The outlook for patients with chronic lymphocytic leukaemia (CLL) has changed drastically over the past decade. These changes come primarily from the advent of new monoclonal antibodies and novel therapies applied to an ageing population with increasing comorbidities.
CLL is a lymphoproliferative disease that produces immunologically immature cells. These cells accumulate in peripheral blood and have a solid component that can be found primarily in lymph nodes and bone marrow. Recent population studies have found that approximately 1174 patients were diagnosed with CLL in 2012, with 342 deaths as a result of the disease. The incidence of the disease increases with age, as does mortality rate.1
The diagnosis of CLL is often made incidentally on a routine full blood count, showing lymphocytosis (total lymphocyte count >5.0 x 109). The immunophenotype displayed on flow cytometry shows a monoclonal population of mature B lymphocytes expressing a unique phenotype of CD19+, CD20+,CD5+ and CD23+. When this cell pattern is seen exclusively on lymph node biopsy with peripheral blood component <5 x 109, the diagnosis is small lymphocytic lymphoma (SLL). The World Health Organization (WHO) considers SLL and CLL to be biologically the same disease.2
The flow cytometry pattern for CLL can also be seen with monoclonal B-cell lymphocytosis (MBL), a premalignant disease. The defining feature of MBL is an absolute lymphocyte count of <5.0 x 109. The risk of progression from MBL to frank CLL occurs in 1–2% of patients per year (Table 1).3
Signs and symptoms
Signs and symptoms of CLL include:
- cytopenias
- anaemia
- leukopenia/neutropenia, with increased risk of infections
- thrombocytopenia, with increased risk of bleeding
- lymphadenopathy and splenomegaly
- constitutional symptoms of malignancy (eg weight loss >10% in six months, fevers, night sweats).
Anaemia can either be a result of disease progression, with replacement of normal marrow with CLL cells, or autoimmune haemolytic anaemia.4 Similarly, thrombocytopenia can be a result of bone marrow failure or from an autoimmune process.
Diagnostic work-up
History, physical examination and simple blood tests are key to the detection of complications of cytopenias and staging of CLL. Blood tests required include:
- full blood count
- urea, electrolytes and creatinine
- liver function tests
- serum immunoglobulin levels and Coombs test
- diagnostic flow cytometry on peripheral blood
- viral serology (ie hepatitis B, hepatitis C, human immunodeficiency virus, Epstein-Barr virus and cytomegalovirus).
Computed tomography (CT) scans of the chest, abdomen and pelvis are used to identify the degree of lymphadenopathy, and are often ordered in the initial diagnostic stages to exclude other differential diagnoses. Bone marrow biopsy is not required for the diagnosis of CLL, but is recommended for the evaluation of unexplained cytopenias.
Additional tests to aid in prognosis and selected therapies
Fluorescent in situ hybridisation (FISH) is used to detect cytogenetic changes (Table 2). Molecular studies are used to detect the mutational status of immunoglobulin heavy chain variable (IgHV) genes. Unmutated IgHV are more prone to genetic errors and, subsequently, have poorer overall survival.5
Additional investigations include ZAP-70 expression and CD38 expression on flow cytometry, which is a surrogate measure of IgHV mutational status. ZAP-70 and CD38 are primarily used in research settings and currently do not influence therapeutic outcomes.
Management
Management of CLL is dictated by the stage, presence of symptoms, and individual patient preference. Current treatment for CLL ranges from monotherapy to combination therapy with chemotherapy and immunomodulatory agents. Currently, the standard therapy for patients who are fit is a combination of fludarabine, cyclophosphamide and rituximab (FCR).
There is no specific age cut-off for therapy. Rather, fitness for therapy is derived from physical fitness and comorbidities. New agents that have become available in the past several years are listed in Table 3.
