The levels of evidence (I–IV) and strength of recommendations (A–C) are defined at the end of the "Major Recommendations" field.
Diagnosis and Prognostic Factors
Diagnostic Investigations
Blood count
Current criteria for the diagnosis of chronic lymphocytic leukaemia (CLL) require a lymphocytosis of >5 x 109/l. Patients whose routine blood count shows a lower level of lymphocytosis may subsequently develop clinically significant CLL. Options for adult patients with a lymphocytosis of between 3 and 5 x109/l and lymphocyte morphology consistent with CLL include immunophenotyping or a follow-up blood count.
Immunophenotyping
Immunophenotyping should be performed in all cases requiring treatment and is of particular value in the following situations: (i) in cases with low lymphocyte counts to confirm the diagnosis of CLL and exclude reactive lymphocytosis; and (ii) in patients with atypical lymphocyte morphology to exclude other B- or T-cell lymphoproliferative disorders.
A recommended panel of monoclonal antibodies and scoring system for the diagnosis of CLL is shown in Table II of the original guideline document.
Management of CLL
Indications for Referral
Indications for referral to a haematology department include: symptomatic disease, the presence of lymphadenopathy or hepatosplenomegaly and the investigation of a lymphocytosis, particularly if the lymphocyte count is high or there is anaemia or thrombocytopenia. The subsequent management of these patients should be discussed at a multi-disciplinary team meeting.
The follow-up of patients seen initially in hospital, who do not require treatment, may be organized in primary care, hospital outpatients or via a homecare service depending on local resources and patient wishes. Asymptomatic elderly patients, with a slight lymphocytosis only, may be managed by primary care teams, providing indications for referral to a haematology department are clearly documented.
Communicating with Patients
Chronic lymphocytic leukaemia is characteristically a condition for which the natural history is measured in years and it is therefore particularly important that patients are able to establish a relationship and trust with the clinician managing their condition.
A frequent dilemma is whether to convey the diagnosis of CLL to an elderly asymptomatic patient with low count stage A disease diagnosed on a routine blood count. Anxiety generated by the use of the word 'leukaemia' can almost always be prevented by a clear and careful explanation of the benign nature of the condition. If a decision not to inform a patient is taken this must be very clearly documented to ensure that other health care workers do not subsequently impart the diagnosis without explaining its significance.
The majority of patients benefit from, and should be offered, information about CLL in general and about their specific management.
Indications for Treatment
The indications for treatment recommended by the National Cancer Institute (NCI) sponsored working group are shown in Table V of the original guideline document.
Assessment of Response
The criteria for assessing complete response (CR) or partial response (PR) to treatment recommended by the NCI working group are shown in Table VI of the original guideline document.
A Treatment Strategy for CLL
Before initiating treatment, consideration must be given to (i) patient-related factors, such as age, performance status, co-morbid conditions and patient wishes; (ii) disease-related factors, such as the severity of symptoms and the presence of adverse prognostic factors; and (iii) treatment-related factors including the degree and duration of response to prior treatments and contra-indications to, and side-effects from, particular treatment modalities. Pharmacoeconomic considerations (see Table VII of the original guideline document) are also important.
An important consideration on beginning treatment in CLL is whether to adopt a palliative approach and treat symptomatic disease with regimens causing minimal treatment-related toxicity, or to aim for prolonged disease-free survival in the hope that this will translate into superior overall survival.
Initial Treatment
Treatment of early stage CLL
Treatment of early stage disease with chlorambucil is not indicated (grade A recommendation, level Ia evidence).
Treatment of Advanced or Progressive Disease
Purine analogues
To prevent transfusion related graft versus host disease (GVHD), all patients treated with a purine analogue should receive irradiated blood products indefinitely thereafter.
Steroids
There is no evidence that prolonged treatment with low, intermediate or high-dose steroids is an effective initial treatment for CLL. However, it is recommended that patients with stage C disease should be given a short course of prednisolone before receiving chlorambucil (grade C recommendation, level IV evidence).
Summary of Recommendations for Initial Treatment
For the majority of patients who are ineligible for a transplant procedure and in whom there is no contraindication to fludarabine (severe renal impairment or an autoimmune cytopenia), entry into the MRC CLL4 study should be offered. This trial randomizes patients to either chlorambucil, fludarabine, or fludarabine and cyclophosphamide and assesses the value of prognostic factors and quality of life issues as well as outcome. Both fludarabine and chlorambucil are options for patients who do not wish to enter the study.
Patients in whom fludarabine is contraindicated and for whom a palliative approach has been adopted should be treated with chlorambucil (grade A recommendation, level Ia evidence).
There is no survival advantage for including an anthracycline with chlorambucil in the initial treatment of advanced chronic lymphocytic leukaemia (CLL) (grade A recommendation, level Ia evidence).
Further studies using standard response criteria are required before high-dose chlorambucil can be recommended as an initial treatment for CLL (grade C recommendation, level IV evidence).
Where a patient is considered suitable for entry into the MRC CLL5 trial or for allogeneic transplantation, then an initial treatment, such as fludarabine or fludarabine and cyclophosphamide, which is likely to result in a complete or very good partial remission, should be chosen (grade C recommendation, level IV evidence).
Alemtuzumab is not recommended for untreated CLL (grade B recommendation, level IIb evidence).
Rituximab monotherapy is not recommended in untreated CLL (grade C recommendation, level III evidence).
Rituximab combined with fludarabine (with or without cyclophosphamide) requires further evaluation in untreated CLL (grade B recommendation, level Ib evidence).
