Chronic lymphocytic leukaemia: diagnosis and management 

Introduction

Chronic lymphocytic leukaemia (CLL) is a form of blood cancer affecting the lymphocytes. The term ‘chronic’ derives from the fact that this type of leukaemia is slow growing, compared to acute leukaemia, which develops more rapidly^​1​. In the UK, CLL is the most common leukaemia in adults, with an incidence of 3–4 per 100,000 per year. Median age at presentation is 72 years and it occurs twice as frequently in males as females^​2​. CLL and small lymphocytic lymphoma (SLL) are the same disease, but CLL cancer cells are found mostly in the blood and bone marrow, while SLL cancer cells are found mostly in the lymph nodes^​3​.

CLL commonly leads to immune dysfunction, especially hypogammaglobulinemia (i.e. decreased immunoglobulin levels), which increases the risk of infection. Infection remains a major cause of mortality and morbidity in CLL, with studies demonstrating that infection accounts for one-third to one-half of all deaths^​4​. 

The treatment for CLL has changed dramatically over the past two decades. First with the introduction of combination of chemo-immunotherapy agents (e.g. combinations with fludarabine, cyclophosphamide, rituximab [an anti-CD20 antibody] and bendamustine, rituximab), and second with the discovery and availability of small molecule pathway inhibitors (e.g. Bruton tyrosine kinase inhibitors [BTKis], phosphoinositide 3-kinase inhibitors [PI3Kis] and B-cell lymphoma 2 inhibitors [BCL2is]). These advances in treatment have improved the progression-free survival (PFS) and overall survival (OS) in people with CLL, as well as forcing clinicians to re-examine the relationship between immunoglobulin deficiencies in CLL, infection risk and survival^​4​.

While changes in the treatment landscape have had a positive impact on patient mortality and morbidity, it poses new challenges for the medical team, including drug–drug interactions, adherence counselling and toxicity. Pharmacists are uniquely trained and equipped to help to manage the changing landscape of CLL care. Additional information can be found in The PJ Pod episode: ‘How can pharmacists best support patients with chronic lymphocytic leukaemia?’, published in September 2024.

Pharmacists can play an integral role in the comprehensive management of patients with CLL. With their unique perspective and medication-related expertise, pharmacists can add value and take the lead on many aspects of care for these patients. This includes providing chemotherapy education and comprehensive medication management to potentially conducting independent clinical follow-up visits^​5​. Treatment with oral anticancer drugs is associated with a broad range of medication errors and side effects. Pharmacist involvement in the care of these patients can have a considerable positive impact on medication errors and patient satisfaction^​6​.

Pathophysiology

The pathogenesis of CLL is multifactorial and dependent on various factors, such as B-cell receptor pathway signalling, somatic mutations, genomic mutations and the CLL micro-environment^​7​. Some patients with CLL have progressive disease and require therapy relatively soon after diagnosis, whereas others have highly indolent disease (one with little or no pain) that does not require treatment for many years; this variability reflects the intrinsic heterogeneity in the disease biology^​7​.

B-cell receptor signalling plays an essential role in pathogenesis of CLL^​7​. Two major molecular subgroups have been identified: those harbouring unmutated IG heavy-chain variable region (IGHV) genes (U-CLL, ≥98% identity with the germline); and those with mutated IGHV genes (MCLL). U-CLL originates from B cells that have not experienced the germinal centre, whereas M-CLL originates from post-germinal centre B cells^​8​.

Several cellular components of the CLL micro-environment have been described, along with the signalling pathways involved in CLL homing, survival and proliferation, which now provides a rationale for targeting the CLL micro-environment^​9​.

Understanding the pathogenesis of CLL has a direct correlation with treatment. For example, inhibitors of BCR signalling pathway are now standard of care for first-line and relapsed CLL. There is evidence that patients with 17p deletions do not respond to chemoimmunotherapy^​10​.

Symptoms

Patients with early stage CLL may not be symptomatic. As the disease progresses, patients may develop recurrent infections, symptoms of anaemia (e.g. persistent tiredness, shortness of breath, easy bruising or bleeding), a high temperature, night sweats, enlarged lymph nodes in neck, axilla or groin, unintentional weight loss^​11​. Other symptoms owing to specific systemic dysfunction are as below:

Symptoms owing to immune dysregulation 

Quantitative and qualitative defects in immune response in almost all patients from the time of diagnosis. Immune suppression is manifested by predisposition to infection^​11​.

