QuestionSBA
QuestionChoice
Serum electrophoresis is commonly used to investigate multiple myeloma or monoclonal gammopathy of uncertain significance (MGUS). While chronic lymphocytic leukaemia may produce IgM paraproteinaemia, it is not routinely used in its diagnosis
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d
Serum electrophoresis
QuestionChoice
This patient most likely has chronic lymphocytic leukaemia. Immunophenotyping detects tumour markers in peripheral blood by labelling the white blood cells with antibodies directed against cell surface proteins. This allows for differentiation of leukaemic cells to show which specific type of leukaemia the patient has and so which treatment would be most appropriate
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a
Immunophenotyping
QuestionChoice
Chronic lymphocytic leukaemia can be subcategorised using immunophenotyping and flow cytometry from peripheral blood. Therefore, evaluation of bone marrow biopsy is not usually necessary unless there is diagnostic doubt from the former tests
33025
c
Bone marrow biopsy
QuestionChoice
Chronic lymphocytic leukaemia can be subcategorised using immunophenotyping and flow cytometry from peripheral blood. Evaluation of lymph node biopsy is not usually necessary unless there is diagnostic doubt from the former tests
33024
b
Lymph node biopsy
QuestionChoice
Iron studies are commonly used to investigate the cause of anaemia and will likely be done in this patient as they are anaemic, but it is not the next best investigation for their leukaemia
33027
e
Iron studies
QuestionComment
Quesbook notes mention bone marrow biopsy but not immunophenotyping 
7690
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lol
9708
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Endoscope Hematoma
QuestionComment
typical

43299
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Kinase Hallux
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Dermis Cystic
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Refs had a stinker here
61818
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Gabriel Magalhaes
Concept
Chapter
# Summary

Chronic Lymphocytic Leukaemia (CLL) is a mature B-cell neoplasm characterized by the accumulation of monoclonal B lymphocytes in the blood, bone marrow, and lymphoid tissues. The CLL cells accumulate because they survive for a very long time, rather than because they divide at an accelerated rate. It is therefore an indolent disease of deregulated programmed cell death. It primarily affects older adults and often progresses slowly. CLL may be asymptomatic, but common symptoms include fatigue, lymphadenopathy, and hepatosplenomegaly. Diagnosis is confirmed through blood counts, flow cytometry, and genetic tests. Treatment is typically indicated for symptomatic or progressive disease and may involve chemotherapy, targeted therapy, and stem cell transplantation.

# Definition

Chronic Lymphocytic Leukaemia (CLL) is a haematologic malignancy characterized by the accumulation of mature monoclonal B lymphocytes in the blood, bone marrow, and lymphoid tissues. These abnormal B cells are often slow-growing and crowd out healthy blood cells.


# Epidemiology

CLL is most common in men over the age of 60 years – incidence is 50 per 100,000 individuals after the age of 70 years and it is the most common leukaemia in Western countries

# Aetiology

The precise cause of CLL is not well-defined, but genetic and environmental factors may contribute to its development. A family history of CLL or exposure to certain chemicals may be associated with an increased risk.


# Signs and Symptoms 

CLL typically presents asymptomatically, but patients may present with:

- Non-tender symmetrical lymphadenopathy
- Hepatosplenomegaly
- B symptoms – weight loss, night sweats and fever 

Features of marrow failure (infection, anaemia and bleeding) are less common than in acute leukaemias.

# Differential Diagnosis

- **Hairy Cell Leukaemia (HCL):** HCL is another mature B-cell leukaemia and may share some clinical features with CLL. However, the distinct hairy appearance of leukaemic cells in HCL helps differentiate the two.
- **Small Lymphocytic Lymphoma (SLL):** SLL is closely related to CLL and is considered the tissue-based counterpart. Differentiating between CLL and SLL depends on whether the predominant site of involvement is in the blood or lymph nodes.
- **Infections:** Some infectious diseases, such as infectious mononucleosis, can mimic lymphadenopathy and other symptoms of CLL.

# Investigations 

- The most common initial blood result is an **incidental lymphocytosis** (80% of cases)
- **Blood film** shows smudge cells – cells damaged as the film is made because they lack a cytoskeletal protein
- **Immunophenotype** of the cells is CD5 and CD23 positive, FMC negative, CD22 and surface immunoglobulin weak
- Chromosomal abnormalities are found in approximately 50% of patients 
- Direct antiglobulin test can be positive – AIHA can complicate CLL
- Hypogammaglobulinaemia is common in advanced disease

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- Other tests include bone marrow biopsy, which will show lymphocytic infiltration of mature lymphocytes, with some smear cells

NICE advise considering an urgent FBC (within 48h) to assess for leukaemia in adults with any of the following:

* Pallor
* Persistent fatigue
* Unexplained fever
* Unexplained persistent or recurrent infection
* Generalized lymphadenopathy
* Unexplained bruising
* Unexplained bleeding
* Unexplained petechiae
* Hepatosplenomegaly

# Staging

The disease is often staged using Binet's system based on lymphoid tissue enlargement, haemoglobin and platelets.