Summary of Recommendations for Second Line and Subsequent Treatment
Patients who relapse after an initial response to low dose chlorambucil may be treated with a further course of chlorambucil (grade B recommendation, level IIb evidence).
Patients refractory to low dose chlorambucil should be treated with fludarabine. Cyclophosphamide, adriamycin, vincristine, prednisolone (CHOP) is an alternative treatment for patients unsuitable for fludarabine (grade B recommendation, level IIb evidence).
Patients who develop progressive disease more than 1 year after receiving fludarabine and whose CLL responded to fludarabine initially, may be treated again with fludarabine alone (grade B recommendation, level IIb evidence).
Patients who develop progressive disease within 1 year of previous fludarabine therapy may be treated with a combination of fludarabine and cyclophosphamide (grade B recommendation, level IIb evidence).
Patients who are refractory or become resistant to fludarabine currently have a poor prognosis. Therapeutic options include the following:
- High-dose methyl prednisolone is recommended as a treatment option for patients who are resistant to fludarabine, particularly in cases with bulky lymphadenopathy and/or p53 abnormalities (grade B recommendation, level III evidence).
- Alemtuzumab is licensed for and recommended in patients without bulky lymphadenopathy, previously treated with alkylating agents and refractory to fludarabine (grade B recommendation, level IIb evidence).
- Rituximab monotherapy is not recommended for previously treated CLL (grade C recommendation, level IIb evidence). Rituximab combined with fludarabine (with or without cyclophosphamide) may be effective in refractory CLL and warrants further evaluation in this setting (grade B recommendation, level IIb evidence).
Autologous transplantation should be considered for patients in complete or good partial remission who are able to withstand high-dose chemotherapy and total body irradiation (TBI). Autologous transplantation should be performed in the context of a randomized trial, such as the MRC CLL5 trial.
The possibility of an allogeneic transplant procedure should be considered for younger patients with good performance status who have been previously treated and have poor risk disease. Suitable patients should be discussed with a transplant centre at an early stage in their disease before the development of drug resistant disease for inclusion into a clinical research protocol (grade B recommendation, level III evidence).
Splenectomy may be beneficial in relieving symptomatic splenomegaly and in improving peripheral cytopenias secondary to hypersplenism or autoantibodies (grade B recommendation, level IIa evidence).
Management of Complications
Prophylaxis
Antibiotic therapy
Prophylaxis against Pneumocystis carinii with septrin or nebulized pentamidine should be administered routinely for all patients receiving purine analogues or alemtuzumab, and continued for a minimum of 6 months after stopping purine analogues or alemtuzumab (grade C recommendation, level IV evidence).
Prophylaxis against herpes zoster/simplex and fungal infections should also be considered for patients receiving purine analogues or alemtuzumab, particularly if there is a previous history of herpetic or fungal infection. Patients treated with high-dose methylprednisolone should receive prophylaxis against candidiasis with fluconazole.
Regular weekly monitoring with cytomegalovirus polymerase chain reaction (CMV PCR) testing should be performed in patients receiving alemtuzumab. A positive quantifiable CMV PCR result is an indication for treatment with intravenous ganciclovir.
Intravenous Immunoglobulin (IVIG)
Patients with hypogammaglobulinaemia and recurrent bacterial infections, especially those in whom prophylactic antibiotics have proved ineffective, should be treated with prophylactic IVIG (grade A recommendation, level Ib evidence).
Treatment of Infections
Patients and their carers need to be educated about the risks of infection and the necessity to seek immediate medical attention as soon as suggestive symptoms occur. Patients with minor infections can be treated as outpatients, but those with major infections will require hospitalization and access to full resuscitation including respiratory support. As many infections are potentially life threatening, broad spectrum antibiotics covering the common likely pathogens should be started as soon as all essential cultures have been taken.
Autoimmune Cytopenias
It is recommended that patients with warm autoimmune hemolytic anemia (AIHA) or immune-mediated thrombocytopenia (ITP) are treated according to the protocols used for patients with idiopathic AIHA or ITP (grade C recommendation, level IV evidence). Autoimmune cytopenias developing following purine analogue therapy are frequently severe and may be fatal. The majority of patients who have developed AIHA post fludarabine have had recurrent haemolysis on re-exposure to fludarabine. There have been reports of small numbers of patients in whom fludarabine has been re-introduced successfully while patients are on ciclosporin A.
However, retreatment with a purine analogue cannot be recommended in a patient who has previously developed a purine analogue-related immune cytopenia (grade B recommendation, level IIa evidence).
Lymphomatous Transformation
No standard treatment can be recommended for Richter's transformation of CLL; existing clinical reports fail to identify consistently effective therapy (grade C recommendation, level IV evidence).
Definitions:
Levels of Evidence
Ia Evidence obtained from meta-analysis of randomised controlled trials
Ib Evidence obtained from at least one randomised controlled trial
IIa Evidence obtained from at least one well-designed, controlled study without randomisation
IIb Evidence obtained from at least one other type of well-designed, quasi-experimental study
III Evidence obtained from well-designed, non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies
IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
Grades of Recommendation
Grade A, evidence level Ia, Ib
Required of overall good quality at least one randomized controlled trial as part of the body of literature and consistency addressing specific recommendation
Grade B, evidence level IIa, IIb, III
Required availability of well-conducted clinical studies but no randomised clinical trials on the topic of recommendation
Grade C, evidence level IV
Required evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities
Indicates absence of directly applicable clinical studies of good quality
