Chronic Lymphocytic Leukemia

Last updated: March 25, 2026

Chronic lymphocytic leukaemia is characterised by a progressive accumulation of monoclonal, mature, non-functional B lymphocytes. It is usually discovered on routine blood tests as an isolated lymphocytosis. It is defined by a > 5000/uL B-lymphocytes in the peripheral blood that are marked CD5+ and CD23+. The aberrant expression of CD5+ (a T-cell marker) is very specific for CLL.

It peaks between 60 and 70 years of age, and affects men more than women.

Rai staging system of CLL – Based on the fact that there is a gradual and progressive increase in the body burden of leukemic lymphocytes that progressively invade other tissues and compromise bone marrow function.

Risk stage	Feature	Median survival
Stage 0	Lymphocytosis alone	> 13 years
Stage I	Lymphocytosis + Lymphadenopathy	8 years
Stage II	Lymphocytosis + spleno- or hepatomegaly	5 years
Stage III	Lymphocytosis + Anaemia	2 years
Stage IV	Lymphocytosis + Thrombocytopenia	1 year

Binet staging of CLL – classifies patients according to the 5 potential sites of involvement (cervical, axillary, inguinal, spleen, and liver) and presence of anaemia and/or thrombocytopenia

Stage	Feature	Prognosis
Stage A	< 3 lymph node sites involved	Comparable to age-matched controls
Stage B	≥ 3 lymph node sites involved	84 months
Stage C	Presence of anemia and thrombocytopenia	24 months

Chronic lymphocytic leukaemia (CLL) and Small lymphocytic lymphoma (SLL)
- SLL is essentially the solid tissue (lymph node) component of CLL.
- The diagnosis of SLL is reserved for:
  - Lymph node biopsy consistent with CLL/SLL: diffusely effaced architecture, naked germinal centers, infiltration of mature-appearing small lymphocytes
  - Absolute peripheral lymphocytosis < 5000/uL
Risk factors for CLL
- Chemical exposure
  - Farmers and agricultural workers
  - Rubber workers
  - Petroleum workers
- Familial history (strongest risk factors)
  - History of CLL
  - History of Low-grade lymphoma
- Mutations, trisomies, and deletions
  - del17p13
Pathophysiology
- Accumulation of genetic changes → clonal expansion of lymphocytes → lymphocytosis, lymphadenopathy, and splenomegaly
- Causes of cytopaenia
  - Leukemic infiltrate of the bone marrow
  - Autoimmune hemolysis and destruction of platelets
  - Hypersplenism
  - Chemotherapy
Signs and symptoms
- Asymptomatic (70%)
- Weight loss and night sweats (constitutional B-symptoms)
- Peripheral lymphadenopathy
- Hepatosplenomegaly (due to invasion and extramedullary hematopoiesis)
- Fatigue, pallor, breathlessness (due to anemia)
- Recurrent infection and fever (due to neutropenia)
- Easy bruising (due to thrombocytopenia)
- Leukemia cutis (due to skin involvement)
  - Macules, plaques, blisters, ulcers, and nodules
Investigations
- Complete Blood Count
  - Absolute lymphocytosis of >5×10^9/L (patients can have counts as high as 100×10^9/L)
- Peripheral Blood Film:
  - Lymphocytosis (cells are small, mature appearing lymphocytes with a dense nucleus, partially aggregated or clumped chromatin without discernible nucleoli, they have a scanty basophilic cytoplasm), “
  - Smudge” cells or “basket” cells (Lymphocytes that appear to have been flattened or smudged in the process of being spread on the glass slide.
- Bone marrow studies are not required to diagnose CLL
  - Bone Marrow Aspirate: normal to increased cellularity with lymphocytes accounting for more than 30% of nucleated cells
  - Trephine Biopsy: exhibits a range of infiltration patterns (focal, non-para trabecular nodules; interstitial infiltrates – CLL cells are admixed with hematopoietic elements and diffuse solid lesions). The pattern of Bone marrow infiltration is useful to distinguish CLL from other differentials.
- Immunophenotyping (Flow cytometry) for diagnosis
  - B-cell markers: CD19+, CD20+, CD23+, CD5+ (Aberrant expression of CD5+ – a T-cell marker – is very specific for CLL) SmIg weak (Only a single IgL chain is expressed, confirming the clonal nature of these cells)
  - T-cell markers: CD3+, CD4+, CD5+, CD8+
- Cytogenetics for pre-treatment evaluation
  - Chromosomal abnormalities: del(13q), del(17p), del(11q), trisomy 12 in more than 80% of CLL cases
  - These alterations are neither sensitive nor specific for the diagnosis of CLL.
Treatment
- Watch and wait strategy for early disease
  - Determines whether the disease is stable or progressing
- Chemotherapy for patients with active, symptomatic disease
  - Fludarabine + cyclophosphamide + rituximab for young, healthy patients
  - Chlorambucil + rituximab for older patients, or patients with comorbidities
- Prednisone or IVIG for autoimmune manifestations
- Splenectomy for autoimmune cytopenia
- Bone marrow transplantation is the definitive treatment
Complications
- Chemotherapy-related complications
- Hypogammaglobulinemia (5-10%)
- Autoimmune complications
  - Autoimmune hemolytic anemia (1-5%)
  - Immune thrombocytopenic purpura (1-5%)
  - Autoimmune agranulocytosis
  - Pure red cell aplasia (1-6%)
- Richter transformation (5%): sudden onset of B-symptoms. Transformation of CLL to high-grade non-Hodgkin lymphoma.