Symptoms owing to autoimmune complications 

Another complication of immune dysregulation is autoimmune cytopenias (e.g. autoimmune haemolytic anaemia and immune thrombocytopenia [ITP]), which affects 4–7% of patients. Autoimmune phenomena are frequently observed in patients with CLL and are mainly attributable to underlying dysfunctions of the immune system^​12​. 

Symptoms owing to bone marrow infiltration

Heavy infiltration of CLL in bone marrow can cause cytopenias that are not immune in nature.  Depending on the nature of the infiltration, it can cause anaemia, neutropenia, thrombocytopenia. This can lead to complications of anaemia, infections and bleeding or bruising, respectively^​12​.

Symptoms owing to Richter’s transformation

Richter syndrome (RS) describes the development of high-grade non-Hodgkin’s lymphoma in patients with chronic lymphocytic leukaemia (CLL/SLL). RS’s transformation to Hodgkin’s lymphoma is a very rare event, occurring in <1% of cases. The symptoms in patients with Richter’s transformation are related to high-grade lymphoma, such as loss of weight, loss of appetite and drenching night sweats. The prognosis for these patients is generally poor^​13​.

Risk factors

The following have been shown to be risk factors for CLL:

• Family history: Research suggests that people with a first-degree relative with CLL have an 8.5 times higher risk of developing the disease than somebody without a family history^​14​;
• Age: Globally, during the last 30 years, CLL-related incidence cases increased significantly with the age-standardised incidence rate rising from 0.76/100,000 persons in 1990 to 1.34/100,000 persons in 2019^​15​;
• Exposure to chemicals: Exposure to certain chemicals has been associated with increased risk of developing CLL. For example, exposure to Agent Orange, a herbicide used during the Vietnam War, led to increased incidence of CLL in war veterans^​16​. Occupational exposure to certain pesticides (such as methomyl) led to increased incidence of CLL^​17​;
• Sex and race: Men are twice as likely to get CLL compared to women^​14​. DNA methylation differences between men and women have been shown to play a role in this^​18​. CLL is more common in individuals of European decent compared to people of Asian or African descent^​19​.

Diagnosis and assessment

The diagnosis of CLL requires the presence of ≥5 × 10⁹/L B lymphocytes (5000/μL) in the peripheral blood for the duration of at least three months^​20​. The clonality of the circulating B lymphocytes needs to be confirmed by flow cytometry. The leukaemia cells found in the blood smear are characteristically small, mature lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially aggregated chromatin^​20​. The definition of SLL requires the presence of lymphadenopathy and the absence of cytopenia’s caused by a clonal marrow infiltrate, with diagnosis confirmed by histopathological evaluation of a lymph node biopsy^​20​.

Staging

Consensus guidelines, published in 2008, detailed the assessments, diagnosis, staging and treatment of patients with CLL^​20​.

The immunophenotype of CLL is that the CLL lymphocytes exhibit a characteristic profile of CD19+, CD5+, CD23+, CD20+ low, CD200+, CD22+ low/negative, CD79b low/negative, CD43+ low, sIgκ+ or sIgλ+ low, sIgM+ low, CD11c+ low/negative, FMC7 negative, CD10 negative and CD103 negative^​21​.

A scoring system allocates points to each of these factors which helps in diagnosis, based on the evaluation of five parameters: CD5+ (1 point), CD23+ (1 point), FMC7 negative (1 point), weak intensity of kappa/lambda chains (1 point), and weak or negative CD22/CD79b (1 point). The CLL score ranges between 5 (typical CLL cases) and 3 (less typical CLL cases). Scores of 0–2 exclude the diagnosis of CLL^​22​. For patients with SLL, a tissue biopsy with presence of these markers would confirm the diagnosis of CLL^​22​. 

The above immunophenotype would help in ruling out other low-grade lymphomas, such as mantle cell lymphoma (CD5+, CD23-), hairy cell leukaemia (CD5-, CD23-, CD103 +) and marginal zone lymphoma (CD5-)^​23​.

