Internal Medicine

Chronic lymphocytic leukaemia (CLL)

Malignancy of CD5+ B-cells characterized by accumulation of small, mature-appearing lymphocytes in blood, marrow and lymphoid tissues.


Monoclonal lymphoproliferative disease characterized by the proliferation and accumulation of morphologically mature but immunologically dysfunctional CD5+ B-cells in blood (smudge cells), marrow and lymphoid tissues.

  • M/C leukaemia in western countries
    • Commonly in elderly (> 60 years) caucasian males
  • Primary disease sites: Peripheral blood, spleen, lymph nodes, and bone marrow


Milestones in biological and clinical CLL research that have paved the way for new targeted therapies: Clinical landmarks include the introduction of steroids and alkylating agents as the first systemic treatments of chronic lymphocytic leukaemia (CLL). This advance was followed 2 decades later by the introduction of the Rai and Binet classification systems, which enable clinical staging of CLL based on physical examination and peripheral blood counts. The introduction of nucleoside analogues, especially fludarabine, was the next step forward in CLL therapy, followed by combination approaches with fludarabine plus cyclophosphamide (FC)53 and, subsequently, addition of the anti- CD20 antibody rituximab to this combination to form the FCR chemoimmunotherapy regimen. FCR was the first regimen to induce high complete remission (CR) rates and to provide an overall survival (OS) benefit when compared with the FC regimen. SYK , BTK , and PI3K inhibitors (fostamatinib, ibrutinib, and idelalisib, respectively) enabled the next breakthroughs in CLL therapy, followed by the apoptosis regulator BCL-2 antagonist venetoclax. On the basis of promising data from early-stage trials, chimeric antigen receptor (CAR) T-cell therapy has the potential | Burger, J.A., O’Brien, S. Evolution of CLL treatment — from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol 15, 510–527 (2018).


Schematic overview of the main types of leukaemia | Khwaja, A., Bjorkholm, M., Gale, R. E., Levine, R. L., Jordan, C. T., Ehninger, G., … Linch, D. C. (2016). Acute myeloid leukaemia. Nature Reviews Disease Primers, 2, 16010. Retrieved from


Risk factors:

  • 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
The cellular origin of chronic lymphocytic leukaemia (CLL): The genetic and epigenetic events leading to chronic lymphocytic leukaemia (CLL) have been suggested to occur in haematopoietic stem cells (HSCs), although this hypothesis remains controversial. After HSCs acquire genetic and epigenetic lesions (indicated by lightning symbols), the nature of which are still unknown, the cellular output of these lesions could be a polyclonal expansion of B cells | Bosch, F., Dalla-Favera, R. Chronic lymphocytic leukaemia: from genetics to treatment. Nat Rev Clin Oncol 16, 684–701 (2019).

Clinical features

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
The Calgary Guide |

Physical examination:

  • 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

Special variants

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.
  • ♂:♀::6:1
  • BRAF mutation
  • Median age: 50 years
  • C/F: Severe neutropenia + monocytopenia + hairy cells in blood & bone marrow
  • CladribinDeoxycoformycin


  • Secondary infections
  • Anaemia
  • Thrombocytopenia

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
Blood smears from patients with CLL: Wright–Giemsa-stained blood smears showing the typical chronic lymphocytic leukaemia (CLL) B lymphocyte (part a), smudge cell (part b) and a prolymphocyte with a prominent nucleolus (part c). Magnification ×500. | H. E. Broome, University of California, San Diego, La Jolla, California, USA.


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
Marrow biopsies from patients with CLL: Tissue sections of a marrow biopsy specimen stained with haemotoxylin and eosin showing interstitial (I) or nodular (N) chronic lymphocytic leukaemia (CLL) cell involvement (part a) or diffuse CLL cell marrow involvement (part b), which is typically associated with advanced-stage disease (original magnification ×100). | H. E. Broome, University of California, San Diego, La Jolla, California, USA.

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
Lymph node of patients with CLL: a | Tissue sections of a lymph node stained with haemotoxylin and eosin showing numerous pale-staining pseudofollicles, which are circled (original magnification ×20). b | Higher (×400) magnification of a proliferation centre. Representative lymphocytes (arrows), prolymphocytes (arrowheads) or paraimmunoblasts (circles) in a proliferation centre are shown. | H.-Y. Wang, University of California, San Diego, La Jolla, California, USA.

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 helps in evaluation to see the degree of lymphadenopathy and organ infiltration in the form of spleen and liver

Molecular analysis:

  • 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

Differential diagnosis:

  • 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 groupClinical featuresMedian life
Low risk
(Rai stage 0/I)
Lymphocytosis without cytopenia, lymphadenopathy or splenomegaly13 years
Intermediate risk
(Rai stage II)
Lymphocytosis, lymphadenopathy and/or splenomegaly, but without cytopenia8 years
High risk
(Rai stage III/IV)
Lymphocytosis and cytopenia (Hb ≤11 g/dl and/or platelet ≤100,000 cells/µl)2 years
*These life-expectancy estimates are increasing with the advent of newer therapies.

Binet staging system:

Risk groupClinical featuresMedian life
Low risk
(Binet stage A)
< 3 palpably enlarged sites‡ without cytopenia13 years
Intermediate risk
(Binet stage B)
≥ 3 palpably enlarged sites without cytopenia8 years
High risk
(Binet stage C)
Cytopenia (Hb ≤10 g/dl
and/or platelet ≤100,000 cells/µl)
2 years
*These life-expectancy estimates are increasing with the advent of newer therapies.
‡There are five sites of lymphoid organs: cervical, axillary and inguinal nodes, the spleen and the liver.


CLL management algorithm | Flow Cytometry. (2019) Chronic Lymphocytic Leukemia: Cancer Management Guidelines: Healthcare Professionals: The Leukemia/Bone Marrow Transplant Program of BC. Retrieved May 07, 2019, from

First-line treatment:

treatment should be initiated in a patient with advanced (Binet C, Rai III–IV) or active, symptomatic disease
First-line treatments for CLL patients. | Ghia, P., & Hallek, M. (2014). Management of chronic lymphocytic leukemia. Haematologica, 99(6), 965–972.

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.
Second-line treatment for CLL patients. | Ghia, P., & Hallek, M. (2014). Management of chronic lymphocytic leukemia. Haematologica, 99(6), 965–972.


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


Kipps, T. J., Stevenson, F. K., Wu, C. J., Croce, C. M., Packham, G., Wierda, W. G., … Rai, K. (2017). Chronic lymphocytic leukaemia. Nature Reviews. Disease Primers, 3, 16096.

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