- M/C leukaemia in western countries
- Commonly in elderly (> 60 years) caucasian males
- Primary disease sites: Peripheral blood, spleen, lymph nodes, and bone marrow
- Occupational risk factors: Rubber manufacturing industries, benzene, heavy solvents, uranium miner population,
- Tobacco users and cigarette smokers
The pathogenesis of CLL/SLL is a two-step process that leads to the clonal replication of malignant B lymphocytes.
First step:Development of MBL cells secondary to multiple factors such as antigenic stimulation, genetic mutations, and cytogenetic abnormalities.
Second step:Progression of MBL to CLL/SLL by the further insult to the B-cell clone, either due to additional genetic abnormalities or changes in the bone marrow microenvironment. B-cell antigen receptor (BCR) expression induces antigen-independent cell-autonomous signaling
Asymptomatic presentation:Patients with CLL are often asymptomatic at the initial presentation, when a routine CBC reveals abnormal lymphocytosis, leading to CLL diagnosis.
Symptomatic presentation :
- B symptoms (5-10%):
- Fever > 100.5°F for > 2 weeks with no evidence of infection;
- Unintentional weight loss ≥ 10% body weight over last 6 months
- Drenching night sweats with no evidence of infection
- Extreme fatigue
- Early satiety
- Localized/generalized lymphadenopathy (50-90% cases)
- M/C sites: Cervical, supraclavicular, and axillary lymph nodes
- On palpation: Nodes are firm, non-tender, round, and freely mobile
- Splenomegaly (#2 M/C enlarged lymphoid organ, 25-55% cases)
- On palpation: Painless/non-tender with a smooth, firm surface
- Hepatomegaly (15-25% cases)
- On palpation: Liver is firm and non-tender with a smooth surface
Skin examination:Skin is the M/C non-lymphoid tissue involved in CLL
- Leukemia cutis (skin lesions): Mainly involve the face and manifest as papules, macules, plaques, ulcers, blisters, or nodules.
- Nonspecific secondary cutaneous lesions: Due to bleeding, vasculitis, and infection
- Exaggerated reactions to insect bites
B cell prolymphocytic leukemia:More aggressive variant, with cells with similar phenotype, but significantly larger than normal lymphocytes and having a prominent nucleolus.
- Males > 60 years
- 25% of T-cell variety
- C/F: Massive splenomegaly + little lymphadenopathy
- Poor prognosis
Hairy-cell leukaemia:Chronic B-CLL variant featuring distinct morphology under the microscope (hairy cell leukaemia cells have delicate, hair-like projections on their surfaces) and unique marker molecule expression.
- BRAF mutation
- Median age: 50 years
- C/F: Severe neutropenia + monocytopenia + hairy cells in blood & bone marrow
- ℞: Cladribin, Deoxycoformycin
- Secondary infections
Richter’s transformation (5% of CLL cases):Rapid development of a histologically proven aggressive lymphoma in a patient with CLL.
- Diffuse large B-cell lymphoma (M/C)
- Variety of non-Hodgkin lymphoma refractory to treatment with bad prognosis
- Hodgkin’s variant
- Composite lymphoma
- Interdigitating dendritic cell sarcoma (very rare)
Peripheral blood smear (PBS):The first step in the diagnosis of CLL is a peripheral blood smear. The peripheral blood smear shows an absolute lymphocyte count of greater than 5000/mcL and smudge cells that confirm CLL.
- Lymphocytosis (first laboratory abnormality found in CLL)
- Leukemic cells: Small, mature lymphocytes with a darkly stained nucleus, condensed chromatin, and indistinguishable nucleoli with a narrow rim of basophilic cytoplasm
- Smudge/basket cells (PATHOGNOMIC): More fragile than normal lymphocytes that are disrupted during the process of being spread on a glass slide
Immunophenotyping:Immunophenotypic analysis of the peripheral circulating lymphocytes by peripheral blood flow cytometry can be performed, which can help to diagnose CLL. Most cases of CLL can be identified using antibody specific panel for CD5, CD19, CD20, CD23, and immunoglobulin light chains.