Two widely used staging systems are Rai and Binet, which were developed in the 1970s and give a good correlation about prognosis of CLL, these can be seen in Table 1^​20,24​.

Prognosis

Apart from staging, there are other factors that are used as prognostic markers, such as, pattern of bone marrow involvement, number of prolymphocytes in blood or bone marrow, age, gender, lymphocyte doubling time, absolute lymphocyte count and β2-microglobulin^​25​.

Cytogenetic and molecular markers are important in confirming diagnosis and predicting prognosis of patients with CLL. Established prognostic markers and emerging ones can be seen in Table 2^​26​.

Genomic aberrations in CLL are important independent predictors of disease progression and survival. More than 80% of patients have some chromosomal alteration, the most frequent being a deletion in 13q (55%), a deletion in 11q (18%), trisomy of 12q (16%), a deletion in 17p (7%) and a deletion in 6q (7%)^​27​.

The international working group for CLL-International Prognostic Index has a prognostic scoring system that combines genetic, biochemical and clinical parameters. A total of 3,472 treatment-naive patients were included in the full analysis dataset from 13 clinical trials. Univariate and multivariate analysis were performed on various baseline factors and overall survival was the end-point. Using a weighted grading of the independent factors, a prognostic index was derived that identified four risk groups within the training dataset with significantly different overall survival at five years, the factors that make up these scores can be seen in Table 3 and Table 4^​28​.

Other investigations

Bone marrow biopsy is generally not needed for diagnosis of CLL, unless patient has cytopenias and the cause is unclear^​29​.

A CT scan is not required for initial evaluation or for follow up^​30​. As a baseline assessment, a staging CT scan of neck, chest, abdomen and pelvis would be useful before starting therapy^​30​.

A lymph node biopsy is generally not required, unless there is diagnostic uncertainty. A lymph node or tissue biopsy is performed to establish the diagnosis of a transformation into an aggressive lymphoma (e.g. Richter transformation)^​30​.

A PET scan can be useful to identify the best lymphoid area for establishing the diagnosis by biopsy^​30​.

Management

Most patients with CLL will not need treatment at diagnosis. Patients without symptoms and Rai stage 0-II or Binet A&B will undergo ‘active monitoring’, a term used when someone is not having treatment. During this period, patients are monitored and followed up regularly to look out for any signs of progression. In CLL, a patient could undergo active monitoring for several years.

Figure 1 outlines the monitoring approach suggested by the iwCLL for patients who do not fulfil the 2018 iwCLL criteria for treatment^​31​.

Reproduced with permission from Hampel et al.

Front-line treatment

At the time of diagnosis, research has shown that 89% of patients had one or more comorbidities and 46% had at least one major comorbidity^​32​; the most common being vascular, upper gastrointestinal, and endocrine^​33​. As a result, fitness is an important factor when deciding type of treatment. 

Chromosome 17p deletion and TP53 mutation status are also important considerations to guide treatment. Results from the German CLL 8 trial have shown that 17p deletion and TP53 mutations are associated with particularly poor outcomes with chemo-immunotherapy^​34​.

For patients who have an intact TP53 status and are not fit for chemo-immunotherapy, treatment options are either combination of venetoclax and obinutuzumab for a fixed duration; continuous treatment with a BTKi, such as acalabrutinib or zanubrutinib; or a combination of ibrutinib and venetoclax for a fixed duration^​35​. All these treatments are permitted by the National Institute for Health and Care Excellence (NICE) via the cancer drug fund (CDF) in England^​35​.

Four-year follow-up results of the CLL 14 trial (n=432) — which compared combination obinutuzumab and venetoclax with combination obinutuzumab and chlorambucil — showed significant improvement of progression-free survival (PFS) in patients with previously untreated CLL and co-existing conditions with venetoclax and obinutuzumab, compared with chlorambucil-obinutuzumab^​36​. The ELEVATE TN study (n=535) showed that acalabrutinib — which is only approved for monotherapy by NICE, with or without obinutuzumab — significantly improved PFS over obinutuzumab-chlorambucil chemo-immunotherapy^​37​. In the SEQUOIA trial (n=590), results showed that zanubrutinib significantly improved PFS versus bendamustine plus rituximab, with an acceptable safety profile^​38​.