# Management 

- Treatment depends on the stage and activity of the disease i.e. rapidly progressive, bulky, with disabling systemic symptoms or there is associated cytopenias or shortened lymphocyte doubling time. 
- There is no evidence that intervening with treatment at an earlier, asymptomatic phase is beneficial. So often, watchful monitoring is often useful at this stage.
- Traditionally, intensive chemotherapy including rituximab was first-line therapy. This has now changed in the world of targeted pathway inhibitors superseding chemotherapy. 
- In a patient with no co-morbidities and TP53 intact, +/- mutated IGHV mutated status, we can now start with Venetoclax (selective inhibitor of B-cell lymphoma-2, BCL-2)-Obinutuzumab (anti-CD20 monoclonal antibody) (Ven-O) upfront. 
- In fit patients with TP53 mutational disruption or any IGHV mutated status, first-line therapy is with Acalabrutinib (bruton tyrosine kinase inhibitor) +/- Obinutuzumab or upfront Ibrutinib (tyrosine kinase inhibitor, TKI) monotherapy. 
- Allogeneic stem cell transplant should be considered in those fit patients who have failed at least 2 of : chemoimmunotherapy, BTKi, BCL2i or have Richter’s transformation (sudden transformation into a significantly more aggressive form of large cell lymphoma). 
- If they are high-risk patients (TP53 disrupted), then an allogenic transplant can be considered after the failure of these therapies.
- Steroids and monoclonal antibody treatments (eg. rituximab) may be useful in autoimmune haemolytic disease. 
- Prevention or treatment of infection with antibiotics or immunoglobulins is also part of the management. 

# Complications

* **Infections:** Patients with CLL are at an increased risk of infections due to compromised immune function.
* **Transformation to Diffuse Large B-Cell Lymphoma (Richter Transformation):** A small percentage of CLL patients may experience aggressive transformation to a high-grade lymphoma, which has a poor prognosis.
* **Autoimmune Haemolytic Anaemia:** Some CLL patients may develop autoimmune complications, such as heamolytic anaemia or immune thrombocytopenia.

# Prognosis 

CLL is a very variable disease: 1/3 of cases don't progress, 1/3 of cases progress slowly, and 1/3 of cases progress actively. 

Factors that affect prognosis are: 

- Disease stage  
- Atypical lymphocyte morphology
- Lymphocyte doubling time <12 months
- Bone marrow trephine showing diffuse involvement
- Chromosomal/genetic abnormalities, in particular TP53
- Unmutated immunoglobulin VH (IGVH) gene status
- Male sex
- High expression CD38

Given the improvement in the CLL therapeutic landscape, CLL prognosis now has a median 5-year survival at 87%.

A small proportion of patients with CLL will progress to a more aggressive type with:

- Refractoriness to treatment
- Increase in systemic symptoms and disease bulk, plus a change in morphological features, specifically 'high-grade lymphomatous (Richter's) transformation'. 



# NICE Guidelines 

[NICE 2ww for Haematological Cancers](https://cks.nice.org.uk/topics/haematological-cancers-recognition-referral/management/referral-for-haematological-cancer/#refer-an-adult-for-suspected-leukaemia)
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Picture
A blood film showing CLL.
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CLL.jpeg
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5xcCBoCBrYVQdlVZqSekqEioEHGwAxk=
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Chronic Lymphocytic Leukaemia (CLL)
Topic
8
Haematology
6605
Immunophenotyping in chronic lymphocytic leukemia (CLL) is a diagnostic process that uses flow cytometry to identify specific cell surface markers, such as CD5, CD19, CD20, and CD23, to confirm the presence of clonal B-cell populations and distinguish CLL from other lymphoid disorders.
A 72-year-old man presents to the GP with 3 months of general fatigue, malaise, and night sweats.


Bloods reveal the following:


||||
|--------------|:-------:|---------------|
|Haemoglobin|78  g/L|(M) 130 - 170, (F) 115 - 155|
|White Cell Count|16.3x10<sup>9</sup>/L|3.0 - 10.0|
|Neutrophils|3.1x10<sup>9</sup>/L|2.0 - 7.5|
|Lymphocytes|8.2x10<sup>9</sup>/L|1.5 - 4.0|


Peripheral blood film shows smudge cells and small mature lymphocytes with round nuclei and clumped chromatin.


Given the likely diagnosis, which of the following is the next best investigation?
a