Characteristic CLL/SLL lymphocyte phenotype:
- M/C immunophenotype expression: Coexpression of CD5, CD19, and CD23
- Low levels of immunoglobulins (M/C, IgM and sometimes both IgM and IgD)
- Expression of B-cell associated antigens: CD19, CD20, CD21, CD23, and/or CD24
- Expression of CD5 (T-cell associated antigen)
Bone marrow biopsy:
- Normocellular/hypercellular bone marrow aspirate with lymphocytes > 30% of all nucleated cells (CONFIRMATORY).
- Reduction of lymphocytic infiltration to < 30% on treatment indicates a complete response
Lymph node biopsy:Excisional lymph node histology demonstrates diffuse effacement of nodal architecture along with some scattered residual likely germinal centers. These lymph node infiltrates are predominantly composed of small lymphocytes.
- Pseudo-follicles (proliferation centers) (PATHOGNOMIC): Large lymphoid cells, such as pro-lymphocytes present in clusters
Spleen biopsy:Spleen histology demonstrates the infiltration of red and white pulp with a more prominent white pulp involvement compared to red pulp.
CT-scan:CT scan helps in evaluation to see the degree of lymphadenopathy and organ infiltration in the form of spleen and liver
- Fluorescence in situ hybridization (FISH): Detect chromosomal abnormalities (17p. deletion, 11q. deletion, 13q. deletion and trisomy 12)
Diagnoses of complications of CLL:
- Autoimmune hemolytic anemia: Positive direct antiglobulin (Coombs) test, increased reticulocyte count, elevated serum LDH, reduced haptoglobin, and elevated serum indirect bilirubin
- Pure red cell aplasia and thrombocytopenia: Peripheral blood smear and a bone marrow aspiration and biopsy
- Hypogammaglobulinemia (< 15% cases): Elevated uric acid level and elevated hepatic enzymes are other findings seen in CLL
- Small lymphocytic lymphoma
- Monoclonal B lymphocytosis
- 5,000 clonal B cells per µl in the blood without other signs of lymphoma, such as enlarged lymph nodes (>1.5 cm)
- Other lymphoproliferative diseases:
- B-cell prolymphocytic leukaemia
- Follicular lymphoma
- Hairy cell leukaemia
- Mantle cell lymphoma
- Marginal zone lymphoma
Rai staging system:
|Risk group||Clinical features||Median life|
(Rai stage 0/I)
|Lymphocytosis without cytopenia, lymphadenopathy or splenomegaly||13 years|
(Rai stage II)
|Lymphocytosis, lymphadenopathy and/or splenomegaly, but without cytopenia||8 years|
(Rai stage III/IV)
|Lymphocytosis and cytopenia (Hb ≤11 g/dl and/or platelet ≤100,000 cells/µl)||2 years|
Binet staging system:
|Risk group||Clinical features||Median life|
(Binet stage A)
|< 3 palpably enlarged sites‡ without cytopenia||13 years|
(Binet stage B)
|≥ 3 palpably enlarged sites‡ without cytopenia||8 years|
(Binet stage C)
|Cytopenia (Hb ≤10 g/dl|
and/or platelet ≤100,000 cells/µl)
‡There are five sites of lymphoid organs: cervical, axillary and inguinal nodes, the spleen and the liver.
First-line treatment:treatment should be initiated in a patient with advanced (Binet C, Rai III–IV) or active, symptomatic disease
Second-line treatment:For relapsed or refractory CLL. In general, the first-line treatment may be repeated if the duration of the first remission exceeds 24–36 months.
Poor prognostic factors:
- Advanced stage & age at diagnosis
- Male sex
- Diffuse pattern of BM-infiltration
- Short lymphocyte doubling time
- High expression of Ki67, p276
- High serum level of β2MG, TK, sCD23, TNFα
- Poor risk cytogenetics: 17p & 11q del, complex karyotype
- High level of CD38 & ZAP-70 expression
- High level of expression of lipoprotein lipase
- Unmutated IgVH gene status, altered micro RNA expression
- Poor response to therapy or short duration of response