Table 1. Rai staging (clinical predictors of prognosis)
|
Rai stage
|
Modified Rai risk
|
Clinical characteristics
|
|---|
|
0
|
Low
|
Lymphocytosis in peripheral blood and bone marrow only
|
|
1
|
Intermediate
|
Lymphocytosis and enlarged lymph nodes
|
|
2
|
Intermediate
|
Lymphocytosis and enlarged liver or spleen
|
|
3
|
High
|
Lymphocytosis and anaemia (haemoglobin <110 g/L)
|
|
4
|
High
|
Lymphocytosis and thrombocytopenia (platelets <100 x 109)
|
Ibrutinib
Ibrutinib is an oral, selective inhibitor of Bruton’s tyrosine kinase, an important regulator in the B-cell receptor signalling pathway, and subsequently inhibits B-cell proliferation. Current indications for the use of ibrutinib in Australia include first‑line therapy for CLL with 17p deletion, and second-line therapy for CLL or SLL (after at least one previous therapy).
Approval for the use of ibrutinib was based on a phase III clinical trial comparison with ofatumumab. Patients received ibrutinib at a dose of 480 mg until disease progression or intolerable adverse events resulted; a majority of patients in the study had unfavourable cytogenetics (eg 17p deletion or 11q deletion).6 Progression-free survival and overall survival were longer for patients treated with ibrutinib than those treated with ofatumumab. Patients with poor-risk disease also had better outcomes.6
Ibrutinib-associated lymphocytosis occurred in 73% of patients, peaking at a median of four weeks, then declining at a rate dictated by the disease risk factors. Patients with good prognosis cytogenetics had slower declines, whereas those with higher risk disease had faster declines. All cases of lymphocytosis were asymptomatic and resolved by week 19.7 Notable adverse events included increased rates of diarrhoea (4% versus 2%), atrial fibrillation (3% versus 0%), infection rates (70% versus 54%) and risk of bleeding.6 Ibrutinib-induced bleeding can either be due to its effect on platelet function or when anticoagulation is used to treat atrial fibrillation.
Idelalisib
Idelalisib is a potent, oral, selective, small‑molecule inhibitor of phosphatidylinositol-3-kinase δ (PI3Kδ), a key component in the B-cell receptor signalling pathway. Phase III data included older patients with heavily pretreated disease who were ineligible for systemic chemotherapy because of cytopenias, and received idelalisib with rituximab or rituximab alone.8 Progression-free survival was higher in the idelalisib group, compared with the control group. Overall survival was also superior, even in those with poor-risk cytogenetics.
Specific adverse effects included cytopenias (eg anaemia, neutropenia, thrombocytopenia) and hepatic aminotransferase elevation. Drug discontinuation due to adverse events was 8% in the trial group and 10% in the placebo group.8 Idelalisib also caused drug-associated lymphocytosis, with an increase in total lymphocytes, which occurred within the first weeks of drug therapy. This peaked at week two and resolved by week 12.8 This elevation is not considered a sign of disease progression.
Ofatumumab
Ofatumumab is a fully human monoclonal antibody, which was found to be effective in the treatment of CLL. It is given by infusion in hospital chemotherapy day units. The results were from an international, randomised phase III trial comparing ofatumumab plus chlorambucil therapy with chlorambucil monotherapy. Ofatumumab led to improved progression-free survival in all patients, including those with poor prognostic factors. It did not have an effect on overall survival.9
Table 2. Cytogenetics (FISH) and median overall survival (OS)17
|
Cytogenetic change
|
Characteristics
|
Median OS
|
|---|
|
Del17p
|
- Associated with rapidly progressive disease
- Potentially warrants different upfront therapy to standard risk disease (eg ibrutinib)
|
33 months
|
|
Del13q
|
- Good prognosis if low allelic burden
- Long response to fludarabine therapy
|
133 months
|
|
Del11q
|
- Seen in younger age, male patients
- Frequently associated with bulky disease and poor prognosis
|
79 months
|
|
12q trisomy
|
|
114 months
|
Obinutuzumab
Obinutuzumab is a humanised type 2 antibody targeting CD20 antigen on B cells. It is given by infusion in a chemotherapy day unit. It is primarily given to older patients who cannot tolerate chemotherapy (eg fludarabine), in whom it is given together with chlorambucil. A phase III trial of 781 previously untreated patients compared obinutuzumab plus chlorambucil, rituximab plus chlorambucil, and chlorambucil alone.10 Obinutuzumab plus chlorambucil, and rituximab plus chlorambucil had increased response rates and progression-free survival, compared with chlorambucil monotherapy. There was no difference in overall survival when obinutuzumab plus chlorambucil was compared with rituximab plus chlorambucil. Obinutuzumab had higher rates of neutropenia, but had similar rates of infections. Patients had higher rates of infusion reactions that were treated well with steroids, paracetamol and antihistamines.10
The summary of the trial revealed that obinutuzumab with chlorambucil was an appropriate treatment for older patients with CLL who are unfit, and had improved outcomes and equivalent overall survival, but higher toxicity, compared with chlorambucil or rituximab plus chlorambucil.