Fludarabine, cyclophosphamide and rituximab (FCR) has previously been the standard of care for patients who have an intact TP53 status and are fit for chemoimmunotherapy. The CLL 8 study (N=817) demonstrated that FCR is associated with significant toxicity in some patients and PFS for IgHV unmutated patients is not as good as IgHV mutated patients^​39​. With the availability of other treatment options, many clinicians would prefer to use these over FCR.

However, the CLL 8 study has shown that among patients with mutated IGHV who receive front-line FCR and obtain an MRD-negative remission, extremely durable responses can be achieved in a large number of these patients^​39​. Therefore, this may still be a viable option in patients who are fit and have IGHV mutated and TP53 unmutated status.

For patients with mutation or deletion of TP53, NICE-approved front-line treatment options are venetoclax plus obinutuzumab, ibrutinib, acalabrutinib, zanubrutinib, or venetoclax monotherapy where a BTKi is contra-indicated. 

Figure 2 shows the treatment flow chart adapted from BCSH guidelines^​35​.

Reproduced with permission from Walewska et al.; Wiley

Relapsed/refractory disease

Relapsed disease is when disease reappears after being in remission. The term ‘refractory’ is used to describe when the disease does not respond to treatment. The current licensed therapies for relapsed CLL are continuous BTKi (ibrutinib, acalabrutinib, zanubrutinib), BCL2i (venetoclax monotherapy or in combination with rituximab) and PI3Ki (idelalisib and rituximab)^​35​. The ‘MURANO’ trial (n=389) showed that among patients with relapsed or refractory CLL, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab — (the two-year rates of progression-free survival were 84.9% and 36.3%, respectively)^​40​.

Continuous versus fixed-duration treatment

The RESONATE2 study demonstrated significant improvement in PFS and overall survival with continuous ibrutinib treatment in front line settings. However, high rates of treatment discontinuation were observed with long-term ibrutinib follow-up^​41​. Real-world data also show significant discontinuation rates with long-term ibrutinib^​42​; discontinuation is thought to be owing to adverse events. 

Acalabrutinib and zanubrutinib, which are second-generation covalent BTKis, have demonstrated superior PFS compared with chemo-immunotherapy in front-line settings in the ELEVATE TN and SEQUOIA trials^​37,38​. In head-to-head trials with ibrutinib, the ELEVATE RR and ALPINE trials demonstrated comparatively lower rates of treatment discontinuation and lower frequencies of common adverse events and cardiac events overall compared with ibrutinib^​43,44​.

Results from the CLL14 (n= 423) and CLL13 (n=926) trials showed that venetoclax plus obinutuzumab achieved superior PFS compared with chemoimmunotherapy for both subgroups^​45,46​.

Fixed-duration treatment offers the advantage of stopping treatment once duration is complete, but requires frequent hospital visits while escalating with venetoclax and attendance to hospital for IV anti-CD 20 antibody infusion. For patients in whom attending hospital frequently can be challenging, continuous BTKi would be preferable.

Important considerations related to BTKi treatment

Toxicities are common and often associated with the off-target effects of BTKi treatment. The most common cardiovascular complications include atrial fibrillation, hypertension, heart failure, ventricular arrythmias and risk of bleeding^​35​. 

Pharmacists can help patients recognise and manage the side effects of BTKIs. Managing drug interactions in certain medication for atrial fibrillation, hypertension or heart failure can be crucial. Some patients may be taking anticoagulants, such as DOACs, which can increase the risk of bleeding when given alongside a BTKi. A review round that major bleeding was observed in 3.1% of 2,838 patients on ibrutinib (without antiplatelet drugs or anticoagulants), this was increased by the addition of antiplatelet therapy with or without anticoagulant therapy to 4.4%, and by the addition of anticoagulant therapy with or without antiplatelet therapy to 6.1%^​47​. Appropriate dose reductions may be advisable, which could be managed by a pharmacist in the clinic.

Additional information on the adverse effects of BTKis and the role of pharmacists in their management can be found in ‘BTK inhibitors: what pharmacists need to know’.