Reference Intervals ›

Biochemistry

ACTH	P: <80 ng/L
ALT	P: 5–35 U/L
Albumin	P: 35–50 g/L
Aldosterone	P: 100–500 pmol/L
Alk. phosphatase	P: 30–130 U/L
α-Amylase	P: 0–180 IU/dL
α-Fetoprotein	S: <10 kU/L
Angiotensin II	P: 5–35 pmol/L
ADH	P: 0.9–4.6 pmol/L
AST	P: 5–35 U/L
Bicarbonate	P: 24–30 mmol/L
Bilirubin	P: 3–17 μmol/L
BNP	P: <50 ng/L
CRP	P: <10 mg/L
Calcitonin	P: <0.1 mcg/L
Calcium (ionized)	P: 1.0–1.25 mmol/L
Calcium (total)	P: 2.12–2.60 mmol/L
Chloride	P: 95–105 mmol/L
Cholesterol	P: <5.0 mmol/L
VLDL	P: 0.128–0.645 mmol/L
LDL	P: <2.0 mmol/L
HDL	P: 0.9–1.93 mmol/L
Cortisol AM	P: 450–700 nmol/L
Cortisol Midnight	P: 80–280 nmol/L
CK ♂	P: 25–195 U/L
CK ♀	P: 25–170 U/L
Creatinine	P: 70–100 μmol/L
Ferritin	P: 12–200 mcg/L
Folate	S: 2.1 mcg/L
FSH	P: 2–8 U/L ♂; >25 menopause
GGT ♂	P: 11–51 U/L
GGT ♀	P: 7–33 U/L
Glucose (fasting)	P: 3.5–5.5 mmol/L
Growth hormone	P: <20 mu/L
HbA1C (DCCT)	B: 4–6%
HbA1C (IFCC)	B: 20–42 mmol/mol
Iron ♂	S: 14–31 μmol/L
Iron ♀	S: 11–30 μmol/L
Lactate (venous)	P: 0.6–2.4 mmol/L
Lactate (arterial)	P: 0.6–1.8 mmol/L
LDH	P: 70–250 U/L
LH	P: 3–16 U/L
Magnesium	P: 0.75–1.05 mmol/L
Osmolality	P: 278–305 mosmol/kg
PTH	P: 0.8–8.5 pmol/L
Potassium	P: 3.5–5.3 mmol/L
Prolactin ♂	P: <450 U/L
Prolactin ♀	P: <600 U/L
PSA	P: 0–4 mcg/mL
Protein (total)	P: 60–80 g/L
Red cell folate	B: 0.36–1.44 μmol/L
Renin (erect)	P: 2.8–4.5 pmol/mL/h
Renin (recumbent)	P: 1.1–2.7 pmol/mL/h
Sodium	P: 135–145 mmol/L
TBG	P: 7–17 mg/L
TSH	P: 0.5–4.2 mU/L
T4	P: 70–140 nmol/L
Free T4	P: 9–22 pmol/L
TIBC	S: 54–75 μmol/L
Triglycerides	P: 0.50–2.3 mmol/L
T3	P: 1.2–3.0 nmol/L
Troponin T	P: <0.1 mcg/L
Urate ♂	P: 210–480 μmol/L
Urate ♀	P: 150–390 μmol/L
Urea	P: 2.5–6.7 mmol/L
Vitamin B12	S: 0.13–0.68 nmol/L
Vitamin D	S: 50 nmol/L

