Once full blood count and immunophenotyping are complete and diagnosis is confirmed, additional assessments are recommended to help inform prognosis and to develop a treatment plan.

The treatment team, after taking a thorough medical history and making a thorough medical examination of the patient, should undertake the following investigations under the guidance of a specialist.

These include:

• careful palpation of all lymph node areas, spleen and liver
• serum chemistry (creatinine, uric acid, bilirubin, lactate dehydrogenase, haptoglobin, transaminases, alkaline phosphatase, ß₂-microglobulin), serum immunoglobulin levels, direct antiglobulin test and serum protein electrophoresis to look for the presence of any paraprotein
• chest radiograph (unless computed tomography [CT] has been performed for other reasons)
• viral serology (hepatitis B, hepatitis C, HIV, Epstein-Barr virus and cytomegalovirus) (Hallek et 2018). The following investigations are only recommended under certain circumstances:
• Marrow aspirate and biopsy – This is only recommended when the cause of any cytopenias (neutropenia, anaemia, thrombocytopenia) is unclear (Hallek et al. 2018), disease phenotype is inconclusive (Eichhorst et 2021) or the exact diagnosis is uncertain.
• CT scans and other imaging – CT scans are not recommended for asymptomatic patients or during routine evaluation. A meta-analysis (Eichhorst et al. 2011) reported that most instances of relapse and disease progression are found during physical exam and by checking blood counts, and that imaging studies only affect relapse treatment decisions in 1 per cent of The International Working Group guidelines for CLL do not recommend routine use of CT scan,

PET scan, MRI or ultrasound for patients with CLL outside of clinical trials. Exceptions include PET scans for patients with confirmed or suspected Richter’s transformation (Hallek et al. 2018).

• Situations where imaging is appropriate can include bulky or painful lymphadenopathy or significant symptoms or physical findings that suggest a local compressive complication.
• For patients who do have symptoms, or where treatment will be initiated, CT scans are necessary to assess the tumour burden and risk of tumour lysis They can also be used in clinical trials to form a baseline and assess treatment response (Eichhorst et al. 2021).

Molecular genetics tests

The following tests aren’t recommended at diagnosis but should be done before initiating treatment or when there are signs of disease progression that may soon lead to treatment initiation:

• interphase fluorescence-in situ hybridisation (FISH) for del(13q), del(11q), del(17p), +12 and DNA sequencing for the presence of a TP53 mutation
• IGHV mutational

IGVH mutational status is invariant and unchanging through an individual patient’s disease course and need only be performed once.

These molecular genetic tests inform the most appropriate therapy (Eichhorst et al. 2021) and are useful to predict prognosis (Hallek et al. 2018).

Five to 10 per cent of patients with CLL will develop a more aggressive form of lymphoma (diffuse large B-cell lymphoma or Hodgkin lymphoma) at some point during their disease course. This

is termed Richter’s transformation. The managing team need to consider this possibility at every instance of disease evaluation and weigh up the potential need for a tissue biopsy to investigate. For more information see the optimal care pathway for people with Hodgkin and diffuse large B-cell lymphomas 

Features that can suggest the presence of Richter’s transformation and prompt tissue biopsy of the most suspicious site include (Petrackova et al. 2021):

• new-onset B symptoms (fevers, sweats, weight loss)
• rapidly growing, or a specific site of dominant or bulky, lymphadenopathy
• markedly elevated serum LDH level or new onset of hypercalcemia
• atypical extranodal site of disease involvement such as central nervous system, kidney, lytic bone lesions etc. or significantly elevated avidity (SUVmax above 5 – 10) on FDG-PET scanning (Wang et al. 2020).