Tumour lysis syndrome

As the most common disease-related emergency encountered by physicians caring for patients with haematologic cancers, tumour lysis syndrome (TLS) develops most often in patients with high-grade non-Hodgkin’s lymphoma or acute leukaemia, and in patients with CLL who start treatment with Venetoclax. TLS occurs when tumour cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalaemia, hyperphosphatemia, and hypocalcaemia^​48,49​. These electrolyte and metabolic disturbances can progress to clinical toxic effects, including renal insufficiency, cardiac arrhythmias, seizures and death owing to multiorgan failure^​48,49​.

A recognised complication of venetoclax, both biochemical and clinical TLS have been reported in clinical trials. Most hospitals now have established protocols for escalating the venetoclax dose to prevent TLS as per the drug prescribing information provided by the manufacturer^​50​.

Pharmacists in clinics can assist in this management by advising on appropriate dosing and fluid intake, supportive drug management, helping with patient education and the promotion of adherence, ensuring the appropriate timing of blood testing during dose escalation, and collaboration with doctors and nurses for actions to be taken if TLS monitoring results are abnormal (e.g. findings of hyperuricemia, hyperkalaemia, hyperphosphatemia, and hypocalcaemia) .

Infusion reactions

The occurrence of infusion-related reactions (IRR), especially during the first infusion, is one of the main concerns of rituximab^​51​.

Infusion reactions can be reduced or prevented by taking the following precautions beforehand:

• Patient should be asked about medical history, previous allergic disorders, atopic status and concomitant treatments; 
• Appropriate pre-medications should be given (e.g. antihistamines and paracetamol)
• An updated protocol for the management of IRs should be at hand, as well as the medical equipment needed for resuscitation^​52​.

Infusion reactions can occur with obinituzumab, similar to rituximab. In one study, it was noted that grade III or IV infusion-related reactions occurred in 20% of patients during the first infusion of obinutuzumab, but there were no grade 3 or 4 reactions during subsequent obinutuzumab infusions. No deaths were associated with infusion-related reactions^​53​. 

Pathophysiology of obinutuzumab IRRs is poorly understood and IRRs are considered to be multifactorial events with some of identified risk factors being drug dose and speed of infusion, premedication, concomitant medications, comorbidities, genetic predisposition and tumour burden^​54​.

Supportive care

CLL associated auto-immune cytopenias are initially managed with steroids, either alone or in association with an anti-CD20 monoclonal antibody, such as rituximab. When these directed therapies are not sufficient to control auto-immune manifestations, a CLL directed treatment is recommended^​12​.

Hypogammaglobulinemia (low serum levels of IgG and IgA with variable IgM) is a frequent complication associated with CLL^​55​. The use of IV immunoglobulin replacement is recommended for individual situations of hypogammaglobulinemia and repeated infections.

NHS England guidelines recommend replacement therapy for patients who:

• Suffer recurrent or severe bacterial infections despite six months of continuous oral antibiotic therapy;
• Have a total IgG <4 g/L; and
• Have documented failure to respond to polysaccharide vaccine challenge^​56​.

People with CLL should receive the seasonal flu vaccine annually owing to their increased risk of mortality from invasive pneumococcal infection. In line with the updated Department of Health recommendations, they should also receive, the pneumococcal conjugate vaccine (PPV13) followed by the pneumococcal polysaccharide vaccine (PPV23) at least two months later^​57​.

Live vaccines should not be given and it is recommended that patients with CLL should avoid contact with children who have received the live nasal influenza vaccine for seven days^​58​. The recombinant varicella (shingles) vaccine is safe and is available for people in the UK with CLL aged 70–79 years^​59​. COVID-19 vaccination is recommended in line with the government guidelines as in the Green Book, which provides the latest information on UK vaccines and vaccination procedures^​60​. 

Information on additional support considerations and how pharmacists can help best support patients undergoing CLL treatment can be found in ‘How can pharmacists best support patients with chronic lymphocytic leukaemia?’

Conclusion

Incorporating pharmacists into CLL clinics alongside doctors and nurses can improve patient care because pharmacists can provide education to patient and care givers, while helping with prescribing, dispensing and distributing of any medication. Pharmacists can also offer help with monitoring and check on compliance.