Arterial Blood Gases

pH	7.35–7.45
PaCO₂	4.7–6.0 kPa
PaO₂	>10.6 kPa
Base excess	±2 mmol/L

Urine

Cortisol (free)	<280 nmol/24h
Hydroxyindole acetic acid	16–73 μmol/24h
Hydroxymethylmandelic acid	16–48 μmol/24h
Metanephrines	0.03–0.69 μmol/mmol cr.
Osmolality	350–1000 mosmol/kg
17-Oxogenic steroids ♂	28–30 μmol/24h
17-Oxogenic steroids ♀	21–66 μmol/24h
17-Oxosteroids ♂	17–76 μmol/24h
17-Oxosteroids ♀	14–59 μmol/24h
Phosphate (inorganic)	15–50 mmol/24h
Potassium	14–120 mmol/24h
Protein	<150 mg/24h
Protein/creatinine ratio	<3 mg/mmol
Sodium	100–250 mmol/24h

Haematology

WCC	4.0–11.0 ×10⁹/L
RBC ♂	4.5–6.5 ×10¹²/L
RBC ♀	3.9–5.6 ×10¹²/L
Hb ♂	130–180 g/L
Hb ♀	115–160 g/L
PCV ♂	0.4–0.54 L/L
PCV ♀	0.37–0.47 L/L
MCV	76–96 fL
MCH	27–32 pg
MCHC	300–360 g/L
RDW	11.6–14.6%
Neutrophils	2.0–7.5 ×10⁹/L (40–75%)
Lymphocytes	1.0–4.5 ×10⁹/L (20–45%)
Eosinophils	0.04–0.44 ×10⁹/L (1–6%)
Basophils	0–0.10 ×10⁹/L (0–1%)
Monocytes	0.2–0.8 ×10⁹/L (2–10%)
Platelets	150–400 ×10⁹/L
Reticulocytes	0.8–2.0% / 25–100 ×10⁹/L
Prothrombin time	10–14 s
APTT	35–45 s

Paediatric

Pulse Rate (bpm)
Neonate	140–160
Infant <1yr	120–140
1–5 years	110–130
5–12 years	80–120
>12 years	70–100
Respiratory Rate (tachypnoea)
0–2 months	≥60/min
2–12 months	≥50/min
1–5 years	≥40/min
>5 years	≥30/min
Blood Pressure (mmHg)
Term	65/45
1 year	75/50
4 years	85/60
8 years	95/65
10 years	100/70
Weight Formulas
3–12 months	(a + 9)/2 kg
1–6 years	2a + 8 kg
>6 years	(7a − 5)/2 kg
Haemoglobin (g/dL)
Term newborn	13–20
1 month	11–18
2 months	10–15
1–2 years	10–13
>2 years	11–14
MUAC (6 months–5 years)
Obese	>17.5 cm
Normal	13.5–17.4 cm
At risk	12.5–13.4 cm
Moderate malnutrition	11.5–12.4 cm
Severe malnutrition	<11.5 cm
Developmental Milestones
Social smile	1.5 months
Head control	4 months
Sits unsupported	7 months
Crawls	10 months
Stands unsupported	10–12 months
Walks	12–13 months
Talks	18 months
CSF WBC (/mm³)
Term newborn	0–25
>2 weeks	0–5

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