph nodes, spleen, liver
CLL – Binet’s stages
Prognostic factor Good prognosis Bad prognosis
Clinical stage according to Binet
Rai A
0
B, C
I, II, III, IV
Bone marrow infiltration in
- bone marrow biopsy
- cytological examination
Leucocytosis
Prolymphocytes in peripheral blood
Leukemia cell doubling time
Non-Difussed infiltration
<=80% lymphocytes
<= 50 x 109/l
<= 10%
> 12 months
Difussed infiltration
> 80% lymphocytes
> 50 x 109/l
>10%
<= 12 months
New prognostic indicators in B-CLL (1)
Prognostic factor Good prognosis Bad prognosis
Serum markers:- lactate dehydrogenase activity (LDH)- ß2-mikroglobulin activity- lymphocyte’s thymidine kinase activity - CD23 expression
Normal range Elevated
Clonal chromosomal abnormalities Normal karyotype isolated del (13q)
Del (11q)
Del (17p)
CD 38 expression <= 30 % > 30%
New prognostic indicators in B-CLL (2)
Prognostic factor Good prognosis Bad prognosis
The mutational status of immunoglobulin variable region of heavy chain genes (IgvH)
mutated unmutated
ZAP–70 expression low (< 20%) high ( > 20 %)
Survivin absence presence
New prognostic indicators in B-CLL (3)
• clinical stage• bone marrow histology (diffuse replacement carries worst
prognosis)• leukemia cell doubling time (less than 1 year - worse prognosis)• percentage of prolymphocyte • high cell-surface expression of CD38• ZAP-70 expression• serum level of: B2-microglobulin; thymidine kinaze, LDH, sCD23• IgVH mutational status• genetic features - FISH cytogenetic
– low-risk: normal kariotype; isolated del(13q)– high-risk: del(17p0, del(11q), trisomy 12
New prognostic indicators in B-CLL (4) - summary
CLL : ZAP-70 ZAP70 is an intracellular protein which is strongly correlated with the
VH status in CLL
• We have to remember: – B-CLL – indolent lymphoma, but incurable– Elderly patients – risk of additional diseases– Course of the disease can be very long, indolent for many years,
patient can die because of another reason which is not connected to B-CLL.
• Decision about treatment depends on clinical stage, prognostic factors and patient’s condition
• Indications to treatment:• III/IV stage according to Rai’s classification• Progressive disease (rapidly increasing lymphadenopathy,
infections, general symptoms)• leukemia cell doubling time <6 (12) months• rapidly increasing organomegaly• Secondary anemia, neutropenia, thrombocytopenia because of
bone marrow infiltration• Richter’s syndrome
CLL – treatment (1)
• Watch and wait• Monotherapy
– Glucocorticoids (autoimmunological complications)– alkylating agents (Chlorambucil, Cyclophosphamide)– purine analogues (Fludarabine, Cladribine, Pentostatin)
• Combination chemotherapy– Chlorambucil/Cyclophosphamide + Prednisone– purine analog (Fludarabine) + Cyclophosphamide +/- Mitoxantrone– CVP, CHOP (Cyclophosphamide, Doxorubicin, Vincristin,
Prednisone) • Monoclonal antibodies (monotherapy and in combination)
– Alemtuzumab (anti-CD52) = CAMPATH – Rituximab (anti-CD20) = Mabthera– antiCD23 etc.– monoclonal antibodies conjugated with radionuclides = Ibritumomab
tiuxetan = Zevalin• Splenectomy (hypersplenism)• Radiotherapy (massive lymphadenopathy)
CLL – treatment (2)
• Hematopoietic stem cell transplantation– autologous - still no cure with auto-SCT– allogenic with reduced intensity conditioning
• Even RIC-SCT is still a risky procedure - indicated only in high-risk disease
• Can allo-SCT cure CLL? - YES• 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)
CLL – treatment (3)
• Complete response (for at least 2 months) – clinical features – normal– morphology – normal (Hb>11 g/dl; Pt>100 000 /ul, lymphocytes
<4000 G/l; neutrofiles >1500 G/l))– bone marrow - lymphocytosis less than 30%
• Partial response• Stable Disease• Progressive Disease
Response criteria (NCI working group 1996)
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