Follow-up
CLL remains an incurable disease, and lifelong follow up of patients is necessary. Evaluation is dictated by patient and disease factors. For those with mild or relatively stable disease, follow-up every three to 12 months is adequate. Warning signs for general practitioners when following up patients with CLL include:
- lymphocytes doubling within three to six months
- lymphadenopathy causing symptoms
- progressive cytopenias as a result of bone marrow failure or autoimmune phenomena
- constitutional symptoms (eg weight loss >10% within six months, fevers, night sweats, significant fatigue).
These are often signs that the patient requires urgent or semi-urgent treatment, and they should be referred to a haematologist as soon as possible.
Transformation into either Hodgkin’s lymphoma or diffuse large B-cell lymphoma (DLBLC) occurs at a rate of 2–15%.11 Clinical signs include increasing cytopenias, increased constitutional symptoms or new lymphadenopathy. Diagnosis is confirmed on lymph node histology, and treatment is based around de novo treatment for the respective condition.
Second malignancies are common in patients with CLL. The most frequently encountered second malignancies are non-melanoma skin cancers. Patients with CLL have increased rates of local recurrence, regional metastasis and death from skin cancers. Education regarding sun protection and frequent skin cancer checks, every six to 12 months, are fundamental.12 Patients are at an increased risk of solid organ cancers, and age-appropriate cancer screening (eg prostate, breast, bowel cancer) should be adhered to.13
Infections are also increased in patients with CLL, owing to disease factors and treatment complications. Hypogammaglobulinaemia is frequently seen because of CLL and therapy (specifically rituximab).14 If the patient has low globulin levels, specifically immunoglobulin G, and frequent bacterial infections, intravenous immunoglobulin monthly, or subcutaneous immunoglobulin weekly can help reduce infections.15 Yearly influenza vaccination and pneumococcal vaccination are also recommended. Specific vaccination schedules are available in the Australian immunisation handbook.16
Table 3. CLL treatment and mechanism of action
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Older treatment
|
Mechanism of action
|
|---|
|
Chlorambucil monotherapy
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Alkylating agent – disrupts DNA
|
|
Fludarabine-based therapy
|
Alkylating agent – disrupts DNA
|
|
Rituximab
|
Anti-CD20 monoclonal antibody
|
|
Newer treatment
|
Mechanism of action
|
|---|
|
Ibrutinib
|
Bruton’s tyrosine kinase inhibitor
|
|
Ofatunumab plus chlorambucil
|
Anti-CD20 monoclonal antibody
|
|
Obinutuzumab plus chlorambucil
|
Anti-CD20 monoclonal antibody
|
|
Idelalisib
|
Phosphatidylinositol-3-kinase inhibitor
|
Key points
- CLL is a rapidly changing disease, owing to more sensitive investigations and new medications.
- CLL is diagnosed most commonly on routine blood tests, before patients experience symptoms.
- Symptoms are related to low blood counts, infections, mass effect from lymph nodes and autoimmune complications.
- Investigations include full blood count, viral serology, flow cytometry and molecular studies (ordered by haematologists).
- New medications include an array of chemotherapy, immunotherapy and targeted therapy, all with unique adverse effects.
- Follow up is generally lifelong, and patients are at increased risk of secondary and skin cancers, and infections.
Author
Ross Tomlinson MBBS, Advanced Trainee, Haematology. rossmtomlinson@gmail.com
Competing interests and funding: None.
Provenance and peer review: Not commissioned, externally peer reviewed.